Clinical trial NCT02352363
Conditions: Idiopathic Parkinson's Disease
Keywords: Parkinson's Disease Motor fluctuations levodopa inhaled drugs OFF episodes
Sponsor: Acorda Therapeutics
Start date: 2015-03-01; Completion date: 2017-05-01
Enrollment: 408 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a 12-month, open-label, randomized, multicenter study which will evaluate the safety and efficacy of CVT-301 for the treatment of up to 5 OFF episodes per day in Parkinson's Disease (PD) patients experiencing motor fluctuations (OFF episodes) and will include a concurrent observational cohort of PD patients managed using the usual standards of care.

Detailed description:
A randomized, double-blind, placebo-controlled, Phase 2b study in patients with PD (CVT-301-003) demonstrated clinically important, and statistically significant CVT-301-associated improvements in motor function at doses of 35 and 50 mg LD FPD, compared with placebo, as measured by the Unified Parkinson's Disease Rating Scale (UPDRS) motor assessment (Part 3); furthermore, CVT-301 was generally safe and well tolerated. A Phase 3, randomized, placebo-controlled study designed to assess the efficacy and safety of 35 mg and 50 mg FPD as an adjunct to a CD/LD regimen in the treatment of OFF symptoms over 12 weeks (CVT-301-004) was conducted in parallel with this study.

Arms: arm 1: Capsules of Levodopa Inhalational Powder (LIP) used up to 5 times per day for OFF episodes, for up to 54 weeks duration. arm 2: Standard of care. Patients in both the CVT-301 treatment group and the observational cohort will be managed with their standard PD treatment throughout the study.
Interventions: intervention 1: CVT-301 intervention 2: Observational cohort
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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1. 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
 
Protocol Title: 
A Phase 3, Randomized Study Investigating the Safety of  
CVT-301 (Levodopa Inhalation Powder) in Parkinson’s Disease 
Patients With Motor Response Fluctuations (OFF Phenomena) 
Compared to an Observational Cohort Control (SUPPORT-PD™) 
Protocol Number: 
CVT-301-005 
EudraCT Number: 
2014-003799-22 
US IND Number: 
115750 
Development Phase: 
Phase 3 
Study Sponsor: 
Civitas Therapeutics, Inc. 
190 Everett Ave 
Chelsea, MA 02150 
USA 
Protocol Version: 
3.0  
Version Date: 
22-September-2015 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Civitas Therapeutics.  Any 
unauthorized copying or use of this document is prohibited. 
 


Civitas Therapeutics, Inc 
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CIVITAS THERAPEUTICS PROTOCOL APPROVAL PAGE 
Acorda Therapeutics, Inc., a duly authorized 
signatory for Civitas Therapeutics, Inc. 
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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
I agree: 
• To assume responsibility for the proper conduct of the study at this site. 
• To conduct the study in compliance with this protocol, any future amendments, and 
with any other study conduct procedures provided by Civitas Therapeutics. 
• Not to implement any changes to the protocol without written agreement from Civitas 
Therapeutics and prior review and written approval from the Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC) except where necessary to 
eliminate an immediate hazard to patients. 
• That I am thoroughly familiar with the appropriate use of the study drug, as described 
in this protocol and any other information provided by Civitas Therapeutics 
including, but not limited to, the current Investigator’s Brochure. 
• That I am aware of, and will comply with, good clinical practice (GCP) and all 
applicable regulatory requirements. 
• To ensure that all persons assisting me with the study are adequately informed about 
the Civitas Therapeutics study drug and have been trained on their study-related 
duties and functions as described in the protocol. 
 
Signature: 
 
 
Date: 
 
 
Name 
(print): 
 
 
 
 
 
Principal Investigator 
 
 
 
 
 


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LIST OF CONTACTS 
Sponsor: 
Civitas Therapeutics, Inc. 
190 Everett Ave 
Chelsea, MA 02150 
USA 
Sponsor’s Responsible Medical Director: 
 
 
 
  
  
 
CRO Global Study Manager: 
  
 
CRO Medical Monitors: 
 
 
 
CRO Safety (Pharmacovigilance) Reporting: 
 
 
 
 
Clinical Laboratory: 
 
 
 
 
 
Spirometry and ECG Central Laboratory 
 
 
DLco-Related Services and Analysis 
 


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USA 
Rater Training, Diary, and Endpoint 
Surveillance 
 
 
 
 


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2. 
SYNOPSIS 
Title of Study: 
A Phase 3, Randomized Study Investigating the Safety of CVT‑301 
(Levodopa Inhalation Powder) in Parkinson’s Disease Patients With 
Motor Response Fluctuations (OFF Phenomena) Compared to an 
Observational Cohort Control 
Protocol Number: 
CVT-301-005 
Investigators/Study Sites: 
This study will be conducted at approximately 100 sites in Europe 
and the United States. 
Phase of Development: 
3 
Objectives: 
Primary Objective 
• 
To characterize the pulmonary safety, as assessed by 
spirometry (forced expiratory volume in 1 second [FEV1], 
forced vital capacity [FVC], and FEV1/ FVC ratio), over a 
12-month period within the CVT-301-treated patients. 
Secondary Objectives 
• 
To characterize the pulmonary safety, as assessed by 
spirometry (FEV1, FVC, and FEV1/FVC ratio), over a 
12-month period in the observational (‘standard of care’) 
cohort. 
• 
To estimate the difference between the CVT-301-treated 
patients and the observational cohort on measures of 
pulmonary safety. 
• 
To characterize the effects of CVT-301 on safety over a 
12-month period:  safety will be assessed by adverse event 
(AE) reports, physical examination, standard and orthostatic 
vital signs (blood pressure [BP], heart rate [HR], and 
respiratory rate [RR]), clinical laboratory tests, 12-lead 
electrocardiograms (ECGs), the Parkinson’s Disease 
Impulsive-Compulsive Disorders Questionnaire (QUIP), the 
Epworth Sleepiness Scale, and the Columbia-Suicide 
Severity Rating Scale (C-SSRS).  
• 
To evaluate the effect of CVT-301 on mean change from 
baseline in the UPDRS Part 4 measures of motor 
fluctuations (dyskinesias [Q32-35] and wearing off 
[Q36-39]) measured pre-dose at 6 and 12 months after the 
initiation of CVT-301 treatment. 
• 
To characterize the occurrence and severity of 
examiner-rated dyskinesia following treatment of patients 
experiencing an OFF episode in the clinic over a 12-month 
period  
• 
To describe the effects of CVT-301 on DLco over a 
12-month period. 
 


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Exploratory Efficacy Objectives 
• 
Change from pre-dose in UPDRS Part 3 motor score at 10, 
20, 30, and 60 minutes following treatment of patients 
experiencing an OFF episode. 
• 
Time curves of the UPDRS response at 10, 20, 30 and 60 
minutes will be evaluated descriptively 
• 
Change from pre-dose in UPDRS Part 3 motor score at 10 to 
60 minutes following treatment of patients experiencing an 
OFF episode. 
• 
Proportion of patients with a ≥ 3, ≥ 6, and ≥ 11-point 
reduction in the UPDRS Part 3 motor score from pre-dose to 
post-dose, at 10 to 60 minutes. 
• 
Proportion of patients achieving resolution of an OFF to an 
ON state within 60 minutes after study drug is administered 
in the clinic, maintaining the ON state at 60 minutes after 
study drug administration (per the examiner’s subjective 
assessment). 
• 
Patient-reported total daily OFF time, total daily ON time 
without dyskinesia, total daily ON time with 
non-troublesome dyskinesia, and total daily ON time with 
troublesome dyskinesia, assessed by the patient and recorded 
in the patient diary. 
• 
Change from baseline visit in the 39-Item Parkinson’s 
Disease Questionnaire (PDQ-39). 
• 
Proportion of patients who improved based on the Patient 
Global Impression of Change (PGI-C) rating scale measured 
pre-dose. 
• 
Change from baseline visit in the Schwab and England 
(S&E) Activities of Daily Living (ADL) score. 
• 
Change from baseline visit UPDRS Part 2 score. 
Study Design: 
This study is a 12-month, open-label, randomized, multicenter study 
which will evaluate the safety and effects of CVT-301 for the 
treatment of up to 5 OFF episodes per day in PD patients 
experiencing motor fluctuations (OFF episodes) and will include a 
concurrent observational cohort of PD patients managed using the 
usual standards of care.  Patients must be CVT-301-naïve, however, 
any patients that were enrolled from the CVT-301-002 and 
CVT-301-003 studies under the previous version of this protocol 
will be allowed to continue in the study. Patients will be randomized 
in a 2:1 ratio to the CVT-301 treatment group (CVT-301 at a target 
nominal respirable dose of 50 mg LD FPD) or the observational 
cohort.  Randomization will be differentiated by the patient’s Hoehn 
and Yahr stage (<2.5 versus ≥2.5) to balance the severity of disease 
across each group and by screening spirometry (FEV1 <60% of 
predicted or FEV1/FVC ratio <70% versus FEV1 ≥60% of predicted 
and FEV1/FVC ratio ≥70%). 
Patients assigned to the CVT-301 treatment group may use the 


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prescribed dose of CVT-301 as needed for the treatment of up to 
5 OFF episodes per day in addition to their standard PD medications 
which may be modified as needed for symptomatic treatment over 
the 12-month study.  Each treated episode will require 2-capsule 
inhalations (i.e., 2 capsules used in the inhaler per treated episode) to 
deliver the dose.  
Patients assigned to the observational cohort will not receive 
CVT-301 but will be permitted to be managed using their standard 
PD medications and other PD treatment modalities, which may be 
modified as needed for symptomatic treatment in accordance with 
usual practice over the 12-month study.   
For both the CVT-301 treatment group and the observational cohort, 
additions to and/or modification of the patient’s usual PD treatment 
regimen may take place.  However, oral “as-needed” (PRN) LD 
formulations are not permitted for CVT-301-treated subjects (refer to 
Section 9.4.2 of the protocol for a list of prohibited treatments and 
prohibited medications).  For CVT-301-treated patients, the total 
daily LD dose of the modified PD treatment regimen (not including 
CVT-301) must not exceed 1600 mg per day.   
The study includes a screening period of up to 35 days (with 
2 screening visits) and a treatment period of approximately 
12 months (52±2 weeks) (with 6 treatment/observational visits) plus 
an additional follow-up at a pulmonary laboratory 4 to 5 weeks after 
the last treatment/observational visit.  A longer screening period may 
be permitted with approval from the Sponsor.  Planned 
treatment/observational visits will occur at 0 (pre-dose, baseline) and 
approximately 1, 3, 6, 9, and 12 months.  For the CVT-301 treatment 
group these visits will be treatment visits, and for the observational 
cohort, these will be observational visits.  All patients, regardless of 
study group, will be required to attend all of the screening visits and 
all of the treatment/observational visits.   
Assessments for DLco will be performed at a pulmonary laboratory 
outside of the clinic prior to the first treatment or observational visit, 
within 2 weeks prior to the 3-, 6-, 9-, and 12-month visits, and 4 to 5 
weeks after Treatment Visit/Observational Visit 6 (TV/OV6).  
If a patient in the CVT-301 treatment group develops significant 
tolerability concerns that in the opinion of the investigator are of a 
severity that should necessitate a reduction in dose, including, but 
not limited to the exacerbation or worsening of troublesome 
dyskinesia, other problematic dopaminergic symptoms, or other 
tolerability concerns, a dose reduction from 2 capsules (50 mg LD 
FPD) to 1 capsule (25 mg LD FPD) per treated episode may be 
permitted.  The medical monitor should be contacted, and the 
investigator should use his/her clinical judgment to determine 
whether an additional visit is required and what assessments should 
be performed (e.g., physical examination, spirometry, etc.).  The 
patient should continue to use 1 capsule (25 mg LD FPD) per treated 
episode for a period of at least 1 week.  If the investigator determines 
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has tolerated this dose for at least 1 week, the patient may at that 
point either resume taking the original dose (2 capsules [50 mg LD 
FPD] per treated episode) or come into the clinic for an unscheduled 
visit to receive a reduced-dose study drug kit (35 mg LD FPD).  
Clinical staff will call the patient 1 to 2 days after the dose escalation 
to see if the patient has any questions or concerns.  If a patient who 
has escalated back to the full dose (50 mg LD FPD per treated 
episode) has another tolerability concern that in the opinion of the 
investigator is of a severity that should necessitate a second 
reduction in dose, an unscheduled visit will be required and a 
reduced-dose study drug kit (35 mg LD FPD per treated episode) 
will be provided.   He/she will remain on the reduced dose (35 mg 
LD FPD) for the remainder of the study; he/she will not be eligible 
for any additional up-titration in dose. 
Safety data will be reviewed by an independent Data Safety 
Monitoring Board (DSMB) that will include relevant medical 
experts asdefined in the DSMB Charter.  Interim analyses, which 
will not affect study conduct, may be performed to support 
regulatory submissions. These analyses will be described in the SAP. 
Screening Period 
All patients will undergo a screening period of up to 35 days before 
entering the treatment period.  The screening period may be 
extended an additional 7 days if repeat screening assessments are 
required.  The screening period will consist of 2 scheduled clinic 
visits:  Screening Visit 1 (SV1) and Screening Visit 2 (SV2).  
Screening Visit 1 (SV1): Within 35 days prior to Treatment 
Visit/Observational Visit 1 (TV/OV1) 
Patients will be instructed to bring all of their medications with them 
to SV1.  Patients will provide written informed consent before any 
study procedures are performed.  Patients will be assessed for 
eligibility based on the inclusion/exclusion criteria.  The patient’s 
medical history (including smoking history) and PD history will be 
documented.  The PD diagnosis will be confirmed using Steps 1 and 
2 of the United Kingdom (UK) Brain Bank Criteria, and the PD 
severity will be staged using the Hoehn and Yahr disease severity 
criteria.  The number of hours of OFF time will be recorded.  
Eligible patients must have, by self-report, motor fluctuations with 
daily OFF time averaging at least 2 hours per day (not including 
early morning OFF time and which will require confirmation using 
the PD Diary over a period of 3 consecutive days).  Each patient’s 
PD medications, including standard LD-containing regimen (number 
of times per day that LD-containing medications are administered 
and the total daily LD dose will be recorded) and other concomitant 
medications will be recorded and reviewed to ensure that specified 
PD and other medications have been stabilized in accordance with 
protocol-defined criteria.  The following assessments will then be 
performed:  Mini Mental State Examination (MMSE) while patient 
is in an ON state; a full physical examination; review of pulmonary 
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Function Baseline Questionnaire; ECG; standard vital signs (BP, 
HR, and RR) and orthostatic vital signs (BP and HR); and 
spirometry for determination of FEV1, FVC, and the FEV1/FVC 
ratio (while the patient is in an ON state).  Patients will undergo 
UPDRS Part 3 assessments while in an ON state, and training on 
self-recognition of ON and OFF states and rating assessments while 
in an ON state. 
Note:  An “ON state” is defined as the time when medication is 
providing benefit with respect to mobility, slowness, and stiffness, 
and may or may not be providing complete alleviation of all PD 
symptoms.  An “OFF state” is defined as the time when medication 
has worn off and is no longer providing benefit with respect to 
mobility, slowness, and stiffness.  OFF episodes may be heralded by 
non-motor symptoms (e.g., pain, anxiety) prior to the appearance of 
motor symptoms.  
Patients will undergo standard home PD Diary training for 
self-rating of OFF states, ON states, and dyskinesia.  Patients will be 
tested (in both ON and OFF states) for competence at self-rating and 
must be within 75% concordance with the ratings of the examiner (at 
least 3 out of 4 half-hour sessions over the course of 2 hours); if 
concordance is not reached, the observation period may be extended 
for an additional 2 hours to obtain agreement on at least 6 of 
8 half-hour sessions.  If needed, the same training and testing may be 
repeated at an unscheduled visit between SV1 and SV2 or at SV2.  If 
patients return for an unscheduled visit between SV1 and SV2 for 
concordance training and testing, the visit must occur more than 3 
days prior to SV2.  If patients do not achieve 75% concordance by 
the end of SV2, they will be considered screen failures. 
Patients will be trained on the proper technique to prepare and use 
the inhaler system using sham (i.e., empty) capsules per the 
Instructions for Use (IFU) while in an ON state.  Patients will 
undergo clinical laboratory tests (patients do not need to be in a 
fasted state, however, fasted status will be documented [fasting will 
be defined as at least 4 hours following the last meal or snack]) 
including serum pregnancy test for women of child-bearing 
potential.  
Patients will remain in the clinic and further PD medications will be 
withheld until they turn into an OFF state.  The spirometry 
evaluations, UPDRS Part 3 assessments, patient training on 
self-report of ON/OFF states, and inhaler training should be repeated 
when patients are in an OFF state.  Note:  If a patient arrives at the 
clinic in an OFF state, these assessments will be done in an OFF 
state first, then they will be repeated in an ON state after the patient 
has taken his/her standard dose of PD medications and reverts to an 
ON state. 
The PD Diary (which will be used to record time OFF, time ON 
without dyskinesia, time ON with non-troublesome dyskinesia, time 
ON with troublesome dyskinesia, and time asleep) and the Screening 
ON/OFF Episodes Log (which will be used to record the discrete 


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number of OFF episodes during their waking day) will be distributed 
to patients, and the instructions for completion will be reviewed.  If 
needed, caregivers will also be trained on how to prepare inhalers for 
patients and how to complete the PD Diary and Screening ON/OFF 
Episodes Log.  The next visit will be scheduled.  Patients will be 
monitored for AEs throughout the visit. 
During the 3 consecutive days prior to SV2, patients will complete 
the PD Diary and the Screening ON/OFF Episodes Log.  Before 
arrival at the clinic for SV2, the patients will take all of their usual 
prescribed non-PD medications and PD medications, including 
LD-containing PD medications.  
Clinic staff will arrange to speak with patients by telephone 
approximately 4 days prior to SV2 to confirm the next study visit 
and to remind patients of the study procedures required prior to the 
next scheduled study visit (including completion of the PD Diary 
and Screening ON/OFF Episodes Log).   
Screening Visit 2 (SV2): At least 4 days after SV1 
For the 3 consecutive days prior to SV2, patients will complete the 
PD Diary and the Screening ON/OFF Episodes Log.  Before arrival 
at the clinic for SV2, the patient will take all of their usual prescribed 
non-PD medications and PD medications, including LD containing 
PD medications. 
At the clinic, the clinic staff will review the PD Diary and Screening 
ON/OFF Episodes Log to determine that patients are able to perform 
these procedures correctly and to determine eligibility.  The staff 
will record any changes in the usual PD medication dose.  Any 
changes in concomitant medications will be recorded.  Patients will 
be trained again on the proper technique to prepare and use the 
inhaler system (using sham capsules) per the IFU.  If the patient has 
undergone training on the inhaler in both the ON and OFF states at 
SV1, the inhaler training at SV2 may be done in either state.  If not, 
the inhaler training at SV2 should be performed in both the ON and 
OFF states.  Patients will be re-trained on how to self-assess their 
ON and OFF states while in ON and OFF states as needed. 
The clinic staff will distribute the PD Diary and the Screening 
ON/OFF Episodes Log and review the instructions for completion.  
The clinic staff will schedule patients to undergo a baseline DLco 
assessment, which will be completed after SV2 and before the first 
treatment or observational visit.  The DLco assessment should be 
performed while the patient is in an ON state (as reported by the 
patient to the pulmonary technician) at the pulmonary function 
facility.  As part of the procedure, a slow vital capacity maneuver 
will be performed, followed by DLco, and then spirometry. 
If needed, the following screening assessments performed at SV1 
may be completed or repeated, if necessary, to verify or re-check 
results:  MMSE (must be assessed in an ON state), full physical 
examination, ECG, standard vital signs (BP, HR, and RR) and 
orthostatic vital signs (BP and HR), spirometry (assessed in both ON 
and OFF states), UPDRS Part 3 (assessed in both ON and OFF 


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states), ON/OFF concordance testing (assessed in both ON and OFF 
states), and clinical laboratory tests (with documentation of fasting 
status) including serum pregnancy test if applicable.   
Patients will be monitored for AEs throughout the visit.  If a patient 
is unable to complete a screening assessment at SV2, an additional 
visit (repeat SV2) may be scheduled prior to 
randomization/treatment assignment. 
The next visit will be scheduled.   
Clinic staff will arrange to speak with patients by telephone 4 to 
6 days prior to TV/OV1 to confirm the DLco assessment has been 
done/scheduled, to confirm the next study visit, to remind patients of 
the study procedures required prior to the next scheduled study visit 
(including completion of the PD Diary and Screening ON/OFF 
Episodes Log).  In addition, clinic staff will remind the patients 
during the call that they must be symptom-free of any flu-like 
syndrome or other respiratory infection for at least 3 days prior to 
TV/OV1 and that they should contact the site if an intervening 
illness occurs prior to TV/OV1.  If a patient has any of these 
symptoms within this time period, the staff will reschedule this visit 
after these symptoms have been resolved for at least 3 days.  The 
screening period may be extended for up to 2 weeks to accommodate 
this recovery.  
During the 3 consecutive days prior to TV/OV1, patients will 
complete the PD Diary and the Screening ON/OFF Episodes Log.  
Before arrival at the clinic for TV/OV1, patients will take all of their 
usual prescribed non-PD medications and PD medications, including 
LD-containing PD medications.   
Randomization/Treatment Assignment 
Following completion of SV2 and prior to randomization, the 
patients’ eligibility criteria will be reviewed by delegated staff.  
Eligible patients will be randomized in a 2:1 ratio to the CVT-301 
treatment group (CVT-301 50 mg PD FPD) or the observational 
cohort.  Randomization will be differentiated by the patient’s Hoehn 
and Yahr stage (<2.5 versus ≥2.5) to balance the severity of disease 
across each treatment group and by screening spirometry (FEV1 
<60% of predicted or FEV1/FVC ratio <70% versus FEV1 ≥60% of 
predicted and FEV1/FVC ratio ≥70%).  Patients who previously 
completed the CVT-301-002 and CVT-301-003 studies will be 
assigned only to the CVT-301 treatment group. Sites must allow 7 
business days between time of randomization and the first treatment 
visit (TV1) to allow time for drug to be shipped and received.   
Treatment/Observational Period 
Patients in both the CVT-301 treatment group and observational 
cohort are required to attend all of the in-clinic treatment/ 
observational visits.  The assessments and procedures for the in-
clinic treatment/observational visits will differ for patients in the 
CVT-301 treatment group compared to the observational cohort.  All 
patients, regardless of treatment group, should continue with their 
usual prescribed standard PD medication regimen for the duration of 


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the study which may be modified for symptomatic treatment during 
the study in accordance with usual practice.  
Treatment Visit/Observational Visit 1 (TV/OV1): At least 7 days 
after SV2 
Patients will complete the Screening ON/OFF Episodes Log and PD 
Diary for the 3 consecutive days prior to TV/OV1.   
Patients will report to the clinic after having taken their usual PD 
medications prior to the visit.  The timing of arrival for TV/OV1 
should be scheduled to increase the likelihood that patients will be in 
the ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at 
home).  Patients will bring to the clinic all of their usual PD 
medications. 
The clinic staff will collect the Screening ON/OFF Episodes Log and 
PD Diary, review the information, sign and date each, and confirm 
that the DLco assessment was performed prior to the visit (and if 
not, the study visit must be re-scheduled).   
Clinic staff will record the time patients took their usual PD 
medications prior to the visit and record any changes in standard PD 
medication dose/regimen.  The following assessments will be 
performed:  review of concomitant medications; PDQ-39 (in an ON 
state); brief physical examination; UPDRS Part 2 (preferably in the 
ON state); S&E ADL scale (preferably in the ON state); ECG; 
standard and orthostatic BP and HR; RR; spirometry (preferably in 
the ON state); clinical laboratory tests (with documentation of 
fasting status) including serum pregnancy test, if applicable; C-
SSRS; Epworth Sleepiness Scale; and the QUIP.   
In addition for the CVT-301 treated group only: 
Clinic staff will distribute the Inhaled Dosing Log for recording the 
number of times the inhaler was used and the number of capsules 
used for each inhalation (to be completed daily throughout the 
12-month treatment period). 
Clinic staff will distribute the PD Diary which will be used to record 
time OFF, time ON without dyskinesia, time ON with non-
troublesome dyskinesia, time ON with troublesome dyskinesia, and 
time asleep (to be completed for the 3 consecutive days prior to the 
treatment visits). The UPDRS Part 4 (Questions 32-35 and 36-39) 
will be completed. 
The clinic staff will provide study drug kits.   
Patients will be trained again on the proper technique to prepare and 
use the inhaler system (using sham capsules) per the IFU.  
Under clinic staff supervision, preferably between 2 and 5 hours 
after receiving their previous dose of oral PD medications (in the 
OFF state), patients will prepare and self-administer their entire dose 
of inhaled study drug.  The dosing time is defined to be when the 
patient’s OFF state is recognized by both the patient and investigator 
to be at a level similar to the investigator-confirmed severity 
experienced at SV1 and preferably between 2 and 5 hours after their 


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prior oral PD medication.    
Vital signs (standard vital signs [BP and HR] and orthostatic vital 
signs [BP and HR]) will be assessed at 20 and 60 minutes post-dose.  
Respiratory rate will be assessed at 10, 20, 30, and 60 minutes 
post-dose.  Patients will be monitored for AEs throughout the visit. 
Upon completion of the 60-minute observations, the patient’s usual 
schedule of standard PD medications will be resumed for the 
remainder of the day (the patient may use the inhaled study drug up 
to 4 more times at home that day after he/she leaves the clinic, if 
needed for OFF episodes).   
Clinic staff will arrange to speak with patients by telephone 1 to 
3 days after the visit to monitor for AEs and to discuss concerns or 
challenges with the inhaler systems or Inhaled Dosing Log.    
All Patients: 
The next study visit will be scheduled.  
Clinic staff will arrange to speak with patients by telephone 2 weeks 
before TV/OV2 to address any concerns or challenges with the 
inhaler systems, PD Diary, or Inhaled Dosing Log (CVT arm only), 
to monitor for any AEs, to confirm the next study visit, to ask the 
patients how many empty study drug kits will be returned at the next 
visit (CVT arm only), and also to remind patients of the study 
procedures required prior to the next scheduled study visit (including 
completion of the PD Diary and applicable, the Inhaled Dosing Log).  
At-Home Dosing for the CVT-301 Treatment Group 
At TV/OV1, TV/OV2, TV/OV3, TV/OV4, and TV/OV5, patients in 
the CVT-301 treatment group will receive study drug kits and the 
IFU to take home with them.  Patients will be instructed to take their 
standard oral PD medications as prescribed on their usual schedule 
of administration, which may be modified as needed for 
symptomatic treatment during the 12-month study.  Additions to 
and/or modification of the patient’s usual PD treatment regimen may 
take place. Oral PRN LD formulations are not permitted for these 
patients (refer to Section 9.4.2 of the protocol for a list of prohibited 
treatments and prohibited medications).  The total daily LD dose of 
the modified PD treatment regimen (not including CVT-301) must 
not exceed 1600 mg per day.   
Patients will be instructed to administer inhaled study drug up to 
5 times during the waking day as close as possible to the time when 
they begin to experience OFF symptoms.  The PD symptomatology 
defining the onset of an OFF state may vary by patient, but typically 
is indicated by the return of PD motor symptoms such as tremor or 
bradykinesia; for some patients, OFF episodes may be heralded by 
non-motor symptoms (e.g., pain or anxiety) shortly prior to the 
appearance of motor symptoms.   
Study drug may not be used for the treatment of early morning OFF 
periods (i.e., morning akinesia).  Patients may not take their inhaled 
study drug within 45 minutes following their previous dose of 
standard oral PD medication.  These patients may not take oral PRN 


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medications to manage OFF states during the study. 
In the event that an OFF state is not sufficiently resolved within 
45 minutes of completing the last capsule inhalation, patients may 
resume their usual prescribed PD medication, if they have not 
already done so (i.e., according to their standard dose 
schedule/regimen); patients may not re-dose with inhaled study drug 
for that episode.  If patients experience more than 5 OFF episodes 
per day that require treatment, they should adhere to their standard 
oral regimen for management of any additional OFF episodes; they 
may not treat these episodes with additional inhalations of study 
drug.  
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV/OV2, TV/OV3, TV/OV4, TV/OV5, and TV/OV6.  Patients 
will complete the Inhaled Dosing Log every day during the 
12-month treatment period.  As described previously, patients will 
be contacted by the clinic staff 1 to 3 days after TV/OV1 and 
2 weeks (± 3 days) prior to each visit for TV/OV2, TV/OV3, 
TV/OV4, TV/OV5, and TV/OV6. 
They will bring the PD Diary, Inhaled Dosing Log, empty capsules, 
inhalers, and unused supplies to the each clinic visit.  Unused 
supplies can be re-dispensed to the patient at each clinic visit, in 
addition to a sufficient number of new study drug kits to supply the 
patient until his/her next visit. Note: Any open kit (even if partially 
unused) may not be re-dispensed. If the patient begins to run low on 
study supplies in between treatment visits, they should contact the 
site. 
Treatment Visit/Observational Visit 2 (TV/OV2): 1 month (4 
weeks ±5 days) after TV/OV1 
Patients will bring their usual PD medications and report to the clinic 
after having taken their usual PD medications prior to the visit.  The 
timing of administration of the usual morning dose of PD medication 
may be adjusted by the investigator to accommodate the patient’s 
and/or clinic’s schedule.  Following their usual morning PD 
medication, no further non-study PD medications will be used until 
following completion of all assessments.  The timing of arrival 
should be scheduled to increase the likelihood that patients will be in 
an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at 
home).  
Clinic staff will record any changes in standard PD medication 
dose/regimen and record the time that patients took their usual PD 
medications prior to the visit.  The following assessments will be 
performed:  recording of any changes in concomitant medications; 
brief physical examination; spirometry (preferably in the ON state); 
standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP 
and HR). 
In addition for the CVT-301 treated group only: 
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV2 and the Inhaled Dosing Log daily throughout the treatment 


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period.  The clinic staff will review, sign, and date the PD Diary and 
Inhaled Dosing Log and collect all used and unused supplies.  
Unused supplies can be re-dispensed to the patient, in addition to a 
sufficient number of new study drug kits to supply the patient until 
his/her next visit. Note: Any open kit (even if partially unused) may 
not be re-dispensed. The staff will also review inhaler training, 
provide the PD Diary and Inhaled Dosing Log and review 
instructions for completion.  Patients will be instructed to collect 
used empty capsules and return them at the next visit along with the 
PD Diary, Inhaled Dosing Log, and other study supplies.  
The patient will remain in the clinic until he/she goes into the OFF 
state.  In the OFF state, the patients will undergo UPDRS Part 3 
assessments, immediately pre-dose, following which the patient will 
prepare and then self-administer (under staff supervision) the entire 
dose of inhaled study drug. The dosing time is defined to be when 
the patient’s OFF state is recognized by both the patient and 
investigator to be at a level similar to the investigator-confirmed 
severity experienced at SV1 and preferably between 2 and 5 hours 
after their prior oral PD medication.    
Exploratory efficacy responses will be assessed by recording:  (1) 
UPDRS Part 3 evaluations at 10, 20, 30, and 60 minutes post-dose; 
(2) the occurrence and severity of dyskinesia; and (3) whether the 
patient converted to an ON state during the 60-minute post-dose time 
period and if so, whether he/she was still in an ON state at 
60 minutes post-dose.  
Adverse events will be monitored throughout the visit. 
Upon completion of the 60-minute observations, resumption of 
normal medications is permitted for the remainder of the day (the 
patient may use the inhaled study drug 4 more times at home after 
he/she leaves the clinic on that day if needed for OFF episodes). 
All patients:  
The next study visit will be scheduled.  The clinic staff will schedule 
patients to undergo DLco at the pulmonary function lab, to occur 
within 2 weeks prior to the next study visit.  The evaluation should 
be performed while the patient is in an ON state (as reported by the 
patient to the pulmonary technician).  As part of the procedure, a 
slow vital capacity will be performed, followed by DLco, and then 
spirometry. 
Clinic staff will arrange to speak with patients by telephone 2 weeks 
(± 3 days) prior to TV/OV3 to address any potential concerns or 
challenges with the PD Diary, inhaler systems or Inhaled Dosing 
Log (CVT arm only), to monitor for any AEs, to confirm that the 
DLco  assessment has been done/scheduled, to confirm the next 
study visit, to ask the patients how many empty study drug kits will 
be returned at the next visit (CVT arm only), and to remind patients 
of the study procedures required before the next visit (including 
completion of the PD Diary and the Inhaled Dosing Log, as 
applicable).   


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Treatment Visit/Observational Visit 3 (TV/OV3): 3 months 
(12±2 weeks) after TV/OV1 
Patients will bring their usual PD medications and report to the clinic 
after having taken their usual PD medications prior to the visit.  The 
timing of administration of the usual morning dose of PD medication 
may be adjusted by the investigator to accommodate the patient’s 
and/or clinic’s schedule.  Following their usual morning PD 
medication, no further non-study PD medications will be used until 
following completion of all assessments.  The timing of arrival 
should be scheduled to increase the likelihood that patients will be in 
an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at 
home). 
Clinic staff will confirm that the DLco assessment has been 
completed within 2 weeks prior to the visit (and if not, re-schedule 
the study visit).  Clinic staff will record any changes in standard PD 
medication dose/regimen and record the time that patients took their 
usual PD medications prior to the visit.  The following assessments 
will be performed:  recording of any changes in concomitant 
medications; C-SSRS; brief physical examination; standard vital 
signs (BP, HR, and RR) and orthostatic vital signs (BP and HR); 
ECG; spirometry (preferably in the ON state); and clinical laboratory 
tests (with documentation of fasting status) including serum 
pregnancy test, if applicable.   
In addition for the CVT-301 treated group only: 
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV3 and the Inhaled Dosing Log daily throughout the treatment 
period.  The clinic staff will review, sign, and date the PD Diary and 
Inhaled Dosing Log and collect all used and unused supplies. 
Unused supplies can be re-dispensed to the patient, in addition to a 
sufficient number of new study drug kits to supply the patient until 
his/her next visit. Note: Any open kit (even if partially unused) may 
not be re-dispensed. The staff will also review inhaler training, 
provide the PD Diary and Inhaled Dosing Log and review 
instructions for completion.  Patients will be instructed to collect 
used empty capsules and return them at the next visit along with the 
PD Diary, Inhaled Dosing Log, and other study supplies. 
The patient will remain in the clinic until he/she goes into the OFF 
state.  In the OFF state, the patient will undergo UPDRS Part 3 
assessments, immediately pre-dose, following which the patient will 
prepare and then self-administer (under staff supervision) the entire 
dose of inhaled study drug. The dosing time is defined to be when 
the patient’s OFF state is recognized by both the patient and 
investigator to be at a level similar to the investigator-confirmed 
severity experienced at SV1 and preferably between 2 and 5 hours 
after their prior oral PD medication.    
Exploratory efficacy responses will be assessed by recording:  (1) 
UPDRS Part 3 evaluations at 10, 20, 30, and 60 minutes post-dose; 


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(2) the occurrence and severity of dyskinesia; and (3) whether the 
patient converted to an ON state during the 60-minute post-dose time 
period and if so, whether he/she was still in an ON state at 
60 minutes post-dose. The PGI-C will be completed, preferably in 
the ON state and must be done before other study evaluations. 
Adverse events will be monitored throughout the visit. 
Upon completion of the 60-minute observations, resumption of 
normal medications is permitted for the remainder of the day (the 
patient may use the inhaled study drug 4 more times at home after 
he/she leaves the clinic on that day if needed for OFF episodes). 
All patients:  
The next study visit will be scheduled.  The clinic staff will schedule 
patients to undergo DLco at the pulmonary function lab, to occur 
within 2 weeks prior to the next study visit.  The evaluation should 
be performed while the patient is in an ON state (as reported by the 
patient to the pulmonary technician).  As part of the procedure, a 
slow vital capacity will be performed, followed by DLco, and then 
spirometry. 
Clinic staff will arrange to speak with patients by telephone 2 weeks 
(± 3 days) prior to TV/OV4 to address any potential concerns or 
challenges with the PD Diary, inhaler systems or Inhaled Dosing 
Log (CVT arm only), to monitor for any AEs, to confirm that the 
DLco assessment has been done/scheduled, to confirm their next 
study visit, to ask the patients how many empty study drug kits will 
be returned at the next visit, and to remind patients of the study 
procedures required before the next visit (including completion of 
the PD Diary and the Inhaled Dosing Log, as applicable).   
Treatment Visit/Observational Visit 4 (TV/OV4): 6 months 
(24±2 weeks) after TV/OV1 
Patients will bring their usual PD medications and report to the clinic 
after having taken their usual PD medications prior to the visit.  The 
timing of administration of the usual morning dose of PD medication 
may be adjusted by the investigator to accommodate the patient’s 
and/or clinic’s schedule.  Following their usual morning PD 
medication, no further non-study PD medications will be used until 
following completion of all assessments.  The timing of arrival 
should be scheduled to increase the likelihood that patients will be in 
an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at 
home).   
They will confirm that the DLco assessment has been completed 
within 2 weeks prior to the visit (and if not, re-schedule the study 
visit).  Clinic staff will record any changes in standard PD 
medication dose/regimen and record the time that patients took their 
usual PD medications prior to the visit.  The following assessments 
will be performed:  recording of any changes in concomitant 
medications; brief physical examination; standard vital signs (BP, 
HR, and RR) and orthostatic vital signs (BP and HR); ECG; 
spirometry (preferably in the ON state); and clinical laboratory tests 


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(with documentation of fasting status) including serum pregnancy 
test, if applicable.   
In addition the following assessments will be recorded: the PDQ-39, 
UPDRS Part 2, and S&E ADL scale (each preferably in the ON 
state); QUIP; Epworth Sleepiness Scale; and C-SSRS. 
In addition for the CVT-301 treated group only: 
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV4 and the Inhaled Dosing Log daily throughout the treatment 
period.  The clinic staff will review, sign, and date the PD Diary and 
Inhaled Dosing Log and collect all used and unused supplies. 
Unused supplies can be re-dispensed to the patient, in addition to a 
sufficient number of new study drug kits to supply the patient until 
his/her next visit. Note: Any open kit (even if partially unused) may 
not be re-dispensed. The staff will also review inhaler training, 
provide the PD Diary and Inhaled Dosing Log and review 
instructions for completion.  Patients will be instructed to collect 
used empty capsules and return them at the next visit along with the 
PD Diary, Inhaled Dosing Log, and other study supplies. The 
UPDRS Part 4 (Questions 32-35 and 36-39) will be completed 
The patient will remain in the clinic until he/she goes into the OFF 
state.  In the OFF state, the patient will undergo UPDRS Part 3 
assessments, immediately pre-dose, following which the patient will 
prepare and then self-administer (under staff supervision) the entire 
dose of inhaled study drug. The dosing time is defined to be when 
the patient’s OFF state is recognized by both the patient and 
investigator to be at a level similar to the investigator-confirmed 
severity experienced at SV1 and preferably between 2 and 5 hours 
after their prior oral PD medication.    
Exploratory efficacy responses will be assessed by recording:  (1) 
UPDRS Part 3 evaluations at 10, 20, 30, and 60 minutes post-dose; 
(2) the occurrence and severity of dyskinesia; and (3) whether the 
patient converted to an ON state during the 60-minute post-dose time 
period and if so, whether he/she was still in an ON state at 
60 minutes post-dose.  The PGI-C will be completed, preferably in 
the ON state and must be done before other study evaluations. 
Adverse events will be monitored throughout the visit. 
Upon completion of the 60-minute observations, resumption of 
normal medications is permitted for the remainder of the day (the 
patient may use the inhaled study drug 4 more times at home after 
he/she leaves the clinic on that day if needed for OFF episodes). 
All patients:  
The next study visit will be scheduled.  The clinic staff will schedule 
patients to undergo DLco at the pulmonary function lab, to occur 
within 2 weeks prior to the next study visit.  The evaluation should 
be performed while the patient is in an ON state (as reported by the 
patient to the pulmonary technician).  As part of the procedure, a 
slow vital capacity will be performed, followed by DLco, and then 
spirometry. 


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Clinic staff will arrange to speak with patients by telephone 2 weeks 
(± 3 days) prior to TV/OV5 to address any potential concerns or 
challenges with the PD Diary, inhaler systems or Inhaled Dosing 
Log (CVT arm only), to monitor for any AEs, to confirm that the 
DLco and spirometry assessments has been done/scheduled, to 
confirm the next study visit, to ask the patients how many empty 
study drug kits will be returned at the next visit, and to remind 
patients of the study procedures required before the next visit 
(including completion of the PD Diary and  the Inhaled Dosing Log, 
as applicable).   
Treatment Visit/Observational Visit 5 (TV/OV5): 9 months 
(36±2 weeks) after TV/OV1  
Patients will bring their usual PD medications and report to the clinic 
after having taken their usual PD medications prior to the visit.  The 
timing of administration of the usual morning dose of PD medication 
may be adjusted by the investigator to accommodate the patient’s 
and/or clinic’s schedule.  Following their usual morning PD 
medication, no further non-study PD medications will be used until 
following completion of all assessments.  The timing of arrival 
should be scheduled to increase the likelihood that patients will be in 
an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at 
home).   
Clinic staff will confirm that the DLco assessment has been 
completed within 2 weeks prior to the visit (and if not, re-schedule 
the study visit).  Clinic staff will record any changes in standard PD 
medication dose/regimen and record the time that patients took their 
usual PD medications prior to the visit.  The following assessments 
will be performed:  recording of any changes in concomitant 
medications; brief physical examination; standard vital signs (BP, 
HR, and RR) and orthostatic vital signs (BP and HR); spirometry 
(preferably in the ON state); clinical laboratory tests (with 
documentation of fasting status) including serum pregnancy test, if 
applicable; and the C-SSRS assessment. 
In addition for the CVT-301 treated group only: 
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV5 and the Inhaled Dosing Log daily throughout the treatment 
period.   
The clinic staff will review, sign, and date the PD Diary and Inhaled 
Dosing Log and will collect all used and unused supplies. Unused 
supplies can be re-dispensed to the patient, in addition to a sufficient 
number of new study drug kits to supply the patient until his/her next 
visit. Note: Any open kit (even if partially unused) may not be re-
dispensed. The staff will also review inhaler training, provide the PD 
Diary and Inhaled Dosing Log and review instructions for 
completion.  Patients will be instructed to collect used empty 
capsules and return them at the next visit along with the PD Diary, 
Inhaled Dosing Log, and other study supplies. 
The patient will remain in the clinic until he/she goes into the OFF 


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state.  In the OFF state, the patient will undergo UPDRS Part 3 
assessments, immediately pre-dose, following which the patient will 
prepare and then self-administer (under staff supervision) the entire 
dose of inhaled study drug. The dosing time is defined to be when 
the patient’s OFF state is recognized by both the patient and 
investigator to be at a level similar to the investigator-confirmed 
severity experienced at SV1 and preferably between 2 and 5 hours 
after their prior oral PD medication.    
The clinic staff will assess: (1) UPDRS Part 3 evaluations at 10, 20, 
30, and 60 minutes post-dose; (2) the occurrence and severity of 
dyskinesia; and (3) whether the patient converted to an ON state 
during the 60-minute post-dose time period and if so, whether he/she 
was still in an ON state at 60 minutes post-dose.  
Adverse events will be monitored throughout the visit. 
Upon completion of the 60-minute observations, resumption of 
normal medications is permitted for the remainder of the day (the 
patient may use the inhaled study drug 4 more times at home after 
he/she leaves the clinic on that day if needed for OFF episodes). 
All patients:  
The next study visit will be scheduled.  The clinic staff will schedule 
patients to undergo DLco at the pulmonary function lab, to occur 
within 2 weeks prior to the next study visit.  The evaluation should 
be performed while the patient is in an ON state (as reported by the 
patient to the pulmonary technician).  As part of the procedure, a 
slow vital capacity will be performed, followed by DLco, and then 
spirometry. 
Clinic staff will arrange to speak with patients by telephone 2 weeks 
(± 3 days) prior to TV/OV6 to address any potential concerns or 
challenges with the PD Diary, inhaler systems or Inhaled Dosing 
Log (CVT arm only), to monitor for any AEs, to confirm that the 
DLco and spirometry assessment has been done/scheduled, to 
confirm their next study visit, to ask the patients how many empty 
study drug kits will be returned at the next visit, and to remind 
patients of the study procedures required before the next visit 
(including completion of the PD Diary and as applicable, the Inhaled 
Dosing Log).   
Treatment Visit/Observational Visit 6 (TV/OV6) / Early 
Withdrawal Visit:12 months (52±2 weeks) after TV/OV1 
Patients will bring their usual PD medications and report to the clinic 
after having taken their usual PD medications prior to the visit.  The 
timing of administration of the usual morning dose of PD medication 
may be adjusted by the investigator to accommodate the patient’s 
and/or clinic’s schedule.  Following their usual morning PD 
medication, no further non-study PD medications will be used until 
following completion of all assessments.  The timing of arrival 
should be scheduled to increase the likelihood that patients will be in 
an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at 
home). 


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Clinic staff will confirm that DLco assessment was performed within 
2 weeks prior to the visit (and if not, re-schedule study visit).  Clinic 
staff will record any changes in standard PD medication 
dose/regimen and record the time that patients took their usual PD 
medications prior to the visit.  The following assessments will be 
performed:  recording of any changes in concomitant medications; 
brief physical examination; standard vital signs (BP, HR, and RR) 
and orthostatic vital signs (BP and HR); ECG; spirometry 
(preferably in the ON state); and clinical laboratory tests (with 
documentation of fasting status) including serum pregnancy test, if 
applicable.   
In addition the following assessments will be recorded: the PDQ-39, 
UPDRS Part 2, and S&E ADL scale (each preferably in the ON 
state); QUIP; Epworth Sleepiness Scale; and C-SSRS. 
In addition for the CVT-301 treated group only:  
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV6 and the Inhaled Dosing Log daily throughout the treatment 
period.  The clinic staff will review, sign, and date the PD Diary and 
Inhaled Dosing Log and collect all used and unused supplies. The 
UPDRS Part 4 (Questions 32-35 and 36-39) will be completed 
The patient will remain in the clinic until he/she goes into the OFF 
state.  Patients will be provided with a new inhaler for dosing at 
TV/OV6 and will use study drug from the supplies brought to the 
visit.  In the OFF state, the patient will undergo UPDRS Part 3 
assessments, immediately pre-dose, following which the patient will 
prepare and then self-administer (under staff supervision) the entire 
dose of inhaled study drug. The dosing time is defined to be when 
the patient’s OFF state is recognized by both the patient and 
investigator to be at a level similar to the investigator-confirmed 
severity experienced at SV1 and preferably between 2 and 5 hours 
after their prior oral PD medication.    
Exploratory efficacy responses will be assessed by recording:  (1) 
UPDRS Part 3 evaluations at 10, 20, 30, and 60 minutes post-dose; 
(2) the occurrence and severity of dyskinesia; and (3) whether the 
patient converted to an ON state during the 60-minute post-dose time 
period and if so, whether he/she was still in an ON state at 
60 minutes post-dose. The PGI-C will be completed, preferably in 
the ON state and must be done before other study evaluations. 
All patients:  
Adverse events will be monitored throughout the visit.  Once all of 
the assessments are complete, patients will be scheduled for a DLco 
assessment 4 to 5 weeks after TV/OV6.  The DLco assessment 
should be performed while the patient is in an ON state (as reported 
by the patient to the pulmonary technician) at the pulmonary 
function facility.  As part of the procedure, a slow vital capacity will 
be performed, followed by DLco, and then spirometry. 
Patients who withdraw prematurely will complete the TV/OV6 
assessments at the time of withdrawal (except the pre-TV/OV6 
DLco assessment) and will be scheduled to undergo a DLco 


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assessment 4 to 5 weeks after TV/OV6. 
Selection of Patients: 
All patients must meet the inclusion criteria and must not meet any 
of the exclusion criteria to be eligible for this study.  Patients 
previously enrolled in the CVT-301-002 and CVT-301-003 studies 
must have completed all of the CVT-301 study visits without any 
safety issues that would preclude participation in this study 
according to the investigator.  Patients who withdrew from either of 
the CVT-301 studies prior to completion, for any reason, will not be 
eligible. 
Inclusion Criteria: 
• 
Has signed and dated an IRB/IEC-approved informed 
consent form before any protocol-specific screening 
procedures are performed. 
• 
Is a male or female aged 30 to 85 years, inclusive.  Women 
of child-bearing potential must use protocol-defined 
contraceptive measures (see Section 11.1.5) and must have a 
negative serum human chorionic gonadotropin (hCG) test at 
screening.  These patients must be willing to remain on their 
current form of contraception for the duration of the study. 
• 
Patients who have idiopathic PD (i.e., not induced by drugs 
or other diseases) as defined by fulfilling Steps 1 and 2 of 
the UK Brain Bank criteria, diagnosed after the age of 30 
years. 
• 
Patients who are classified as Stage 1 to 3 (in the ON state) 
on the modified Hoehn and Yahr scale for staging of PD 
severity. 
• 
Patients who have experienced motor fluctuations for a 
minimum of 2 hours of average daily OFF time per waking 
day (excluding early morning OFF time) by self-report and 
confirmed by the PD Diary (on 3 consecutive days) during 
the screening period. 
• 
Patients who are on a LD-containing therapy, not including 
Rytary (or equivalent), must be stable on oral LD-containing 
therapy for at least 2 weeks prior to SV1 with a 
LD/dopamine decarboxylase inhibitor (DDI)-containing 
regimen.  
• 
Patients who are on a LD containing therapy, when 
including Rytary (or equivalent), should be on a stable dose 
for at least 6 weeks prior to SV1 
• 
The frequency of L-dopa administrations must be at least 3 
times during the waking day and a total daily LD dose of 
≤1600 mg (exclusive of PRN LD-containing medications).   
• 
Patients should be stable on other PD medications for at 
least 4 weeks prior to SV1.   
• 
Patients must have a ≥25% difference between UPDRS Part 
3 scores recorded in their ON and OFF states at screening. 
• 
Patients must have normal cognition as confirmed by a score 


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of ≥25 on the MMSE, performed in the ON state. 
• 
Patients must be able to perform a spirometry maneuver in 
the ON and OFF states, and must have a screening 
FEV1 ≥50% of predicted and an FEV1/FVC ratio >60% in 
the ON state at screening.  (A pulmonologist will review the 
spirometry tracings/morphology of any patient with an 
FEV1 that is ≥50% to <60% of predicted or an FEV1/FVC 
ratio that is >60% to <70% in order to determine potential 
eligibility.  All CVT-301-naïve patients with an FEV1/FVC 
ratio of >60% to <70% will be required to undergo a 
bronchodilator challenge and the results must be reviewed 
prior to entry into the study.  Patients with an FEV1/FVC 
ratio that is >60% to <70% will complete spirometry before 
and after the administration of a bronchodilator in a 
pulmonary function laboratory.  Testing will be performed 
in accordance with the 2005 ATS/European Respiratory 
Society [ERS] criteria prior to randomization.  The results of 
the bronchodilator challenge will be reviewed by a 
pulmonologist prior to potential randomization.)   
Exclusion Criteria: 
• 
Patients who have dyskinesia of a severity that would 
significantly interfere with their ability to participate or 
perform study procedures. 
• 
Pregnant or lactating females or females wishing to become 
pregnant. 
• 
Patients who have any known contraindication to the use of 
LD, including a history of malignant melanoma or a history 
of narrow-angle glaucoma.   
• 
Patients who have had previous surgery for PD (including 
but not limited to deep brain stimulation [DBS] or cell 
transplantation). 
• 
Patients with a history of psychotic symptoms requiring 
treatment, or suicide ideation or attempt within the prior 
12 months (stable regimens [for at least 4 weeks prior to 
SV1] of anti-depressant and certain low-dose atypical 
antipsychotic medications are permitted, in case they are 
indicated to treat symptoms other than psychotic symptoms).   
• 
Patients who have cancer with the exception of the 
following:  basal cell carcinoma or successfully treated 
squamous cell carcinoma of the skin; cervical carcinoma in 
situ; prostatic carcinoma in situ; or other malignancies 
curatively treated and with no evidence of disease recurrence 
for at least 3 years. 
• 
Patients taking certain prohibited medications (see 
Section 9.4.2). 
• 
Patients with a history of drug or alcohol abuse within the 
prior 12 months. 


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• 
Patients with chronic obstructive pulmonary disease 
(COPD), asthma, or other chronic respiratory disease within 
the last 5 years. 
• 
Patients with any contraindication to performing routine 
spirometry or who are unable to perform a spirometry 
maneuver (see Appendix 20 for a list of contraindications).  
• 
Patients with a current history of symptomatic orthostatic 
hypotension despite adequate treatment.   
• 
Patients with any condition that in the investigator’s opinion 
would make patients unsuitable or interfere with their 
participation in the study.  Potential issues of concern should 
be raised to the medical monitor during eligibility review. 
• 
Patients who have any clinically significant abnormality or 
finding from examination, tests, or history that may 
compromise patient safety.  
• 
Patients who have been treated with an investigational drug 
within 4 weeks or 5 half-lives (whichever is longer) prior to 
the beginning of the screening period  (this includes 
investigational formulations of marketed products). 
• 
Prior exposure to CVT-301. 
Planned Sample Size: 
Approximately 250 CVT-301 treatment patients and 115 control 
patients will be enrolled in this study. It is assumed that the drop-out 
rate will be approximately 25%. 
Investigational Therapy (for 
the CVT-301 treatment 
group): 
CVT-301 (levodopa inhalation powder [LIP]) 
Each dose will be administered using 2 sequential inhalations of 
CVT-301-filled capsules.  CVT-301 capsules will be delivered using 
the CVT-301 inhalers.  
 
 
 
 The capsules provided to the 
CVT-301 treatment group (target nominal respirable dose of 
approximately 50 mg LD FPD) will deliver approximately 25 mg 
LD FPD to the lung per capsule inhalation. 
Reference Therapy: 
There will be no reference therapy or placebo.   
Patients in both the CVT-301 treatment group and the observational 
cohort will be managed with their standard PD treatment throughout 
the study; modification of the standard PD treatment is permissible, 
as outlined in this protocol.  
Treatment Duration: 
The planned treatment period will be 52 ±2 weeks.  Each patient in 
the CVT-301 treatment group will self-administer up to 5 doses of 
inhaled study drug per day.  The maximum planned screening period 
is approximately 5 weeks.  A follow-up pulmonary evaluation will 
occur at 4 to 5 weeks after the treatment period ends. 
Criteria for Evaluation: 
Safety 
Pulmonary safety will be evaluated from assessments of lung 


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function, as measured from spirometry (FEV1, FVC, FEV1/FVC 
ratio).  In addition, DLco will be evaluated. 
Safety will also be assessed from physical examinations, AE reports, 
standard and orthostatic vital signs (BP, HR, and RR), clinical 
laboratory values (hematology and biochemistry), ECGs, the QUIP, 
Epworth Sleepiness Scale, the C-SSRS, UPDRS Part 4 (Questions 
32-35 and 36-39), and occurrence and severity of examiner-rated 
dyskinesia after study drug is administered in the clinic.  
Exploratory Efficacy  
• 
UPDRS Part 3 motor score, assessed pre-dose and at 10, 20, 
30, and 60 minutes following treatment in the clinic. 
Occurrence of an ON state during the 60-minute post-dose 
period and if an ON state occurs during the 60-minute 
post-dose, whether or not the patient is still in the ON state 
at 60 minutes post-dose. 
• 
Occurrence of an ON state during the 60-minute post-dose 
period and if an ON state occurs during the 60-minute 
post-dose, whether or not the patient is still in the ON state 
at 60 minutes post-dose  
• 
PD diary information on total daily ON time without 
dyskinesia, total daily ON time with troublesome dyskinesia, 
total daily ON time with non-troublesome dyskinesia, and 
total daily OFF time for the 3 consecutive days prior to each 
treatment visit  
• 
PDQ-39  
• 
PGI-C  
• 
S&E ADL 
• 
UPDRS Part 2 
Statistical Methods and 
Planned Analyses: 
For all statistical analyses of the CVT-301 treatment group, the visit 
at which the CVT-301 treatment was initiated will be used as the 
baseline.  However, for all enrolled patients who were previously 
included in the CVT-301-002 or CVT-301-003 studies, TV/OV1 of 
the CVT-301-005 study will be used as baseline.  For the 
observational cohort, the assessments at TV/OV1 will be used as 
baseline.   
All patients who are enrolled in CVT-301-005 and receive at least 
1 dose of CVT-301 will be included in the safety and exploratory 
endpoint analyses.  Patients in the observational cohort will be 
included in the analyses if they provide any data after TV/OV1. 
Safety Analyses  
The extent of exposure to study treatment will be summarized for the 
patients who received CVT-301 treatment.  The time period between 
TV/OV1 and TV/OV6 (or Early Withdrawal Visit) will be used as 
the measure of extent of exposure for patients randomized to the 
observational cohort.  Adverse events will be tabulated by treatment 
group according to the Medical Dictionary for Regulatory Activities 
(MedDRA).  Study-emergent and treatment-emergent adverse events 


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(TEAEs) will be summarized by body system and preferred term.  
For patients in the observational cohort, the AEs collected between 
TV/OV1 and TV/OV6 (or Early Withdrawal Visit) will be 
considered as TEAEs.  Furthermore, the time of onset of the TEAEs 
will be summarized.  For vital signs, ECG parameters, spirometry 
measurements, and DLco, the changes from pre-dose to post-dose 
assessments of the corresponding day will be calculated and 
described using descriptive statistics.  For spirometry, DLco, and 
safety laboratory variables, the differences in pre-dose values 
between the study days will be described.  Furthermore, the changes 
in the spirometry values and difference between the groups will be 
estimated using a Mixed Model for Repeated Measurements 
(MMRM) similar to the one used for the exploratory endpoint 
variables.  The proportion of patients with abnormal spirometry 
values will be tabulated using different criteria for the threshold 
(e.g., at least 10% or 20% change from baseline at any single visit, at 
least 10% or 20% change from baseline on at least 2 consecutive 
visits).  The proportions of patients meeting ATS quality criteria 
(and also for those ‘rejected’) will be summarized.  All spirometry 
analyses will be performed both for all patients regardless of the 
ATS quality criteria and separately excluding the assessments not 
meeting the ATS quality criteria.  Changes from baseline to follow-
up in the rating scales for assessing suicidality, somnolence, and 
impulse control disorders will be summarized descriptively.  
Demographics and baseline characteristics will be summarized 
descriptively. 
Exploratory Endpoint Analyses 
The objectives related to the exploratory endpoints will primarily be 
assessed for the CVT-301-treated patients.  The same objectives will 
be explored for the pool of CVT-301 naïve patients and patients who 
were previously enrolled in the CVT-301-002 or CVT-301-003 
studies, if feasible.   
The changes from baseline in continuous exploratory endpoint 
variables will be estimated using an MMRM.  The model will 
include visit and the stratification variables (Hoehn and Yahr stage 
and screening FEV1 and/or FEV1/FVC) as fixed factors.  The 
baseline value will be used as a covariate..   
The categorical data will be primarily evaluated descriptively.  Each 
visit will be evaluated separately for the categorical endpoints. 
The exploratory endpoint data collected from the patients in the 
observational cohort will be summarized with descriptive statistics. 
 
 


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3. 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
CIVITAS THERAPEUTICS PROTOCOL APPROVAL PAGE ...................................................2 
INVESTIGATOR PROTOCOL AGREEMENT PAGE .................................................................3 
LIST OF CONTACTS .....................................................................................................................4 
2. 
SYNOPSIS ...................................................................................................................6 
3. 
TABLE OF CONTENTS ...........................................................................................28 
4. 
LIST OF ABBREVIATIONS.....................................................................................31 
5. 
INTRODUCTION ......................................................................................................34 
5.1. 
Background and Rationale ..........................................................................................34 
5.2. 
Rationale .....................................................................................................................36 
6. 
STUDY OBJECTIVES ..............................................................................................40 
7. 
INVESTIGATIONAL PLAN .....................................................................................41 
8. 
STUDY POPULATION .............................................................................................43 
8.1. 
Inclusion Criteria ........................................................................................................43 
8.2. 
Exclusion Criteria .......................................................................................................44 
8.3. 
Removal of Patients from Study .................................................................................45 
9. 
TREATMENTS ..........................................................................................................46 
9.1. 
Details of Study Treatment for the CVT-301 Treatment Group ................................46 
9.2. 
Randomization and Administration of Study Treatment ............................................48 
9.3. 
Treatment Accountability and Compliance (for the CVT-301 Treatment 
Group) .........................................................................................................................48 
9.4. 
Prior and Concomitant Illnesses and Medications ......................................................49 
10. 
STUDY PROCEDURES ............................................................................................51 
10.1. 
Screening Period .........................................................................................................51 
10.2. 
Randomization to Study Drug ....................................................................................55 
10.3. 
Treatment/Observational Period .................................................................................55 
11. 
DESCRIPTION OF ASSESSMENTS .......................................................................75 
11.1. 
Safety Assessments .....................................................................................................75 
11.2. 
Exploratory Efficacy Assessments .............................................................................83 
11.3. 
Other Assessments Used for Baseline Disease Characteristics for all Patients ..........85 
11.4. 
Appropriateness of Measurements .............................................................................86 


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12. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS...................................86 
12.1. 
Determination of Sample Size ....................................................................................87 
12.2. 
Study Populations .......................................................................................................87 
12.3. 
Definition of Baseline .................................................................................................87 
12.4. 
Background and Demographic Characteristics ..........................................................87 
12.5. 
Safety Analysis ...........................................................................................................88 
12.6. 
Exploratory Efficacy Analysis ....................................................................................89 
13. 
STUDY MANAGEMENT .........................................................................................90 
13.1. 
Approval and Consent ................................................................................................90 
13.2. 
Financing and Insurance .............................................................................................90 
13.3. 
Discontinuation of the Study by the Sponsor .............................................................90 
13.4. 
Study Documentation .................................................................................................91 
13.5. 
Data Handling .............................................................................................................91 
13.6. 
Study Monitoring and Auditing ..................................................................................91 
13.7. 
Retention of Records ..................................................................................................92 
13.8. 
Use of Study Findings ................................................................................................92 
13.9. 
Publication ..................................................................................................................92 
14. 
REFERENCES ...........................................................................................................94 
15. 
APPENDICES – TABLE OF CONTENTS ...............................................................96 
APPENDIX 1:  OVERALL VISIT SCHEDULE SCHEMATIC ..................................................98 
APPENDIX 2:  TIME AND EVENTS TABLE—SCREENING VISIT 1 (SV1) 
(WITHIN 35 DAYS PRIOR TO TV/OV1) ................................................................99 
APPENDIX 3:  TIME AND EVENTS TABLE—SCREENING VISIT 2 (SV2) (AT 
LEAST 4 DAYS AFTER SV1) ................................................................................100 
APPENDIX 4:  TIME AND EVENTS TABLE—TREATMENT VISIT 1 (TV1) (AT 
LEAST 7 DAYS AFTER SV2) ................................................................................101 
APPENDIX 5:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 1 (OV1) 
(AT LEAST 7 DAYS AFTER SV2) ........................................................................103 
APPENDIX 6:  TIME AND EVENTS TABLE—TREATMENT VISIT 2 (TV2) (1 
MONTH [4 WEEKS ±5 DAYS] AFTER TV1) .......................................................104 
APPENDIX 7:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 2 (OV2) 
(1 MONTH [4 WEEKS ±5 DAYS] AFTER OV1) ..................................................106 
APPENDIX 8:  TIME AND EVENTS TABLE—TREATMENT VISIT 3 (TV/OV3) (3 
MONTHS [12±2 WEEKS] AFTER TV1) ...............................................................107 


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APPENDIX 9:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 3 (OV3) 
(3 MONTHS [12±2 WEEKS] AFTER OV1) ...........................................................109 
APPENDIX 10:  TIME AND EVENTS TABLE—TREATMENT VISIT 4 (TV4) (6 
MONTHS [24±2 WEEKS] AFTER TV1) ...............................................................110 
APPENDIX 11:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 4 (OV4) 
(6 MONTHS [24±2 WEEKS] AFTER OV1) ...........................................................112 
APPENDIX 12:  TIME AND EVENTS TABLE—TREATMENT VISIT 5 (TV5) (9 
MONTHS [36±2 WEEKS] AFTER TV1) ...............................................................113 
APPENDIX 13:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 5 (OV5) 
(9 MONTHS [36±2 WEEKS] AFTER OV1) ...........................................................115 
APPENDIX 15:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 6 (OV6) 
VISIT (12 MONTHS [52±2 WEEKS] AFTER OV1)/EARLY 
WITHDRAWAL VISIT ...........................................................................................118 
APPENDIX 16:  IN-CLINIC ASSESSMENT OF ON/OFF STATES AND 
DYSKINESIA ..........................................................................................................119 
APPENDIX 17:  LABORATORY PARAMETERS ...................................................................120 
APPENDIX 18:  UK PARKINSON’S DISEASE SOCIETY BRAIN BANK  
CLINICAL DIAGNOSTIC CRITERIA* .................................................................121 
APPENDIX 19:  MODIFIED HOEHN AND YAHR PD SEVERITY SCALE 
ASSESSMENT .........................................................................................................123 
APPENDIX 20:  CONTRAINDICATIONS TO PERFORMING ROUTINE 
SPIROMETRY .........................................................................................................124 
APPENDIX 21:  CVT-301 SYSTEM ADDITIONAL INFORMATION ...................................125 
 
LIST OF IN-TEXT TABLES 
Page 
Table 1 
Details of Study Drug .................................................................................................46 
Table 2 
Details of Reduced-Dose Study Drug1 .......................................................................47 
Table 3 
Classification of Adverse Events by Intensity ............................................................79 
Table 4 
Classification of Adverse Events by Relationship to Study Medication ....................80 
 
 


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4. 
LIST OF ABBREVIATIONS 
ADL 
Activities of Daily Living 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATS 
American Thoracic Society 
AUC 
area under the plasma concentration-time curve 
AUClast 
area under the plasma concentration-time curve from time zero to the time of the 
last quantifiable concentration 
BP 
blood pressure 
CD 
carbidopa 
CD/LD 
carbidopa/levodopa 
CFR 
Code of Federal Regulations 
Cmax 
maximal plasma concentration 
COMT 
catechol-O-methyltransferase 
COPD 
chronic obstructive pulmonary disease 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DDI 
dopamine decarboxylase inhibitor 
DPPC 
dipalmitoyl phosphatidylcholine 
DBP 
diastolic blood pressure 
DBS 
deep brain stimulation 
DLco 
carbon monoxide diffusing capacity 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ERS 
European Respiratory Society 
FEV1 
forced expiratory volume in 1 second 
FPD 
fine particle dose (i.e., pulmonary-delivered dose) 
FDA 
Food and Drug Administration 
FVC 
forced vital capacity 
GCP 
good clinical practice 
GI 
gastrointestinal  
hCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 


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HPMC 
hydroxypropyl methylcellulose 
HR 
heart rate 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LD 
levodopa 
LIP 
levodopa inhalation powder (CVT-301) 
MAO-B 
monoamine oxidase-B 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters mercury 
MMRM 
Mixed Model for Repeated Measurements 
MMSE 
Mini Mental State Examination 
NaCl 
sodium chloride 
NHANES III 
Third National Health and Nutrition Examination Survey 
NOAEL 
no-observed-adverse-effect level 
PD 
Parkinson’s disease 
PDQ-39 
39-Item Parkinson’s Disease Questionnaire 
PGI-C 
Patient Global Impression of Change 
PK 
pharmacokinetic 
PRN 
as needed 
QUIP 
Parkinson’s Disease Impulsive-Compulsive Disorders Questionnaire 
RR 
respiratory rate 
S&E 
Schwab and England 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
SV1 
Screening Visit 1 
SV2 
Screening Visit 2 
T0 
time of completion of inhalation of the last capsule of inhaled study treatment 
administered 
tmax 
time to maximal drug concentration 
TEAE 
treatment-emergent adverse event 


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TV/OV1 
Treatment Visit/Observational Visit 1 
TV/OV2 
Treatment Visit/Observational Visit 2 
TV/OV3 
Treatment Visit/Observational Visit 3 
TV/OV4 
Treatment Visit/Observational Visit 4 
TV/OV5 
Treatment Visit/Observational Visit 5 
TV/OV6 
Treatment Visit/Observational Visit 6 
UK 
United Kingdom 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
USA 
United States of America 
 
 


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5. 
INTRODUCTION 
5.1. 
Background and Rationale 
5.1.1. 
Background on Motor Fluctuations in Parkinson’s Disease Patients 
Levodopa (LD) remains the “standard of care” for the management of motor symptoms for 
Parkinson’s disease (PD) patients.  However, long-term treatment with LD is complicated by the 
development of motor fluctuations, also referred to as hypomobility or OFF episodes.  The 
development of OFF episodes relates to both pharmacokinetic (PK) and pharmacodynamic 
factors.  Over time, patients frequently experience a progressive shortening of the duration of LD 
clinical effect, leaving patients vulnerable to episodic OFF episodes which may be disabling.  It 
is estimated that up to half of LD-treated PD patients develop such motor fluctuations within 5 
years (Parkinson Study Group 1996, LeWitt 2008, Stocchi 2010). 
Following oral ingestion, LD is absorbed through an active transport mechanism that is specific 
for large neutral L-amino acids in the proximal small intestine.  The absorption of LD is subject 
to considerable inter- and intra-patient variability and is affected significantly by alterations in 
gastrointestinal (GI) motility and food intake.  Frequently, poor absorption following 
administration of a standard oral LD dose results in sub-therapeutic levels, leaving patients 
susceptible to the development of OFF episodes (Baruzzi 1987, Pfeiffer 1996, Olanow 2006). 
Treatment options for patients with motor response fluctuations are limited.  Various strategies 
may be employed to enhance the clinical effectiveness of central dopaminergic stimulation to 
reduce the frequency of motor fluctuations, including the use of dopamine agonists, 
catechol-O-methyltransferase (COMT) inhibitors, extended-release oral LD formulations, or 
modified dosage of their standard oral LD preparations (LeWitt 2008, Olanow 2009). 
Management of OFF episodes is done frequently through adjustment of the inter-dose interval of 
standard oral LD preparations or through administration of unscheduled partial or full doses of 
oral LD-containing products.  However, following treatment with oral LD preparations, 
resumption of motor function is unreliable owing to the challenges in GI transit and LD 
absorption (Ondo 2010), and the development of intermittent OFF episodes remains a significant 
issue despite attempts to manage patients using oral LD agents alone. 
 
 CVT-301 (LD 
inhalation powder) is being developed for the treatment of episodic motor fluctuations (OFF 
episodes) in patients with PD, as an adjunct, as needed (PRN) therapy to provide relief from 
intermittent motor fluctuations (OFF episodes) that affect many PD patients. 
5.1.2. 
Background on CVT-301 (Levodopa Inhalation Powder) 
CVT-301 is a dry powder LD formulation (levodopa inhalation powder [LIP]) designed for 
inhaled delivery using a proprietary delivery system.  Using this technology, a variety of 
medications have been administered previously to humans, including proteins (e.g., insulin, 
human growth hormone) and small molecules (e.g., epinephrine, trospium) (Rave 2007, 


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Chipman 2005, Walvoord 2009, Dewey 2001, Dunbar 2004, Oleson 2010).  This delivery system 
is capable of delivering therapeutics with high efficiency over a range of inspiratory flow rates 
using a passive, breath-actuated device (DeLong 2005). 
CVT-301 is being developed as treatment for episodic motor fluctuations (OFF episodes) in 
patients with PD.  CVT-301 will be used as an adjunct to the patient’s existing decarboxylase 
inhibitor (i.e., carbidopa [CD] or benserazide)-inclusive PD medication regimen. 
In nonclinical studies, CVT-301 pulmonary delivery was associated with rapid LD absorption, 
and was associated with a shorter and less variable time to maximal drug concentration (tmax) 
and less variable maximal plasma concentration (Cmax) compared to oral LD administration.  
These PK attributes translated to pharmacodynamic advantages in a nonclinical model of PD 
(Bartus 2004). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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5.2. 
Rationale 
Attainment of therapeutic plasma concentrations and restoration of motor function following 
administration of oral LD to PD patients is variable, unreliable, and frequently delayed, not 
uncommonly requiring 1 hour or more to attain therapeutic responses.  
 
 
 
 
  
The more rapid LD absorption following inhaled CVT-301 administration is expected to 
translate to rapid alleviation of motor OFF symptoms in patients experiencing OFF episodes.   
This 12-month study will employ a randomized open-label methodology to investigate the safety 
and effects of CVT-301 (50 mg LD FPD) and will include a concurrent observational cohort of 
PD patients who will not receive study medication, but will continue to take their usual PD 
medications.  Patients must be CVT-301-naïve, however, any patients that were enrolled from 
the CVT-301-002 and CVT-301-003 studies under the previous version of this protocol will be 
allowed to continue in the study Patients will be randomized in a 2:1 ratio to the CVT-301 
treatment group (50 mg LD FPD) or the observational cohort.   
During the 12-month treatment period, patients in the CVT-301 treatment group will 
self-administer an inhaled study drug dose as needed when they experience OFF episodes; study 
medication may be used up to 5 times daily.  Every day during the treatment period, the 
CVT-301 patients will record the following information in the Inhaled Dosing Log:  the number 
of times the inhaler was used and the number of capsules used for each inhalation treatment.  
Patients in each group will continue their standard PD medications, which may be modified 
during the study if needed.  Patients in each group will be required to attend the screening visits 
(Screening Visit 1 [SV1] and Screening Visit 2 [SV2]) and the 6 in-clinic 
treatment/observational visits (Treatment Visit/Observational Visit 1 [TV/OV1], Treatment 
Visit/Observational Visit 2 [TV/OV2], Treatment Visit/Observational Visit 3 [TV/OV3], and 
Treatment Visit/Observational Visit 4 [TV/OV4], Treatment Visit/Observational Visit 5 
[TVOV5], and Treatment Visit/Observational Visit 6 [TV/OV6]).  For the patients in the 
CVT-301 treatment group, these visits will be treatment visits and for the observational cohort, 
these visits will be observational visits. 


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CVT-301-treated patients will be followed in the clinic for the following efficacy measures: 
serial assessments of UPDRS Part 3 motor score following treatment in the clinic, the occurrence 
and severity of dyskinesia following treatment in the clinic, the occurrence of ON states during 
the post-treatment period, the 39-Item Parkinson’s Disease Questionnaire (PDQ-39), the Patient 
Global Impression of Change (PGI-C) rating scale, the Schwab and England (S&E) Activities of 
Daily Living (ADL) score; UPDRS Part 2 score, and UPDRS Part 4 (Questions 32-35 and 36-39) 
score.  In addition, the total daily ON time without dyskinesia, total daily ON time with 
troublesome dyskinesia, total daily ON time with non-troublesome dyskinesia, and total daily 
OFF time will be evaluated in the CVT-301-treated patients based on the PD Diary, which will 
be completed for the 3 consecutive days prior to SV2, TV/OV1, TV/OV2, TV/OV3, TV/OV4, 
TV/OV5, and TV/OV6. 
All patients, regardless of treatment assignment, will undergo the safety assessments.  Patient 
safety will be evaluated using adverse event (AE) reports, physical examination, vital signs 
(blood pressure [BP], heart rate [HR], and respiratory rate [RR]), clinical laboratory tests, 
12-lead electrocardiograms (ECGs), spirometry, carbon monoxide diffusing capacity (DLco) 
maneuver, the Parkinson’s Disease Impulsive-Compulsive Disorders Questionnaire (QUIP), the 
Epworth Sleepiness Scale, and the Columbia-Suicide Severity Rating Scale (C-SSRS).   
The use of a randomized observational cohort in this study is to permit long-term 
contemporaneous temporal comparison to CVT-301-treated patients to describe any potential 
effects of CVT-301 with respect to lung function measurements.  These control patients, who are 
eligible to use any approved treatments to manage their PD motor symptoms, represent a 
randomized study population that remains naïve to inhalation treatment (to avoid potential 
confounding interpretation of lung function data) for their PD which is required to ascertain the 
underlying variability in spirometry and DLco endpoints.  Only a limited number of efficacy 
assessments will be evaluated in the patients randomized to the observational cohort.  Selected 
efficacy measures to assess effects of CVT-301 will be evaluated in the open-label 
CVT-301-treated patients who use CVT-301 inhalation as a treatment of OFF symptoms.   
 
 
 
 
5.2.1. 
Rationale for Selection of Dose 
Because CVT-301 contains LD only (i.e., with no DDI), study drug will be administered only to 
patients taking a DDI-containing LD formulation (e.g., CD or benserazide).  The study is 
designed to evaluate the safety and effect of adjunctive therapy (CVT-301 plus usual prescribed 
standard PD medication regimen).  All patients, regardless of treatment assignment, will 
continue with their usual prescribed standard PD medication regimen for the study duration.   


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The dose level being studied has been observed to be clinically effective, safe, and tolerated in 
healthy adult volunteers as well as in PD patients in 2 completed CVT-301 clinical studies.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The PK data from the selected CVT-301 dose level (50 mg LD FPD) has been well-characterized 
from healthy adult volunteers in 
   
CVT-301 (Levodopa Inhalation Powder) 
 
 
 
 
 
   
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 


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  The dose level of 50 mg LD FPD was selected for further evaluation in this study. 
6. 
STUDY OBJECTIVES 
Primary Objective 
• To characterize the pulmonary safety, as assessed by spirometry (forced expiratory 
volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/ FVC ratio), over 
a 12-month period within the CVT-301-treated patients. 
Secondary Objectives 
• To characterize the pulmonary safety, as assessed by spirometry (FEV1, FVC, and 
FEV1/FVC ratio), over a 12-month period in the observational (‘standard of care’) 
cohort. 
• To estimate the difference between the CVT-301-patients and the observational 
cohort on measures of pulmonary safety. 
• To characterize the effects of CVT-301 on safety over a 12-month period:  safety will 
be assessed by AE reports, physical examination, standard and orthostatic vital signs 
(BP, HR, and RR), clinical laboratory tests, 12-lead ECGs, QUIP, the Epworth 
Sleepiness Scale, and the C-SSRS.  
• To evaluate the effect of CVT-301 on mean change from baseline in the UPDRS 
Part 4 measures of motor fluctuations (dyskinesias [Q32-35] and wearing off 
[Q36-39]) measured pre-dose at 6 and 12 months after the initiation of CVT-301 
treatment. 
• To characterize the occurrence and severity of examiner-rated dyskinesia following 
treatment of patients experiencing an OFF episode in the clinic over a 12-month 
period.  
• To describe the effects of CVT-301 on DLco over a 12-month period. 
Exploratory Efficacy Objectives 
• Change from pre-dose in UPDRS Part 3 motor score at 10, 20, 30, and 60 minutes 
following treatment of patients experiencing an OFF episode. 
• Time curves of the UPDRS response at 10, 20, 30 and 60 minutes will be evaluated 
descriptively 


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• Change from pre-dose in UPDRS Part 3 motor score at 10 to 60 minutes following 
treatment of patients experiencing an OFF episode. 
• Proportion of patients with a ≥ 3, ≥ 6, and ≥ 11-point reduction in the UPDRS Part 3 
motor score from pre-dose to post-dose, at 10 to 60 minutes. 
• Proportion of patients achieving resolution of an OFF to an ON state within 60 
minutes after study drug is administered in the clinic, maintaining the ON state at 60 
minutes after study drug administration (per the examiner’s subjective assessment). 
• Patient-reported total daily OFF time, total daily ON time without dyskinesia, total 
daily ON time with non-troublesome dyskinesia, and total daily ON time with 
troublesome dyskinesia, assessed by the patient and recorded in the patient diary. 
• Change from baseline visit in the 39-Item Parkinson’s Disease Questionnaire (PDQ-
39). 
• Proportion of patients who improved based on the Patient Global Impression of 
Change (PGI-C) rating scale measured pre-dose. 
• Change from baseline visit in the Schwab and England (S&E) Activities of Daily 
Living (ADL) score. 
• Change from baseline visit in the UPDRS Part 2 score. 
7. 
INVESTIGATIONAL PLAN 
This study is a 12-month, open-label, randomized, multicenter study which will evaluate the 
safety and effects of CVT-301 for the treatment of up to 5 OFF episodes per day in PD patients 
experiencing motor fluctuations (OFF episodes) and will include a concurrent observational 
cohort of PD patients managed using the usual standards of care.  Patients must be 
CVT-301-naïve, however, any patients that were enrolled from the CVT-301-002 and 
CVT-301-003 studies under the previous version of this protocol will be allowed to continue in 
the study.  Patients will be randomized in a 2:1 ratio to the CVT-301 treatment group (CVT-301 
at a target nominal respirable dose of 50 mg LD FPD) or the observational cohort.  
Randomization will be differentiated by the patient’s Hoehn and Yahr stage (<2.5 versus ≥2.5) to 
balance the severity of disease across each group and by screening spirometry (FEV1 <60% of 
predicted or FEV1/FVC ratio <70% versus FEV1 ≥60% of predicted and FEV1/FVC ratio 
≥70%). 
Patients assigned to the CVT-301 treatment group may use the prescribed dose of CVT-301 as 
needed for the treatment of up to 5 OFF episodes per day in addition to their standard PD 
medications which may be modified as needed for symptomatic treatment over the 12-month 
study.  Each treated episode will require 2-capsule inhalations (i.e., 2 capsules used in the inhaler 
per treated episode) to deliver the dose.  
Patients assigned to the observational cohort will not receive CVT-301 but will be permitted to 
be managed using their standard PD medications and other PD treatment modalities, which may 
be modified as needed for symptomatic treatment in accordance with usual practice over the 
12-month study.   


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For both the CVT-301 treatment group and the observational cohort, additions to and/or 
modification of the patient’s usual PD treatment regimen may include any PD treatments that are 
currently approved in the patient’s region.  However, oral PRN LD formulations are not 
permitted for CVT-301-treated subjects (refer to Section 9.4.2 for a list of prohibited treatments 
and prohibited medications).  For CVT-301-treated patients, the total daily LD dose of the 
modified PD treatment regimen (not including CVT-301) must not exceed 1600 mg per day. 
The study includes a screening period of up to 35 days (with 2 screening visits) and a treatment 
period of approximately 12 months (52±2 weeks) (with 6 treatment/observational visits) plus an 
additional follow-up at a pulmonary laboratory 4 to 5 weeks after the last treatment/observational 
visit.  A longer screening period may be permitted with approval from the Sponsor.  Planned 
treatment/observational visits will occur at 0 (pre-dose, baseline) and approximately 1, 3, 6, 9, 
and 12 months.  For the CVT-301 treatment group, these visits will be treatment visits and for 
the observational cohort, these will be observational visits.  All patients, regardless of treatment 
group, will be required to attend all of the screening visits and all of the treatment/observational 
visits.  Assessments for DLco will be performed at a pulmonary laboratory outside of the clinic 
prior to the TV/OV1, within 2 weeks prior to the 3-, 6-, 9-, and 12-month visits, and 4 to 5 weeks 
after TV/OV6.  
If a patient in the CVT-301 treatment group develops significant tolerability concerns that in the 
opinion of the investigator are of a severity that should necessitate a reduction in dose, including, 
but not limited to the exacerbation or worsening of troublesome dyskinesia, other problematic 
dopaminergic symptoms, or other tolerability concerns, a dose reduction from 2 capsules (50 mg 
LD FPD) to 1 capsule (25 mg LD FPD) per treated episode may be permitted.  The medical 
monitor should be contacted, and the investigator should use his/her clinical judgment to 
determine whether an additional visit is required and what assessments should be performed 
(e.g., physical examination, spirometry, etc.).  The patient should continue to use 1 capsule (25 
mg LD FPD) per treated episode for a period of at least 1 week.  If the investigator determines 
that the tolerability issue has adequately resolved and that the patient has tolerated this dose for 
at least 1 week, the patient may at that point either resume taking the original dose (2 capsules 
[50 mg LD FPD] per treated episode) or come into the clinic for an unscheduled visit to receive a 
reduced-dose study drug kit (35 mg LD FPD).  Clinical staff will call the patient 1 to 2 days after 
the dose escalation to see if the patient has any questions or concerns.  If a patient who has 
escalated back to the full dose (50 mg LD FPD per treated episode) has another tolerability 
concern that in the opinion of the investigator is of a severity that should necessitate a second 
reduction in dose, an unscheduled visit will be required and a reduced-dose study drug kit (35 
mg LD FPD per treated episode) will be provided.   He/she will remain on the reduced dose (35 
mg LD FPD) for the remainder of the study; he/she will not be eligible for any additional 
up-titration in dose. 
Safety data will be reviewed by an independent Data Safety Monitoring Board (DSMB) that will 
include relevant medical experts (including a neurologist and pulmonologist), an independent 
statistician, and additional representatives (as will be defined in the DSMB Charter).  Safety 
data, including but not limited to AEs, spirometry, vital signs, and ECG data will be reviewed.  
The safety review will be documented in a DSMB Charter prior to the start of the study.  In the 
event that potential safety issues are identified, the committee may recommend modification of 
the study design or study termination, which will be communicated promptly with investigators, 


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Institutional Review Boards (IRBs), Independent Ethics Committees (IECs), and regulatory 
agencies, in accordance with legal and regulatory requirements.   
An overview of the study visit schedule is presented in Appendix 1.  Details on the assessments 
and procedures performed at each visit are presented in Appendix 2 through Appendix 15 and in 
Section 10. 
8. 
STUDY POPULATION 
All patients must meet the inclusion criteria and must not meet any of the exclusion criteria to be 
eligible for this study.  Patients previously enrolled in the CVT-301-002 and CVT-301-003 
studies must have completed all of the CVT-301 study visits without any safety issues that would 
preclude participation in this study according to the investigator.  Patients who withdrew from 
either of the CVT-301 studies prior to completion, for any reason, will not be eligible. 
8.1. 
Inclusion Criteria 
In order to be eligible to enter the study, patients must meet all of the following criteria: 
1. Has signed and dated an IRB/IEC-approved informed consent form before any 
protocol-specific screening procedures are performed. 
2. Is a male or female aged 30 to 85 years, inclusive.  Women of child-bearing potential 
must use protocol-defined contraceptive measures (see Section 11.1.5) and must have a 
negative serum human chorionic gonadotropin (hCG) test at screening.  These patients 
must be willing to remain on their current form of contraception for the duration of the 
study. 
3. Patients who have idiopathic PD (i.e., not induced by drugs or other diseases) as defined 
by fulfilling Steps 1 and 2 of the United Kingdom (UK) Brain Bank criteria, diagnosed 
after the age of 30 years. 
4. Patients who are classified as Stage 1 to 3 (in the ON state) on the modified Hoehn and 
Yahr scale for staging of PD severity. 
5. Patients who have experienced motor fluctuations for a minimum of 2 hours of average 
daily OFF time per waking day (excluding early morning OFF time) by self-report and 
confirmed by the PD Diary (on 3 consecutive days) during the screening period. 
6a. Patients who are on a LD-containing therapy, not including Rytary (or equivalent), must 
be stable on oral LD-containing therapy for at least 2 weeks prior to SV1 with a 
LD/DDI-containing regimen 
6b. Patients who are on a LD-containing therapy, when including Rytary (or equivalent), 
should be on a stable dose for at least 6 weeks prior to SV1. 
6c. The frequency of L-dopa administrations must be at least 3 times during the waking day 
and a total daily LD dose of ≤ 1600 mg.   
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8. Patients must have a ≥25% difference between UPDRS Part 3 scores recorded in their 
ON and OFF states at screening. 
9. Patients must have normal cognition as confirmed by a score of ≥25 on the Mini Mental 
State Examination (MMSE), performed in the ON state. 
10. 10. Patients must be able to perform a spirometry maneuver in the ON and OFF states, 
and must have a screening FEV1 ≥50% of predicted and an FEV1/FVC ratio >60% in the 
ON state at screening.  (A pulmonologist will review the spirometry tracings/morphology 
of any patient with an FEV1 that is ≥50% to <60% of predicted or an FEV1/FVC ratio 
that is >60% to <70% in order to determine potential eligibility.  All CVT-301-naïve 
patients with an FEV1/FVC ratio that is >60% to <70% will be required to undergo a 
bronchodilator challenge and the results must be reviewed prior to entry into the study.  
Patients with an FEV1/FVC ratio that is >60% to <70% will complete spirometry before 
and after the administration of a bronchodilator in a pulmonary function 
laboratory.  Testing will be performed in accordance with the 2005 ATS/European 
Respiratory Society [ERS] criteria prior to randomization.  The results of the 
bronchodilator challenge will be reviewed by a pulmonologist prior to potential 
randomization.)   
8.2. 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria at screening will not be enrolled in the 
study: 
1. Patients who have dyskinesia of a severity that would significantly interfere with their 
ability to participate or perform study procedures. 
2. Pregnant or lactating females or females wishing to become pregnant. 
3. Patients who have any known contraindication to the use of LD, including a history of 
malignant melanoma or a history of narrow-angle glaucoma.   
4. Patients who have had previous surgery for PD (including but not limited to deep brain 
stimulation [DBS] or cell transplantation). 
5. Patients with a history of psychotic symptoms requiring treatment, or suicide ideation or 
attempt within the prior 12 months (stable regimens [for at least 4 weeks prior to SV1] of 
anti-depressant and certain low-dose atypical antipsychotic medications are permitted in 
case they are indicated to treat symptoms other than psychotic symptoms).  
6. Patients who have cancer with the exception of the following:  basal cell carcinoma or 
successfully treated squamous cell carcinoma of the skin; cervical carcinoma in situ; 
prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence 
of disease recurrence for at least 3 years. 
7. Patients taking certain prohibited medications (see Section 9.4.2). 
8. Patients with a history of drug or alcohol abuse within the prior 12 months. 
9. Patients with chronic obstructive pulmonary disease (COPD), asthma, or other chronic 
respiratory disease within the last 5 years. 


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10. Patients with any contraindication to performing routine spirometry or who are unable to 
perform a spirometry maneuver (see Appendix 20 for a list of contraindications).  
11. Patients with a current history of symptomatic orthostatic hypotension despite adequate 
treatment.   
12. Patients with any condition that in the investigator’s opinion would make patients 
unsuitable or interfere with their participation in the study.  Potential issues of concern 
should be raised to the medical monitor during eligibility review. 
13. Patients who have any clinically significant abnormality or finding from examination, 
tests, or history that may compromise patient safety.  
14. Patients who have been treated with an investigational drug within 4 weeks or 5 half-lives 
(whichever is longer) prior to the beginning of the screening period  (this includes 
investigational formulations of marketed products). 
15. Prior exposure to CVT-301. 
Note:  An active or recent (within 3 days) respiratory infection will not disqualify a patient from 
enrolling in the study.  However, all symptoms should be resolved for at least 3 days prior to the 
baseline visit (TV/OV1) (the screening period may be extended for up to 2 weeks to 
accommodate this recovery). 
8.3. 
Removal of Patients from Study 
A patient may withdraw from the study at any time at his/her own request, or may be withdrawn 
at any time at the discretion of the investigator for safety, behavioral, or administrative reasons.  
If a patient is discontinued prematurely at any time after entering the study, the investigator will 
make every effort to see the patient and complete the TV/OV6 assessments as shown 
(for patients in the CVT-301 treatment group) or Appendix 15 (for patients in the 
observational cohort).  If a patient is withdrawn due to an AE, the event must be followed, when 
possible, until resolution. 
An end-of-study page in the electronic case report form (eCRF) should be completed for every 
patient who receives study drug (if in the CVT-301 treatment group) or enters the TV/OV1 visit 
(if in the observational cohort), whether or not the patient completes the study.  The reason for 
any early discontinuation should be indicated on this form.  The primary reason for a patient 
withdrawing prematurely should be selected from the following standard categories of early 
termination: 
• Adverse Event:  Clinical or laboratory events occurred that in the medical judgment of 
the investigator for the best interest of the patient are grounds for discontinuation.  
This includes serious and non-serious AEs regardless of relation to study medication. 
• Death:  The patient died. 
• Withdrawal of Consent:  The patient desired to withdraw from further participation in 
the study in the absence of an investigator-determined medical need to withdraw.  If 
the patient gave a reason for withdrawing, it should be recorded in the eCRF. 
14 
Appendix 


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• Protocol Violation:  Significant findings indicating that the study investigator or 
patient failed to adhere to the protocol requirements (e.g., drug noncompliance, 
failure to return for defined number of visits).  The violation necessitated premature 
termination of the patient from the study. 
• Lost to Follow-Up:  The patient stopped coming for visits, and study personnel were 
unable to contact the patient. 
• Other:  The patient was terminated for a reason other than those listed above (to be 
specified on the eCRF). 
9. 
TREATMENTS 
9.1. 
Details of Study Treatment for the CVT-301 Treatment Group 
Basic information about the study drug for the CVT-301 treatment group is provided in Table 1 
and details regarding the reduced-dose study drug for patients with tolerability issues are 
provided in 
 
Table 1 
Details of Study Drug 
 
CVT-301 (Test Product) 
Table 2.
Name 
CVT-301 (levodopa inhalation powder) 
Manufacturer 
Civitas Therapeutics, Inc. 
Doses 
2 CVT-301 capsules delivering a target nominal respirable dose of 
approximately 50 mg LD FPD 
Route 
Inhaled via the CVT-301 inhaler 
Formulation 
Capsules of levodopa inhalation powder 
Capsule Strength 
Capsule fill weight of LD:  42 mg 
Respirable LD dose/FPD per capsule: 25.0 mg  
(Emitted LD per capsule:  35 mg) 
Abbreviations:  FPD=fine particle dose; LD=levodopa. 
 
 


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Table 2 
Details of Reduced-Dose Study Drug1 
 
CVT-301 (Test Product) 
Name 
CVT-301 (levodopa inhalation powder) 
Manufacturer 
Civitas Therapeutics, Inc. 
Doses 
2 CVT-301 capsules delivering a target nominal respirable dose of 
approximately 35 mg LD FPD 
Route 
Inhaled via the CVT-301 inhaler 
Formulation 
Capsules of levodopa inhalation powder 
Capsule Strength 
Capsule fill weight of LD:  30 mg 
Respirable LD dose/FPD per capsule: 17.5 mg  
(Emitted LD per capsule:  25 mg) 
Abbreviations:  FPD=fine particle dose; LD=levodopa. 
1 Reduced-dose study drug kits will be permitted for patients with tolerability issues.  Refer to Section 10.3 
for details on when this dose may be utilized. 
9.1.1. 
CVT-301 Capsule for Inhalation (Test Product) 
 
 
 
 
 
CVT-301 capsules are packaged into blister strips composed of foil-foil blister strips.  
9.1.2. 
Sham Capsule for Inhalation 
Sham inhalation capsules are empty size 00 HPMC capsules that will be used with the inhaler to 
train both staff and patients on the use of the CVT-301 inhaler.  Sham capsules are packaged into 
foil-foil blister strips.  A training inhaler and sham capsules will be provided to patients for the 
inhaler training sessions. 
9.1.3. 
Civitas CVT-301 Inhaler 
CVT-301 capsules will be delivered using the CVT-301 inhaler, which is a 5-inch-long, 
single-capsule-based, breath-actuated inhaler.   
9.1.4. 
Packaging of Inhaled Study Treatment 
Study drug supplies will be packaged into study drug kits.  Each study drug kit will contain 
20 blister strips of CVT-301 capsules (an 8-day supply), an inhaler, and the IFU.  At TV1, TV2, 
TV3, TV4, and TV5, each patient in the CVT-301 treatment group will be issued a sufficient 
supply of study drug kits to accommodate the visit windows.  Kits will be stored at room 
temperature environment (25°C [77°F]) at the clinical sites and may not be stored in excessive 


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heat (i.e., above 40˚C [104˚F]) or excessive cold (i.e., below 2˚C [36˚F]).  Patients will be told to 
store the kits containing the inhalers and study drug at room temperature and will be required to 
return unused study drug, used capsules, and the inhaler from each kit at their subsequent clinic 
visit. 
Reduced-dose study drug kits (at a target nominal dose of 35 mg LD FPD) will be packaged, 
stored, and accounted for in a similar manner.  These kits are to be utilized for patients unable to 
tolerate CVT-301 at a target nominal dose of 50 mg LD FPD, as described in Section 10.3. 
All Investigational Product Complaints must immediately be reported to the sponsor.  
Site study personnel should immediately notify the Site Monitor and provide a description of the 
complaint. Sponsor representatives from IP Supply or Quality Assurance Departments will work 
with the Site Monitor or site study personnel to gather further information needed. Note that this 
is for IP quality complaint notification, not for AE reporting. 
9.2. 
Randomization and Administration of Study Treatment  
9.2.1. 
Randomization and Assignment of Study Treatment  
Following completion of SV2 and prior to randomization, the patients’ eligibility criteria will be 
reviewed by delegated staff.  Upon confirmation of eligibility, the site will randomize an eligible 
patient using the Interactive Web Response System (IWRS).  Sites must allow 7 business days 
between time of randomization and the first treatment visit (TV1) to allow time for drug to be 
shipped and received. 
Eligible patients will be randomized in a 2:1 ratio to CVT-301 treatment (CVT-301 50 mg PD 
FPD) or the observational cohort.  Randomization will be differentiated by the patient’s Hoehn 
and Yahr stage (<2.5 versus ≥2.5) to balance the severity of disease across each treatment group 
and by screening spirometry (FEV1 <60% of predicted or FEV1/FVC ratio <70% versus FEV1 
≥60% of predicted and FEV1/FVC ratio ≥70%).  Patients who previously completed the 
CVT-301-002 and CVT-301-003 studies will be assigned only to the CVT-301 treatment group.  
The study is an open-label study, so patients and clinical staff will not be blinded to study group 
assignment. 
9.2.2. 
Defining “Time 0” (T0) (for the CVT-301 Treatment Group) 
During inhaler training, patients will be instructed to hold their breath following each inhalation 
for approximately 5 seconds after administration of each capsule, in accordance with the IFU.  
For the purposes of timing study assessments, “Time 0” (T0) is defined as the time of completion 
of inhalation of the last capsule of inhaled study treatment administered (i.e., beginning of the 
final breath hold).  In the event that a capsule needs to be re-inhaled, T0 is at the end of the re-
inhalation administration. 
9.3. 
Treatment Accountability and Compliance (for the CVT-301 
Treatment Group) 
The pharmacist or study coordinator will maintain records of study kits delivered to the study 
site, the inventory at the site, the distribution to and use by each patient, and the return of 
materials to the Sponsor for storage or disposal.  These records should include dates, quantities, 


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batch/serial numbers, expiration dates, in-clinic temperature log, and unique code numbers 
assigned to the product and trial patients.  Investigators will maintain records that document 
adequately that the patients were provided with the correct study treatment kits and will reconcile 
the products received from the drug dispensing center.  Investigational product will not be 
returned until accountability has been fully monitored. 
In-clinic administration of study drug will be supervised by study personnel, and at-home PD 
Diary data will be reviewed to ensure patient compliance. 
9.4. 
Prior and Concomitant Illnesses and Medications 
9.4.1. 
Prior and Concomitant Illnesses 
Investigators should document all prior significant illnesses that the patient has experienced 
within 5 years prior to screening.  New illnesses present at the time when informed consent is 
given and for the duration of the study are to be documented as AEs on the eCRF. 
Clinic staff will contact patients 4 to 6 days prior to TV/OV1 to remind them that they must be 
symptom-free of any flu-like syndrome or other respiratory infection for at least 3 days prior to 
the visit and that they should contact the site if an intervening illness occurs prior to TV/OV1.  If 
the patient has any of these symptoms within this time period, this visit will be rescheduled once 
these symptoms have been resolved for at least 3 days.  The screening period may be extended 
for up to 2 weeks to accommodate this recovery. 
9.4.2. 
Prior and Concomitant Medications  
Any medication or therapy that is taken by or administered to the patient during the course of the 
study must be recorded in the eCRF.  The entry must include the dose, regimen, route, 
indication, and dates of use.  In addition, medications taken by or administered to the patient for 
3 months prior to SV1 will be recorded in the eCRF.   
Patients must be stable on oral LD-containing therapy for at least 2 weeks prior to SV1 with an 
LD/DDI-containing regimen, when not including Rytary, and stable for at least 6 weeks prior to 
SV1 when including Rytary. The oral LD regimen must include doses at least 3 times during the 
waking day and a total daily LD dose of ≤1600 mg (exclusive of PRN LD-containing 
medications).  During the study, all patients’ standard PD medication regimen may be altered as 
needed to manage PD symptoms.  Additions to and/or modification of the patient’s usual PD 
treatment regimen may include any PD treatments that are currently approved in the patient’s 
region.  Oral PRN LD formulations are not permitted for CVT-301-treated subjects from 
TV/OV1 to TV/OV6.  For CVT-301-treated patients, the total daily LD dose of the modified PD 
treatment regimen (not including CVT-301) must not exceed 1600 mg per day.  In the event that 
the dose or schedule of the patient’s oral LD-containing medication does change during the 
treatment period, record all changes in medication, including the total LD dose, in the eCRF.   
If the patient is treated with dopamine agonists, COMT inhibitors, monoamine oxidase-B 
(MAO-B) inhibitors, he/she must be on a stable dose for at least 4 weeks prior to SV1 and must 
remain stable throughout the study.  If the patient is on anti-depressant medication or other non-
LD-containing PD medications, the dose must be stable for at least 4 weeks prior to SV1. 


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In countries and/or municipalities where the use of marijuana-based products is legal for medical 
purposes, patients who may be using medical marijuana as a treatment for their PD may be 
enrolled into the study as long as they meet the following parameters: 
1. Medical marijuana has been prescribed to the patient prior to the date of informed 
consent.  Patients who have not already been prescribed medical marijuana prior to 
beginning study participation may not begin medical marijuana use during their 
participation in the study. 
2. Medical marijuana is not being used to treat any contraindicated condition as defined in 
the protocol (i.e., glaucoma, cancer, etc.). 
3. Patients meet all other eligibility criteria (including spirometry). 
4. Patients must agree not to use medical marijuana (smoking, ingestion or any other 
potential route of administration) on clinic days, before coming to the clinic or while in 
the clinic, until all procedures have been completed and they are discharged. 
All patients in this study will take their usual prescribed PD medications during the study 
including on the morning of each in-clinic treatment/observational visit.  The timing of the 
administration of the usual morning dose of PD medications may be adjusted by the investigator 
to accommodate the patient’s and/or clinic’s schedule.  On designated in-clinic dosing days for 
CVT-301-treated patients, if the patient converts to an ON state after the study drug has been 
administered, and all post-treatment study procedures have been performed, the patients will 
resume their standard schedule of PD medications. 
In addition, for CVT-301-treated patients, the inhaled study drug will be used for the treatment 
of OFF episodes in accordance with this protocol.  Patients should not take inhaled study drug 
within 45 minutes following their prior dose of standard oral PD medication.  Also, patients 
should not use inhaled study drug for the treatment of early morning OFF.  Otherwise, study 
drug may be used during the waking day for the treatment of OFF episodes that occur in between 
doses of the patients’ standard oral PD medications.  Patients in the CVT-301 treatment group 
should not take oral PRN PD medications to manage their OFF states throughout the treatment 
period. 
During in-clinic evaluation days, if inhaled study drug does not provide sufficient relief of the 
OFF state to enable the patient to return to an ON state by 60 minutes post-dose, patients will 
receive their usual oral dose of PD medication(s) and may be discharged home when all study 
assessments are completed.  At home, in the event that an OFF state is not sufficiently resolved 
within 45 minutes of completing the last inhalation of CVT-301, patients will be permitted to 
take their next scheduled dose of their usual prescribed PD medication; patients may not re-dose 
with inhaled study drug for that OFF episode.  Patients may use inhaled study drug to manage 
only up to 5 OFF episodes per day.  If patients experience more than 5 OFF episodes per day, 
they should adhere to their usual standard oral regimen to manage these additional episodes. 
Prohibited Therapies 
Medication to treat study-emergent and treatment-emergent illness(es) is generally permitted; 
however, the following therapies/products are expressly prohibited throughout the study: 


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• Apomorphine.  Use of apomorphine is restricted to a frequency of once per day. 
Concomitant use of study medication (CVT-301) with apomorphine, i.e. use within 
the same OFF episode, is excluded. 
• Reserpine.  Patients must not have used reserpine for at least 3 months prior to SV1 
and must not use it for the duration of the study. 
• Antipsychotic medications.  Patients must not have used antipsychotic medications 
for at least 12 months prior to SV1 and must not use them for the duration of the 
study.  Exceptions:  certain low-dose atypical antipsychotic agents are allowed if the 
dose has been stable for at least 4 weeks prior to screening (for example, quetiapine 
≤50 mg/day, risperidone ≤1 mg/day, and olanzapine ≤2.5 mg/day) if used for non-
psychosis-related conditions. 
• Other non-neuroleptic dopamine antagonists or non-specific monoamine oxidase 
inhibitors (MAOIs).  Patients must not have used any of these agents for at least 3 
months prior to SV1 and must not use them for the duration of the study.  Exception:  
In regions where it is approved, domperidone is permitted during the study if the 
maximum daily dose does not exceed 60 mg and if the dose has been stable for at 
least 4 weeks prior to screening. 
• Investigational drugs.  Patients must not have taken any investigational drugs 
(including investigational formulations of marketed products) for at least 4 weeks or 5 
half-lives (whichever is longer) prior to SV1 and must not use them for the duration 
of the study. 
• Smoking.  Current smokers are permitted to participate in the study provided that they 
meet other eligibility requirements (spirometry and concomitant respiratory illness). 
They must agree to and are able to abstain from smoking on the day of each in-clinic 
visit while in-clinic through completion of all assessments for that visit day (including 
screening visits and in-clinic treatment/observational visits). 
• Oral PRN PD medications for CVT-301-treated patients during the treatment period.  
All patients are permitted to take oral PRN PD medications during the screening 
period.  However, oral PRN PD medications are not permitted during the treatment 
period for CVT-301-treated patients. 
10. 
STUDY PROCEDURES 
The overall schedule of assessments is provided in Appendix 1, and specific time and events 
schedules for the screening visits and in-clinic treatment/observational visits are provided in 
Appendix 2 through Appendix 15.  Unless otherwise specified, all assessments will be performed 
by the investigator or other assigned personnel.  
10.1. 
Screening Period 
Patients will undergo a screening period of up to 35 days before entering the treatment period.  
The screening period will consist of 2 scheduled clinic visits: SV1 and SV2.  The screening 
period may be extended an additional 7 days if repeat screening assessments are required.  At 


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SV1, after patients have provided informed consent, they will be assessed for study eligibility in 
ON and OFF states.  At SV2, any screening assessment performed at SV1 will be repeated if 
needed to verify or re-check results, and inhaler training will be performed. 
Patients who do not develop an adequate OFF or ON period at SV1 will be invited to re-attend 
on a subsequent day, but will be withdrawn if further observation shows they are unable to turn 
OFF during a regularly scheduled study visit in accordance with the procedures.  In addition, if a 
patient is unable to complete all assessments or training at the scheduled SV1, he/she may be 
rescheduled to repeat the visit, and/or to return to the clinic for additional training. 
10.1.1. 
Screening Visit 1 (within 35 days prior to TV/OV1) 
Patients should be instructed to bring all of their medications with them to SV1.  The following 
list is a suggested schedule for this visit, with assessments outlined in Appendix 2.  (Note:  If a 
patient arrives at the clinic in an OFF state, assessments will be done in an OFF state first, then 
they will be repeated in an ON state after the patient has taken his/her standard dose of 
LD-containing medications and converted to an ON state.) 
1. Give the patient an explanation of the purpose and nature of the study, and receive his/her 
voluntary written informed consent before any study procedures are performed. 
2. Determine eligibility according to inclusion/exclusion criteria. 
3. Record medical history (including smoking history), concurrent medical conditions, and 
PD history. 
4. Confirm diagnosis of PD using Steps 1 and 2 of the UK Brain Bank criteria in the ON 
state.  (Refer to Section 11.3.1 and Appendix 18.) 
5. Use the modified Hoehn and Yahr scale to assess PD severity (in an ON state).  (Refer to 
Appendix 19.) 
6. Record the estimated average number of hours of OFF time during the waking day (not 
including early morning OFF time) as reported by the patient.  Eligible patients must 
have, by self-report, motor fluctuations with daily OFF time averaging at least 2 hours 
per day (not including early morning OFF time and which will require confirmation using 
the PD Diary over a period of 3 consecutive days).   
7. Check and record all PD medications (including the number of times per day that 
LD-containing medications are administered and total daily LD dose) and other 
concomitant medications.  Confirm that the patient is on stable dosages of PD 
medications (at least 2 weeks for the LD-containing medication, and 4 weeks for the 
other PD medications).  Ensure that specified concomitant medications have been 
stabilized in accordance with protocol-defined criteria. 
8. Perform the MMSE (in an ON state). 
9. Perform a full physical examination. 
10. Complete the Pulmonary Function Baseline Questionnaire. 
11. Record a 12-lead ECG (after patient has been in a supine position for at least 5 minutes, 
as per Section 11.1.3). 


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12. Measure standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and HR).  
Standard vital signs should be taken after the patient has rested in a supine or semi-supine 
position for at least 5 minutes, and orthostatic vital signs should be taken after the patient 
has been standing for 2 minutes (see Section 11.1.2 for suggested detailed procedures). 
13. Perform spirometry to measure FEV1, FVC, and FEV1/FVC ratio to assess lung function 
(this must be performed with the patient in the ON state). 
14. Perform UPDRS Part 3 in an ON state. 
15. Train patients on how to assess their ON and OFF states and how to record their waking 
ON/OFF status in a screening PD Diary (time OFF, time ON without dyskinesia, time 
ON with non-troublesome dyskinesia, time ON with troublesome dyskinesia, and time 
asleep). 
16. Perform concordance testing with the patients (while in the ON and OFF states) for 
recognizing different ON/OFF states and recording them appropriately in the PD Diary.  
Patients will be tested for competence at self-rating and must be within 75% concordance 
with the ratings of the examiner (at least 3 out of 4 half-hour sessions over the course of 2 
hours); if concordance is not reached, the observation period may be extended for an 
additional 2 hours to obtain agreement on at least 6 of 8 half-hour sessions.  The same 
training and testing may be repeated at an unscheduled visit between SV1 and SV2 or at 
SV2.  If patients return for an unscheduled visit between SV1 and SV2 for concordance 
training and testing, the visit must occur more than 3 days prior to SV2.  If patients do not 
achieve 75% concordance by the end of SV2, they will be considered screen failures. 
17. Introduce the inhaler and perform inhaler training using sham capsules with the CVT-301 
inhaler while in the ON state. 
18. Take samples for clinical laboratory tests, including a serum pregnancy test for females 
of childbearing potential (see Appendix 17 for a list of laboratory parameters assessed).  
Patients do not need to be in a fasted state at the time of the laboratory sample; however, 
fasted status will be documented (with fasting defined as at least 4 hours following the 
last meal or snack). 
19. Patients will remain in the clinic and further PD medications will be withheld until they 
turn into an OFF state. 
20. Perform the assessments in the following suggested order while the patient is in an OFF 
state:  spirometry, UPDRS Part 3, patient training on self-report of ON/OFF states, and 
inhaler training using sham capsules with the CVT-301 inhaler. 
21. Distribute the PD Diary; train patients to record time OFF, time ON without dyskinesia, 
time ON with non-troublesome dyskinesia, time ON with troublesome dyskinesia, and 
time asleep for the 3 consecutive days prior to SV2. 
22. Distribute the Screening ON/OFF Episodes Log; train patients to record the number of 
OFF episodes experienced by the patients during their waking day for the 3 consecutive 
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23. If needed, train caregivers on how to prepare inhalers for patients and how to complete 
the PD Diary and Screening ON/OFF Episodes Log (diaries will be completed based on 
the patient report). 
24. Monitor for AEs throughout the visit. 
25. Review with patients (and their caregivers) the planned schedule of events for the 
remaining study visits, and the responsibilities of self-administration of study drug and of 
recording information in the at-home diaries.  Schedule the next visit. 
26. Ask patients to bring the PD Diary, the Screening ON/OFF Episodes Log, and all of their 
PD medications with them at SV2, to take their usual morning medications prior to the 
visit, and to note the time when they took them. 
The next visit will be scheduled.  The site will call the patient approximately 4 days before SV2 
to confirm the next study visit and to remind patients of the study procedures and the 
requirements noted in 
 in the above list. 
10.1.2. 
Screening Visit 2 (at least 4 days after SV1) 
The purpose of this visit is as follows:  (a) to repeat any screening assessment performed at SV1 
if needed to verify or re-check results for eligibility and safety, (b) to review the PD Diary and 
Screening ON/OFF Episodes Log to confirm eligibility (if these were not done correctly, the site 
may have to reschedule this visit) (c) to perform spirometry and vital signs, if needed to verify or 
re-check results, and (d) to re-train the patient on proper inhalation technique with the inhaler 
and on recording PD Diary and Screening ON/OFF Episodes Log information.  For the 3 
consecutive days prior to SV2, patients will complete the PD Diary and the Screening ON/OFF 
Episodes Log.  Before arrival at the clinic for SV2, the patient will take all of their usual 
prescribed non-PD medications and PD medications, including LD-containing PD medications. 
The following list is a suggested schedule for this visit: 
1. Upon the patient’s arrival to the clinic, reconfirm eligibility from SV1, including review 
of the PD Diary and the Screening ON/OFF Episodes Log.  In the PD Diary, if <80% of 
the awake time is filled in for the 3-day period, the diary training and concordance testing 
must be repeated.  The training and concordance testing will also be repeated if the 
patient has not reached 75% or greater concordance with the examiner at SV1 or at an 
unscheduled visit between SV1 and SV2. 
2. Record any changes in the usual PD medication dose and regimen. 
3. Review concomitant medications. 
4. Perform inhaler re-training using sham capsules with the CVT-301 inhaler and IFU.  If 
the patient has undergone inhaler training in both the ON and OFF states at SV1, it may 
be done in either state at this visit. 
5. Patient training on assessment of the ON/OFF state will be repeated while the patient is 
in the ON and OFF states as needed. 
6. Distribute a new PD Diary and Screening ON/OFF Episodes Log, and instruct the 
patients to complete both of them for the 3 consecutive days prior to TV/OV1. 
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7. Schedule a DLco assessment to be performed at an outside pulmonary laboratory after 
SV2 and prior to treatment assignment/randomization.  The assessment should be 
performed while the patient is in an ON state (as reported by the patient to the pulmonary 
technician) at the pulmonary function facility.  As part of the procedure, a slow vital 
capacity maneuver will be performed, followed by DLco, and then spirometry. 
8. If needed, the following assessments from SV1 may be completed or repeated:  MMSE 
(in ON state); full physical examination; 12-lead ECG; standard vital signs (BP, HR, and 
RR) and orthostatic vital signs (BP and HR); spirometry (in ON and OFF states); UPDRS 
Part 3 (in ON and OFF states); ON/OFF concordance testing (in ON and OFF states); and 
clinical laboratory test, including serum pregnancy test, if applicable (with documentation 
of fasting status).  
9. Monitor for AEs throughout the visit. 
If a patient is unable to complete a screening assessment at SV2, an additional visit (repeat SV2) 
may be scheduled prior to eligibility determination and randomization.  Any repeat assessments 
should be performed in the respective motor state as described for SV1.  The site will contact 
patients by telephone 4 to 6 days prior to TV/OV1 to confirm the DLco assessment has been 
done, to confirm the next study visit, and to remind patients of the study procedures required 
prior to the next scheduled study visit (including completion of the PD Diary and Screening 
ON/OFF Episodes Log).  In addition, the site should remind the patients during the call that they 
must be symptom-free of any flu-like syndrome or other respiratory infection for at least 3 days 
prior to prior to TV/OV1 and that they should contact the site if an intervening illness occurs 
prior to TV/OV1.  If the patient has any of these symptoms within this time period, this visit will 
be rescheduled once these symptoms have been resolved for at least 3 days.  The screening 
period may be extended for up to 2 weeks to accommodate this recovery. 
10.2. 
Randomization to Study Drug 
Following completion of SV2 and prior to randomization, the patients’ eligibility criteria will be 
reviewed by delegated staff.  Eligible patients will be randomized in a 2:1 ratio to CVT-301 
treatment group (CVT-301 50 mg PD FPD) or the observational cohort.  Randomization will be 
differentiated by the patient’s Hoehn and Yahr stage (<2.5 versus ≥2.5) to balance the severity of 
disease across each treatment group and by screening spirometry (FEV1 <60% of predicted or 
FEV1/FVC ratio <70% versus FEV1 ≥60% of predicted and FEV1/FVC ratio ≥70%).  Sites 
must allow 7 business days between time of randomization and the first treatment visit (TV1) to 
allow time for drug to be shipped and received. 
10.3. 
Treatment/Observational Period 
Patients in both the CVT-301 treatment group and observational cohort are required to attend all 
of the in-clinic treatment/observational visits.  For the CVT-301 treatment group, these visits will 
be treatment visits and for the observational cohort, these will be observational visits.  The 
assessments and procedures for the in-clinic treatment/observational visits will differ for patients 
in the CVT-301 treatment group compared to the observational cohort.   


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All patients, regardless of treatment assignment, should continue with their usual prescribed 
standard PD medication regimen for the duration of the study which may be modified for 
symptomatic treatment during the study in accordance with usual practice.  
Patients assigned to the CVT-301 treatment group may use the prescribed dose of CVT-301 as 
needed for the treatment of up to 5 OFF episodes per day in addition to their standard PD 
medications which may be modified as needed for symptomatic treatment over the 12-month 
study.  Each treated episode will require 2-capsule inhalations (i.e., 2 capsules used in the inhaler 
per treated episode) to deliver the dose.  
Patients assigned to the observational cohort will not receive CVT-301 but will be managed with 
their prescribed PD medications, which may be modified as needed for symptomatic treatment 
over the 12-month study.   
For both the CVT-301 treatment group and the observational cohort, additions to and/or 
modification of the patient’s usual PD treatment regimen may include any PD treatments that are 
currently approved in the patient’s region.  However, oral PRN LD formulations are not 
permitted for CVT-301-treated subjects (refer to Section 9.4.2 for a list of prohibited treatments 
and prohibited medications).  For CVT-301-treated patients, the total daily LD dose of the 
modified PD treatment regimen (not including CVT-301) must not exceed 1600 mg per day.  
Changes in the medications, doses, or frequency of medication administration will be 
documented in the eCRF.   
During this period, CVT-301 patients will self-administer inhaled study treatment (CVT-301 50 
mg LD FPD) up to 5 times daily to treat OFF episodes during their waking day.  The first dose of 
open-label study drug will be given in the clinic at TV1; patients will be given study drug kits at 
TV1, TV2, TV3, TV4, and TV5. 
The treatment/observational period includes 6 separate in-clinic treatment/observational visits 
over approximately 1 year.  The sequence of timing the patient’s morning dose of PD 
medications and clinic arrival should be discussed with the patient to increase the likelihood that 
the patient will reliably be in an ON state upon arrival and turn OFF during the office visit.  
Patients will take their morning dose of PD medications and should eat their standard breakfast 
prior to arrival at the clinic. 
If a patient in the CVT-301 treatment group develops significant tolerability concerns that in the 
opinion of the investigator are of a severity that should necessitate a reduction in dose, including, 
but not limited to the exacerbation or worsening of troublesome dyskinesia, other problematic 
dopaminergic symptoms, or other tolerability concerns, a dose reduction from 2 capsules (50 mg 
LD FPD) to 1 capsule (25 mg LD FPD) per treated episode may be permitted.  The medical 
monitor should be contacted, and the investigator should use his/her clinical judgment to 
determine whether an additional visit is required and what assessments should be performed 
(e.g., physical examination, spirometry, etc.).  The patient should continue to use 1 capsule (25 
mg LD FPD) per treated episode for a period of at least 1 week.  If the investigator determines 
that the tolerability issue has adequately resolved and that the patient has tolerated this dose for 
at least 1 week, the patient may at that point either resume taking the original dose (2 capsules 
[50 mg LD FPD] per treated episode) or come into the clinic for an unscheduled visit to receive a 
reduced-dose study drug kit (35 mg LD FPD).  Clinical staff will call the patient 1 to 2 days after 
the dose escalation to see if the patient has any questions or concerns.  If a patient who has 


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escalated back to the full dose (50 mg LD FPD per treated episode) has another tolerability 
concern that in the opinion of the investigator is of a severity that should necessitate a second 
reduction in dose, an unscheduled visit will be required and a reduced-dose study drug kit (35 
mg LD FPD per treated episode) will be provided.   He/she will remain on the reduced dose (35 
mg LD FPD) for the remainder of the study; he/she will not be eligible for any additional 
up-titration in dose. 
Refer to Appendix 2 through Appendix 15 for tables of study assessments at each visit during the 
treatment period. 
10.3.1. 
Telephone Calls Before Treatment/Observational Visits 
• Telephone calls should be made to patients 4 to 6 days before TV/OV1 for the 
following reasons:  to confirm the DLco assessment has been done (must be 
completed prior to TV/OV1); to confirm the next study visit; to remind patients to 
complete the PD Diary and the Screening ON/OFF Episodes Log for the 
3 consecutive days prior to the visit; to remind them to bring the PD Diary, Screening 
ON/OFF Episodes Log, and all of their PD medications with them to the visit; to 
remind them to take their usual morning medications and eat their standard breakfast 
prior to the visit; and to remind them to note the time when they take these morning 
medications.  In addition, the site should remind patients that they must be 
symptom-free of any flu-like syndrome or other respiratory infection for at least 
3 days prior to the visit and that they should contact the site if an intervening illness 
occurs prior to TV/OV1.  If a patient has any of these symptoms within this time 
period, reschedule this visit after these symptoms have been resolved for at least 3 
days.  The screening period may be extended for up to 2 weeks to accommodate this 
recovery. 
• Telephone calls should be made to patients in the CVT-301 treatment arm 1 to 3 days 
after TV1 to address any potential concerns or challenges with the inhaler systems or 
Inhaled Dosing Log.    
• Telephone calls should be made to patients in the CVT-301 treatment group 2 weeks 
(± 3 days) before TV2, TV3, TV4, and TV5, and TV6 for the following reasons:  to 
address any concerns or challenges with the inhaler systems, PD Diary, or Inhaled 
Dosing Log; to monitor for any AEs; to confirm the DLco assessment has been 
done/scheduled (prior to TV3, TV4, TV5, and TV6); to confirm the next study visit; 
to remind patients to complete the PD Diaries for the 3 consecutive days prior to 
TV2, TV3, TV4, TV5, and TV6; to remind patients to complete the Inhaled Dosing 
Log every day during the treatment period; to remind them to bring their PD Diaries, 
Inhaled Dosing Logs, study drug kits, and all of their PD medications with them to 
the visits; to remind them to take their usual morning medications and eat their 
standard breakfast prior to the visits; to ask how many empty study drug kits will be 
returned at the next visit; and to remind them to note the time when they take their 
usual morning medications. 
• Telephone calls should be made to the patients in the observational cohort 2 weeks (± 
3 days) prior to OV2 to monitor for AEs and to confirm the next study visit, and prior 


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to OV3, OV4, OV5, and OV6 to monitor for AEs, to confirm that the DLco 
assessment has been done/scheduled, and to confirm the next study visit. 
10.3.2. 
Treatment Visit/Observational Visit 1 (at least 7 days after SV2) 
10.3.2.1. Treatment Visit 1 for the CVT-301 Treatment Group 
Patients will complete the Screening ON/OFF Episodes Log and PD Diary for the 3 consecutive 
days prior to TV1.   
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of arrival for TV1 should be scheduled to increase the likelihood that patients will be 
in the ON state upon arrival (i.e., they should arrive to the clinic as shortly as feasible after 
taking their standard oral PD medications at home).  Patients will bring to the clinic all of their 
usual prescribed PD medications. 
On Arrival to the Clinic  
The following list is a suggested schedule for this visit: 
• Collect, review, sign, and date the PD Diary and Screening ON/OFF Episodes Log 
and document whether these were completed correctly. 
• Confirm that the DLco assessment has been performed.  If the DLco assessment has 
not been completed prior to the visit, the study visit must be re-scheduled. 
• Record the time that patients took their usual PD medications prior to the visit. 
• Record any changes in the usual PD medication dose/regimen. 
• Record all concomitant medications. 
• Perform the PDQ-39 in an ON state. 
• Perform a brief physical examination. 
• Patients will complete the UPDRS Part 2 and S&E ADL scales (preferably in the ON 
state). 
• Patients will complete the UPDRS Part 4 (Questions 32-35 and 36-39). 
• Perform a 12-lead ECG. 
• Record standard and orthostatic BP and HR.  Record RR. 
• Perform spirometry (preferably performed in the ON state; record the patient’s motor 
state on the spirometry source record). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Perform the baseline assessments using the C-SSRS, Epworth Sleepiness Scale, and 
the QUIP. 
• Distribute the PD Diary and review instructions for completion for recording time 
asleep, time OFF, time ON without dyskinesia, time ON with non-troublesome 


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dyskinesia, and time ON with troublesome dyskinesia (to be completed for the 
3 consecutive days prior to TV2, TV3, TV4, TV5, and TV/6). 
• Distribute the Inhaled Dosing Log and review instructions for completion for 
recording the number of times the inhaler was used and the number of capsules used 
for each inhalation treatment (to be completed daily throughout the 12-month 
treatment period). 
• Distribute study drug kits to patients.  Instruct patients to collect used empty capsules 
and return them at the next visit along with the PD Diary, Inhaled Dosing Log, and 
other study supplies. 
• Re-train patients on the proper use of the inhaler with sham capsules, including a 
review of the IFU. 
Study Drug Dosing 
Immediately pre-dose, perform a spirometry assessment (record the patient’s ON/OFF state on 
the spirometry source record).  Under clinic staff supervision, preferably between 2 and 5 hours 
after receiving their standard dose of PD medication (in the OFF state), patients will prepare and 
self-administer their first dose of study drug from the study drug kits provided (i.e., 2 capsule 
inhalations of CVT-301).  Patients will be permitted sips of water between capsule inhalations as 
needed. The dosing time is defined to be when the patient’s OFF state is recognized by both the 
patient and investigator to be at a level similar to the investigator-confirmed severity experienced 
at SV1 and preferably between 2 and 5 hours after their prior oral PD medication.   
Note: Instructions for how to properly use the CVT-301 system are outlined in the Instructions 
for Use document that is included with every CVT-301 study kit.  Refer to 
 for 
additional system information. 
Post-dose (10 – 60 minutes) 
The following post-dose safety evaluations will be performed: 
• Record vital signs (standard and orthostatic BP and HR) at 20 and 60 minutes. 
post-dose.   
• Record RR at 10, 20, 30, and 60 minutes post-dose. 
• Monitor for AEs throughout the visit. 
Upon completion of the 60-minute observations, resumption of normal medications is permitted 
for the remainder of the day (the patient may use the inhaled study drug 4 more times at home 
after he/she leaves the clinic on that day if needed for OFF episodes).  The next visit will be 
scheduled.  Clinic staff will arrange to speak with patients by telephone 1 to 3 days after 
TV/OV1 to monitor for AEs and to address any potential concerns or challenges with the inhaler 
systems or Inhaled Dosing Log.  Additionally, clinic staff will arrange to speak with patients by 
telephone 2 weeks (± 3 days) before each visit for TV2, TV3, TV4, TV5, and TV6 to address 
any concerns or challenges with the inhaler systems, PD Diary, or Inhaled Dosing Log, to 
monitor for any AEs, to confirm the DLco assessment has been done/scheduled (prior to TV3, 
TV4, TV5, and TV6), to confirm the next study visit, to ask the patients how many empty study 
drug kits will be returned at the next visit, and also to remind patients of the study procedures 
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required prior to the next scheduled study visit (including completion of the PD Diary and 
Inhaled Dosing Log). 
10.3.2.2. Observational Visit 1 for the Observational Cohort  
Patients will complete the Screening ON/OFF Episodes Log and PD Diary for the 3 consecutive 
days prior to OV1.   
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of arrival for OV1 should be scheduled to increase the likelihood that patients will be 
in the ON state upon arrival (i.e., they should arrive to the clinic as shortly as feasible after 
taking their standard oral PD medications at home).  Patients will bring to the clinic all of their 
usual PD medications. 
On Arrival to the Clinic  
The following list is a suggested schedule for this visit: 
• Collect, review, sign, and date the PD Diary and Screening ON/OFF Episodes Log 
and document whether these were completed correctly. 
• Confirm that the DLco assessment has been performed.  If the DLco assessment has 
not been completed prior to the visit, the study visit must be re-scheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record all concomitant medications. 
• Perform the PDQ-39 in an ON state 
• Perform a brief physical examination. 
• Patients will complete the UPDRS Part 2 and S&E ADL scales (preferably in the ON 
state). 
• Record standard and orthostatic BP and HR.  Record RR. 
• Perform a 12-lead ECG. 
• Perform spirometry (preferably performed in the ON state; record the patient’s motor 
state on the spirometry source record). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Perform the baseline assessments using the C-SSRS, Epworth Sleepiness Scale, and 
the QUIP. 
• Monitor for AEs. 
The next visit will be scheduled and the patient will be discharged from the visit. 
10.3.3. 
At-Home Dosing for the CVT-301 Treatment Group 
At TV1, TV2, TV3, TV4, and TV5, patients in the CVT-301 treatment group will receive study 
drug kits and the IFU to take home with them.  Patients will be instructed to take their standard 


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oral PD medications as prescribed on their usual schedule of administration, which may be 
modified as needed for symptomatic treatment during the 12-month study.  Additions to and/or 
modification of the patient’s usual PD treatment regimen may include any PD treatments that are 
currently approved in the patient’s region.  Oral PRN LD formulations are not permitted for 
these patients (refer to Section 9.4.2 for a list of prohibited treatments and prohibited 
medications).  The total daily LD dose of the modified PD treatment regimen (not including 
CVT-301) must not exceed 1600 mg per day.   
Patients will be instructed to administer inhaled study drug up to 5 times during the waking day 
as close as possible to the time when they begin to experience OFF symptoms.  The PD 
symptomatology defining the onset of an OFF state may vary by patient, but typically is 
indicated by the return of PD motor symptoms such as tremor or bradykinesia; for some patients, 
OFF episodes may be heralded by non-motor symptoms (e.g., pain or anxiety) shortly prior to 
the appearance of motor symptoms.   
Study drug may not be used for the treatment of early morning OFF periods (i.e., morning 
akinesia).  Patients may not take their inhaled study drug within 45 minutes following their 
previous dose of standard oral PD medication.  These patients may not take oral PRN 
medications to manage OFF states during the study. 
In the event that an OFF state is not sufficiently resolved within 45 minutes of completing the 
last capsule inhalation, patients may resume their usual prescribed PD medication, if they have 
not already done so (i.e., according to their standard dose schedule/regimen); patients may not 
re-dose with inhaled study drug for that episode.  If patients experience more than 5 OFF 
episodes per day that require treatment, they should adhere to their standard oral regimen for 
management of any additional OFF episodes; they may not treat these episodes with additional 
inhalations of study drug.  
Patients will complete the PD Diary for the 3 consecutive days prior to TV2, TV3, TV4, TV5, 
and TV6.  Patients will complete the Inhaled Dosing Log every day during the 12-month 
treatment period.  As described previously, patients will be contacted by the clinic staff 1 to 
3 days after TV1 and 2 weeks (± 3 days) prior to each visit for TV2, TV3, TV4, TV5, and TV6. 
They will bring the PD Diary, Inhaled Dosing Log, empty capsules, inhalers, and unused 
supplies to the each clinic visit.  If the patient begins to run low on study supplies in between 
treatment visits, they should contact the site.  Unused supplies can be re-dispensed to the patient 
at each clinic visit, in addition to a sufficient number of new study drug kits to supply the patient 
until his/her next visit. Note: Any open kit (even if partially unused) may not be re-dispensed. 
10.3.4. 
Treatment Visit/Observational Visit 2 (1 month [4 weeks ±5 days] after 
TV/OV1) 
10.3.4.1. Treatment Visit 2 for the CVT-301 Treatment Group 
Patients will complete the PD Diary for the 3 consecutive days prior to TV2 and the Inhaled 
Dosing Log daily throughout the treatment period.  Patients will bring their usual PD 
medications, the PD Diary, Inhaled Dosing Log, used supplies, including empty capsules and 
inhalers, as well as any unused supplies to the clinic visit.   


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Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further non-study PD medications will be used until following 
completion of all assessments.  The timing of arrival should be scheduled to increase the 
likelihood that patients will be in an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at home).  
The following procedures will be done: 
• Collect, review, sign, and date the PD Diary and Inhaled Dosing Log.   
• Collect used empty capsules and inhalers and unused supplies. 
• Record any changes in the usual PD medication dose/regimen. 
• Record the time that patients took their usual PD medications prior to the visit. 
• Record any changes in concomitant medications. 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Perform the C-SSRS. 
• Distribute new study drug kits.  
• Review inhaler training with the patient. 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion. 
• Instruct patients to collect used empty capsules, the PD Diary, Inhaled Dosing Log, 
and other study supplies and to bring these items to the next visit. 
• The patient will remain in the clinic until they go into the OFF state.  After 
confirmation of an OFF state (between 2 and 5 hours after the patient has taken 
his/her oral PD medication), record the time of the OFF state and then perform a pre-
dose UPDRS Part 3 assessment. Under clinic staff supervision, patients will prepare 
and self-administer their entire dose of inhaled CVT-301. The dosing time is defined 
to be when the patient’s OFF state is recognized by both the patient and investigator 
to be at a level similar to the investigator-confirmed severity experienced at SV1 and 
preferably between 2 and 5 hours after their prior oral PD medication.    
• Perform serial UPDRS Part 3 assessments at 10, 20, 30, and 60 minutes post-dose. 
• Observe the patient for the appearance of dyskinesia and note in the eCRF if the 
patient experiences dyskinesia at any time within the 60-minute post-dose period.  


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Also, if applicable, record the maximum severity of dyskinesia during the 60-minute 
post-dose period.  
• Observe the patient for the occurrence of an ON state during the 60-minute post-dose 
period and note whether this occurs.  If the patient converts to the ON state, note 
whether or not the patient is still in the ON state at 60 minutes post-dose. 
• Monitor patients for AEs throughout the visit. 
Upon completion of the 60-minute observations, resumption of normal medications is permitted 
for the remainder of the day (the patient may use the inhaled study drug 4 more times at home 
after he/she leaves the clinic on that day if needed for OFF episodes). 
The next visit will be scheduled.  Clinic staff will arrange to speak with patients by telephone 
2 weeks (± 3 days) before TV3 to address any concerns or challenges with the inhaler systems, 
PD Diary, or Inhaled Dosing Log, to monitor for any AEs, to confirm the DLco assessment has 
been done/scheduled, to confirm the next study visit, to ask the patients how many empty study 
drug kits will be returned at the next visit, and to remind patients of the study procedures 
required before the next visit (including completion of the PD Diary and Inhaled Dosing Log).  
Clinic staff will also schedule a DLco assessment within 2 weeks prior to TV3.  The DLco 
assessment should be performed in an ON state (as reported by the patient to the pulmonary 
technician) in the pulmonary function facility.  As part of the procedure, a slow vital capacity 
maneuver will be first, followed by DLco, and then spirometry. 
10.3.4.2. Observational Visit 2 for the Observational Cohort 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further PD medications will be used until following completion of 
all assessments.  The timing of arrival should be scheduled to increase the likelihood that patients 
will be in an ON state upon arrival (i.e., they should arrive to the clinic as shortly as feasible after 
taking their standard oral PD medications at home).  Patients will bring to the clinic all usual PD 
medications. 
The following procedures will be done: 
• Record any changes in the usual PD medication dose/regimen. 
• Record any changes in concomitant medications. 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Perform the C-SSRS. 
• Monitor patients for AEs. 


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The next study visit will be scheduled.  Clinic staff will arrange to speak with patients by 
telephone 2 weeks (± 3 days) prior to OV3 to monitor for AEs, to confirm that the DLco 
assessment has been done/scheduled, and to confirm the next study visit.  The DLco assessment 
will be scheduled to occur within 2 weeks prior to the next visit and should be performed while 
the patient is in an ON state (as reported by the patient to the pulmonary technician) at the 
pulmonary function facility.  As part of the procedure, a slow vital capacity will be performed, 
followed by DLco, and then spirometry. 
10.3.5. 
Treatment Visit/Observational Visit 3 (3 months [12±2 weeks] after TV/OV1) 
10.3.5.1. Treatment Visit 3 for the CVT-301 Treatment Group 
Patients will complete the PD Diary for the 3 consecutive days prior to TV3 and the Inhaled 
Dosing Log daily throughout the treatment period.  Patients will bring their usual PD 
medications, the PD Diary, Inhaled Dosing Log, used supplies, including empty capsules and 
inhalers, as well as any unused supplies to the clinic visit. 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further non-study PD medications will be used until following 
completion of all assessments.  The timing of arrival should be scheduled to increase the 
likelihood that patients will be in an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at home).  Patients will bring 
to the clinic all usual PD medications. 
The following procedures will be done: 
• Collect, review, sign, and date the PD Diary and Inhaled Dosing Log.   
• Collect used empty capsules and inhalers and unused supplies. 
• Confirm that the DLco assessment was performed within 2 weeks prior to TV3.  If 
the DLco assessment has not been completed prior to the visit, the study visit must be 
re-scheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record the time that patients took their usual PD medications prior to the visit. 
• Record any changes in concomitant medications. 
• Patients should complete the PGI-C preferably in the ON state, and this must be done 
prior to other study assessments. 
• The C-SSRS should be completed. 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform a 12-lead ECG. 


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• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Distribute new study drug kits. 
• Review inhaler training with the patient. 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion. 
• Instruct patients to collect used empty capsules, the PD Diary, Inhaled Dosing Log, 
and other study supplies and to bring these items to the next visit. 
• The patient will remain in the clinic until they go into the OFF state.  After 
confirmation of an OFF state (between 2 and 5 hours after the patient has taken 
his/her oral PD medication), record the time of the OFF state and then perform a pre-
dose UPDRS Part 3 assessment.Under clinic staff supervision, patients will prepare 
and self-administer their entire dose of inhaled CVT-301. The dosing time is defined 
to be when the patient’s OFF state is recognized by both the patient and investigator 
to be at a level similar to the investigator-confirmed severity experienced at SV1 and 
preferably between 2 and 5 hours after their prior oral PD medication.    
• Perform serial UPDRS Part 3 assessments at 10, 20, 30, and 60 minutes post-dose. 
• Observe the patient for the appearance of dyskinesia and note in the eCRF if the 
patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of dyskinesia during the 60-minute 
post-dose period. 
• Observe the patient for the occurrence of an ON state during the 60-minute post-dose 
period and note whether this occurs.  If the patient converts to the ON state, note 
whether or not the patient is still in the ON state at 60 minutes post-dose. 
• Monitor patients for AEs throughout the visit. 
Upon completion of the 60-minute observations, resumption of normal medications is permitted 
for the remainder of the day (the patient may use the inhaled study drug 4 more times at home 
after he/she leaves the clinic on that day if needed for OFF episodes). 
The next visit will be scheduled.  Clinic staff will arrange to speak with patients by telephone 
2 weeks (± 3 days) before TV4 to address any concerns or challenges with the inhaler systems, 
PD Diary, or Inhaled Dosing Log, to monitor for any AEs, to confirm the DLco assessment has 
been done/scheduled, to confirm the next study visit, to ask the patients how many empty study 
drug kits will be returned at the next visit, and to remind patients of the study procedures 
required before the next visit (including completion of the PD Diary and Inhaled Dosing Log).  
Clinic staff will also schedule a DLco assessment within 2 weeks prior to TV4.  The DLco 
assessment should be performed in an ON state (as reported by the patient to the pulmonary 


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technician) in the pulmonary function facility.  As part of the procedure, a slow vital capacity 
maneuver will be first, followed by DLco, and then spirometry. 
10.3.5.2. Observational Visit 3 for the Observational Cohort 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further PD medications will be used until following completion of 
all assessments.  The timing of arrival should be scheduled to increase the likelihood that patients 
will be in an ON state upon arrival (i.e., they should arrive to the clinic as shortly as feasible after 
taking their standard oral PD medications at home).  Patients will bring to the clinic all usual PD 
medications. 
The following procedures will be done: 
• Confirm that the DLco assessment was performed within 2 weeks prior to OV3.  If 
the DLco assessment has not been completed prior to the visit, the study visit must be 
re-scheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record any changes in concomitant medications. 
• Perform the C-SSRS. 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform a 12-lead ECG. 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Monitor patients for AEs. 
The next visit will be scheduled, and clinic staff will arrange to speak with patients by telephone 
2 weeks (± 3 days) prior to OV4 to monitor for AEs, to confirm the DLco assessment has been 
done/scheduled, and to confirm the next study visit.  The DLco assessment will be scheduled to 
occur within 2 weeks prior to the next visit and should be performed while the patient is in an 
ON state (as reported by the patient to the pulmonary technician) at the pulmonary function 
facility.  As part of the procedure, a slow vital capacity will be performed, followed by DLco, 
and then spirometry. 


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10.3.6. 
Treatment Visit/Observational Visit 4 (6 months [24±2 weeks] after TV/OV1) 
10.3.6.1. Treatment Visit 4 for the CVT-301 Treatment Group 
Patients will complete the PD Diary for the 3 consecutive days prior to TV4 and the Inhaled 
Dosing Log daily throughout the treatment period.  Patients will bring their usual PD 
medications, the PD Diary, Inhaled Dosing Log, used supplies, including empty capsules and 
inhalers, as well as any unused supplies to the clinic visit. 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further non-study PD medications will be used until following 
completion of all assessments.  The timing of arrival should be scheduled to increase the 
likelihood that patients will be in an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at home). 
The following procedures will be done: 
• Collect, review, sign, and date the PD Diary and Inhaled Dosing Log.   
• Collect used empty capsules and inhalers and unused supplies. 
• Confirm that the DLco assessment was performed within 2 weeks prior to TV4.  If 
the DLco assessment has not been completed prior to the visit, the study visit must be 
re-scheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record the time that patients took their usual PD medications prior to the visit. 
• Record any changes in concomitant medications. 
• PDQ-39, PGI-C, UPDRS Part 2, and S&E ADL should be completed, preferably in 
an ON state, and must be done prior to other study evaluations. 
• Patients will complete the UPDRS Part 4 (Questions 32-35 and 36-39). 
• The C-SSRS, Epworth Sleepiness Scale, and QUIP should be completed. 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform a 12-lead ECG. 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Distribute new study drug kits.  


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• Review inhaler training with the patient. 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion. 
• Instruct patients to collect used empty capsules, the PD Diary, Inhaled Dosing Log, 
and other study supplies and to bring these items to the next visit. 
• The patient will remain in the clinic until they go into the OFF state.  After 
confirmation of an OFF state (between 2 and 5 hours after the patient has taken 
his/her oral PD medication), record the time of the OFF state and then perform a pre-
dose UPDRS Part 3 assessment. Under clinic staff supervision, patients will prepare 
and self-administer their entire dose of inhaled CVT-301. The dosing time is defined 
to be when the patient’s OFF state is recognized by both the patient and investigator 
to be at a level similar to the investigator-confirmed severity experienced at SV1 and 
preferably between 2 and 5 hours after their prior oral PD medication.    
• Perform serial UPDRS Part 3 assessments at 10, 20, 30, and 60 minutes post-dose. 
• Observe the patient for the appearance of dyskinesia and note in the eCRF if the 
patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of dyskinesia during the 60-minute 
post-dose period. 
• Observe the patient for the occurrence of an ON state during the 60-minute post-dose 
period and note whether this occurs.  If the patient converts to the ON state, note 
whether or not the patient is still in the ON state at 60 minutes post-dose. 
• Monitor patients for AEs throughout the visit. 
Upon completion of the 60-minute observations, resumption of normal medications is permitted 
for the remainder of the day (the patient may use the inhaled study drug 4 more times at home 
after he/she leaves the clinic on that day if needed for OFF episodes). 
The next visit will be scheduled.  Clinic staff will arrange to speak with patients by telephone 
2 weeks (± 3 days) before TV5 to address any concerns or challenges with the inhaler systems, 
PD Diary, or Inhaled Dosing Log, to monitor for any AEs, to confirm the DLco assessment has 
been done/scheduled, to confirm the next study visit, to ask the patients how many empty study 
drug kits will be returned at the next visit, and to remind patients of the study procedures 
required before the next visit (including completion of the PD Diary and Inhaled Dosing Log).  
Clinic staff will also schedule a DLco assessment within 2 weeks prior to TV5.  The DLco 
assessment should be performed in an ON state (as reported by the patient to the pulmonary 
technician) at the pulmonary function facility.  As part of the procedure, a slow vital capacity 
maneuver will be performed, followed by DLco, and then spirometry.   
10.3.6.2. Observational Visit 4 for the Observational Cohort 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further PD medications will be used until following completion of 


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all assessments.  The timing of arrival should be scheduled to increase the likelihood that patients 
will be in an ON state upon arrival (i.e., they should arrive to the clinic as shortly as feasible after 
taking their standard oral PD medications at home).  Patients will bring to the clinic all usual PD 
medications. 
The following procedures will be done: 
• Confirm that the DLco assessment was performed within 2 weeks prior to OV4.  If 
the DLco assessment has not been completed prior to the visit, the study visit must be 
re-scheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record any changes in concomitant medications. 
• Perform the PDQ-39, UPDRS Part 2, and S&E ADL (each preferably in the ON state 
and must be done prior to other study evaluations). 
• Perform the C-SSRS, Epworth Sleepiness Scale, and the QUIP. 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform a 12-lead ECG. 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Monitor patients for AEs. 
The next visit will be scheduled and the clinic staff will arrange to call the patient 2 weeks prior 
to OV5 to monitor for AEs, to confirm the DLco assessment has been done/scheduled, and to 
confirm the next study visit.  The DLco assessment will be scheduled to occur within 2 weeks 
prior to the next visit and should be performed while the patient is in an ON state (as reported by 
the patient to the pulmonary technician) at the pulmonary function facility.  As part of the 
procedure, a slow vital capacity will be performed, followed by DLco, and then spirometry. 
10.3.7. 
Treatment Visit/Observational Visit 5 (9 months [36±2 weeks] after TV/OV1) 
10.3.7.1. Treatment Visit 5 for the CVT-301 Treatment Group 
Patients will complete the PD Diary for the 3 consecutive days prior to TV5 and the Inhaled 
Dosing Log daily throughout the treatment period.  Patients will bring their usual PD 
medications, the PD Diary, Inhaled Dosing Log, used supplies, including empty capsules and 
inhalers, as well as any unused supplies to the clinic visit. 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 


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investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further non-study PD medications will be used until following 
completion of all assessments.  The timing of arrival should be scheduled to increase the 
likelihood that patients will be in an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at home).   
The following procedures will be done: 
• Collect, review, sign, and date the PD Diary and Inhaled Dosing Log.   
• Collect used empty capsules and inhalers and unused supplies. 
• Confirm that the DLco assessment was performed within 2 weeks prior to TV5.  If 
the DLco assessment has not been completed prior to the visit, the study visit must be 
re-scheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record the time that patients took their usual PD medications prior to the visit. 
• Record any changes in concomitant medications. 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Perform the C-SSRS. 
• Distribute new study drug kits. 
• Review inhaler training with the patient. 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion. 
• Instruct patients to collect used empty capsules, the PD Diary, Inhaled Dosing Log, 
and other study supplies and to bring these items to the next visit. 
• The patient will remain in the clinic until they go into the OFF state.  After 
confirmation of an OFF state (between 2 and 5 hours after the patient has taken 
his/her oral PD medication), record the time of the OFF state and then perform a pre-
dose UPDRS Part 3 assessment. Under clinic staff supervision, patients will prepare 
and self-administer their entire dose of inhaled CVT-301. The dosing time is defined 
to be when the patient’s OFF state is recognized by both the patient and investigator 
to be at a level similar to the investigator-confirmed severity experienced at SV1 and 
preferably between 2 and 5 hours after their prior oral PD medication.    


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• Perform serial UPDRS Part 3 assessments at 10, 20, 30, and 60 minutes post-dose. 
• Observe the patient for the appearance of dyskinesia and note in the eCRF if the 
patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of dyskinesia during the 60-minute 
post-dose period. 
• Observe the patient for the occurrence of an ON state during the 60-minute post-dose 
period and note whether this occurs.  If the patient converts to the ON state, note 
whether or not the patient is still in the ON state at 60 minutes post-dose. 
• Monitor patients for AEs throughout the visit. 
Upon completion of the 60-minute observations, resumption of normal medications is permitted 
for the remainder of the day (the patient may use the inhaled study drug 4 more times at home 
after he/she leaves the clinic on that day if needed for OFF episodes). 
The next visit will be scheduled.  Clinic staff will arrange to speak with patients by telephone 
2 weeks (± 3 days) before TV6 to address any concerns or challenges with the inhaler systems, 
PD Diary, or Inhaled Dosing Log, to monitor for any AEs, to confirm the DLco assessment has 
been done/scheduled to confirm the next study visit, to ask the patients how many empty study 
drug kits will be returned at the next visit, and to remind patients of the study procedures 
required before the next visit (including completion of the PD Diary and Inhaled Dosing Log).  
Clinic staff will also schedule a DLco assessment within 2 weeks prior to TV6.  The DLco 
assessment should be performed in an ON state (as reported by the patient to the pulmonary 
technician) in the pulmonary function facility.  As part of the procedure, a slow vital capacity 
maneuver will be first, followed by DLco, and then spirometry. 
10.3.7.2. Observational Visit 5 for the Observational Cohort 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further non-study PD medications will be used until following 
completion of all assessments.  The timing of arrival should be scheduled to increase the 
likelihood that patients will be in an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at home).  Patients will bring 
to the clinic all usual PD medications. 
The following procedures will be done: 
• Confirm that the DLco assessment was performed within 2 weeks prior to OV5.  If 
the DLco assessment has not been completed prior to the visit, the study visit must be 
re-scheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record any changes in concomitant medications. 
• Perform a brief physical examination. 


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• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Perform the C-SSRS. 
• Monitor patients for AEs. 
The next visit will be scheduled and the clinic staff will arrange to call the patient 2 weeks prior 
to OV6 to monitor for AEs, to confirm that the DLco assessment has been done/scheduled, and 
to confirm the next study visit.  The DLco assessment will be scheduled to occur within 2 weeks 
prior to the next visit and should be performed while the patient is in an ON state (as reported by 
the patient to the pulmonary technician) at the pulmonary function facility.  As part of the 
procedure, a slow vital capacity will be performed, followed by DLco, and then spirometry. 
10.3.8. 
Treatment Visit/Observational Visit 6 / Early Withdrawal Visit (12 months 
[52±2 weeks] after TV/OV1) 
10.3.8.1. Treatment Visit 6 / Early Withdrawal Visit for the CVT-301 Treatment Group 
Patients will complete the PD Diary for the 3 consecutive days prior to TV6 and the Inhaled 
Dosing Log daily up until TV6.  Patients will bring their usual PD medications, the PD Diary, 
Inhaled Dosing Log, used supplies including empty capsules and inhalers, as well as any unused 
supplies to the clinic visit. 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further non-study PD medications will be used until following 
completion of all assessments.  The timing of arrival should be scheduled to increase the 
likelihood that patients will be in an ON state upon arrival (i.e., they should arrive to the clinic as 
shortly as feasible after taking their standard oral PD medications at home).  Patients will bring 
to the clinic all usual PD medications. 
The following procedures will be done: 
• Collect, review, sign, and date the PD Diary and Inhaled Dosing Log.   
• Collect used empty capsules and inhalers and unused supplies. 
• Confirm that the DLco assessment was performed within 2 weeks prior to TV6.  If 
the DLco has not been completed prior to the visit, the visit must be rescheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record the time that patients took their usual PD medications prior to the visit. 
• Record any changes in concomitant medications. 


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• Perform the PDQ-39, PGI-C, UPDRS Part 2, and S&E ADL (each preferably in the 
ON state and must be done before other assessments). 
• Patients will complete the UPDRS Part 4 (Questions 32-35 and 36-39). 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform a 12-lead ECG. 
• The C-SSRS, Epworth Sleepiness Scale, and QUIP should be completed. 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• The patient will remain in the clinic until they go into the OFF state.  After 
confirmation of an OFF state (between 2 and 5 hours after the patient has taken 
his/her oral PD medication), record the time of the OFF state and then perform a pre-
dose UPDRS Part 3 assessment. Under clinic staff supervision, patients will prepare 
and self-administer their entire dose of inhaled CVT-301.  The dosing time is defined 
to be when the patient’s OFF state is recognized by both the patient and investigator 
to be at a level similar to the investigator-confirmed severity experienced at SV1 and 
preferably between 2 and 5 hours after their prior oral PD medication.   A new inhaler 
will be provided for this dose, and patients will use study drug from the supplies 
brought to the visit. 
• Perform serial UPDRS Part 3 assessments at 10, 20, 30, and 60 minutes post-dose. 
• Observe the patient for the appearance of dyskinesia and note in the eCRF if the 
patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of dyskinesia during the 60-minute 
post-dose period. 
• Observe the patient for the occurrence of an ON state during the 60-minute post-dose 
period and note whether this occurs.  If the patient converts to the ON state, note 
whether or not the patient is still in the ON state at 60 minutes post-dose. 
• Monitor patients for AEs throughout the visit. 
Once all of the assessments are complete, schedule the patient to undergo a DLco assessment 
4 to 5 weeks after completion of TV6.  The DLco assessment should be performed in an ON 
state (as reported by the patient to the pulmonary technician) in the pulmonary function facility.  
As part of the procedure, a slow vital capacity maneuver will be first, followed by DLco, and 
then spirometry. 


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10.3.8.2. Observational Visit 6 / Early Withdrawal Visit for the Observational Cohort 
Patients will report to the clinic after having taken their usual PD medications prior to the visit.  
The timing of administration of the usual morning dose of PD medication may be adjusted by the 
investigator to accommodate the patient’s and/or clinic’s schedule.  Following their usual 
morning PD medication, no further PD medications will be used until following completion of 
all assessments.  The timing of arrival should be scheduled to increase the likelihood that patients 
will be in an ON state upon arrival (i.e., they should arrive to the clinic as shortly as feasible after 
taking their standard oral PD medications at home).  Patients will bring to the clinic all usual PD 
medications. 
The following procedures will be done: 
• Confirm that the DLco assessment was performed within 2 weeks prior to OV6.  If 
the DLco assessment has not been completed prior to the visit, the study visit must be 
re-scheduled. 
• Record any changes in the usual PD medication dose/regimen. 
• Record any changes in concomitant medications. 
• Perform the PDQ-39, UPDRS Part 2, and S&E ADL (each preferably in the ON state 
and must be before other study evaluations). 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Perform 12-lead ECG. 
• Perform spirometry assessment (preferably in the ON state; however, if the patient is 
not in an ON state, perform the evaluation and record the motor state with each 
assessment). 
• The C-SSRS, Epworth Sleepiness Scale, and QUIP should be completed. 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Monitor patients for AEs. 
Once all of the assessments are complete, schedule the patient for a DLco assessment 4 to 
5 weeks after OV6.  The DLco assessment should be performed while the patient is in an ON 
state (as reported by the patient to the pulmonary technician) at the pulmonary function facility.  
As part of the procedure, a slow vital capacity will be performed, followed by DLco, and then 
spirometry. 
10.3.9. 
Early Withdrawal Visit 
Patients in the CVT-301 treatment group who withdraw prematurely will complete the TV6 
assessments for the CVT-301 patients (see Section 10.3.8.1), except for the pre-TV6 DLco 
assessment, at the time of withdrawal.  Patients in the observational cohort who withdraw 


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prematurely will complete the OV6 assessments for the observational cohort (see 
Section 10.3.8.2), except for the pre- OV6 DLco assessment, at the time of withdrawal.   
All patients who withdraw early, regardless of treatment group, will be scheduled to undergo a 
DLco assessment 4 to 5 weeks after completion of the Early Withdrawal Visit.  The DLco 
assessment should be performed in an ON state (as reported by the patient to the pulmonary 
technician) in the pulmonary function facility.  As part of the procedure, a slow vital capacity 
maneuver will be first, followed by DLco, and then spirometry. 
10.3.10. 
Unscheduled Visits 
An unscheduled visit may occur when indicated at the discretion of the Investigator.  The 
following are potential circumstances for unplanned visits: 
• If concordance is not reached during SV1, the same training and testing may be 
repeated at an unscheduled visit between SV1 and SV2 or at SV2.  If patients return 
for an unscheduled visit between SV1 and SV2 for concordance training and testing, 
the visit must occur more than 3 days prior to SV2.   
• If a patient is unable to complete a screening assessment at SV2 (repeat SV2), an 
additional visit may be scheduled prior to eligibility determination and 
randomization.  Any repeat assessments should be performed in the respective motor 
state as described for SV1.   
• If a patient develops significant tolerability concerns that in the opinion of the 
investigator are of a severity that should necessitate a reduction in dose, including, 
but not limited to, exacerbation or worsening of troublesome dyskinesia, other 
problematic dopaminergic symptoms, or other tolerability concerns, a dose reduction 
(from 2- to 1-capsule inhalation per dose) will be permitted.  The medical monitor 
should be contacted, and the investigator should use his/her clinical judgment to 
determine if an additional unscheduled visit is required and what assessments should 
be performed (e.g., physical examination, spirometry, etc.).   
11. 
DESCRIPTION OF ASSESSMENTS 
11.1. 
Safety Assessments 
Safety will be assessed from physical examination, AE reporting, standard and orthostatic vital 
signs (BP, RR, and HR), clinical laboratory values (hematology and biochemistry), ECGs, and 
spirometry and DLco for evaluation of pulmonary function.  In addition, UPDRS Part 4, and 
evaluations for assessing suicidality, somnolence, and impulse control disorders will be done. 
11.1.1. 
Physical Examination 
A complete physical examination (head, eyes, ears, nose, and throat [HEENT], heart, lungs, 
abdomen, skin, cervical and axillary lymph nodes, neurological, and musculoskeletal systems) 
will be performed at the visits specified in Appendix 2 through Appendix 15.  Genital, rectal, and 
breast examination may be excluded if not clinically indicated.  Height (cm) and weight (kg) will 
be assessed at screening by qualified personnel.  Physical examinations will be performed by a 


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physician.  In addition, medical history will be recorded at screening, including smoking history, 
if applicable. 
A brief physical exam to verify continued patient eligibility and to follow up any change in 
medical history will be performed at visits specified in Appendix 2 through Appendix 15.  
Symptom-driven brief physical examinations will be performed as clinically indicated at any 
study visit.  All changes identified as clinically noteworthy must be recorded as AEs. 
11.1.2. 
Vital Signs 
Standard Vital Signs 
Vital sign measurements will include RR, BP (systolic [SBP] and diastolic [DBP]), and HR after 
the patient has rested in a supine or semi-supine position for at least 5 minutes. 
Blood pressure must be assessed using an appropriate device, and the arm position must be 
standardized for each patient using a cuff size that is appropriate for the patient.  These 
measurements are to be taken in the same arm for the duration of the study.  The position of the 
cuff on the arm should be in line with the heart with the arm lying next to the patient when semi-
supine and should be in line with the heart at approximately a 45-degree angle from horizontal 
for the standing measurements.  “Standard” BP and HR measurements should be taken after 
resting in a supine or semi-supine position for at least 5 minutes. 
Respiratory rate should be recorded for 30 seconds, and the value multiplied by 2 for the rate per 
minute. 
Vital sign measurements will be repeated if clinically significant or machine/equipment errors 
occur.  If out-of-range BP, RR, or HR results are observed, the assessments may be repeated at 
the investigator’s discretion.  Any confirmed, clinically significant vital sign measurements must 
be recorded as AEs. 
Orthostatic Vital Signs 
At screening (SV1 or SV2) and at each subsequent study visit and in the event of a clinically 
significant finding that could be suggestive of symptomatic orthostatic hypotension (e.g., 
dizziness, lightheadedness, or other AE), orthostatic vital signs will be performed.  During the 
orthostatic vital signs assessment, at least one other staff member familiar with the study (not 
measuring vital signs) must be present should symptoms or an AE occur.   
In order to obtain orthostatic vital signs, patients should undergo the following procedures in 
sequential order: 
1. After the supine/semi-supine BP and HR measurements have been done, the patient will 
be asked to sit on the edge of the bed/table with feet on the floor (or with feet dangling 
from the bed/tableside depending on the height of the bed/table) for approximately 30 
seconds. 
2. The person performing the assessment will then ask the question, “Are you ready to 
stand?” 
• If the patient responds in the affirmative, the patient will proceed to stand and then be 
asked to remain standing for 2 minutes.  After standing for 2 minutes, BP and HR will 
be recorded. 


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• If the patient states that he or she is not ready to stand, the patient will be allowed to 
sit as positioned for 1 additional minute and will be asked again if they are ready to 
stand.  The patient will proceed to stand.  After standing for 2 minutes, one 
measurement will be taken for BP and HR. 
• If the individual is still unable to stand, vital signs will be measured while the patient 
is in an upright seated position. 
Orthostatic hypotension will be defined as a reduction in SBP of 20 mmHg or more, and/or a 
reduction in DBP of 10 mmHg or more, for the standing measurement compared to the 
semi-supine measurement.  If orthostatic hypotension is suspected, the measurement process 
may be repeated at the investigator’s discretion.  Any changes of potential clinical concern will 
be recorded as AEs. 
11.1.3. 
Electrocardiogram 
Standard 12-lead ECGs will be obtained after the patient has rested in a supine position for at 
least 5 minutes.  Electrocardiograms will be measured using an ECG machine that automatically 
calculates the HR and measures PR, QRS, QT, QT interval corrected using Bazett’s formula 
(QTcB) and QT interval corrected using Fridericia’s formula (QTcF).   
Please refer to Appendix 2 through Appendix 15 regarding specific times of ECG assessments at 
individual study visits.  
Electrocardiogram equipment will be provided to each study site to perform all assessments. 
Electrocardiograms will be repeated if clinically significant abnormalities are observed or 
artifacts are present.  Electrocardiograms will be reviewed by qualified staff and over-read by the 
Central ECG Laboratory. 
11.1.4. 
Laboratory Parameters 
Hematology, clinical chemistry, and additional laboratory parameters to be tested are listed in 
Appendix 17.  Patients do not need to be in a fasted state at the time of any laboratory sample; 
however, fasted status will be documented (with fasting defined as at least 4 hours following the 
last meal or snack). 
Laboratory samples will be analyzed by a central laboratory (ACM Global Central Laboratory) to 
ensure consistent interpretation of results.  In the event of an unexplained clinically significant 
abnormal laboratory test value, the test should be repeated immediately and followed up until it 
has returned to the normal range and/or an adequate explanation of the abnormality is found. 
11.1.5. 
Pregnancy Status 
Women of child-bearing potential must have a negative pregnancy test (serum hCG test) at 
screening.  A serum hCG test will be performed at screening (SV1 or SV2) and at TV/OV1, 
TV/OV3, TV/OV4, TV/OV5, and TV/OV6, if applicable. 
If sexually active and the female is of child-bearing potential, the patient (and his/her partner) 
should use adequate contraceptive measures for the duration of the study.  Adequate measures 
should consist of 2 forms of contraception (except in cases of surgical sterilization), at least 1 of 
which must be a barrier method (e.g., male partner uses condoms, plus female partner uses 


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diaphragm and spermicidal gel, or cervical cap and spermicidal gel, or intrauterine device, or 
oral contraceptive pill). 
Female patients found to be pregnant will be withdrawn from further treatment, but will be 
followed for the duration of their pregnancy. 
11.1.6. 
Spirometry 
The following is a description of the pulmonary function testing at clinical sites: 
Pulmonary function will be measured by spirometry using the guideline specified by the Third 
National Health and Nutrition Examination Survey (NHANES III) (Hankinson 1999).  
Spirometry (with the exception of spirometry being performed in conjunction with DLco) will be 
performed by trained and qualified staff at each study site.  Spirometry data will be reviewed by 
a central spirometry laboratory (Biomedical Systems, Inc.) which will provide a quality 
over-read of all evaluations based on acceptability and repeatability metrics in accordance with 
ATS criteria (Miller  et al., 2005).  FEV1, FVC and FEV1/FVC ratio will be recorded from the 
single “best test” (based on effort with highest summed FEV1 and FVC).  Variables and 
comparisons will include the actual and expected forced FEV1, FVC, and FEV1/FVC ratio.  
Patients with FEV1 <50% of predicted for race, age, sex, and height, or FEV1/FVC ratio ≤60% 
in the ON state at screening will be excluded from the study.  A pulmonologist will review the 
spirometry tracings/morphology of any patient with an FEV1 that is ≥50% to <60% of predicted 
or an FEV1/FVC ratio that is >60% to <70% at screening in order to determine eligibility.  All 
patients with an FEV1/FVC ratio that is >60% to <70% at screening will complete spirometry 
before and after the administration of a bronchodilator in a pulmonary function 
laboratory.  Testing will be performed in accordance with the 2005 ATS/ERS criteria.  The 
results of the bronchodilator challenge will be reviewed by a pulmonologist. Any subject 
requiring pulmonary adjudication at screening will not be randomized until after full 
pulmonologist review and approval. 
Spirometry assessments will be done at the time points indicated in Appendix 2 through 
Appendix 15.  The patient’s motor state at the time of each spirometry assessment will be 
recorded.  At SV1, spirometry assessments should be done while the patient is in both the ON 
and OFF states.  At SV2, spirometry assessments will be done only if a repeat measurement is 
needed for assessing eligibility. 
Spirometry equipment will be provided to each study site to perform all spirometry assessments. 
11.1.7. 
Carbon Monoxide Diffusing Capacity  
Patients will undergo diffusing capacity of the lungs for carbon monoxide (DLco) assessments, 
which will be performed in accordance with ATS criteria (Miller  et al., 2005), at a dedicated 
pulmonary function facility after SV2 (and prior to TV/OV1), within 2 weeks prior to TV/OV3, 
TV/OV4, TV/OV5, and TV/OV6, and at 4 to 5 weeks after TV/OV6, as described in the 
Appendix 2 through Appendix 15.  These assessments should be performed while the patient is 
in the ON state (as reported by the patient to the pulmonary technician).  Trained and qualified 
pulmonary function facility technicians will perform a slow vital capacity maneuver, followed by 
DLco, and then spirometry. 


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DLco and slow vital capacity maneuvers will be assessed and processed in accordance with 
ATS/ERS standards.  Spirometry procedures will be conducted at the same visits in the same 
manner as those conducted at clinical sites in accordance with ATS criteria (see Section 11.1.6). 
All DLco data collected at pulmonary function labs will be sent to and reviewed by a central 
Pulmonary Function Testing reviewer (TechEd Consultants).   
11.1.8. 
Adverse Events 
An AE is any symptom, physical sign, syndrome, or disease that either emerges during the study 
or, if present at the start of the study, worsens during the study, regardless of the suspected cause 
of the event.  Changes in conditions present at screening and new symptoms, physical signs, 
syndromes, or diseases should be noted on the AE page of the eCRF during the study.  Any AEs 
reported prior to the first study treatment (or TV/OV1) will be considered baseline AEs, and AEs 
reported from first treatment (or TV/OV1) will be considered treatment-emergent adverse events 
(TEAEs).  
AEs may be volunteered spontaneously by the patient, discovered as a result of general 
questioning by the study staff, or determined by physical examination.  At each visit, the patient 
will be asked, “Have you experienced any problems since your last visit?”  All AEs will be 
recorded on the eCRF.  For all AEs, the investigator must pursue and obtain information 
adequate both to determine the outcome of the AE and to assess whether it meets the criteria for 
classification as a serious AE requiring immediate notification.  Follow-up of the AE, even after 
the date of therapy discontinuation, is required if the AE persists until the event resolves or 
stabilizes at a level acceptable to the investigator. 
In order to avoid vague, ambiguous, or colloquial expressions, all AEs should be recorded in 
standard medical terminology rather than the patient’s own words.  Each AE will also be 
described in terms of duration, frequency, intensity, association with the study medication, 
assessment of possible causes, actions taken, and outcome, using choices given on the eCRF.  
Specific guidelines for classifying AEs by intensity and relationship to study medication are 
given in Table 3 and 
 respectively. 
Table 3 
Classification of Adverse Events by Intensity 
MILD:  An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities. 
Table 4,
MODERATE:  An event that is sufficiently discomforting to interfere with normal everyday 
activities. 
SEVERE:  An event that prevents normal everyday activities. 
 
 


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Table 4 
Classification of Adverse Events by Relationship to Study Medication 
Definitely not related:  The AE is definitely not related to the drug.  This designation should be 
reserved for those events which occur prior to study treatment or for those events which cannot be 
even remotely related to study participation (e.g., injuries sustained in an automobile accident as a 
passenger). 
Unlikely related:  There is no reasonable association between the study treatment and the suspected 
event and the event could have been produced by the patient's clinical state or other modes of therapy 
administered to the patient. 
Possibly related:  The suspected adverse event may or may not follow a reasonable temporal 
sequence from study treatment administration but seems to be the type of reaction that cannot be 
dismissed as unlikely.  The event could have been produced or mimicked by the patient's clinical state 
or by other modes of therapy concomitantly administered to the patient. 
Probably related:  The suspected adverse event follows a reasonable temporal sequence from study 
treatment administration, abates upon discontinuation of the treatment, and cannot be reasonably 
explained by the known characteristics of the patient's clinical state. 
Definitely related:  This designation should be reserved for those events which have no uncertainty 
in their relationship to treatment administration. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the experience should be noted.  If the intensity category changes over a number of 
days, then those changes should be recorded separately (with distinct onset dates). 
11.1.9. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any AE that meets 1 or more of the following 
criteria: 
• The event results in death. 
• The event is life-threatening. 
• The event is permanently disabling (incapacitating or interfering with the ability to 
resume usual life patterns). 
• The event results in unplanned inpatient hospitalization or prolongation of existing 
hospitalization. 
• The event is a congenital anomaly. 
• The event requires medical intervention of any kind in order to prevent any of the 
aforementioned outcomes. 
A serious AE is not necessarily severe; for example, an overnight hospitalization for a diagnostic 
procedure must be reported as a serious AE even though the occurrence is not medically serious.  
By the same token, a severe AE is not necessarily serious:  for example, nausea of several hours’ 
duration may be rated as severe but may not be considered serious. 
An SAE occurring during the study or within 4 weeks of stopping the treatment must be reported 
to the 
 and will be communicated to the Sponsor.  Any such SAE 
due to any cause, whether or not related to the study medication, must be reported within 


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24 hours of occurrence or when the investigator becomes aware of the event.  Notification 
can be made using the following fax or email address for the 
: 
  
 
The event must also be recorded on the standard AE eCRF.  Preliminary reports of SAEs must be 
followed by detailed descriptions later on, including clear and anonymized photocopies of 
hospital case reports, consultant reports, autopsy reports, and other documents when requested 
and applicable.  SAE reports must be made whether or not the investigator considers the event to 
be related to the investigational drug. 
Appropriate remedial measures should be taken to treat the SAE, and the response should be 
recorded.  Clinical, laboratory, and diagnostic measures should be employed as needed in order 
to determine the etiology of the problem.  The investigator must report all additional follow-up 
evaluations to the 
 within 10 calendar days.  All SAEs will be 
followed until the investigator and Sponsor agree the event is satisfactorily resolved. 
11.1.10. 
Suspected Unexpected Serious Adverse Reactions 
Adverse events which meet all of the following criteria will be classified as suspected 
unexpected serious adverse reactions (SUSARs) and will be reported to the appropriate 
regulatory authorities in accordance with applicable regulatory requirements for expedited 
reporting: 
• Serious 
• Unexpected (i.e., is not consistent with the applicable product information such as the 
Investigator's Brochure for an unapproved investigational product or summary of 
product characteristics or product insert for an authorized product) 
• There is at least a reasonable possibility that there is a causal relationship between the 
event and the medicinal product.  
It is the Sponsor’s responsibility to report SUSARs to the IRBs, IECs, and regulatory agencies in 
each country, although this responsibility may be delegated to the contract research organization 
(CRO).  The procedures for notifying the health authorities and the IRBs/IECs of all 
SAEs/SUSARs (as appropriate) will be documented in the CRO study-specific and Sponsor 
standard operating procedure (SOP).  SUSARs will be reported to the appropriate health 
authorities within 7 or 15 days (as appropriate). 
11.1.11. 
Other Significant Adverse Events 
To ensure patient safety, the investigator should also notify the medical monitor should any AE 
occur that is considered significant but does not meet criteria for an SAE, or that is considered 
unexpected.  An unexpected AE is an AE that is not identified in nature, intensity, or frequency 
in the investigational drug brochure.  The medical monitor and/or Sponsor may then choose to 
discontinue the patient from the study.  In addition, any field monitor who notes a significant AE 


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or medical condition while reviewing the eCRFs or source documents at the site must 
immediately convey this information to the medical monitor. 
11.1.12. 
Other Safety Assessments 
11.1.12.1. UPDRS Part 4 (CVT-301 Treatment Group) and Examiner-Rated Dyskinesia 
The UPDRS Part 4 is an assessment of potential complications of PD therapies.  Questions 32-35 
(related to dyskinesias) and 36-39 (related to clinical fluctuations) only will be completed for the 
CVT-301 patients as indicated in the time and events tables in Appendix 2 through Appendix 15.   
Additionally, during the post-dosing follow-up period at TV/OV2, TV/OV3, TV/OV4, TV/OV5, 
and TV/OV6, observe the patient for the appearance of dyskinesia, and note in the eCRF if the 
patient experiences dyskinesia within the 60-minute post-dose period.  If applicable, record the 
maximum severity of any dyskinesia during the 60-minute post-dose period.  The examiner will 
also note if the patient converts to the ON state during the 60-minute post-dose period and if so, 
whether the patient is still in the ON state at 60 minutes post-dose. 
11.1.12.2. Columbia-Suicidality Severity Rating Scale 
The C-SSRS is a measure of suicidal ideation and behavior.  The rating scale has 4 general 
categories:  suicidal ideation, intensity of ideation, suicidal behavior, and actual attempts.  An 
initial baseline version will be given at TV/OV1, and a “since last visit” version will be given at 
all treatment visits to detect any emergence of suicidal ideation or behavior.  The clinic staff 
should address any emerging neuropsychiatric needs in the event that the C-SSRS indicates 
active suicidal ideation. 
11.1.12.3. Epworth Sleepiness Scale 
The Epworth Sleepiness Scale is used to determine the level of daytime sleepiness.  There are 
8 situations listed (e.g., sitting and reading, watching television) for which patients rate their 
likelihood of dozing or sleeping (0=would never doze or sleep, 1=slight chance of dozing or 
sleeping, 2=moderate chance of dozing or sleeping, and 3=high chance of dozing or sleeping).  A 
score of 10 or more is considered sleepy, and a score of 18 or more is very sleepy.  The baseline 
assessment will be completed at TV/OV1 of this study.  As described in the time and events 
tables in Appendix 2 through Appendix 15, additional assessments will be completed at TV/OV4 
and TV/OV6. 
11.1.12.4. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
The QUIP is an instrument used to measure the extent of impulsive and compulsive behaviors in 
PD patients.  The QUIP has 3 sections:  Section 1 assesses gambling, sexual, buying, and eating 
disorders; Section 2 assesses other compulsive behaviors (punding, hobbyism, and walkabout); 
and Section 3 assesses compulsive medication use.  The baseline assessment will be completed 
at TV/OV1 of this study.  As described in the time and events tables in Appendix 2 through 
Appendix 15, additional assessments will be completed at TV/OV4 and TV/OV6. 


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11.2. 
Exploratory Efficacy Assessments  
Exploratory efficacy will be evaluated primarily for the CVT-301-treated patients.  Exploratory 
fficacy will be evaluated from both in-clinic, at-home assessments, and patient-reported 
assessments as outlined by the criteria below.  A limited number of patient-reported assessments 
identified in the subsections below (i.e., the PDQ-39, UPDRS Part 2, and S&E ADL) will also be 
performed in the observational cohort. 
In-Clinic Criteria: 
• UPDRS Part 3 motor score 
• Occurrence of an ON state during the 60-minute post-dose period and if an ON state 
occurs during the 60-minute post-dose, whether or not the patient is still in the ON 
state at 60 minutes post-dose 
At-Home Criteria and/or Patient-Reported Assessments: 
• Total daily OFF time at home, total daily ON time without dyskinesia, total daily ON 
time with non-troublesome dyskinesia, and total daily ON time with troublesome 
dyskinesia, based on the PD Diary.  
• PDQ-39 
• PGI-C 
• S&E ADL 
• UPDRS Part 2 
11.2.1. 
Assessment of ON and OFF States and Dyskinesia (CVT-301 Treatment Group) 
An “OFF state” is defined as the time when medication is not providing benefit with respect to 
mobility, slowness, and stiffness.  OFF episodes may be heralded by non-motor symptoms (e.g., 
pain, anxiety) prior to the appearance of motor symptoms.   
An “ON state” is defined as the time when medication is providing benefit with respect to 
mobility, slowness, and stiffness, and may or may not be providing complete alleviation of all 
PD symptoms. 
For recording motor state in the PD Diary, when patients are in an ON state, the presence and 
extent of dyskinesia (involuntary twisting, turning movements that are an effect of medication) 
will also be noted: 
• ON with no dyskinesia 
• ON with non-troublesome dyskinesia (ON with dyskinesia that does not interfere 
with function or cause meaningful discomfort) 
• ON with troublesome dyskinesia (ON with dyskinesia that interferes with function or 
causes meaningful discomfort) 
These ON and OFF definitions are to be used in training the patients to recognize and record 
their ON and OFF states.  Patients will record their ON and OFF states in their diaries at home.   


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11.2.1.1. In-Clinic Assessments (CVT-301 Treatment Group) 
See Section 11.1.12.1. 
11.2.1.2. At-Home Assessments 
11.2.1.2.1. PD Diary 
During the 3 consecutive days prior to SV2 and TV/OV1, TV/OV2, TV/OV3, TV/OV4, 
TV/OV5, and TV/OV6, patients in the CVT-301 treatment group will record their waking 
ON/OFF status (time OFF, time ON without dyskinesia, time ON with non-troublesome 
dyskinesia, time ON with troublesome dyskinesia) and time asleep in the PD Diary (also referred 
to as the PD Home Diary or “Hauser diary”) (Hauser 2000).   
Patients in the observational cohort will complete the PD Diary for 3 consecutive days prior to 
SV2 and TV/OV1, but will not be required to complete the PD Diary for the remainder of the 
study.  
New diaries will be distributed to appropriate patients at each study visit, except for TV/OV6, 
and patients will bring the completed diaries to the following clinic visit.  Information in the 
diaries will be reviewed, signed, and dated by clinic staff. 
11.2.1.2.2. Screening ON/OFF Episodes Log (for the Screening Period) 
All patients will record the discrete number of OFF episodes experienced by the patient during 
their waking day in the Screening ON/OFF Episodes Log for the 3 consecutive days prior to SV2 
and TV/OV1.  These logs will be distributed at SV1 and SV2, and patients will bring the 
completed logs to the clinic at SV2 and TV/OV1.  Information in the logs will be reviewed, 
signed, and dated by clinic staff. 
11.2.1.2.3. Inhaled Dosing Log (for the Treatment Period) for CVT-301 Treatment Group 
Every day during the treatment period, patients in the CVT-301 treatment group will record the 
number of times the inhaler was used and the number of capsules used for each inhalation 
treatment.  New logs will be distributed at TV/OV1, TV/OV2, TV/OV3, TV/OV4, and TV/OV5, 
and patients will bring the completed logs to the clinic at TV/OV2, TV/OV3, TV/OV4, TV/OV5, 
and TV/OV6.  Information in the logs will be reviewed and recorded by clinic staff. 
11.2.2. 
UPDRS Part 3 (CVT-301 Treatment Group) 
The UPDRS Part 3 is the motor section of the UPDRS examination, given by interview with 
actions by the patient.  Some questions require multiple ratings to be assigned to each extremity.  
The areas addressed by this exam include speech, facial expression, tremor at rest, postural 
tremor, rigidity, finger taps, hand movements, rapid alternating movement (hands), leg agility, 
arising from a chair, posture, gait, postural stability, and body bradykinesia/ hypokinesia. 
The UPDRS Part 3 will be assessed at screening in both ON and OFF states to familiarize the 
patient with the study evaluations as well as to document each patient’s response to his/her own 
PD medications; to enter the study, the difference between UPDRS Part 3 scores in the ON and 
OFF states must be ≥25%.  


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The percent difference is calculated as follows: 
([UPDRS III value in OFF state] – [UPDRS III value in ON state])/ UPDRS III value in OFF state 
The UPDRS Part 3 assessments will be done for the CVT-301 patients at TV/OV2, TV/OV3, 
TV/OV4, TV/OV5 and TV/OV6, immediately before and at various time points after study 
medication dosing, as indicated in the time and events tables in Appendix 2 through Appendix 
15. 
11.2.3. 
PDQ-39 
The PDQ-39 is a self-report questionnaire that covers 8 aspects of quality of life:  mobility, 
activities of daily living, emotions, stigma, social support, cognitions, communication, and 
bodily discomfort.  Scores are reported for each of the 8 quality of life scales and for the total of 
all 39 items. 
The PDQ-39 will be completed upon arrival for patients assigned to the CVT-301 treatment 
group and the observational cohort as indicated in the time and events tables in Appendix 2 
through Appendix 15. 
11.2.4. 
PGI-C (CVT-301 Treatment Group) 
For this study, the PGI-C is a 7-point scale that requires the patient to rate their overall condition 
with regard to PD by answering the following question:  How has the addition of study drug 
changed your Parkinson’s disease?  This change is rated as 1 = much improved; 2 = improved; 
3 = a little improved; 4 = no change; 5 = a little worse; 6 = worse; or 7 = much worse.  If the 
assessment is not done, then the score is marked as 0; any values of zero are not included in any 
analyses and thus are treated as missing. 
The PGI-C scale will be completed by the patients in the CVT-301 treatment group as indicated 
in the time and events tables in Appendix 2 through Appendix 15. 
11.2.5. 
Schwab & England Activities of Daily Living 
The S&E ADL scale will be completed by a qualified rater upon arrival for patients assigned to 
the CVT-301 treatment group and the observational cohort as indicated in the time and events 
tables in Appendix 2 through Appendix 15, preferably while the patient is in the ON state. 
11.2.6. 
UPDRS Part 2 
The UPDRS Part 2 is an evaluation of the ADL; this will be completed by a qualified rater upon 
arrival for patients assigned to the CVT-301 treatment group and the observational cohort as 
indicated in the time and events tables in Appendix 2 through Appendix 15, preferably while the 
patient is in the ON state.   
11.3. 
Other Assessments Used for Baseline Disease Characteristics for all 
Patients 
Patients’ PD diagnosis will be documented by the UK Brain Bank criteria, and PD severity will 
be staged using the modified Hoehn and Yahr disease severity scale.  The MMSE is used to 
assess the patient’s cognitive state. 


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11.3.1. 
UK Brain Bank Criteria 
Steps 1 and 2 of the UK Brain Bank criteria will be used to confirm the patient’s PD diagnosis.  
Step 1 requires that the patient have certain signs and symptoms of Parkinsonian syndrome, and 
Step 2 lists exclusion criteria that the patient must not have to be diagnosed with PD.  The UK 
Brain Bank criteria are presented in Appendix 18 and discussed in Hughes (1992). 
11.3.2. 
Modified Hoehn and Yahr PD Severity Scale Assessment 
PD severity will be staged using the modified Hoehn and Yahr disease severity scale (refer to 
Appendix 19). 
11.3.3. 
MMSE 
The MMSE is a brief, 30-point test used to screen for cognitive impairment.  The categories 
tested include orientation to time, orientation to place, registration, attention and calculation, 
recall, language, repetition, and complex commands.  Any score ≥25 points is considered 
normal.  Scores below 25 can indicate mild (21-24 points), moderate (10-20), or severe (0-9) 
cognitive impairment. 
11.3.4. 
Pulmonary Function Baseline Questionnaire 
The patient’s pulmonary history will be recorded by completing the Pulmonary Function 
Baseline Questionnaire at screening.  Site staff will administer the Pulmonary Function Baseline 
Questionnaire to all patients.  The questionnaire includes sections for recording asthma, COPD, 
and other lung or airway disease symptom history.  There is also a section for recording patient-
reported instances of current pulmonary symptomology. 
11.4. 
Appropriateness of Measurements 
All safety assessments to be used in this study are commonly used, standard measurements 
frequently seen in PD studies and/or pulmonary studies.  The modified Hoehn and Yahr disease 
severity scale is a validated method of assessing the severity of PD, and the UPDRS Part 3 is a 
validated tool measuring the motor aspects of a PD patient.  The UPDRS Part 2, UPDRS Part 4, 
and S&E ADL rating scales are also standard tools for the assessment of PD patients.  Rater 
training in UPDRS Part 2, UPDRS Part 3, UPDRS Part 4, S&E ADL and C-SSRS scales will be 
given to clinic staff members who plan to administer the tests.  The PDQ-39 is a validated 
quality of life measure for PD patients.  The PGI-C scale is a tool for assessing patient-perceived 
changes in their overall disease condition.  The PD Diary to be used in this study (also referred to 
as the Hauser diary) has been validated for use in PD patients as a tool to assess patient-defined 
clinical status at home over a period of time (recording daily OFF time, ON time, and time with 
non-troublesome and troublesome dyskinesia). 
12. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS 
Completed eCRFs for this study will be entered by electronic data capture (EDC) into the study 
database.  The statistical analysis of these data will be performed by the Sponsor or its 
representative.  The statistical evaluation will be performed using the Statistical Analysis 
Software (SAS®) Version 9.3 or higher (SAS Institute, Cary, NC).  All data will be listed, and 


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summary tables will be provided.  Summary statistics will be presented by treatment group 
(when applicable). 
This section describes the statistical analysis as it is foreseen at the time of planning the study.  
Any major deviations from this plan, the reasons for such deviations, and all alternative or 
additional statistical analyses that may be performed will be described in the statistical analysis 
plan (SAP), which will give a detailed technical description of all statistical analyses.   The SAP 
will serve as a compliment to the protocol and supersedes it in case of differences. 
12.1. 
Determination of Sample Size 
Approximately 250 CVT-301 treatment patients and 115 control patients will be enrolled in this 
study. It is assumed that the drop-out rate will be approximately 25%. 
Assuming that there is no difference in the changes from baseline between the CVT-301-treated 
patients and the observational cohort in regards to FEV1, the study has the following power for 
the comparison between the 2 groups.  The upper limit of the 95% confidence interval for the 
difference between the 2 groups in change from baseline in FEV1 will be less than 0.121 L with 
90% power, assuming 188 and 86 patients completing the study in the CVT-301 treatment group 
and observational cohort, respectively.   
12.2. 
Study Populations 
All patients who are enrolled in CVT-301-005 and receive at least 1 dose of CVT-301 will be 
included in the safety population.  The patients in the observational cohort will be included in the 
analyses if they provide any data after TV/OV1. 
12.3. 
Definition of Baseline 
In all statistical analyses of the CVT-301 treatment group, the visit at which the CVT-301 
treatment was initiated will be used as the baseline.  However, for all patients who were included 
in the CVT-301-002 or CVT-301-003 studies, TV/OV1 of the CVT-301-005 study will be used 
as baseline.  For the observational cohort, the assessments at TV/OV1 will be used as baseline.   
12.4. 
Background and Demographic Characteristics 
Demographics and baseline characteristics will be summarized descriptively for patients treated 
with CVT-301 and for the patients in the observational cohort.  In addition to the total CVT-301 
group, the data from the CVT-301 naïve patients who are enrolled in this study and from the 
patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies will be 
summarized separately.  At least the following variables will be summarized: 
• Demographics (age, gender, race, height, weight) 
• Smoking history (current, former, never: pack-years for current and former smoker) 
• History of PD (UK Brain Bank criteria, time since diagnosis of PD, duration of LD 
treatment) 


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• LD treatment at baseline (total daily dose, dosing frequency, decarboxylase inhibitor 
[CD or benserazide], use of standard/quick/controlled release LD, use of COMT 
inhibitor) 
• Other antiparkinsonian treatment at baseline (use of dopamine agonists, MAO-B 
inhibitors, anticholinergics, amantadine, or other treatment) 
• Disease severity (modified Hoehn and Yahr stage [in the ON state], UPDRS Part 3 at 
screening) 
• Cognitive status (MMSE) 
• Average daily number of OFF episodes experienced (determined from Screening 
ON/OFF Episodes and Treatment Log. 
12.5. 
Safety Analysis 
The disposition of the patients will be summarized by tabulating the number of screened, 
randomized, completed, and discontinued patients.  The reasons for premature discontinuations 
will be tabulated. 
The extent of exposure to study treatment will be summarized for the patients who received 
CVT-301 treatment.  The time period between TV/OV1 and TV/OV6 (or Early Withdrawal 
Visit) will be used as the measure of extent of exposure for the patients randomized to the 
observational cohort.  Adverse events will be tabulated by treatment group according to the 
Medical Dictionary for Regulatory Activities (MedDRA).  Study-emergent and 
treatment-emergent adverse events (TEAEs) will be summarized by body system and preferred 
term.  For patients in the observational cohort, the AEs collected between TV/OV1 and TV/OV6 
(or Early Withdrawal Visit) will be considered as TEAEs.   Furthermore, the time of onset of the 
TEAEs will be summarized.  
For vital signs, ECG parameters, spirometry measurements, and DLco, the changes from 
pre-dose to post-dose assessments of the corresponding day will be calculated and described 
using descriptive statistics.  For spirometry, DLco, and safety laboratory variables, the 
differences in pre-dose values between the study days will be described.  Furthermore, the 
changes in the spirometry values and difference between the groups will be estimated using a 
Mixed Model for Repeated Measurements (MMRM) similar to the one used for the efficacy 
variables.  The proportion of patients with abnormal spirometry values will be tabulated using 
different criteria for the threshold (e.g., at least 10% or 20% change from baseline at any single 
visit, at least 10% or 20% change from baseline on at least 2 consecutive visits).  The proportions 
of patients meeting ATS quality criteria (and also for those ‘rejected’) will be summarized.  All 
spirometry analyses will be performed both for all patients regardless of the ATS quality criteria 
and separately excluding the assessments not meeting the ATS quality criteria.   
At least the following variables will be analyzed: 
• Vital signs:  standard and orthostatic systolic and diastolic BP and HR. 
• ECG:  HR, PR, QRS, QT and RR intervals, QTcB (Bazett's correction formula 
calculated as QT/RR1/2) and QTcF (Fridericia's correction formula calculated as 


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QT/RR1/3).  ECG parameter values or parameter changes of potential clinical concern 
will be tabulated.  
• Spirometry: FEV1, FVC, and the FEV1/FVC ratio during specified treatment visits 
and over the course of the study will be evaluated.  The number and proportion of 
patients with pre-specified changes in spirometry parameters will be tabulated. 
Changes from baseline to follow-up in the rating scales for assessing suicidality, somnolence, 
and impulse control disorders will be summarized descriptively.   
12.5.1. 
Interim Safety Data Review 
Safety data will be reviewed by a DSMC that will include relevant medical experts (including a 
neurologist and pulmonologist), an independent statistician, and additional representatives (as 
will be defined in the DSMC Charter).  Safety data, including but not limited to AEs, spirometry, 
vital signs, and ECG data will be reviewed.  The safety review will be documented in a DSMC 
Charter prior to the start of the study.  In the event that potential safety issues are identified, the 
committee may recommend modification of the study design or study termination, which will be 
communicated promptly with investigators, IRBs, IECs, and regulatory agencies, in accordance 
with legal and regulatory requirements.  Interim analyses, which will not affect study conduct, 
may be performed to support regulatory submissions. These analyses will be described in the 
SAP. 
12.6. 
Exploratory Efficacy Analysis 
The derivation of the exploratory efficacy variables will be defined in detail in the SAP. 
The changes from baseline in continuous exploratory efficacy variables will be estimated using 
an MMRM.  The model will include visit and the stratification variables (Hoehn and Yahr stage 
and screening FEV1 and/or FEV1/FVC) as fixed factors.  The baseline value will be used as a 
covariate.  For variables which do not have a pre-treatment baseline assessment, OFF-state 
baseline UPDRS Part 3 score will be used as the baseline covariate.  An unstructured covariance 
structure will be applied for the MMRM.  In case the model will not converge with the 
unstructured covariance structure, compound symmetry will be used instead.  
The sensitivity analyses will be specified in the SAP.  Sensitivity analysis will be performed at 
least for the method to handle missing data (e.g., last observation carried forward, pattern 
mixture model using multiple imputation instead of MMRM), definition of analysis population 
(e.g., patients completing the study instead of observed cases), and statistical method (e.g., 
analysis of covariance [ANCOVA] models separately for each visit instead of MMRM). 
The categorical data will be primarily evaluated descriptively.  Each visit will be evaluated 
separately for the categorical endpoints. 
The exploratory efficacy data collected from the patients in the observational cohort will be 
summarized with descriptive statistics. 


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13. 
STUDY MANAGEMENT 
13.1. 
Approval and Consent 
13.1.1. 
Regulatory Guidelines 
The study will be performed under good clinical practice (GCP) in accordance with the 
guidelines of the International Conference on Harmonisation (ICH), in accordance with United 
States of America (USA) Investigational New Drug (IND) regulations (21 Code of Federal 
Regulations [CFR] 312), and the local national laws (as applicable). 
13.1.2. 
Institutional Review Board/Independent Ethic Committees 
Conduct of the study must be approved by an appropriately constituted IRB or IEC.  Approval is 
required for the study protocol, investigational drug brochure, protocol amendments, informed 
consent forms, patient information sheets, and advertising materials.  No drug will be shipped to 
a site until written IRB or IEC authorization has been received by the Sponsor or its 
representative. 
13.1.3. 
Informed Consent 
For each study patient, written informed consent will be obtained prior to any protocol-related 
activities.  As part of this procedure, the principal investigator or one of his/her associates must 
explain orally and in writing the nature, duration, and purpose of the study, and the action of the 
drug in such a manner that the patient is aware of the potential risks, inconveniences, or adverse 
effects that may occur.  The patient should be informed that he/she may withdraw from the study 
at any time, and the patient will receive all information that is required by local regulations and 
ICH guidelines.  The principal investigator will provide the Sponsor or its representative with a 
copy of the IRB/IEC-approved informed consent form prior to the start of the study. 
13.2. 
Financing and Insurance 
Prior to the trial commencing, the Sponsor (or its designee) and the investigator (or the 
institution, as applicable) will agree on costs necessary to perform the study.  This agreement 
will be documented in a financial agreement that will be signed by the investigator (or the 
institution signatory) and the Sponsor (or its designee). 
The Sponsor has insurance coverage for trial-related, medicine-induced injury, and other 
liabilities incurred during clinical trials which will provide compensation for any study-related 
injury according to the guidelines set out by the Association of the British Pharmaceutical 
Industry, namely “Clinical Trials Compensation for Medicine Induced Injury.”  The Sponsor will 
provide local country-specific insurance, as required. 
13.3. 
Discontinuation of the Study by the Sponsor 
The Sponsor reserves the right to discontinue the study at this site or at multiple sites for safety 
or administrative reasons at any time.  In particular, a site that does not recruit at a reasonable 
rate may be discontinued.  Should the study be terminated and/or the site closed for whatever 
reason, all documentation, clinical supplies, and study medication pertaining to the study must be 
returned to the Sponsor or its representative. 


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13.4. 
Study Documentation 
By signing a copy of country-specific regulatory forms, the principal investigator acknowledges 
that he/she has received a copy of the investigational drug brochure on CVT-301 and assures the 
Sponsor that he/she will comply with the protocol and the provisions stated in the country-
specific forms.  No changes in this protocol can be made without the Sponsor’s written approval. 
The investigator (CRO, if applicable) will supply the Sponsor with the following documents: 
• Original, signed Food and Drug Administration (FDA) Form 1572 and other 
country-specific forms 
• Original signed FDA financial disclosure forms 
• Curricula vitae for all investigators listed on country-specific forms 
• Copy of principal investigator’s medical licensure/medical registration number 
• Signed protocol signature page 
• List of IRB/IEC members and their occupations/affiliations or multiple assurance 
number 
• Letter indicating IRB/IEC approval to conduct the protocol 
• Copy of IRB/IEC-approved informed consent form 
• The Sponsor will supply the investigator with the following documents: 
• Clinical study protocol 
• Investigational drug brochure 
• Sample informed consent form 
• Case report forms/ instruction manual 
• Insurance letter 
13.5. 
Data Handling 
Any data to be recorded directly in the eCRF (to be considered as source data) will be identified 
at the start of the trial. 
Accurate and reliable data collection will be assured by 100% verification and cross-check of the 
eCRFs against the investigator’s records by the study monitor.  A comprehensive validation 
check program will verify the data, and queries will be generated for resolution by the 
investigator.  During monitoring visits, the monitor will also generate data queries via the eCRF 
system for resolution by the investigator. 
13.6. 
Study Monitoring and Auditing 
This study will be monitored at all stages of its development by the clinical research personnel 
employed by the Sponsor or its representative.  Monitoring will include personal visits and 
telephone communication to assure that the investigation is conducted according to protocol and 
in order to comply with guidelines of GCP.  On-site review of eCRFs will include a review for 


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completeness and clarity, and consistency with source documents available for each patient.  
Note that a variety of original documents, data, and records may be considered as source 
documents in this trial. 
Medical advisors and clinical research associates or assistants may request to witness patient 
evaluations occurring as part of this protocol.  The investigator and appropriate personnel will be 
periodically requested to attend meetings/workshops organized by the Sponsor to assure 
acceptable protocol execution.  The study may be subject to audit by the Sponsor, by the CRO, 
or by regulatory authorities.  If such an audit occurs, the investigator must agree to allow access 
to required patient records.  By signing this protocol, the investigator grants permission to 
personnel from the Sponsor, its representatives, and appropriate regulatory authorities for on-site 
monitoring of all appropriate study documentation, as well as on-site review of the procedures 
employed in eCRF generation, where clinically appropriate. 
13.7. 
Retention of Records 
The investigator agrees to comply with all applicable federal, state, and local laws and 
regulations relating to the privacy of patient health information, including, but not limited to, the 
Standards for Individually Identifiable Health Information, 45 CFR, Parts 160 and 164 (the 
Health Insurance Portability and Accountability Act of 1996 [HIPAA] Privacy Regulation) or 
equivalent. The investigator shall ensure that study patients authorize the use and disclosure of 
protected health information in accordance with HIPAA Privacy Regulation and in a form 
satisfactory to the Sponsor. 
The investigator must arrange for retention of study records at the site.  The nature of the records 
and the duration of the retention period must meet the requirements of the relevant regulatory 
authority.  In addition, because this is an international study, the retention period must meet the 
requirements of the most stringent authority.  The investigator should take measures to prevent 
accidental or premature destruction of these documents. 
13.8. 
Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for the 
purposes of national and international registration.  If necessary, the authorities will be notified 
of the investigator’s name, address, qualifications, and extent of involvement.  Reports covering 
clinical and biometric aspects of the study will be prepared by the Sponsor or its representative. 
13.9. 
Publication 
As a multicenter trial, the Sponsor intends to publish clinical data from all centers participating 
in the investigation.  A publication committee selected by the Sponsor will submit draft 
manuscripts to an assigned authorship committee for their comments.  In conformity with the 
uniform requirements for manuscripts submitted to biomedical journals published by the 
International Committee of Medical Journal Editors, investigators whose contribution consists 
solely in the collection of data will not be named individually as authors (Kassirer 1991).  
Rather, those investigators will receive a collective authorship as the “CVT-301 Study Group” 
and will be identified in a note. 


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Individual investigators and/or their associates subsequently may publish additional findings of 
this study in scientific journals or present them at scientific meetings, provided that the Sponsor 
is given ample opportunity to review any proposed abstract, manuscript, or slide presentation 
prior to its submission.  This review is required to ensure that the Sponsor is aware of all written 
and oral presentations of the data and does not imply any editorial review or restriction of the 
contents of the presentation or use. 
 


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14. 
REFERENCES 
Bartus RT, Emerich D, Snodgrass-Belt P, Fu K, Salzberg-Brenhouse H, Lafreniere D, Novak L, 
Lo E-S, Cooper T, Basile AS. A pulmonary formulation of L-dopa enhances its 
effectiveness in a rat model of Parkinson’s disease. JPET 2004; 310 (2):828-835. 
 
Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of PD – 2009. 
Neurology 2009; 72(Suppl 4):S1-136. 
Olanow CW, Obeso JA, Stocchi F. Continuous dopamine receptor treatment of Parkinson’s 
disease: scientific rationale and clinical implications. Lancet Neurology 2006; 5:677-687. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 
26:319-338. 
LeWitt PA. Levodopa for the Treatment of Parkinson’s Disease. N Engl J Med 2008; 359:2468-
2476. 
Kassirer JP, Angell M. On authorship and acknowledgments. N Engl J Med 1991; 325(21): 
1510-1512. 
Hauser RA, Friedlander J, Zesiewicz TA, Adler CH, Seeberger LC, O’Brien CF, Molho ES, 
Factor SA. A home diary to assess functional status in patients with Parkinson’s disease 
with motor fluctuations and dyskinesia. Clin Neuropharmacol 2000; 23(2):75-81. 
Hankinson JL, Odencrantz JR, Fedan, KB. Spirometric reference values from a sample of the 
general US population. Am J Respir Crit Care Med 1999; 159:179-187. 
Dunbar J, Illeperuma A, Milovanovic J, Loewy J, Osborn C, Ahluwalia P, Richards J, Ehrich 
EW. A placebo- and active-comparator-controlled dose escalation study of the 
pharmacokinetics, pharmacodynamics, and safety of inhaled large porous particle (AIR®) 
epinephrine in normal volunteers. J Allergy Clin Immunol 2004; Abstract 937: S260. 
Dewey RB, Hutton JT, LeWitt PA, Factor SA. A randomized, double-blind, placebo-controlled 
trial of subcutaneously injected apomorphine for Parkinsonian off-state events. Arch 
Neurol 2001; 58:1385-1392. 
DeLong M, Wright J, Dawson M, Meyer T, Sommerer K, Dunbar C. Dose delivery 
characteristics of the AIR® pulmonary delivery system over a range of inspiratory flow 
rates. J Aerosol Med 2005; 18 (4):452-459. 
Chipman J, Lucas R, Jackson B, Blizzard C, Mant T, Cleverly A, Spaldin V, Johnston L, Cutler 
G. Pharmacokinetic and safety results of a human single-dose comparison of somatropin
inhalation powder (SIP) vs. subcutaneous (SC) injection of somatropin. Program of the 
87th Annual Meeting of the Endocrine Society, San Diego, CA, 2005. 
Baruzzi A, Contin M, Riva R, et al. Influence of meal ingestion time on pharmacokinetics of 
orally administered levodopa in Parkinsonian patients. Clin Neuropharmacol 1987; 10 
(6):527-37. 
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic 
Parkinson’s disease: a clinico-pathological study of 100 cases. JNNP 1992; 55:181-184. 


Civitas Therapeutics, Inc 
 
22-Sep-2015 
CVT-301-005 
 Page 95 
Version 3.0 
Walvoord EC, de la Pena A, Park S, Silverman B, Cuttler L, Rose SR, Cutler G, Drop S, 
Chipman JJ. Inhaled growth hormone (GH) compared with subcutaneous GH in children 
with GH deficiency: pharmacokinetics, pharmacodynamics, and safety. J Clin Endocrinol 
Metab 2009; 94:2052–2059.
Stocchi F, Rascol O, Kieburtz K, Poewe W, Jankovic J, Tolosa E, Barone P, Lang AE, Olanow 
CW. Initiating levodopa/carbidopa therapy with and without entacapone in early 
Parkinson’s disease: the STRIDE-PD study. Ann Neurol 2010; 68:18-27. 
Rave K, de la Pena A, Tibaldi FS, Zhang L, Silverman B, Hausmann M, Heinemann L, 
Muchmore DB. AIR inhaled insulin in subjects with chronic obstructive pulmonary 
disease: pharmacokinetics, glucodynamics, safety, and tolerability. Diabetes Care 2007; 
30 (7):1777-1782. 
Pfeiffer RF. Antiparkinsonian agents: drug interactions of clinical significance. Drug Safety 
1996; 14 (5):343-354. 
Parkinson Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in 
DATATOP subjects requiring carbidopa/levodopa. Ann Neurol 1996; 39:37–45. 
Ondo WG, Shinawi L, Moore S. Comparison of orally dissolving carbidopa/levodopa (Parcopa) 
to conventional oral carbidopa/levodopa: a single-dose, double-blind, double-dummy, 
placebo-controlled, crossover trial. Movement Disorders 2010; 25(16):2724-2727. 
Oleson L, Turncliff RZ, Silberman B, Fogarty C, Ehrich E. ALKS 27 (Trospium Inhalation 
Powder) improves lung function following single administration in subjects with COPD. 
Am J Respir Crit Care Med 2010; 181:A4457. 


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15. 
APPENDICES – TABLE OF CONTENTS 
Appendix 1 
Overall Visit Schedule Schematic 
Appendix 2 
Time and Events Table—Screening Visit 1 (SV1) (within 35 days 
prior to TV/OV1) 
Appendix 3 
Time and Events Table—Screening Visit 2 (SV2) (at least 4 days 
after SV1) 
Appendix 4 
Time and Events Table—Treatment Visit 1 (TV1) (at least 7 days 
after SV2)  
Appendix 5 
Time and Events Table—Observational Visit 1 (OV1) (at least 7 
days after SV2)  
Appendix 6 
Time and Events Table—Treatment Visit 2 (TV2) (1 Month 
[4 Weeks ±5 days] after TV1) 
Appendix 7 
Time and Events Table—Observational Visit 2 (OV2) (1 Month 
[4 Weeks ±5 days] after OV1) 
Appendix 8 
Time and Events Table—Treatment Visit 3 (TV3) (3 Months 
[12±2 Weeks] after TV1) 
Appendix 9 
Time and Events Table—Observational Visit 3 (OV3) (3 Months 
[12±2 Weeks] after OV1) 
Appendix 10 
Time and Events Table—Treatment Visit 4 (TV4) (6 Months 
[24±2 Weeks] after TV1)  
Appendix 11 
Time and Events Table—Observational Visit 4 (OV4) (6 Months 
[24±2 Weeks] after OV1)  
Appendix 12 
Time and Events Table—Treatment Visit 5 (TV5) (9 Months 
[36±2 Weeks] after TV1) 
Appendix 13 
Time and Events Table—Observational Visit 5 (OV5) (9 Months 
[36±2 Weeks] after OV1) 
Appendix 14 
Time and Events Table—Treatment Visit 6 (TV6) (12 Months 
[52±2 Weeks] after TV1)/ Early Withdrawal Visit 
Appendix 15 
Time and Events Table—Observational Visit 6 (OV6) (12 Months 
[52±2 Weeks] after OV1)/ Early Withdrawal Visit 


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Appendix 16 
In-Clinic Assessment of ON/OFF States and Dyskinesia 
Appendix 17 
Laboratory Parameters 
Appendix 18 
UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic 
Criteria 
Appendix 19 
Modified Hoehn and Yahr PD Severity Scale Assessment 
Appendix 20 
Contraindications to Performing Routine Spirometry 
 


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APPENDIX 1:  OVERALL VISIT SCHEDULE SCHEMATIC 
Abbreviations:  DLco = carbon monoxide diffusing capacity; M = month; SV = screening visit; TV/OV = Treatment Visit/Observational Visit; W = weeks. 


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APPENDIX 2:  TIME AND EVENTS TABLE—SCREENING VISIT 1 (SV1) (WITHIN 35 DAYS PRIOR 
TO TV/OV1) 
Procedures1 
At arrival 
(assess in ON or 
OFF state) 
Assess in  
ON state2 
 
Assess in 
OFF state 
End of SV1 
Post-SV1 
Telephone 
Contact 
Consent 
X 
 
 
 
 
Eligibility according to inclusion/exclusion criteria 
X 
 
 
 
 
Medical history including PD history and smoking history 
X 
 
 
 
 
Confirm PD diagnosis and severity (UK Brain Bank/Modified Hoehn 
and Yahr scale) 
 
X 
 
 
 
Record average number of OFF hours during waking 
X 
 
 
 
 
PD medications (confirm as stable) 
X 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
MMSE 
 
X 
 
 
 
Physical examination (full) 
X 
 
 
 
 
Pulmonary Function Baseline Questionnaire 
X 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and HR)  
X 
 
 
 
 
Spirometry 
 
X 
X 
 
 
UPDRS Part 3 
 
X 
X 
 
 
Patient training on self-report of ON/OFF states  
 
X 
X 
 
 
ON/OFF concordance testing 
 
X 
X 
 
 
Inhaler training using sham capsules 
 
X 
X 
 
 
Clinical laboratory tests (including serum pregnancy test, if applicable) 
X3 
 
 
 
 
Distribute PD Diary and Screening ON/OFF Episodes Log and review 
instructions for completion4 
 
 
 
X 
 
Monitor for AEs 
X 
 
Schedule next visit 
 
 
 
X 
 
Post-SV1 telephone contact: call patient ~4 days prior to SV2 
 
 
 
 
X 
1Procedures appear in the table in the suggested order of completion. 
2If patient arrives in OFF state, perform OFF assessments first, then have patient take next regularly scheduled dose of PD meds and complete ON assessments. 
3Document whether patient is fasting (≥4 hours after last snack or meal). 
4The PD Diary and Screening ON/OFF Episodes Log are to be completed for the 3 consecutive days prior to SV2. 


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APPENDIX 3:  TIME AND EVENTS TABLE—SCREENING VISIT 2 (SV2) (AT LEAST 4 DAYS AFTER 
SV1) 
Procedures1 
At arrival 
(assess in ON or 
OFF state) 
Assess in  
ON state 
Assess in 
OFF state 
End of 
SV2 
Post-SV2 
Telephone 
Contact 
Confirm eligibility through review of complete PD Diary and Screening 
ON/OFF Episodes Log2 
X 
 
 
 
 
Record any changes in usual PD medication dose/regimen 
X 
 
 
 
 
Record any changes in concomitant medications 
X 
 
 
 
 
Inhaler training using sham capsules and IFU3 
 
X 
X 
 
 
Patient training on assessment of ON/OFF state 
 
X 
X 
 
 
Distribute PD Diary and Screening ON/OFF Episodes Log and review 
instructions for completion4 
 
 
 
X 
 
Monitor for AEs 
X 
 
Schedule DLco assessment (to be completed prior to TV/OV1) and next visit 
 
 
 
X 
 
Post-SV2 telephone contact: call patient 4 to 6 days prior to TV/OV1 
 
 
 
 
X 
Screening procedures from SV1 that can be completed/repeated at SV2, 
if necessary: 
At arrival 
(assess in ON or 
OFF state) 
Assess in  
ON state 
Assess in 
OFF state 
 
 
MMSE 
 
X 
 
 
 
Physical examination (full) 
X 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and HR) 
X 
 
 
 
 
Spirometry 
 
X 
X 
 
 
UPDRS Part 3 
 
X 
X 
 
 
ON/OFF concordance testing 
 
X 
X 
 
 
Clinical laboratory tests (including serum pregnancy test, if applicable) 
X5 
 
 
 
 
1Procedures appear in the table in the preferred order of completion. 
2Refer to Section 10.1.2 of protocol for management of incorrect or incomplete patient diaries. 
3If the patient has undergone inhaler training in both the ON and OFF states at SV1, it may be done in either state at this visit. 
4The PD Diary and Screening ON/OFF Episodes Log are to be completed for the 3 consecutive days prior to TV/OV1. 
5Document whether patient is fasting (≥4 hours after last snack or meal). 


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APPENDIX 4:  TIME AND EVENTS TABLE—TREATMENT VISIT 1 (TV1) (AT LEAST 7 DAYS 
AFTER SV2) 
Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 
min 
Post-
dose 
15 
min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV1 
Post-TV1 
Telephone 
Contacts 
Collect, review, sign, and date Screening ON/OFF 
Episodes Log and PD Diary 
X 
 
 
 
 
 
 
 
 
 
Confirm DLco assessment2 has been completed prior to 
visit; if DLco not done, the study visit must be 
re-scheduled 
X 
 
 
 
 
 
 
 
 
X 
Record time of patient’s prior usual PD medication dose 
X 
 
 
 
 
 
 
 
 
 
Record any changes in usual PD medication dose/regimen 
X 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
PDQ-39 (in ON state) 
X 
 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
 
UPDRS Part 2 (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
 
S&E ADL (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
 
UPDRS Part 4 (Questions 32-35 and 36-39)  
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X3 
 
 
 
 
 
 
 
 
Standard and orthostatic BP and HR 
X3 
 
 
 
X 
 
X 
 
 
Respiratory rate 
X3 
 
X 
 
X 
X 
X 
 
 
Spirometry 
X4 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (including serum pregnancy test, 
if applicable) 
X3,5 
 
 
 
 
 
 
 
 
C-SSRS  
X3 
 
 
 
 
 
 
 
 
Epworth sleepiness scale  
X3 
 
 
 
 
 
 
 
 
QUIP  
X3 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing Log and review 
instructions for completion 
X6 
 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
 
Review inhaler training 
X 
 
 
 
 
 
 
 
 
 
Self-administration of study drug 
 
 
X1 
 
 
 
 
 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
 
 
 
 
 
 
 
X 
 
Post-TV1 telephone contact:  call patient 1-3 days after 
TV1 
 
 
 
 
 
 
 
 
 
X 


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Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 
min 
Post-
dose 
15 
min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV1 
Post-TV1 
Telephone 
Contacts 
Post-TV1 telephone contact:  call patient 2 weeks (± 3 
days)  before TV2 
 
 
 
 
 
 
 
 
 
X 
1First dose of study medication occurs preferably between 2 and 5 hours after patient has taken normal morning dose of PD medication and after all pre-dose 
assessments are complete.  
2 DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
3Procedures can be done at any point after arrival but must be completed before dosing. 
4Preferably in the ON state. 
5Document whether patient is fasting (≥4 hours after last snack or meal). 
6The PD Diary is to be completed for the 3 consecutive days prior to TV2; the Inhaled Dosing Log is to be completed daily through TV6. 
 


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APPENDIX 5:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 1 (OV1) (AT LEAST 7 DAYS 
AFTER SV2) 
Procedures 
Assess in Either ON or OFF 
State Unless Otherwise 
Noted 
End of OV1 
Post- OV1 
Telephone 
Contact 
Collect, review, sign, and date Screening ON/OFF Episodes Log and PD Diary 
X 
 
 
Confirm DLco assessment1 has been performed prior to visit; and if not complete, 
re-schedule study visit 
X 
 
X 
Record any changes in usual PD medication dose/regimen 
X 
 
 
Concomitant medications 
X 
 
 
PDQ-39 (in ON state) 
X (ON) 
 
 
UPDRS Part 2 (preferably in ON state) 
X (ON) 
 
 
S&E ADL (preferably in ON state) 
X (ON) 
 
 
Physical examination (brief) 
X 
 
 
Standard and orthostatic BP and HR 
X 
 
 
Respiratory rate 
X 
 
 
Electrocardiogram 
X 
 
 
Spirometry (preferably in ON state) 
X (ON) 
 
 
Clinical laboratory tests (including serum pregnancy test, if applicable) 
X2 
 
 
C-SSRS  
X 
 
 
Epworth sleepiness scale  
X 
 
 
QUIP  
X 
 
 
Monitor for AEs 
X 
 
Schedule next visit 
 
X 
 
Post-OV1 telephone contact:  call patient 2 weeks (± 3 days)  before OV2 
 
 
X 
1DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
2Document whether patient is fasting (≥4 hours after last snack or meal). 
 
 


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APPENDIX 6:  TIME AND EVENTS TABLE—TREATMENT VISIT 2 (TV2) (1 MONTH [4 WEEKS ±5 
DAYS] AFTER TV1) 
Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV2 
Post-TV2 
Telephone 
Contact 
Collect, review, sign, and date PD Diary and Inhaled Dosing Log 
X 
 
 
 
 
 
 
 
 
Collect empty capsules, inhalers, and unused supplies 
X 
 
 
 
 
 
 
 
 
Record any changes in usual PD medication dose/regimen 
X 
 
 
 
 
 
 
 
 
Record time of patient’s prior usual PD medication dose 
X 
 
 
 
 
 
 
 
 
Record any changes in concomitant medications 
X 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and 
HR) 
X3 
 
 
 
 
 
 
 
Spirometry (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
C-SSRS  
X 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
Review inhaler training 
X 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing Log and review 
instructions for completion 
X4 
 
 
 
 
 
 
 
 
UPDRS Part 3 
 
X5 
 
X 
X 
X 
X 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 
 
 
 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
 
 
 
 
 
 
X 
 
Schedule DLco visit at pulmonary site (14±3 days before next 
visit)2  
 
 
 
 
 
 
 
X 
 
Post-TV2 telephone contact: call patient 2 weeks (± 3 days)  
before TV3 
 
 
 
 
 
 
 
 
X 
1Dosing of study medication occurs preferably between 2 and 5 hours after patient has taken normal morning dose of PD medication and after all pre-dose 
assessments are complete. 
2DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
3Assessment can be done at any point after arrival but must be completed before dosing. 


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4The PD Diary is to be completed for the 3 consecutive days prior to TV3; the Inhaled Dosing Log is to be completed daily through TV6. 
5Confirm patient is in the OFF state prior to pre-dose UPDRS Part 3 assessment. 


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APPENDIX 7:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 2 (OV2) (1 MONTH [4 
WEEKS ±5 DAYS] AFTER OV1) 
Procedures 
Assess in Either ON or 
OFF State Unless 
Otherwise Noted 
End of OV2 
Post- OV2 
Telephone 
Contact 
Record any changes in usual PD medication dose/regimen 
X 
 
 
Record any changes in concomitant medications 
X 
 
 
Physical examination (brief) 
X 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and HR) 
X 
 
 
Spirometry (preferably in ON state) 
X (ON) 
 
 
C-SSRS  
X 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
X 
 
Schedule DLco visit at pulmonary site (14±3 days before next visit)1  
 
X 
 
Post- OV2 telephone contact:  call patient 2 weeks (± 3 days)  before OV3 
 
 
X 
1 DLco to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
 


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APPENDIX 8:  TIME AND EVENTS TABLE—TREATMENT VISIT 3 (TV/OV3) (3 MONTHS [12±2 
WEEKS] AFTER TV1) 
Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV3 
Post-TV3 
Telephone 
Contact  
Collect, review, sign, and date PD Diary and Inhaled Dosing Log 
X 
 
 
 
 
 
 
 
 
Collect empty capsules, inhalers, and unused supplies 
X 
 
 
 
 
 
 
 
 
Confirm DLco assessment2 has been completed prior to visit; if 
not done, the study visit must be re-scheduled 
X 
 
 
 
 
 
 
 
 
X 
Record any changes in usual PD medication dose/regimen 
X 
 
 
 
 
 
 
 
 
Record time of patient’s prior usual PD medication dose 
X 
 
 
 
 
 
 
 
 
Record any changes in concomitant medications 
X 
 
 
 
 
 
 
 
 
PGI-C (preferably in an ON state) 
X3 
 
 
 
 
 
 
 
 
C-SSRS 
X 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and HR) 
X3 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
Spirometry (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (including serum pregnancy test, if 
applicable) 
X4 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
Review inhaler training 
X 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing Log and review 
instructions for completion 
X5 
 
 
 
 
 
 
 
 
UPDRS Part 3 
 
X6 
 
X 
X 
X 
X 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 
 
 
 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
 
 
 
 
 
 
X 
 
Schedule DLco visit at pulmonary site (14±3 days before next 
visit)  
 
 
 
 
 
 
 
X 
 


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Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV3 
Post-TV3 
Telephone 
Contact  
Post-TV3 telephone contact:  call patient 2 weeks (± 3 days)  
before TV4 
 
 
 
 
 
 
 
 
X 
1Dosing of study medication occurs at least 1 hour after patient has taken normal morning dose of PD medication and after all pre-dose assessments are complete. 
2DLco to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
3Assessment can be done at any point after arrival but must be completed before dosing. 
4Document whether patient is fasting (≥4 hours after last snack or meal). 
5The PD Diary is to be completed for the 3 consecutive days prior to TV4; the Inhaled Dosing Log is to be completed daily through TV6. 
6Confirm patient is in the OFF state prior to pre-dose UPDRS Part 3 assessment. 
 
 


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APPENDIX 9:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 3 (OV3) (3 MONTHS [12±2 
WEEKS] AFTER OV1) 
Procedures 
Assess in Either ON or 
OFF State Unless 
Otherwise Noted 
End of OV3 
Post- OV3 
Telephone 
Contact 
Confirm DLco assessment1 has been performed prior to visit; and if not complete, 
re-schedule study visit 
X 
 
 
X 
Record any changes in usual PD medication dose/regimen 
X 
 
 
Record any changes in concomitant medications 
X 
 
 
C-SSRS  
X 
 
 
Physical examination (brief) 
X 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and HR) 
X 
 
 
Electrocardiogram 
X 
 
 
Spirometry (preferably in ON state) 
X (ON) 
 
 
Clinical laboratory tests (including serum pregnancy test, if applicable) 
X2 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
X 
 
 Schedule DLco visit at pulmonary site (14±3 days before next visit)  
 
X 
 
Post- OV3 telephone contact: call patient 2 weeks (± 3 days)  before OV4 
 
 
X 
1DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
2Document whether patient is fasting (≥4 hours after last snack or meal).  
 


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APPENDIX 10:  TIME AND EVENTS TABLE—TREATMENT VISIT 4 (TV4) (6 MONTHS [24±2 
WEEKS] AFTER TV1) 
Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV4 
Post-TV4 
Telephone 
Contact 
Collect, review, sign, and date PD Diary and Inhaled Dosing Log 
X 
 
 
 
 
 
 
 
 
Collect empty capsules, inhalers, and unused supplies 
X 
 
 
 
 
 
 
 
 
Confirm DLco assessment2 has been completed prior to visit; if 
not done, the study visit must be re-scheduled 
X 
 
 
 
 
 
 
 
 
X 
Record any changes in usual PD medication dose/regimen 
X 
 
 
 
 
 
 
 
 
Record time of patient’s prior usual PD medication dose 
X 
 
 
 
 
 
 
 
 
Record any changes in concomitant medications 
X 
 
 
 
 
 
 
 
 
PDQ-39 (preferably in ON state) 
X3 
 
 
 
 
 
 
 
 
PGI-C (preferably in ON state) 
X3 
 
 
 
 
 
 
 
 
UPDRS Part 2 (preferably in ON state) 
X3 
 
 
 
 
 
 
 
 
S&E ADL (preferably in ON state) 
X3 
 
 
 
 
 
 
 
 
UPDRS Part 4 (Questions 32-35 and 36-39) 
X 
 
 
 
 
 
 
 
 
C-SSRS  
X 
 
 
 
 
 
 
 
 
Epworth Sleepiness Scale  
X 
 
 
 
 
 
 
 
 
QUIP  
X 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and 
HR) 
X4 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
Spirometry (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (including serum pregnancy test, if 
applicable) 
X5 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
Review inhaler training 
X 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing Log and review 
instructions for completion 
X6 
 
 
 
 
 
 
 
 


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Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV4 
Post-TV4 
Telephone 
Contact 
UPDRS Part 3 
 
X7 
 
X 
X 
X 
X 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 
 
 
 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
 
 
 
 
 
 
X 
 
Schedule DLco visit at pulmonary site (14±3 days before next 
visit) 
 
 
 
 
 
 
 
X 
 
Post-TV4 telephone contact: call patient 2 weeks (± 3 days)  
before TV5 
 
 
 
 
 
 
 
 
X 
1Dosing of study medication occurs at least 1 hour after patient has taken normal morning dose of PD medication and after all pre-dose assessments are complete. 
2DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
3Preferably in the ON state; but these must be performed before any other study evaluation. 
4Assessment can be done at any point after arrival but must be completed before dosing. 
5Document whether patient is fasting (≥4 hours after last snack or meal). 
6The PD Diary is to be completed for the 3 consecutive days prior to TV/OV5; the Inhaled Dosing Log is to be completed daily through TV/OV6. 
7Confirm patient is in the OFF state prior to pre-dose UPDRS Part 3 assessment. 
 
 


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APPENDIX 11:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 4 (OV4) (6 MONTHS [24±2 
WEEKS] AFTER OV1) 
Procedures 
Assess in Either ON or 
OFF State Unless 
Otherwise Noted 
End of OV4 
Post- OV4 
Telephone 
Contact 
Confirm DLco assessment1 has been performed prior to visit; and if not complete, 
re-schedule study visit 
X 
 
 
X 
Record any changes in usual PD medication dose/regimen 
X 
 
 
Record any changes in concomitant medications 
X 
 
 
PDQ-39 (preferably in ON state) 
X (ON)2 
 
 
UPDRS Part 2 (preferably in ON state) 
X (ON)2 
 
 
S&E ADL (preferably in ON state) 
X (ON)2 
 
 
C-SSRS  
X 
 
 
Epworth Sleepiness Scale  
X 
 
 
QUIP  
X 
 
 
Physical examination (brief) 
X 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and HR) 
X 
 
 
Electrocardiogram 
X 
 
 
Spirometry (preferably in ON state) 
X (ON) 
 
 
Clinical laboratory tests (including serum pregnancy test, if applicable) 
X3 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
X 
 
 Schedule DLco visit at pulmonary site (14±3 days before next visit)  
 
X 
 
Post- OV4 telephone contact:  call patient 2 weeks (± 3 days)  before OV5 
 
 
X 
1 DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
2Preferably in the ON state; but these must be performed before any other study evaluation. 
3Document whether patient is fasting (≥4 hours after last snack or meal).  
 


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APPENDIX 12:  TIME AND EVENTS TABLE—TREATMENT VISIT 5 (TV5) (9 MONTHS [36±2 
WEEKS] AFTER TV1) 
Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV5 
Post-TV5 
Telephone 
Contact 
Collect, review, sign, and date PD Diary and Inhaled Dosing 
Log 
X 
 
 
 
 
 
 
 
 
Collect empty capsules, inhalers, and unused supplies 
X 
 
 
 
 
 
 
 
 
Confirm DLco assessment2 has been completed prior to visit; if 
not done, the study visit must be re-scheduled 
X 
 
 
 
 
 
 
 
 
X 
Record any changes in usual PD medication dose/regimen 
X 
 
 
 
 
 
 
 
 
Record time of patient’s prior usual PD medication dose 
X 
 
 
 
 
 
 
 
 
Record any changes in concomitant medications 
X 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and 
HR) 
X3 
 
 
 
 
 
 
 
Spirometry (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (serum pregnancy test, if applicable) 
X4 
 
 
 
 
 
 
 
 
C-SSRS  
X 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
Review inhaler training 
X 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing Log and review 
instructions for completion 
X5 
 
 
 
 
 
 
 
 
UPDRS Part 3 
 
X6 
 
X 
X 
X 
X 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 
 
 
 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
 
 
 
 
 
 
X 
 
Schedule DLco visit at pulmonary site (14±3 days before next 
visit)  
 
 
 
 
 
 
 
X 
 
Post-TV5 telephone contact:  call patient 2 weeks (± 3 days)  
before TV6 
 
 
 
 
 
 
 
 
X 


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1Dosing of study medication occurs at least 1 hour after patient has taken normal morning dose of PD medication and after all pre-dose assessments are complete. 
2DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
3Assessment can be done at any point after arrival, but must be completed before dosing. 
4Document whether patient is fasting (≥4 hours after last snack or meal). 
5The PD Diary is to be completed for the 3 consecutive days prior to TV6; the Inhaled Dosing Log is to be completed daily through TV6. 
6Confirm patient is in the OFF state prior to pre-dose UPDRS Part 3 assessment. 
 
 


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APPENDIX 13:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 5 (OV5) (9 MONTHS [36±2 
WEEKS] AFTER OV1) 
Procedures 
Assess in Either ON or 
OFF State Unless 
Otherwise Noted 
End of OV5 
Post- OV5 
Telephone 
Contact 
Confirm DLco assessment1 has been performed prior to visit; and if not complete, 
re-schedule study visit 
X 
 
 
X 
Record any changes in usual PD medication dose/regimen 
X 
 
 
Record any changes in concomitant medications 
X 
 
 
Physical examination (brief) 
X 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and HR) 
X 
 
 
Spirometry (preferably in ON state) 
X (ON) 
 
 
Clinical laboratory tests (serum pregnancy test, if applicable) 
X2 
 
 
C-SSRS  
X 
 
 
Monitor for AEs 
X 
Schedule next visit 
 
X 
 
Schedule DLco visit at pulmonary site (14±3 days before next visit) 
 
X 
 
Post- OV5 telephone contact:  call patient 2 weeks (± 3 days)  before OV6 
 
 
X 
1DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
2Document whether patient is fasting (≥4 hours after last snack or meal). 
 
 


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APPENDIX 14:  TIME AND EVENTS TABLE—TREATMENT VISIT 6 (TV6) (12 MONTHS [52±2 
WEEKS] AFTER TV1)/EARLY WITHDRAWAL VISIT 
Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV6 
Post-TV6 
Assessment
s 
Collect, review, sign, and date PD Diary and Inhaled Dosing 
Log 
X 
 
 
 
 
 
 
 
 
Collect empty capsules, inhalers, and unused supplies 
X 
 
 
 
 
 
 
 
 
Confirm DLco assessment2 has been completed prior to visit; if 
not done, the study visit must be re-scheduled3 
X 
 
 
 
 
 
 
 
 
Record any changes in usual PD medication dose/regimen 
X 
 
 
 
 
 
 
 
 
Record time of patient’s prior usual PD medication dose 
X 
 
 
 
 
 
 
 
 
Record any changes in concomitant medications 
X 
 
 
 
 
 
 
 
 
PDQ-39 (preferably in ON state) 
X4 
 
 
 
 
 
 
 
 
PGI-C (preferably in ON state) 
X4 
 
 
 
 
 
 
 
 
UPDRS Part 2 (preferably in ON state) 
X4 
 
 
 
 
 
 
 
 
S&E ADL (preferably in ON state) 
X4 
 
 
 
 
 
 
 
 
UPDRS Part 4 (Questions 32-35 and 36-39) 
X 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR and RR and orthostatic BP and 
HR) 
X5 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
C-SSRS  
X 
 
 
 
 
 
 
 
 
Epworth Sleepiness Scale  
X 
 
 
 
 
 
 
 
 
QUIP  
X 
 
 
 
 
 
 
 
 
Spirometry (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (including serum pregnancy test, if 
applicable) 
X6 
 
 
 
 
 
 
 
 
Provide new inhaler for treatment 
 
X 
 
 
 
 
 
 
 
UPDRS Part 3 
 
X7 
 
X 
X 
X 
X 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 


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Procedures 
Arrival 
Pre-
dose 
Time 0 
(Dosing)1 
10 min 
Post-
dose 
20 min 
Post-
dose 
30 min 
Post-
dose 
60 min 
Post-
dose 
End of 
TV6 
Post-TV6 
Assessment
s 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
 
 
Schedule DLco visit2 to occur at pulmonary site in 4-5 weeks 
 
 
 
 
 
 
 
X 
 
Post-TV6 DLco assessment2 at 4-5 weeks after TV6 or Early 
Withdrawal Visit3 
 
 
 
 
 
 
 
 
X 
1Dosing of study medication occurs at least 1 hour after patient has taken normal morning dose of PD medication and after all pre-dose assessments are complete. 
2DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
3Patients who withdraw early will undergo all of the TV6 assessments except the pre-TV6 DLco assessment.  Patients will be scheduled to undergo the post-TV6 DLco assessment 
4-5 weeks after completion of the Early Withdrawal Visit. 
4Preferably in the ON state, but these must be performed before any other study evaluation. 
5Assessment can be done at any point after arrival but must be completed before dosing. 
6Document whether patient is fasting (≥4 hours after last snack or meal). 
7Confirm patient is in the OFF state prior to pre-dose UPDRS Part 3 assessment. 
 
 


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APPENDIX 15:  TIME AND EVENTS TABLE—OBSERVATIONAL VISIT 6 (OV6) VISIT (12 MONTHS 
[52±2 WEEKS] AFTER OV1)/EARLY WITHDRAWAL VISIT 
Procedures 
Assess in Either ON or 
OFF State Unless 
Otherwise Noted 
End of OV6 
Post- OV6 
Assessments 
Confirm DLco assessment1  has been performed prior to visit; and if not complete, 
re-schedule study visit2 
X 
 
 
Record any changes in usual PD medication dose/regimen 
X 
 
 
Record any changes in concomitant medications 
X 
 
 
PDQ-39 (preferably in ON state) 
X (ON)3 
 
 
UPDRS Part 2 (preferably in ON state) 
X (ON)3 
 
 
S&E ADL (preferably in ON state) 
X (ON)3 
 
 
Physical examination (brief) 
X 
 
 
Vital signs (standard BP, HR, and RR and orthostatic BP and HR) 
X 
 
 
Electrocardiogram 
X 
 
 
Spirometry (preferably in ON state) 
X (ON) 
 
 
C-SSRS  
X 
 
 
Epworth Sleepiness Scale  
X 
 
 
QUIP  
X 
 
 
Clinical laboratory tests (including serum pregnancy test, if applicable) 
X3 
 
 
Monitor for AEs 
X 
 
 
Schedule DLco visit1 to occur at pulmonary site in 4-5 weeks 
 
X 
 
Post- OV6 DLco assessment1 at 4-5 weeks after OV6 or Early Withdrawal Visit2 
 
 
X 
 
1DLco is to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. Preferably in the ON state. 
2 Patients who withdraw early will undergo all of the OV6 assessments except the pre- OV6 DLco assessment.  Patients will be scheduled to undergo the post- OV6 DLco assessment 4-5 
weeks after completion of the Early Withdrawal Visit. 
3Preferably in the ON state, but these must be performed before any other study evaluation. 
4Document whether patient is fasting (≥4 hours after last snack or meal). 
 
 


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APPENDIX 16:  IN-CLINIC ASSESSMENT OF ON/OFF STATES AND 
DYSKINESIA 
An “OFF state” is defined as the time when medication has worn off and is no longer providing 
benefit with respect to mobility, slowness, and stiffness.  OFF episodes may be heralded by non-
motor symptoms (e.g., pain, anxiety) prior to the appearance of motor symptoms.   
An “ON state” is defined as the time when medication is providing benefit with respect to 
mobility, slowness, and stiffness, and may or may not be providing complete alleviation of all 
PD symptoms. 
For recording motor state in the PD Diary, when patients are in an ON state, the presence and 
extent of dyskinesia (involuntary twisting, turning movements that are an effect of medication) 
will also be noted: 
• ON with no dyskinesia 
• ON with non-troublesome dyskinesia (ON with dyskinesia that does not interfere 
with function or cause meaningful discomfort) 
• ON with troublesome dyskinesia (ON with dyskinesia that interferes with function or 
causes meaningful discomfort) 
These ON and OFF definitions are to be used in training the patients to recognize and record 
their ON and OFF states.  Patients will record their ON and OFF states in their diaries at home.   
In the clinic, the examiner will note the occurrence of dyskinesia during the 60-minute post-dose 
period and the maximum severity (mild, moderate, or severe) of any dyskinesia during the 
60-minute post-dose period.  The examiner will also note if the patient converts to the ON state 
during the 60-minute post-dose period and if so, whether the patient is still in the ON state at 
60 minutes post-dose. 
 


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APPENDIX 17:  LABORATORY PARAMETERS 
Hematology 
Platelet Count  
RBC Indices: 
Automated WBC Differential: 
RBC Count 
MCV 
Neutrophils 
WBC Count (absolute)  
MCH 
Lymphocytes 
Reticulocyte Count 
MCHC 
Monocytes 
Hemoglobin 
 
Eosinophils 
Hematocrit 
 
Basophils 
 
Clinical Chemistry 
Urea 
Potassium 
AST (SGOT) 
Total and direct bilirubin 
Creatinine 
Chloride 
ALT (SGPT) 
Uric Acid 
Glucose 
Total CO2 
GGT 
Albumin 
Sodium 
Calcium 
Alkaline phosphatase 
Total Protein 
 
Other screening tests 
Pregnancy test (serum) at screening (SV1 or SV2) and at TV/OV1, TV/OV3, TV/OV4, TV/OV5, and 
TV/OV6, if applicable; magnesium; C-Reactive Protein 
 
 


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APPENDIX 18:  UK PARKINSON’S DISEASE SOCIETY BRAIN BANK  
CLINICAL DIAGNOSTIC CRITERIA* 
Step 1. Diagnosis of Parkinsonian syndrome 
• Bradykinesia 
• At least one of the following 
o Muscular rigidity 
o 4-6 Hz rest tremor 
o Postural instability not caused by primary visual, vestibular, cerebellar, or 
proprioceptive dysfunction 
Step 2. Exclusion criteria for Parkinson’s disease 
• History of repeated strokes with stepwise progression of parkinsonian features 
• History of repeated head injury 
• History of definite encephalitis 
• Oculogyric crises 
• Neuroleptic treatment at onset of symptoms 
• More than one affected relative 
• Sustained remission 
• Strictly unilateral features after 3 years 
• Supranuclear gaze palsy 
• Cerebellar signs 
• Early severe autonomic involvement 
• Early severe dementia with disturbances of memory, language, and praxis 
• Babinski sign 
• Presence of cerebral tumor or communication hydrocephalus on imaging study 
• Negative response to large doses of levodopa in absence of malabsorption 
• MPTP exposure 
Step 3. Supportive prospective positive criteria for Parkinson’s disease 
Three or more required for diagnosis of definite Parkinson’s disease in combination with 
: 
• Unilateral onset 
• Rest tremor present 
• Progressive disorder 
Step 1


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• Persistent asymmetry affecting side of onset most 
• Excellent response (70-100%) to levodopa 
• Severe levodopa-induced chorea 
• Levodopa response for 5 years or more 
• Clinical course of ten years or more 
*From: Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. 
A clinico-pathological study of 100 cases. JNNP 1992;55:181-184. 
 
 


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APPENDIX 19:  MODIFIED HOEHN AND YAHR PD SEVERITY SCALE 
ASSESSMENT 
The modified Hoehn and Yahr PD severity assessment uses the following scale: 
• Stage 0 = No signs of disease. 
• Stage 1 = Unilateral disease. 
• Stage 1.5 = Unilateral plus axial involvement. 
• Stage 2 = Bilateral disease, without impairment of balance. 
• Stage 2.5 = Mild bilateral disease, with recovery on pull test. 
• Stage 3 = Mild to moderate bilateral disease; some postural instability; physically 
independent. 
• Stage 4 = Severe disability; still able to walk or stand unassisted. 
• Stage 5 = Wheelchair-bound or bedridden unless aided. 
 
 


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APPENDIX 20:  CONTRAINDICATIONS TO PERFORMING ROUTINE 
SPIROMETRY 
• Recent myocardial infarction or unstable angina within 1 month 
• Hemoptysis 
• Pneumothorax, current or within prior 3 months 
• Pulmonary embolus within prior 3 months 
• Thoracic, abdominal, or cerebral aneurysms 
• Recent eye surgery within prior 3 months 
• Presence of an acute disease process that might interfere with test performance 
• Recent surgery of thorax or abdomen 
• Any history of syncope associated with forced exhalation 
 
 


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APPENDIX 21:  CVT-301 SYSTEM ADDITIONAL INFORMATION 
All instructions for how to properly use the CVT-301 system are outlined in the Instructions for 
Use document that is included with every CVT-301 study kit.  The following additional 
observations by patients when using the system have been noted by some investigational sites: 
• Patients may experience black sputum. No clinical correlate to this finding occurred 
(small number of patients) 
• Patients may see powder emitted from the inhaler while completing an inhalation. 
• Patients may see powder emitted from their mouths when exhaling after use of the 
system. 
• Patients may note some built-up powder falling off of the inhaler following multiple 
uses. Although cleaning is not necessary, system cleaning instructions are noted 
under the “More Information” section of the Instructions for Use. 
• Patients may attempt to push the capsule through the foil instead of peeling the blister 
open which can damage the capsule and impair drug delivery.  Make sure patients are 
informed not to push the capsule through the foil. 
• Patients may not hear the “whirl” of the capsule upon inhalation.   As noted in the 
Instructions for Use, if this occurs patients should repeat the inhalation steps to ensure 
that the drug is delivered.  If whirling sound is still not heard, patients should: 
o Check that a capsule is inserted 
o Make sure mouthpiece is firmly attached 
o Inhale deeper or longer 

SAP_001.pdf: 
CVT-301 (Levodopa Inhalation Powder) 
 
Civitas Therapeutics, Inc 
Clinical Study Report: CVT-301-005 
Date of Final Interim Report: 05 Jun 2017 
Page 1 of 335 
16.1.9  
Documentation of Statistical Methods 
16.1.9.1 Statistical Analysis Plans 
Statistical Analysis Plan version 1.0 dated 22 December 2015 
Statistical Analysis Plan version 2.0 dated 13 January 2017 
16.1.9.2 Method for Analysis of Abuse Related Adverse Events 
Abuse Assessment Section Terms 


Document 
Type: 
Template 
Document ID: 
 
Issue Date:          02 APR 2012 
Effective Date:  30 APR 2012       
 
 
Sponsor Name: 
Civitas Therapeutics, Inc. 
Protocol Number and Title: 
 
CVT-301-005 
A Phase 3, Randomized Study Investigating the 
Safety of CVT-301 (Levodopa Inhalation 
Powder) in Parkinson’s Disease Patients With 
Motor Response Fluctuations (OFF Phenomena) 
Compared to an Observational Cohort Control 
(SUPPORT-PD™) 
  
Protocol Version and Date: 
Version 3.0, 19-Aug-2015 
INC Research Project Code: 
 
Author(s): 
  
 
  
  
   
SAP Version: 
  Final Version 1.0 
SAP Version Date:  
22-Dec-2015 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Civitas Therapeutics, 
Inc. Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Civitas Therapeutics, Inc. However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, INC Research should be notified 
promptly. 
 
 
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• :nc 
Research' 
Acorda Therapeutics, Inc. 
CVT-301 ·005 
... 
Final Version 1.0 
Statistical Analysis Plan 
Version: 
Final Version 1.0 
Version Date: 
22-Dec-2015 
I confirm t hat I have reviewed this document and agree with the content. 
APPROVALS 
( 
 
 
 
 
 
 
 
 
 
 
 
 
  
Senior Revie
Date (dd·Mmm·yyyy) 
.:ri 
t:- ; 
, 
'* 
. '. 
. 
' 
·.' ' .! 
 
 
 
 
 
  
 
 of Civitas Therapeutics, Inc. 
Date (dd·Mmm·myl 
This document ts proprietary and confidential to INC Research LLC. 
03.007A.OO 
INC Research 0 LLC 
Page 2 of 66 


TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ....................................................................... 6 
2. 
PURPOSE ......................................................................................................... 9 
2.1. 
Responsibilities ..................................................................................................................... 9 
2.2. 
Timings of Analyses .............................................................................................................. 9 
3. 
STUDY OBJECTIVES AND STUDY DESIGN ...................................................... 10 
3.1. 
Primary Objective .............................................................................................................. 10 
3.2. 
Secondary Objectives ......................................................................................................... 10 
3.3. 
Exploratory Efficacy Objectives ........................................................................................ 10 
3.4. 
Patient Selection ................................................................................................................ 11 
3.4.1. 
Inclusion Criteria ......................................................................................................... 12 
3.4.2. 
Exclusion Criteria ........................................................................................................ 13 
3.5. 
Determination of Sample Size ........................................................................................... 14 
3.6. 
Treatment Assignment & Blinding ..................................................................................... 15 
3.7. 
Administration of Study Medication .................................................................................. 15 
3.8. 
Study Procedures and Flowchart ...................................................................................... 16 
4. 
ENDPOINTS .................................................................................................... 19 
4.1. 
Primary Endpoint ................................................................................................................ 19 
4.2. 
Secondary Endpoints .......................................................................................................... 19 
4.3. 
Exploratory EffiCacy Endpoints ......................................................................................... 20 
5. 
ANALYSIS SETS .............................................................................................. 24 
5.1. 
All Available Population (AAP) .......................................................................................... 24 
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5.2. 
Safety population ............................................................................................................... 24 
5.3. 
Intent-to-Treat population (ITT) ....................................................................................... 24 
5.4. 
Protocol Deviations ............................................................................................................ 24 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ......................................... 26 
6.1. 
General Methods ................................................................................................................. 26 
6.2. 
Key Definitions.................................................................................................................... 27 
6.3. 
Missing Data......................................................................................................................... 29 
6.4. 
Visit Windows ...................................................................................................................... 30 
6.5. 
Pooling of sites .................................................................................................................... 31 
6.6. 
Subgroups ............................................................................................................................ 31 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION .... 32 
7.1. 
Patient Disposition and Withdrawals ................................................................................ 32 
7.2. 
Demographic and Other Baseline Characteristics ........................................................... 32 
7.3. 
Medical History ................................................................................................................... 34 
7.4. 
Medication ........................................................................................................................... 34 
8. 
SAFETY .......................................................................................................... 36 
8.1. 
Spirometry .......................................................................................................................... 36 
8.2. 
Extent of Exposure ............................................................................................................. 38 
8.3. 
Treatment Compliance ...................................................................................................... 39 
8.4. 
Adverse Events ................................................................................................................... 39 
8.5. 
Laboratory Evaluations ...................................................................................................... 41 
8.6. 
Vital Signs ............................................................................................................................ 42 
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8.7. 
Electrocardiogram .............................................................................................................. 43 
8.8. 
Physical Examination ......................................................................................................... 44 
8.9. 
Columbia-Suicidality Severity Rating Scale ...................................................................... 44 
8.10. 
Epworth Sleepiness Scale ................................................................................................... 45 
8.11. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease ................... 45 
8.12. 
UPDRS part 4 ....................................................................................................................... 46 
8.13. 
examiner-rated dyskinesia ................................................................................................ 46 
9. 
EXPLORATORY EFFICACY ............................................................................. 47 
9.1. 
Exploratory Efficacy Endpoint and Analysis ..................................................................... 47 
10. 
INTERIM ANALYSES .................................................................................... 50 
11. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL .................................. 51 
12. 
PROGRAMMING CONSIDERATIONS ............................................................. 52 
12.1. 
General Considerations ...................................................................................................... 52 
12.2. 
Table, Listing, and Figure Format .................................................................................... 52 
12.2.1. 
General ........................................................................................................................ 52 
12.2.2. 
Headers ....................................................................................................................... 52 
12.2.3. 
Display Titles ............................................................................................................... 53 
12.2.4. 
Column Headers .......................................................................................................... 53 
12.2.5. 
Body of the Data Display ............................................................................................. 53 
12.2.6. 
Footnotes .................................................................................................................... 54 
13. 
QUALITY CONTROL.................................................................................... 56 
14. 
INDEX OF TABLES ...................................................................................... 57 
15. 
INDEX OF LISTINGS .................................................................................... 64 
16. 
INDEX OF FIGURES ..................................................................................... 66 
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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AAP 
All Available Population 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical  
ATS 
American Thoracic Society  
BMI 
Body Mass Index 
BMS 
Biomedical Systems  
BP 
Blood Pressure 
CI 
confidence interval  
CMH 
Cochran-Mantel-Haenszel 
COPD 
Chronic Obstructive Pulmonary Disease 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicidality Severity Rating Scale 
DBP 
diastolic  blood pressure 
DDI 
Dopamine Decarboxylase Inhibitor 
DL 
Dose Level 
DLco 
Carbon Monoxide Diffusion Capacity 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ERS 
European Respiratory Society 
ET 
Early Termination 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
Hb 
hemoglobin 
HR 
Heart Rate 
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Abbreviation 
Description 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat  
IWRS 
Interactive Web Response System 
LD 
Levodopa 
LS 
least square 
MAR 
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMSE 
Mini Mental State Examination  
MMRM 
Mixed Model for Repeated Measures 
PCS 
potentially clinically significant values  
PCSC 
potentially clinically significant changes 
PD 
Parkinson’s Disease  
PDQ-39 
39-Item Parkinson’s Disease Questionnaire  
PGI-C 
Patient Global Impression of Change 
PMM 
Pattern Mixture Models 
PRN 
As needed 
PT 
Preferred Term  
QUIP 
Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
RR 
Respiratory Rate 
S&E 
Schwab and England 
SAP 
Statistical Analysis Plan 
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Abbreviation 
Description 
SBP 
systolic blood pressure 
SD 
Standard Deviation  
SEM 
Standard Error of the Mean 
SI 
International System of Units  
SOC 
System Organ Class  
SV 
Screening Visit 
TEAE 
Treatment-Emergent Adverse Event 
TLF 
tables, listings, figure 
TV 
Treatment Visit 
UPDRS 
Unified Parkinson’s Disease Rating Scale  
WHO-DD 
World Health Organization Drug Dictionary  
 
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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives. 
This SAP describes the statistical analysis as it is foreseen at the time of planning the 
study.  The SAP will serve as a compliment to the study protocol and supersedes it in 
case of differences.  In case of major differences between the study protocol and SAP 
(e.g. changes in the analysis related to the primary endpoint) protocol amendment will 
be considered.  The SAP may be updated during the conduct of the study and will be 
finalized before database lock. However, because this is an open-label study, the 
analyses defined after the first patient has been randomized to the study will be 
considered as exploratory. 
2.1. 
RESPONSIBILITIES 
INC Research will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings. Acorda (or it’s designee) will 
review and approve all statistical work done by INC Research as agreed between INC 
Research and Acorda. 
2.2. 
TIMINGS OF ANALYSES 
The primary analysis of safety and efficacy is planned after all patients complete the 
final study visit or terminate early from the study, and database is cleaned and locked. 
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3. 
STUDY OBJECTIVES AND STUDY DESIGN 
3.1. 
PRIMARY OBJECTIVE 
To characterize the pulmonary safety, as assessed by spirometry (forced expiratory 
volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/ FVC ratio), over a 
12-month period within the CVT-301-treated patients. 
3.2. 
SECONDARY OBJECTIVES 
• 
To characterize the pulmonary safety, as assessed by spirometry (FEV1, FVC and 
FEV1/FVC ratio), over a 12-month period in the observational (‘standard of care’) 
cohort. 
 
• 
To estimate the difference between the CVT-301-treated patients and the 
observational cohort on measures of pulmonary safety. 
 
• 
To characterize the effects of CVT-301 on safety over a 12-month period:  safety 
will be assessed by adverse event (AE) reports, physical examination, standard and 
orthostatic vital signs (blood pressure [BP], heart rate [HR], and respiratory rate 
[RR]), clinical laboratory tests, 12-lead electrocardiograms (ECGs), the Parkinson’s 
Disease Impulsive-Compulsive Disorders Questionnaire (QUIP), the Epworth 
Sleepiness Scale, and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
 
• 
To evaluate the effect of CVT-301 on mean change from baseline in the UPDRS 
Part 4 measures of motor fluctuations (dyskinesias [Q32-35] and wearing off 
[Q36-39]) measured at baseline and at 6 and 12 months after the initiation of CVT-
301 treatment. 
 
• 
To characterize the occurrence and severity of examiner-rated dyskinesia following 
treatment of patients experiencing an OFF episode in the clinic over a 12-month 
period. 
 
• 
To describe the effects of CVT-301 on Carbon Monoxide Diffusion Capacity (DLco) 
over a 12-month period. 
 
3.3. 
EXPLORATORY EFFICACY OBJECTIVES 
The following exploratory objectives related to the efficacy endpoints will primarily be 
assessed for the CVT-301-treated patients.    The same objectives will be explored for 
the pool of CVT-301-naïve patients and patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies, if feasible. 
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• 
Change from pre-dose in UPDRS Part 3 motor score at 10, 20, 30, and 60 minutes 
following treatment of patients experiencing an OFF episode. 
• 
Time curves of the UPDRS response at 10, 20, 30 and 60 minutes will be evaluated 
descriptively 
• 
Change from pre-dose in the average UPDRS Part 3 motor score at 10 to 60 minutes 
following treatment of patients experiencing an OFF episode. 
• 
Proportion of patients with a ≥ 3, ≥ 6, and ≥ 11 point reduction in the UPDRS Part 3 
motor score from pre-dose to post-dose, at 10, 20, 30, and 60 minutes. 
• 
Proportion of patients achieving resolution of an OFF to an ON state within 60 
minutes after study drug is administered in the clinic, maintaining the ON state at 
60 minutes after study drug administration (per the examiner’s subjective 
assessment). 
• 
Total daily OFF time, total daily ON time without dyskinesia, total daily ON time 
with non-troublesome dyskinesia, and total daily ON time with troublesome 
dyskinesia, assessed by the patient and recorded in the patient diary. 
• 
Change from baseline in 39-Item Parkinson’s Disease Questionnaire (PDQ-39). 
• 
Proportion of patients who improved based on the Patient Global Impression of 
Change (PGI-C) rating scale. 
• 
Change from baseline in Schwab and England (S&E) Activities of Daily Living (ADL). 
• 
Change from baseline in UPDRS Part 2 score. 
3.4. 
PATIENT SELECTION 
The study population for this study is PD patients experiencing motor fluctuations (OFF 
episodes) that meet the following inclusion criteria and do not meet any of the 
following exclusion criteria. 
Patients may have been previously enrolled in the CVT-301-002 or CVT-301-003 studies, 
or may be CVT-301-naïve i.e. no previous exposure to CVT-301.  Patients previously 
enrolled in the CVT-301-002 and CVT-301-003 studies must have completed all of the 
CVT-301 study visits without any safety issues that would preclude participation in this 
study according to the investigator.  Patients who withdrew from either of the CVT-301 
studies prior to completion, for any reason, will not be eligible. 
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3.4.1. 
Inclusion Criteria 
In order to be eligible to enter the study, patients must meet all of the following 
criteria:  
 
• 
Has signed and dated an IRB/IEC-approved informed consent form before any 
protocol-specific screening procedures are performed. 
 
• 
Is a male or female aged 30 to 85 years, inclusive.  Women of child-bearing 
potential must use protocol-defined contraceptive measures (see 
) 
and must have a negative serum human chorionic gonadotropin (hCG) test at 
screening.  These patients must be willing to remain on their current form of 
contraception for the duration of the study. 
 
• 
Patients who have idiopathic PD (i.e., not induced by drugs or other diseases) as 
defined by fulfilling Steps 1 and 2 of the UK Brain Bank criteria, diagnosed after 
the age of 30 years. 
 
• 
Patients who are classified as Stage 1 to 3 (in the ON state) on the modified 
Hoehn and Yahr scale for staging of PD severity. 
 
• 
Patients who have experienced motor fluctuations for a minimum of 2 hours of 
average daily OFF time per waking day (excluding early morning OFF time) by 
self-report and confirmed by the PD Diary (on 3 consecutive days) during the 
screening period. 
 
• 
Patients who are on a LD-containing therapy, not including Rytary (or 
equivalent), must be stable on oral LD-containing therapy for at least 2 weeks 
prior to SV1 with a LD/dopamine decarboxylase inhibitor (DDI)-containing 
regimen.  
 
• 
Patients who are on a LD containing therapy, when including Rytary (or 
equivalent), should be on a stable dose for at least 6 weeks prior to SV1 
 
• 
The frequency of L-dopa administrations must be at least 3 times during the 
waking day and a total daily LD dose of ≤1600 mg (exclusive of PRN LD-
containing medications).   
 
• 
Patients should be stable on other PD medications for at least 4 weeks prior to 
SV1.   
 
Section 11.1.5
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• 
Patients must have a ≥ 25% difference between UPDRS Part 3 scores recorded in 
their ON and OFF states at screening. 
 
• 
Patients must have normal cognition as confirmed by a score of ≥ 25 on the 
MMSE. 
 
• 
Patients must be able to perform a spirometry maneuver in the ON and OFF 
states, and must have a screening FEV1 ≥ 50% of predicted and an FEV1/FVC 
ratio >60% in the ON state at screening.  (A pulmonologist will review the 
spirometry tracings/morphology of any patient with an FEV1 that is ≥ 50% to 
<60% of predicted or an FEV1/FVC ratio that is >60% to <70% in order to 
determine potential eligibility.  All CVT-301-naïve patients with an FEV1/FVC 
ratio of >60% to <70% will be required to undergo a bronchodilator challenge and 
the results must be reviewed prior to entry into the study.  Patients with an 
FEV1/FVC ratio that is >60% to <70% will complete spirometry before and after 
the administration of a bronchodilator in a pulmonary function 
laboratory.  Testing will be performed in accordance with the 2005 
ATS/European Respiratory Society [ERS] criteria prior to randomization.  The 
results of the bronchodilator challenge will be reviewed by a pulmonologist prior 
to potential randomization.) 
 
3.4.2. 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria at screening will not be enrolled 
in the study:  
 
• 
Patients who have dyskinesia of a severity that would significantly interfere with 
their ability to participate or perform study procedures. 
 
• 
Pregnant or lactating females or females wishing to become pregnant. 
 
• 
Patients who have any known contraindication to the use of LD, including a 
history of malignant melanoma or a history of narrow-angle glaucoma.   
 
• 
Patients who have had previous surgery for PD (including but not limited to deep 
brain stimulation [DBS] or cell transplantation). 
 
• 
Patients with a history of psychotic symptoms requiring treatment, or suicide 
ideation or attempt within the prior 12 months (stable regimens [for at least 4 
weeks prior to SV1] of anti-depressant and certain low-dose atypical 
antipsychotic medications are permitted, in case they are indicated to treat 
symptoms other than psychotic symptoms). 
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• 
Patients who have cancer with the exception of the following:  basal cell 
carcinoma or successfully treated squamous cell carcinoma of the skin; cervical 
carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively 
treated and with no evidence of disease recurrence for at least 3 years. 
 
• 
Patients taking certain prohibited medications (see 
). 
 
• 
Patients with a history of drug or alcohol abuse within the prior 12 months. 
 
• 
Patients with chronic obstructive pulmonary disease (COPD), asthma, or other 
chronic respiratory disease within the last 5 years. 
 
• 
Patients with any contraindication to performing routine spirometry or who are 
unable to perform a spirometry maneuver (see 
 for a list of 
contraindications).  
 
• 
Patients with a current history of symptomatic orthostatic hypotension despite 
adequate treatment.   
 
• 
Patients with any condition that in the investigator’s opinion would make 
patients unsuitable or interfere with their participation in the study.  Potential 
issues of concern should be raised to the medical monitor during eligibility 
review. 
 
• 
Patients who have any clinically significant abnormality or finding from 
examination, tests, or history that may compromise patient safety. 
 
• 
Patients who have been treated with an investigational drug within 4 weeks or 5 
half-lives (whichever is longer) prior to the beginning of the screening 
period  (this includes investigational formulations of marketed products). 
 
• 
Prior exposure to CVT-301. 
 
3.5. 
DETERMINATION OF SAMPLE SIZE 
Approximately 250 CVT-301 treatment patients and 115 control patients will be enrolled 
in this study.  It is assumed that the drop-out rate will be approximately 25%. 
 
The primary objective of this study will be to characterize the pulmonary safety within 
the CVT-301-treated patients and the differences between the groups will be estimated 
as a secondary objective.  However, for the secondary comparison of FEV1 change 
Appendix 20
Section 9.4.2
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between the CVT-301 treatment group and the randomized observational cohort, the 
standard deviation of FEV1 change from baseline is expected to be 0.281 L, 
 
.  Assuming that there is no difference in the changes from 
baseline between the CVT-301-treated patients and the observational cohort, the study 
has the following power for the comparison between the 2 groups.  The upper limit of 
the 95% confidence interval for the difference between the 2 groups in change from 
baseline in FEV1 will be less than 0.121 L with 90% power, assuming 188 and 86 patients 
completing the study in the CVT-301 treatment group and observational cohort, 
respectively.  The sample size calculation was performed using nQuery Advisor, Version 
7.0. 
 
3.6. 
TREATMENT ASSIGNMENT & BLINDING 
This study is a 12-month, open-label, randomized, multicenter study which will evaluate 
the safety and effects of CVT-301 for the treatment of up to 5 OFF episodes per day in 
PD patients experiencing motor fluctuations (OFF episodes) and will include a 
concurrent observational cohort of PD patients managed using the usual standards of 
care.  Patients may have been previously enrolled in the CVT-301-002 or CVT-301-003 
studies, or may be CVT-301-naïve.  Patients who were previously enrolled in the CVT-
301-002 and CVT-301-003 studies will be assigned to the CVT-301 treatment group (CVT-
301 at a target nominal respirable dose of 50 mg LD fine particle dose [FPD]), in this 
study.  Patients who are CVT-301-naïve will be randomized in a 2:1 ratio to the CVT-301 
treatment group (CVT-301 at a target nominal respirable dose of 50 mg LD FPD) or the 
observational cohort.  Randomization will be stratified by the patient’s Hoehn and Yahr 
stage (<2.5 versus ≥2.5) to balance the severity of disease across each group and by 
screening spirometry (FEV1 <60% of predicted or FEV1/FVC ratio <70% versus FEV1 ≥60% 
of predicted and FEV1/FVC ratio ≥70%). 
 
Following completion of SV2 and prior to randomization, the patients’ eligibility criteria 
will be reviewed by delegated staff. Upon confirmation of eligibility, the site will 
randomize an eligible patient using the Interactive Web Response System (IWRS).  The 
study is an open-label study, so patients and clinical staff will not be blinded to study 
group assignment. 
 
3.7. 
ADMINISTRATION OF STUDY MEDICATION 
Prior to the self-administration of inhaled study treatment, study staff will ensure that 
patients are adequately trained on the use of the inhaler according to the Instructions 
for Use (IFU).  The IFU will be provided to each patient and will be part of the 
permanent study record. 
 
Since this is an open-label study, the patient, investigator, and study site personnel, the 
Sponsor, representatives of the Contract Research Organization (CRO) involved in 
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monitoring, data management, or other aspects of the study, and Core Laboratories will 
be not blinded to the inhaled study treatment. 
 
During inhaler training, patients will be instructed to use the inhalation system in 
accordance with the IFU which includes a breath hold of 5 seconds following each 
capsule inhalation.  For the purposes of timing study assessments in the clinic, “Time 0” 
(T0) is defined as the time of completion of inhalation of the last capsule of inhaled 
study treatment administered (i.e., beginning of the final breath hold).  In the event 
that a capsule needs to be reinhaled, T0 is at the end of the reinhalation 
administration. 
 
During the treatment period, patients will self-administer inhaled study treatment 
(CVT-301 DL1, CVT-301 DL2) up to 5 times daily to treat OFF episodes during their 
waking day. 
 
3.8. 
STUDY PROCEDURES AND FLOWCHART 
This study has 3 periods: screening period, treatment period, and follow-up period; and 
a total of 9 planned visits: 2 screening visits, 6 treatment visits, and 1 follow-up visit.  
For each patient, the planned treatment period will be approximately 52 weeks, and 
maximum anticipated study duration, including screening and follow-up, will be 
approximately 62 weeks. 
The screening period, which takes place within 35 days prior to Day 1 of the treatment 
period, will have 2 separate visits:  SV1 and SV2 must be separated by at least 4 days.  
The screening period may be extended an additional 7 days if repeat screening 
assessments are required. 
Before patients return to the clinic for TV/OV1, they will be randomized to treatment.  
The treatment period includes 6 separate in-clinic visits over approximately 52 weeks.  
The first dose of study drug will be given in the clinic at TV/OV1.  The subsequent visits 
during the treatment period take place as follows: 
• 
TV/OV2: Week 4; 28±5 days after TV/OV1. 
• 
TV/OV3: Week 12; 84±14 days after TV/OV1. 
• 
TV/OV4: Week 24; 168±14 days after TV/OV1. 
• 
TV/OV5: Week 36; 252±14 days after TV/OV1. 
• 
TV/OV6: Week 52; 364±14 days after TV/OV1. 
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Patients who terminate the study early will complete TV/OV6 and return for the Follow-
up DLco visit 4-5 weeks after TV/OV6. 
Refer to 
 to 
 for tables of study assessments at each visit. 
15
Protocol Appendices 1
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In Clinic Assessments  
SV1 
SV2 
TV/OV1  
TV/OV2 
TV/OV3 
TV/OV4 
TV/OV5 
TV/OV6 
ON 
OFF 
ON 
OFF 
ON* 
ON 
ON 
ON 
ON 
ON 
MMSE 
x 
  
  
  
  
  
  
  
  
  
UPDRS Part 1 
  
  
  
  
  
  
  
  
  
  
UPDRS Part 2 
  
  
  
  
x 
  
  
x 
  
x 
UPDRS Part 3 
x 
x 
  
  
  
x** 
x** 
x** 
x** 
x** 
UPDRS Part 4 
  
  
  
  
x 
  
  
x*** 
  
x*** 
C-SSRS 
  
  
  
  
x 
x 
x 
x 
x 
x 
Epworth Sleep Scale 
  
  
  
  
x 
  
  
x 
  
x 
QUIP 
  
  
  
  
x 
  
  
x 
  
x 
PDQ-39 
  
  
  
  
x 
  
  
x 
  
x 
PGI-C 
  
  
  
  
  
  
  
x*** 
  
x*** 
S&E ADL 
  
  
  
  
x 
  
  
x 
  
x 
At home for patients 
PD Diary (only treatment after screening) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ON/OFF logs (both groups) 
x 
x 
  
  
  
  
  
  
  
  
Inhaled dosing (CVT-301 only) 
  
  
  
  
x 
x 
x 
x 
x 
x 
 
 
*      For the CVT 301 arm these assessments are performed pre-dose 
**    Performed pre-dose, 10, 20, 30, and 60 min post dose (only performed in CVT 301 arm) 
***  CVT 301 arm only 
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4. 
ENDPOINTS 
4.1. 
PRIMARY ENDPOINT 
The primary endpoints related to the primary objective of the study are the pulmonary 
safety measures, FEV1, FVC and FEV1/ FVC ratio, assessed over a 12 month period. 
FEV1, FVC and FEV1/FVC ratio will be recorded from the single “best test” (based on 
effort with highest summed FEV1 and FVC).  Variables will include the absolute FEV1, 
FVC, and FEV1/FVC ratio and FEV1 and FVC expressed as % of predicted value. Changes 
from baseline (TV/OV1) for each variable will be calculated at each subsequent visit.  
Percent Predicted = 100 * (Observed) / Predicted, where predicted is calculated and 
provided to INC by Biomedical Systems (BMS). 
4.2. 
SECONDARY ENDPOINTS 
The following endpoints related to the secondary objectives will be calculated. 
 
• 
Standard safety endpoints; for definitions see Section 8 of this SAP  
o Adverse Event (AE) reports 
o Physical examination 
o Standard and orthostatic vital signs (BP, HR and RR) 
o Clinical laboratory tests (hematology, clinical chemistry, and additional 
laboratory parameters) 
o 12-lead ECGs (HR, PR, QRS, QT, QT interval corrected using Bazett’s formula 
[QTcB] and QT interval corrected using Fridericia’s formula [QTcF]) 
o Parkinson’s Disease Impulsive-Compulsive Disorders Questionnaire (QUIP)  
o Epworth Sleepiness Scale 
o Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
• 
Change from TV/OV1 (baseline) in the UPDRS Part 4 sum scores of dyskinesias 
(UPDRS items 32-35) and wearing-off (UPDRS items 36-39).  The dyskinesia score will 
be calculated as the sum of the individual items 32-35 and the wearing-off score as 
sum of 36-39.  Missing individual items will not be imputed and the sum score will be 
missing in case of 1 or more missing items. 
 
• 
Occurrence and severity of examiner-rated dyskinesia following treatment of 
patients experiencing an OFF episode in the clinic.  The occurrence will be based on 
the examiner’s subjective assessment and no further derivation will be performed.  
Among the patients with reported dyskinesia, the severity will be classified as mild, 
moderate, severe or missing based on the examiner’s subjective assessment and no 
further derivation will be performed.  Only observed cases will be used for this 
endpoint and the visits with missing data will not be included in the analysis. 
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• 
Carbon Monoxide Diffusion Capacity (DLco) assessed over a 12 month period within 
the CVT 301 treated and the observational (‘standard of care’) cohorts. Variables 
will include the absolute DLco values and DLco expressed as % of predicted value. 
 
4.3. 
EXPLORATORY EFFICACY ENDPOINTS  
The following endpoints related to the exploratory efficacy objectives will be 
calculated. 
• 
Change from pre-dose in UPDRS Part 3 motor score at 10, 20, 30, and 60 minutes 
following treatment of patients experiencing an OFF episode.  
 
o The UPDRS Part 3 total score will be calculated as the sum of the individual 
items of the UPDRS Part 3 questionnaire (UPDRS items 18-31) separately at 
each time point, i.e. the scores will range from 0 to 108.  Missing individual 
items will be imputed using the 2 non-missing values at time points adjacent 
to the missing item on the same date.  The maximum of the 2 adjacent 
values will be assigned as the score for the missing item.  However, pre-dose 
values will not be assigned as post-dose values and if one of the adjacent 
values for a post-dose value is a pre-dose value, only 1 adjacent value will be 
used.  The total score for UPDRS Part 3 assessments will be calculated after 
imputation of the missing item(s).  Missing items at screening will not be 
imputed.  If a pre-dose value is missing, the pre-dose value at the prior visit 
will be used.  A missing TV/OV1 pre-dose value will be imputed using the last 
screening value in OFF state. 
 
• 
Time curve of the UPDRS response shown as change from pre-dose in UPDRS Part 3 
motor score to 10, 20, 30 and 60 minutes following treatment of patients 
experiencing an OFF episode in the clinic. The UPDRS Part 3 scores will be derived 
as described above.   
 
• 
Change from pre-dose in the average UPDRS Part 3 score at 10 to 60 minutes 
following treatment of patients experiencing an OFF episode in the clinic. The 
change from pre-dose to the average of the 4 UPDRS Part 3 total scores (assessments 
scheduled at 10, 20, 30 and 60 minutes) will be used as the response variable in the 
statistical analysis.   
 
• 
A ≥3, ≥6, and ≥11 point reduction in the UPDRS Part 3 motor score from pre-dose to 
post-dose, at 10 to 60 minutes following treatment in the clinic (cumulative and 
non-cumulative).  The non-missing UPDRS Part 3 motor scores at each time point 
(10, 20, 30 and 60 minutes post-dose) are classified as a reduction of ≥3 points or 
not, reduction of ≥6 points or not and reduction of ≥11 points or not.  Furthermore, 
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for the purpose of the cumulative analysis, the time point (10, 20, 30 and 60 
minutes post-dose) when the reduction of ≥3, ≥6 or ≥11 points occurs for the first 
time will be defined.  The categorical scheduled time point is used in this analysis.  
The missing assessment regarding single items will be managed similarly as describe 
above. The missing values regarding visits will be managed by considering the 
missing visits as non-responses. 
 
• 
Proportion of patients achieving resolution of an OFF to an ON state within 60 
minutes after study drug is administered in the clinic and maintaining the ON at 60 
minutes after study drug administration (per the examiner’s subjective assessment).  
This endpoint will be based on the examiner’s subjective assessment. In case the 
assessment of turning on within 60 minutes is missing but the assessment of 
maintaining the ON at 60 minutes has been done, the patient will be classified based 
on the available assessment. In case the assessment of maintenance of ON at 60 
minutes is missing, the patient will be classified as having missing data. 
 
• 
Change from baseline (3 consecutive days prior to TV/OV1, or in case of missing 
data, the last 3 recorded days before TV/OV1) in patient-recorded total daily OFF 
time, assessed by the patient and recorded in the PD Diary for 3 consecutive days 
prior to in-clinic visits (or in case of missing data, the last 3 recorded days before 
the visit).  The validity of the PD diary entries will be checked prior to including a 
diary day in the summary calculations. Only valid diary days will be included in the 
diary summarizations. Change from baseline in total daily ON time without 
dyskinesia, total daily ON time with non-troublesome dyskinesia, and total daily ON 
time with troublesome dyskinesia will be calculated similarly. 
 
o A day will be considered as being valid if at least 80% of the entries during 
the day have been completed per instructions.  That is, for each half hour 
period, only one entry among the responses (Asleep, OFF, ON without 
dyskinesia, ON with non-troublesome dyskinesia, or ON with troublesome 
dyskinesia) has been checked.  The entry will not be used if no responses are 
checked or more than one response is checked.  However, if the proportion 
of entries rejected due to multiple checked responses is large, sensitivity 
analysis will be performed by using the worst case out of the entries that had 
been checked.  The worst case will be defined in the following order: OFF, 
ON with troublesome dyskinesia, ON with non-troublesome dyskinesia, ON 
without dyskinesia, Asleep.  In case there are duplicate entries (i.e., 
multiple entries recorded with same date and time interval), the worst entry 
will be used for the date and time interval in question.  The worst entry will 
be selected in the order defined above. 
 
o All diary data will be normalized to 16 awake hours per day.  The daily OFF 
time will be extrapolated to a 16 hour period by determining the percentage 
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of OFF time among accurately recorded entries, excluding Asleep time and 
missing/non-valid recordings, and by multiplying this percentage by 16 hours.  
 
 
Off Time / (Total time recorded – Asleep Time – missing time interval) 
x 16 
 
o The mean daily OFF time prior to each visit will be calculated as mean value 
of the valid days documented in the patient’s diary prior to that visit.  In 
case there are gaps within the 3 days preceding the visit, the last 3 recorded 
days before the visit will be used regardless of the gaps.  If there are more 
than 3 valid days, only the last 3 days will be used.  If there are only 1 or 2 
valid days, the average of these days will be used. 
• 
Change from TV/OV1 (baseline) in PDQ-39 sub-scores (mobility score, activities of 
daily living, bodily discomfort score, emotional wellbeing score, social support 
score, communication score, cognitive impairment score, and stigma score) and 
summary index score. The questionnaire provides scores on eight dimensions as 
outlined below: 
 
o mobility (10 items, #1 to 10)  
o activities of daily living (6 items, #11 to 16)  
o emotional well-being (6 items, #17 to 22)  
o stigma (4 items, #23 to 26)  
o social support (3 items, #27 to 29)  
o cognitions (4 items, #30 to 33)  
o communication (3 items, #34 to 36)  
o bodily discomfort (3 items, #37 to 39) 
 
Items are scored from 0 (never) to 4 (always).  Dimension scores are obtained by 
dividing the sum of the item scores by the maximum possible score for any given 
dimension and expressing this as a percentage.  For example: 
 
o mobility = (sum of scores of #1 to 10)/(4 x 10) x 100 
o activities of daily living = (sum of scores of #11 to 16)/(4 x 6) x 100 
 
For social support, if the response indicates that a patient does not have a spouse or 
partner for #28, social support can be calculated as [(sum of scores of #27 and 
29)/(4 x 2) x 100]. 
 
A summary index is then calculated as the sum of the total score of the dimensions 
divided by the number of dimensions, i.e. (sum of dimension scores / 8).  If any item 
score is missing, the relevant dimension score and the summary index will be 
missing. 
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• 
The PGI-C score.  The non-missing values will be categorized as improvements (much 
improved, improved, a little improved) or non-improvements (no change, a little 
worse, worse, much worse). 
• 
Change from TV/OV1 (baseline) Schwab and England (S&E) Activities of Daily Living 
(ADL). No further derivation will be done for the S&E scores. 
• 
Change from TV/OV1 (baseline) in the UPDRS Part 2 score.  The UPDRS Part 2 score 
will be calculated as the sum of the individual items of the UPDRS Part 2 
questionnaire (UPDRS items 5-17).  Missing individual items will not be imputed and 
the sum score will be missing in case of 1 or more missing items.  
 
 
 
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5. 
ANALYSIS SETS 
5.1. 
ALL AVAILABLE POPULATION (AAP) 
The AAP will include all patients who have consented for the study, including screening 
failures.  Unless specified otherwise, the AAP will be used for patient listings and for 
the summary of patient disposition. 
 
5.2. 
SAFETY POPULATION  
The Safety Population will include all randomized patients who received at least 1 dose 
of inhaled CVT-301 and patients from the Observational Cohort.  Patients will be 
analyzed according to study treatment that they received.  The Safety Population will 
be used for all analyses of safety endpoints and summaries of patient demographics and 
baseline characteristics.  
 
5.3. 
INTENT-TO-TREAT POPULATION (ITT) 
The ITT population will include all patients from the safety population. Patients will be 
analyzed according to randomized treatment. The ITT Population will be used for all 
analyses of exploratory efficacy endpoints.   
 
5.4. 
PROTOCOL DEVIATIONS 
A protocol deviation is any significant finding indicating that the study investigator or 
patient failed to adhere to the protocol requirements (e.g., drug noncompliance, failure 
to return for defined number of visits or within an acceptable visit window for 
completion of study assessments). The deviation may necessitate premature 
termination of the patient from the visit assessments, or from the study. 
 
The deviations will be classified during a review process with the Sponsor and other 
study personnel (as appropriate) before database lock. The deviations will be classified 
as minor or major with/without impact on pulmonary assessments during the review 
process.  All decisions regarding major deviations will also be discussed between the 
Sponsor, other study personnel (as appropriate), and the study statistician prior to 
commencing the final analysis on the locked database. The following deviations will be 
identified, but do not necessarily represent a complete list of potential deviations: 
• 
Administration of PD medications after the usual morning dose of PD medication 
and before study drug administration 
• 
Incorrect study drug administered at a visit 
• 
Drug non-compliance including but not limited to unapproved dose modification 
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• 
Failure to return for defined study visits or within an acceptable visit window for 
completion of study assessments 
The number of subjects with minor, major with/without impact on pulmonary 
assessments protocol deviations will be summarized by treatment groups and overall. 
All protocol deviations will be listed. 
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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
All patient data will be included in listings.  All patients entered into the database will 
be included in patient data listings.  The listings will be generally sorted by Patient ID 
(and by visit and by time point, if applicable), unless specified otherwise.  
 
All applicable data will be summarized by treatment group (Observational Cohort or 
CVT-301) and overall in tables, unless specified otherwise. The CVT-301 group will be 
broken down into CVT-301-naïve patients and patients who were previously enrolled in 
the CVT-301-002 or CVT-301-003 studies.  Where appropriate, data will be summarized 
by visit and/or time point in addition to treatment group.  Unscheduled or repeat 
assessments will not be included in summary tables, but will be included in listings. 
 
For the Observational Cohort, the “start of treatment” will be defined as attendance of 
TV/OV1, unless specified otherwise. Baseline will be defined as the assessments 
performed at TV/OV1. In case of missing data, the last non-missing screening 
assessment will be used as the baseline value. 
 
Continuous variables will be summarized using the number of observations (n), mean, 
SD, median, minimum, and maximum.  Standard error of the mean (SEM) will also be 
provided for summaries of UPDRS and other exploratory efficacy endpoints, if relevant.  
The same number of decimal places as in the raw data will be presented when reporting 
minimum and maximum, 1 more decimal place than in the raw data will be presented 
when reporting mean and median, and 2 more decimal places than in the raw data will 
be presented when reporting SD and SEM.  
 
Descriptive statistics for categorical/qualitative data will include frequency counts and 
percents.  The total number of patients in the treatment group overall (N) will be used 
as the denominator for percent calculations, unless stated otherwise in the table shell.  
All percents will be presented with one decimal point, unless specified otherwise.  
Percents equal to 100 will be presented as 100% and percents will not be presented for 
zero frequencies.  
Significance testing will be 2-tailed using α = 0.05, unless otherwise specified.  All 
analyses and summaries will be produced using SAS® version 9.3 (or higher). 
Deviations from the statistical plan will be reported in the clinical study report, 
including the rationale for use. 
 
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6.2. 
KEY DEFINITIONS 
Age 
 
Age, as an integer, will be calculated using the date of birth and the date of informed 
consent. 
 
Age = int ((date of informed consent- date of birth)/365.25) 
 
Body Mass Index (BMI) 
 
BMI will be calculated as follows and rounded to 1 decimal place: 
 
BMI (kg/m2) = weight (kg) / [height (m)]2 
 
Parkinson’s Disease History 
 
The following parameters will be calculated for the PD history: 
 
Time since diagnosis of PD (months) =  
Date of Screening Visit 1 (M/Y) - Date of diagnosis (M/Y) 
 
Duration of levodopa treatment (months) =  
Date of Screening Visit 1 (M/Y) - Start date of levodopa treatment (M/Y) 
 
Time since onset of wearing off episodes (months) =  
Date of Screening Visit 1 (M/Y) - Date of onset of wearing off episodes (M/Y) 
 
If the month is missing, the first month of the year will be used. 
 
Change from pre-dose to post-dose   
 
The change from pre-dose to post-dose within each visit will be calculated for each 
post-dose assessment as: 
 
Change from Pre-dose to Post-dose = Post-dose value – Pre-dose value 
 
Percent change from pre-dose to post-dose  
 
The percent change from pre-dose to post-dose within each visit will be calculated for 
each post-dose assessment as: 
 
Percent Change from Pre-dose to Post-dose =  
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(Post-dose value – Pre-dose value)*100/Pre-dose value 
 
Baseline 
 
For CVT-301 patients, baseline is defined as the last non-missing assessment before the 
first dose of study drug, unless specified otherwise. For the Observational Cohort, 
baseline is defined as TV/OV1, or, in the case of missing data, the last non-missing 
assessment before TV/OV1, unless specified otherwise. However, for all patients who 
were included in the CVT 301-002 or CVT-301-003 studies, TV/OV1 of the CVT-301-005 
study will be used as baseline. 
 
Change from baseline  
 
The change from baseline will be calculated for each post-baseline assessment as: 
 
Change from Baseline = Post-baseline value – Baseline value 
 
Percent change from baseline  
 
The percent change from baseline will be calculated for specified post-baseline 
assessments as: 
 
Percent Change from Baseline = 
(Post-baseline value – Baseline value)*100/Baseline value 
 
DLCO predicted and DLCO predicted, adjusted for hemoglobin (Hb) 
 
DLCO predicted  
DLCO predicted will be calculated by Miller equation. (Miller A, Thornton JC, Warshaw R, 
Anderson H, Teirstein AS, Selikoff IJ. Single breath diffusing capacity in a representative of 
Michigan, a large industrial state. Am Rev Resp Dis 1983; 127: 270-277). 
• 
Men  predicted DLCO = 12.9113 - (0.229 x age) + (0.418 x height in)  
• 
Women predicted DLCO = 2.2382 - (0.1111 x age) + (0.4068 x height in)  
Where age is the age at the time of assessment taken, height is measured in inches. 
 
DLCO Predicted, adjusted for Hb  
DLCO predicted adjusted for Hb is calculated using the Cotes method, according to the 
2005 ATS/ERS guidelines for DLco. 
 
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• 
DLCO predicted, adjusted for Hb in adult men:  
DLCO predicted for Hb = DLCO predicted 1.7* Hb / (10.22 + Hb) 
 
• 
DLCO predicted, adjusted for Hb in adult women: 
DLCO predicted for Hb = DLCO predicted 1.7 *Hb / (9.38 + Hb) 
Where DLCOpredicted is the DLCO calculated from Miller equation; Hb = hemoglobin, 
measured in g/dL. The Hb closest to the date/time of DLCO taken will be used.  
Percent predicted of FEV1 and FVC 
The percent predicted of FEV1 and FVC will be calculated using the following equation. 
Percent Predicted = 100 * (Observed) / Predicted 
where observed value is the value provided by TechEd, and the predicted value is the 
predicted value that provided by BMS and is the values closest to the date of observed 
value taken. The details are listed in table below. 
DLCOpredicted, percent predicted of 
FEV1 and FVC  
Value selection for Hb, predicted FEV1 and FVC 
Screening  (prior to randomization) 
From TV/OV1 or the value closest to the date of DLCO 
assessment if the value at TV/OV1 is missing 
TV/OV3, within 2 weeks  prior to 3 
From TV/OV3 or the value closest to the date of DLCO 
assessment if the value at TV/OV3 is missing 
TV/OV4, within 2 weeks  prior to 6 
From TV/OV4 or the value closest to the date of DLCO 
assessment if the value at TV/OV4 is missing 
TV/OV5, within 2 weeks  prior to 9 
From TV/OV5 or the value closest to the date of DLCO 
assessment if the value at TV/OV5 is missing 
TV/OV6, within 2 weeks  prior to 12 
From TV/OV6 or the value closest to the date of DLCO 
assessment if the value at TV/OV6 is missing 
4 to 5 weeks after TV/OV6 
The latest non-missing Hb that closest to the date of 
DLCO assessment taken. 
6.3. 
MISSING DATA 
Several different methods to handle the missing data will be used. 
 
• 
For calculation of the UPDRS part 3 scores, the missing single UPDRS items will be 
imputed as described in Section 4.3. 
 
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• 
For the primary analysis of spirometry and selected explorative efficacy endpoints, 
likelihood-based modeling approach will be used to handle incomplete data.  For 
this purpose, Mixed Model for Repeated Measures (MMRM) will be applied, see 
Section 8.1. 
 
• 
Sensitivity analysis for spirometry and selected explorative efficacy endpoints will 
be conducted using the Multiple Imputation (MI) approach, i.e. by replacing each 
missing value with a set of plausible values that represent the uncertainty about the 
right value to impute, see Section 8.1. 
 
• 
For the binary explorative efficacy endpoints, sensitivity analyses will be conducted 
using worst case imputation, where visits with missing data are counted as non-
resolved (primary method), see 
.  
 
• 
For AEs, the overall incidence of TEAEs, normalized for duration of exposure will be 
calculated to account for the shorter follow-up time in patients who discontinue the 
study prematurely, see Section 8.4. 
 
The Safety and ITT populations will be used for the analysis of the primary, secondary 
and exploratory endpoints. The patients with no post-baseline data will not contribute 
to the analyses performed with the MMRM approach, but they do contribute to the 
sensitivity analyses using the MI approach.  Due to this, no additional population, like a 
modified ITT population including only the patients with post-baseline will be defined.  
 
6.4. 
VISIT WINDOWS 
The visits recorded in database will be used for all analyses.  There is no plan to  
re-assign visits based on actual visit dates. 
 
For the patients who discontinue the study prematurely, a set of assessments is 
scheduled to be performed at the Early Termination (ET) visit (PDQ-39, UPDRS Part 2, 
UPDRS Part 4, S&E ADL score and safety assessments). CVT 301 treated patients will also 
perform the UPDRS Part 3 assessments at 10, 20, 30, and 60 minutes post dose as well 
as the PGI-C. The following rules will be used to analyze the data collected at the ET 
visit: 
 
• 
For the PDQ-39, PGI-C, UPDRS Part 2, UPDRS Part 3, UPDRS Part 4 and S&E ADL 
score, the data from the ET visit will be re-assigned to TV/OV6 in case there is no 
TV/OV6 assessment. 
 
• 
In case there are PD diary assessments performed during the three days before the 
ET visit, these assessments will be re-assigned to the first visit at which the PD diary 
assessments were scheduled but are missing due to the premature withdrawal. 
Section 9.1
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• 
The safety assessment assessments performed at the ET visit will be re-assigned to 
the first time point at which the corresponding safety assessments were scheduled 
but are missing due to the premature withdrawal. 
 
• 
Any other data collected at the ET visit will not be used. 
 
6.5. 
POOLING OF SITES 
Not applicable. 
 
6.6. 
SUBGROUPS 
At least the following subgroup analyses have been pre-planned.  The subgroup analyses 
will be performed for selected efficacy endpoints (at least the Change from pre-dose in 
UPDRS Part 3 motor score at 30 minutes post-dose and the mean daily OFF time).  
Selected baseline data will be presented for the subgroups as well. 
• 
Patients with baseline PD severity < 2.5 points on the Hoehn & Yahr scale versus 
patients with baseline PD severity ≥ 2.5 points on the Hoehn & Yahr scale 
• 
Patients who are dyskinetic before TV/OV1 versus non-dyskinetic patients. The 
classification will be done based on the Parkinson’s disease diary data. The 
patients who have recorded at least 1 hour of dyskinesia (either ON with non-
troublesome dyskinesia or ON with troublesome dyskinesia) on at least 2 days 
before TV/OV1 will be classified as dyskinetic 
• 
Patient with the baseline daily levodopa dose less than or equal to the median 
versus the patients with the baseline daily levodopa dose higher than the median 
• 
Patients who have less than 4.5 hours of PD diary mean daily OFF time before 
TV/OV1 versus patients who have 4.5 hours or more of OFF time 
• 
Patients with FEV1 <60% of predicted or FEV1/FVC ratio <70% at baseline versus 
patients with FEV1 ≥60% of predicted and FEV1/FVC ratio ≥70% 
• 
Non-elderly (<65 years) versus elderly (≥65 years) patients 
• 
Female versus male patients. 
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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
PATIENT DISPOSITION AND WITHDRAWALS 
The patient disposition table will summarize the following and will be presented for 
each treatment group, as applicable, and overall.  The percentages will be calculated 
based on the number of randomized patients, unless otherwise specified). The 
randomized set will include all randomized patients as well as those from CVT-301-002 
and CVT-301-003 studies who were assigned to the CVT 301 treatment group. 
 
• 
The number of patients screened (i.e. the number of patients in the AAP 
population) 
• 
The number of patients who failed screening 
• 
The number (%) of patients randomized into the study (% calculated from the 
AAP population) 
• 
The number (%) of patients in the different study populations (Safety and ITT 
populations) 
• 
The number (%) of patients who completed the study (based on end-of-study 
case record page) 
• 
The number (%) of patients who withdrew from the study and associated reasons 
(% calculated from the Safety population) 
 
 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized descriptively for the 
Safety population by treatment group and overall. The following variables will be 
summarized: 
 
• 
Demographics (age (continuous), age categorized as <65 years versus ≥65 years, 
gender, ethnicity, race, height, weight, BMI, country)  
• 
Smoking history (current, former, never, Number of Years Smoked and Number 
of Cigarettes/Day) 
• 
Cognitive status (MMSE)  
• 
Average number of daily OFF episodes experienced from the Screening ON/OFF 
Log. The screening ON/OFF log data collected on 3 days prior to TV/OV1 will be 
used as baseline. If the data are only available on 1 or 2 days prior to TV/OV1, 
the available data will be used as baseline. If there is no data prior to TV/OV1, 
the data collected on 3 days prior to SV2 will be used as baseline.  
 
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• 
Proportion of patients who changed the timing of their usual levodopa 
medication and proportion of patients who took an extra dose of levodopa or 
other PD medication from the Screening ON/OFF Log. The screening ON/OFF log 
data collected on 3 days prior to TV/OV1 will be used as baseline. If the data are 
only available on 1 or 2 days prior to TV/OV1, the available data will be used as 
baseline. If there is no data prior to TV/OV1, the data collected on 3 days prior 
to SV2 will be used as baseline. 
• 
Average daily OFF time, ON time Without Dyskinesia, ON time with troublesome 
and non-troublesome dyskinesia (from PD diary before TV/OV1) 
• 
Proportion of patients with total daily OFF time <4.5 hours or ≥4.5 hours (from 
PD diary before TV/OV1) 
• 
Distribution of average daily OFF time in 30-minute intervals (00:00 – 00:30, 
00:30 – 01:00, …). The percentage based on the total daily OFF time will also be 
presented and is calculated as the average of total OFF time collected three 
days prior to TV1 and is normalized to 16 awake hours per day. 
• 
PD history (time since diagnosis of PD, duration of levodopa treatment, time 
since onset of wearing off episodes) 
• 
Total daily levodopa dose, number of levodopa doses per day 
• 
PD disease severity (Modified Hoehn and Yahr Staging in “ON” State) 
• 
UPDRS Part 3 Motor score in ON/OFF (from screening assessment); the change 
from OFF to ON state in UPDRS part 3 Motor score at the Screening will also be 
classified as ≥6 points, or ≥11 points reduction.  
• 
Baseline Dyskinesia (Dyskinetic before TV/OV1, Non-dyskinetic before TV/OV1). 
The classification will be done based on the Parkinson’s disease diary data. The 
patients who have recorded at least 1 hour of dyskinesia (either ON with non-
troublesome dyskinesia or ON with troublesome dyskinesia) on at least 2 days 
before TV will be classified as dyskinetic. 
• 
Proportion of patients with FEV1 <60% of predicted or FEV1/FVC ratio <70% at 
baseline versus FEV1 ≥60% of predicted and FEV1/FVC ratio ≥70% (based on the 
randomization strata). 
• 
Screening  spirometry data: FEV1, FVC, and FEV1/FVC ratio, presented for each 
motor status, ON or OFF, separately. 
 
Demographics and PD disease data will also be summarized by subgroups (Patients with 
baseline PD severity < 2.5 points on the Hoehn & Yahr scale versus ≥ 2.5 points; Patients 
who are dyskinetic before TV/OV1 versus non-dyskinetic; Patient with the baseline  less 
than or equal to the median versus above median; Patients who have less than 4.5 hours 
of PD diary mean daily OFF time before TV/OV1 versus 4.5 hours or more; Patients with 
FEV1 <60% of predicted or FEV1/FVC ratio <70% at baseline versus FEV1 ≥60% of 
predicted and FEV1/FVC ratio ≥70%, Non-elderly (<65 years) versus elderly (≥65 years) 
patients, Female versus Male patients). 
 
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7.3. 
MEDICAL HISTORY  
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 17.0. The medical history data will be summarized with frequencies 
and percentages of patients with at least one medical history item, and patient 
frequencies and percentages on the system organ class (SOC) and preferred term (PT) 
levels. The events will also be summarized. The table, using the Safety population, will 
be sorted by overall descending frequency of SOC and then, within a SOC, by overall 
descending frequency of PT. 
7.4. 
MEDICATION 
All medications will be classified using the Anatomical Therapeutic Chemical (ATC) 
classification codes and preferred drug names from the World Health Organization Drug 
Dictionary (WHO-DD), Q1March2014.  
 
For the medications recorded on CRF page “Prior and Concomitant Medications”, 
medications with a stop date before the first date of study drug dosing or TV/OV1 for 
the observational cohort will be considered prior medications. Medications with start 
date or stop date on or after the first date of study drug dosing will be considered 
concomitant medications. 
 
Tables will be generated for the Safety Population. Summaries of baseline PD treatment 
medications (medications which start with ATC code N04) will be presented in tabular 
form using the ATC Level 4 and preferred term. Other prior medications and 
concomitant medications will be presented in tabular form using the ATC Level 1, ATC 
Level 2, and PT. Frequencies and percentages will be presented by treatment group and 
overall. The counts of medications will also be summarized. The tables will be sorted by 
overall descending frequency of ATC Level(s) and then, within an ATC Level, by overall 
descending frequency of PT. 
If the medication start date is incomplete, then it will be imputed as follows for the 
purpose of determining concomitance only:  
• 
If the start date is completely missing, the start date will be equal to the first 
dose date. However, if the stop date is not missing and is before the first dose 
date, then the stop date will be used instead.  
• 
If the start day is missing, the first day of the month will be used.  
• 
If the start day and month are missing, then the first day of the first month 
(January) will be used. 
 
If the medication stop date is partial, then it will be imputed as follows for the purpose 
of determining concomitance only:  
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• 
If the stop date is completely missing and the medication is not ongoing, the 
stop date will be equal to the last dose date or date of completion/withdrawal, 
whichever is the latest.  
• 
If the stop day is missing, the last day of the month will be used.  
• 
If the stop day and month are missing, then the last day of the last month 
(December) will be used. 
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8. 
SAFETY 
The population used for safety analyses will be the Safety Population.  The analyses are 
outlined below. 
8.1. 
SPIROMETRY 
Spirometry will be performed by trained and qualified staff at each study site.  
Spirometry data obtained in the study site will reviewed by a central spirometry 
laboratory (Biomedical Systems, Inc.) which will provide a quality over read of all 
evaluations based on acceptability and repeatability metrics in accordance with ATS 
criteria.  FEV1, FVC and FEV1/FVC ratio will be recorded from the single “best test” 
(based on effort with highest summed FEV1 and FVC).  Variables will include the 
absolute FEV1, FVC, and FEV1/FVC ratio and FEV1 and FVC expressed as % of predicted 
value. 
 
FEV1, FVC, FEV1/FVC ratio and DLco will be summarized descriptively by treatment 
group and overall. For screening data, the summary will be presented for each motor 
status, ON or OFF, separately. For other visits, data in ON or OFF state will be combined 
for summary. The following will be summarized: 
 
• 
Change from baseline to other visits Arrival values for each parameter. The 
baseline is defined as the TV/OV1 Arrival value. If the TV/OV1 Arrival value is 
missing, the last available value in ON state before the first dose of study drug 
will be used. 
• 
Number and percentage of patients with FEV1/FVC < 60% and <70% by Visit  
• 
Spirometry data will also be provided to indicate whether specific 
determinations met American Thoracic Society (ATS) quality criteria. The 
proportion of spirometry data measurements meeting or not meeting ATS quality 
criteria will be summarized by treatment group and overall. The summary will 
also be performed for ON state measurements, OFF state measurements, and all 
measurements, separately. The reasons for not meeting ATS quality criteria will 
be classified as not meeting the criteria for acceptability, not meeting the 
criteria for repeatability or as other/unknown and summarized. 
 
The spirometry analyses will be repeated for the subset of assessments meeting the ATS 
quality criteria. 
 
Another subset analysis will be performed by excluding the spirometry data from 
patients with a very high intra-individual variability. For the purpose of this analysis, all 
patients who have a co-efficient of variation (CV) value >7.5% for FEV1 will be excluded. 
The CV will be calculated for each patient as standard deviation divided by the mean. 
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The screening visit FEV1 data (assessed in ON state) and arrival values at subsequent 
visits will be used for the calculation. 
 
In addition to the descriptive statistics, the changes in the spirometry values within 
each treatment group and differences between the treatment groups will be estimated 
with MMRM. The model will include the treatment group (CVT-301 or observational 
cohort), visit (visits at 1, 3, 6, 9, and 12 months), the stratification variables (Hoehn 
and Yahr stage and screening FEV1 and/or FEV1/FVC) and the interaction between the 
treatment group and visit as fixed factors. The baseline spirometry value will be 
included as a covariate. An unstructured covariance structure will be applied for MMRM.  
In case the model will not converge with the unstructured covariance structure, the 
heterogeneous compound symmetry (CSH) or the heterogeneous Toeplitz structure 
(TOEPH) will be used instead.  If the unstructured covariance structure will be used, the 
denominator degrees of freedom will be computed using the Kenward-Roger method. In 
case of other covariance structures, the BETWITHIN option will be used for the 
denominator degrees of freedom. The least square (LS) mean, standard error, and LS 
mean difference between CVT-301 and observational cohort at each visit; along with 
the 95% confidence interval (CI) will be provided in a table. Treatment difference will 
be assessed with a 2-sided alpha level of 0.05, unless specified otherwise.  
 
The SAS code planned for the analysis is outlined below. 
 
proc mixed data=&data; 
class pdsevbl fev1bl trta avisit usubjid; 
model chg=base pdsevbl fev1bl trta avisit trta*avisit / ddfm=kr; 
repeated avisit / subject=usubjid(trtp) type=un; 
lsmeans trtp*avisit / cl; 
estimate 'CVT vs OBS Month 1'  
        trta 1 -1 trta*avisit 1 0 0 0 0 -1 0 0 0 0 / cl; 
estimate 'CVT vs OBS Month 3'  
        trta 1 -1 trta*avisit 0 1 0 0 0 0 -1 0 0 0 / cl; 
estimate 'CVT vs OBS Month 6'  
        trta 1 -1 trta*avisit 0 0 1 0 0 0 0 -1 0 0 / cl; 
estimate 'CVT vs OBS Month 9'  
        trta 1 -1 trta*avisit 0 0 0 1 0 0 0 0 -1 0 / cl; 
estimate 'CVT vs OBS Month 12'  
        trta 1 -1 trta*avisit 0 0 0 0 1 0 0 0 0 -1 / cl; 
run; 
 
The Safety population will be used for the primary analysis. 
 
Sensitivity analyses of the spirometry data 
 
The following sensitivity analysis will be performed for the primary endpoint. 
 
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• 
MI analysis:  MI techniques based on Pattern Mixture Models (PMM) will be applied 
(Ratitch et al., 2011) as a further sensitivity analysis in the Safety population.  This 
methodology will structure data based on missing data patterns.  The method will 
be based on a missingness pattern having a monotone structure, i.e. if among the 
observations over time one data value is missing, all other values after this missing 
value will also be treated as missing.  For patients with intermittent missing values, 
before performing MI based on the PMM, it will be necessary to create a monotone 
missingness pattern.  Intermittent missing values will be imputed using the Markov 
Chain Monte Carlo (MCMC) methodology which assumes a multivariate normal 
distribution over all variables included in the imputation model.  The MI procedure 
in SAS will be used for this purpose and this first MI step is planned to be repeated 
100 times, creating several different datasets with a monotone missing data 
structure.  Seed value of 201508 will be used in the MI procedure.  The imputation is 
based on the missing at random (MAR) assumption, i.e. the missing data are assumed 
to follow the same model as the other patients in their respective treatment arm 
that have complete data. 
 
After this, the remaining missing data can be imputed using a method for monotone 
missingness, also based on the MAR assumption.  Thus, for each of the created 
datasets with a monotone missing data pattern, the MI procedure in SAS will used to 
impute missing values based on a sequential procedure reflecting the monotone 
missing data pattern.  Patients with the first missing value occurring at visit at 
Month 1 will have their missing Month 1 value replaced by an imputed value from a 
regression model with treatment group, baseline spirometry value and the 
stratification factors as explanatory variables.  In the next step, patients with their 
Month 3 value missing will have their missing Month 3 value replaced by an imputed 
value from a regression model with treatment group, baseline spirometry value, 
stratification factors and the Month 1 value as explanatory variables.  Similar 
procedure will be used to replace the missing values at Month 6, 9 and 12. 
 
The imputed datasets generated with the approach described above do contain only 
non-missing values and are used as input in the model for the primary endpoint.  
MMRM models similar as described above will thus be run on each of the generated 
imputed datasets and the difference between the treatment groups will be 
estimated. The MMRM model will be similar to the primary analysis. Finally, the 
MIANALYZE procedure in SAS will be applied to combine the results from these 
several datasets to derive an overall estimate of the within-group changes and 
treatment differences.  Estimates and corresponding 95% confidence intervals will 
be calculated. 
8.2. 
EXTENT OF EXPOSURE 
The following information will be summarized for CVT-301 treated subjects: 
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• 
The number of patients with dose change 
• 
Duration of exposure (days) 
• 
Total exposure to study treatment, expressed as person years (sum of exposure 
to study treatment over all CVT – 301 treated patients) 
• 
Total number of doses and capsules taken, by visit and overall. Average number 
of daily doses and number of capsules, by visit and overall 
• 
Proportion of days with 5, 4, 3, 2, 1 or 0 doses administered 
• 
Proportion of patients using 5, 4, 3, 2, 1 or 0 doses/day at least once 
 
In addition, these in-clinic data will be summarized by treatment group and visit: 
 
• 
Standard morning dose of LD-containing medications to in-clinic OFF (mins) 
• 
In-clinic OFF to start of study drug inhalation (mins)  
• 
Standard morning dose of LD-containing medications to start of study drug 
inhalation (mins) 
• 
Duration of study drug inhalation (mins), calculated as (Completion time of last 
inhalation – Time of start of first capsule inhalation). 
 
Furthermore, the distribution of time of intake of study medication (00:00 – 00:30, 
00:30 – 01:00, …) as percentage of the total number of study medication intakes will be 
displayed during the whole treatment period.  This data will be collected on the Inhaled 
Dosing Log. 
 
All study drug data will be listed.  A listing will also be provided to show how many 
times each patient will take study drug and the capsules taken for each day. 
 
8.3. 
TREATMENT COMPLIANCE  
Patients will be instructed to administer inhaled study drug up to 5 times each day 
during the treatment period. In-clinic administration of study drug will be supervised by 
study personnel, and at-home diary data will be reviewed to ensure patient compliance. 
Since there are no fixed scheduled doses for each day, compliance will not be 
calculated for this study; alternatively, study drug use will be evaluated based on the 
inhaled medication treatment log by summarizing the proportion of days with >5, 5, 4, 
3, 2, 1 or 0 doses administered.  
8.4. 
ADVERSE EVENTS 
All AEs will be coded using the MedDRA version 17.0.  
 
Treatment-emergent adverse events (TEAEs) are defined as all AEs that start after the 
patient receives the first dose of study drug.  For the observational cohort, TEAE will 
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be defined as events that occur during/after TV/OV1. Events will be classified as drug-
related if the AE is classified as possibly, probably, or definitely related to study drug. 
 
Events with a missing start time, but with a start date equal to the date of first dose of 
study drug will be considered treatment-emergent.  If the AE start date is incomplete, 
then it will be imputed as follows for the purpose of determining TEAE:  
 
• 
If the start date is completely missing, the start date will be equal to the first 
dose date.  However, if the stop date is not missing and is before the first dose 
date, then the stop date will be used instead.  
• 
If the start day is missing, the first day of the month will be used.  
• 
If the start day and month are missing, then the first day of the first month 
(January) will be used. 
The original date and time will be shown on all listings of AEs.  Listings will be provided 
for all AEs, serious AEs, AEs leading to study drug discontinuation, AEs leading to dose 
reduction, and deaths. 
 
TEAEs will be summarized by SOC and PT for each treatment group and overall total.  
TEAEs with onset after the treatment period are attributed to the treatment group and 
dose level during the treatment period.  Both event and patient counts, where 
applicable, will be summarized.  The counts will be complemented by percentages will 
be calculated for the patient counts unless otherwise specified. In addition, the 
incidence of TEAEs, normalized for duration of exposure will be presented (number of 
TEAEs divided by the total exposure to CVT 301 or observation, measured as patient 
years). 
• 
An overall summary of the number and percentage of patients reporting TEAEs 
and the number of TEAE events, drug-related TEAEs, severe TEAEs, serious 
TEAEs, TEAEs leading to dose interruption, TEAEs leading to study drug 
discontinuation, TEAEs leading to dose reduction and TEAEs leading to death 
• 
TEAEs by SOC and PT, both as event and patient counts 
• 
TEAEs by PT, both as event and patient counts  
• 
Drug-related TEAEs by SOC and PT, both as event and patient counts 
• 
Severe TEAEs by SOC and PT, both as event and patient counts 
• 
Drug-related TEAEs by SOC, PT and severity, as event counts; percentages will 
be calculated for the event count out of total number of events 
• 
Drug-related TEAEs by SOC, PT and relationship, as event counts; percentages 
will be calculated for the event count out of total number of events 
• 
Serious TEAEs by SOC and PT, both as event and patient counts 
• 
TEAEs leading to study drug interruption, both as event and patient counts  
• 
TEAEs leading to study drug withdrawal, both as event and patient counts  
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• 
TEAEs leading to dose reduction, both as event and patient counts 
• 
Most common AEs, both as event and patient counts, most common TEAEs is 
defined any AE preferred term occurred in greater than 10% total patients. 
• 
Time to first onset of most common AEs, classified as 0-1 months, >1-3 months, 
>3-6 months, >6-9 months and after 9 months, where the date of TEAE onset will 
be used as the time point for classification.   
The tables will be sorted by overall descending frequency of SOC and then, within a 
SOC, by overall descending frequency of PT based on the patient count for the Total 
column.  If only event count is presented, the sorting will be done based on the event 
count. 
 
8.5. 
LABORATORY EVALUATIONS 
Laboratory samples for hematology and clinical chemistry will be analyzed by a central 
laboratory (located in the United Kingdom for EU sites and the United States for US 
sites) to ensure consistent interpretation of results.  In the event of an unexplained 
clinically significant abnormal laboratory test value, the test should be repeated 
immediately and followed up until it has returned to the normal range and/or an 
adequate explanation of the abnormality is found. 
 
All parameters will be converted to consistent units according to the International 
System of Units (SI) before summarization.  The following will be summarized by 
treatment group and overall: 
 
• 
Actual values and change from baseline, if applicable, at each visit for each 
parameter (for handling of data from the ET visit, see Section 6.4) 
• 
Number and percentage of patients with normal or “abnormal” (i.e., out of 
reference range) labs at each visit for each parameter 
• 
Number and percentage of patients with potentially clinically significant (PCS) 
lab values at each visit for each parameter 
• 
Number and percentage of patients with potentially clinically significant changes 
(PCSC) in lab values at each post-baseline visit for each parameter 
PCS and PCSC will be identified for specific laboratory parameters as outlined in the 
following table. 
Laboratory 
Parameter 
Units 
Criteria for PCS Values (Actual 
values) 
Criteria for PCSC values 
(Changes from baseline 
values) 
 
 
High  
Low  
% increase  
% decrease  
Hemoglobin  
g/L  
> 10 above ULN  
>20 below LLN  
NA  
25%  
Hematocrit  
1  
>0.04 above ULN  
>0.05 below LLN  NA  
25%  
WBC  
GI/L  
>5 above ULN  
>1 below LLN  
100%  
50%  
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Neutrophils  
GI/L  
NA  
<0.5xLLN  
100%  
50%  
Neutrophils  
%  
NA  
<0.5xLLN  
100%  
50%  
Lymphocytes  
GI/L  
NA  
<0.5xLLN  
100%  
50%  
Lymphocytes  
%  
NA  
<0.5xLLN  
100%  
50%  
Total bilirubin  
μmol/L  
>1.5xULN  
NA  
300%  
NA  
Total protein  
g/L  
>15 above ULN  
>15 below LLN  
200%  
60%  
Albumin  
g/L  
>5 above ULN  
>5 below LLN  
NA  
60%  
AST  
U/L  
>3xULN  
NA  
300%  
NA  
ALT  
U/L  
>3xULN  
NA  
300%  
NA  
Alkaline 
Phosphatase  
U/L  
>3xULN  
NA  
300%  
NA  
GGT  
U/L  
>3xULN  
NA  
300%  
NA  
Creatinine  
μmol/L  
>1.5xULN  
NA  
200%  
NA  
Urea  
mmol/L  
>2.5xULN  
NA  
300%  
NA  
Uric Acid  
μmol/L  
>3xULN  
NA  
300%  
NA  
Sodium  
mmol/L  
>5 above ULN  
>5 below LLN  
10%  
10%  
Potassium  
mmol/L  
>1 above ULN  
>0.5 below LLN  
25%  
20%  
Carbon dioxide  
mmol/L  
>40  
<16  
25%  
25%  
Calcium  
mmol/L  
>2.99  
<1.78  
30%  
30%  
Glucose (fasting)* 
mmol/L  
>11.1  
<2.8  
300%  
40%  
ULN = Upper limit of normal range, LLN = Lower limit of normal range 
Baseline is defined as the visit 3 assessment. If the visit 3 assessment is missing, the last non-
missing screening assessment will be used as baseline. * fasting defined as ≥4 hr from prior meal 
The tables showing the normal/abnormal values, PCS values and PCSCs will be done 
both as summaries of all data and as shift tables (i.e., classified by the baseline status). 
 
Values which fall outside the central laboratory normal range will be flagged as “L” – 
below normal range, or “H” – above normal range, on the data listings. PCS and PCSC 
values will also be flagged. All repeated values will be presented on the data listings but 
not included in the summaries showing data by visit.  
 
8.6. 
VITAL SIGNS  
Standard vital sign measurements will include RR, systolic and diastolic BP (SBP, DBP), 
and HR.  At SV1 (or SV2) and each of the subsequent study visits, and in the event of a 
clinically significant finding that could be suggestive of symptomatic orthostatic 
hypotension (e.g., dizziness, lightheadedness, or other AE), orthostatic vital signs will 
be performed.  Orthostatic vital sign measurements will include SBP, DBP, and HR.  
 
The following will be summarized: 
• 
Change from baseline to other visit for each parameter. The baseline is defined 
as the TV/OV1. If TV/OV1, the last non-missing screening assessment will be 
used as baseline. 
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• 
Actual values and change from pre-dose to post-dose time points at TV/OV1 by 
time point for each parameter for CVT-301 treated patients 
• 
Number and percentage of patients with PCS values at each applicable visit and 
time point for each standard vital sign parameter 
• 
Number and percentage of patients with PCSC values at each applicable visit and 
time point for each standard vital sign parameter 
• 
Number and percentage of patients with Orthostatic hypotension at each 
applicable visit  
PCS and PCSC for standard vital sign will be identified as outlined in the following table. 
 
Vital Sign 
Units 
Criteria for PCS Values 
(Actual values) 
Criteria for PCSC values 
(Change from Baseline or 
pre-dose values *) 
 
 
High  
Low  
increase  
decrease  
Pulse rate 
bpm  
>120  
<40  
2x  
0.5x  
Respiration Rate  
brpm  
>32  
<8  
1.5x  
NA  
Systolic Blood 
Pressure (supine)  
mmHg  
>200  
<85  
1.6x  
0.2x  
Diastolic Blood 
pressure (supine)  
mmHg  
>120  
<40  
 
0.2x  
*Pre-dose values will be used for corresponding post-dose values assessment at TV/OV1.  
Otherwise baseline values are used. 
 
Orthostatic hypotension will be defined as a reduction in SBP of 20 mmHg or more, 
and/or a reduction in DBP of 10 mmHg or more, for the standing measurement 
compared to the supine/semi-supine measurement. 
 
8.7. 
ELECTROCARDIOGRAM 
Standard 12-lead ECGs will be obtained after the patient has rested in a supine position 
for at least 5 minutes.  Electrocardiograms will be measured using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, QT interval corrected using 
Bazett’s formula (QTcB) and QT interval corrected using Fridericia’s formula (QTcF).   
 
The following will be summarized: 
• 
Change from baseline to other visit for each parameter. The baseline is defined 
as the TV/OV1 value. If TV/OV1 value is missing, the last non-missing screening 
assessment will be used as baseline. 
• 
Number and percentage of patients with PCS values at each applicable visit for 
each parameter 
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• 
Number and percentage of patients with PCSC values at each applicable visit for 
each parameter 
PCS and PCSC will be identified as outlined in the following table. 
 
ECG 
Units 
Criteria for PCS Values 
(Actual values) 
Criteria for PCSC values (Change from 
Baseline) 
 
 
High  
Low  
increase  
decrease  
PR interval  
msec  
>300  
NA  
>25% for baseline ≥200  
>50% for baseline <200  
NA  
QRS interval  msec  
>200  
NA  
>25% for baseline ≥100  
>50% for baseline <100  
NA  
QTcB  
msec  
>500  
NA  
>15% for baseline ≥440  
>30% for baseline <440 
>30 msec increase 
>60 msec increase  
Change>30 and value>500  
Change>60 and value>500 
NA  
QTcF  
msec  
>500  
NA  
>15% for baseline ≥440  
>30% for baseline <440 
>30 msec increase 
>60 msec increase 
>Change>30 and value>500  
Change>60 and value>500 
NA  
Heart Rate  
bpm  
>120  
<35  
NA  
NA  
 
 
8.8. 
PHYSICAL EXAMINATION 
A complete physical examination (head, eyes, ears, nose, and throat [HEENT], heart, 
lungs, abdomen, skin, cervical and axillary lymph nodes, neurological, and 
musculoskeletal systems) will be performed at screening.  Genital, rectal, and breast 
examination may be excluded if not clinically indicated. 
 
The following will be summarized: 
 
• 
Total number and percentage of patients reporting abnormal clinically 
significant physical examination results 
8.9. 
COLUMBIA-SUICIDALITY SEVERITY RATING SCALE 
The C-SSRS is a measure of suicidal ideation and behavior.  The rating scale has 4 
general categories: suicidal ideation, intensity of ideation, suicidal behavior, and actual 
attempts.  All C-SSRS data will be listed.  The frequency and percentage of patients 
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with each response for suicidal ideation, intensity of ideation, and suicidal behavior 
items will be summarized as appropriate by treatment group and overall.  
 
A shift from baseline table will be constructed to assess any changes in the subjects’ 
suicidal ideation and behavior during the treatment period. 
 
8.10. EPWORTH SLEEPINESS SCALE 
The Epworth Sleepiness Scale is used to determine the level of daytime sleepiness.  
There are 8 situations listed for which patients rate their likelihood of dozing or 
sleeping (0=would never doze or sleep, 1=slight chance of dozing or sleeping, 
2=moderate chance of dozing or sleeping, and 3=high chance of dozing or sleeping).  
The total score is the sum of 8 item scores and can range between 0 and 24.  In case of 
missing item scores, the missing value will be replaced by the average of non-missing 
scores at the same visit from the same patient.  In case all item scores are missing, the 
total score will be set as missing.  The higher total score indicates the higher level of 
daytime sleepiness.  A score of 10 or more is considered sleepy, and a score of 18 or 
more is very sleepy.  
 
All Epworth Sleepiness Scale data will be listed.  The total score and change from 
baseline will be summarized by treatment group and overall (for handling of data from 
the ET visit, see Section 6.4). 
 
8.11. QUESTIONNAIRE FOR IMPULSIVE-COMPULSIVE DISORDERS IN 
PARKINSON’S DISEASE 
The QUIP is an instrument used to measure the extent of impulsive and compulsive 
behaviors in PD patients.  The QUIP has 3 sections: Section 1 assesses any impulsive 
control disorder (gambling, sexual, buying, and eating disorders); Section 2 assesses 
other compulsive behaviors (punding, hobbyism, and walkabout); and Section 3 assesses 
compulsive medication use.  
 
The frequency and percentage of patients with positive response for each of the item 
within each section will be summarized by visit treatment group and overall.  The 
assessment of positive response for each item will be based on the table below. 
 
Section and Item 
Number of items with positive response 
A. Impulse Control Disorders  
 
Compulsive gambling  
any 2 of the 5 gambling items  
Compulsive sexual behavior  
any 1 of the 5 sexual behavior items  
Compulsive buying  
any 1 of the 5 buying items  
Compulsive eating  
any 2 of the 5 eating items  
B. Other Compulsive Behaviors  
 
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Hobbyism 
 item #1A  
Punding  
 item #1B  
Walkabout  
 item #1C  
C. Compulsive Medication Use  
items #1 and #4  
 
8.12. UPDRS PART 4 
Changes from baseline to the subsequent visits in UPDRS Part 4 sum scores (dyskinesia 
sum score, wearing-off sum score) will be analyzed using a similar MMRM as for the 
UPDRS Part 3 scores (described below) to estimate the within-group changes. 
Otherwise, the data will be presented with descriptive statistics only classified by visit 
for CVT treated patients.  The observed cases will be used in the analysis and 
summaries. 
 
8.13. EXAMINER-RATED DYSKINESIA 
The occurrence and severity will be tabulated by treatment group and visit.  The 
observed cases will be used in the summaries.  No formal statistical methods will be 
used. 
 
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9. 
EXPLORATORY EFFICACY 
9.1. 
EXPLORATORY EFFICACY ENDPOINT AND ANALYSIS 
The ITT population will be used for the exploratory efficacy analysis. Patients will be 
analyzed according to randomized treatment.  The within group changes from baseline 
in continuous efficacy variables will be estimated using an MMRM. No between group 
differences will be calculated, unless otherwise specified. The model will include visit 
and the stratification variables (Hoehn and Yahr stage and screening FEV1 and/or 
FEV1/FVC) as fixed factors.  The baseline value will be used as a covariate.  For 
variables which do not have a pretreatment baseline assessment, OFF-state baseline 
UPDRS Part 3 score will be used as the baseline covariate.  An unstructured covariance 
structure will be applied for the MMRM.  In case the model will not converge with the 
unstructured covariance structure, compound symmetry will be used instead. For all 
patients, categorical data will be evaluated descriptively.  Each visit will be evaluated 
separately for the categorical endpoints. The exploratory efficacy endpoints and 
associated analyses are as follows. For the detailed definition of the endpoints, see 
Section 4.3. 
 
• 
Change from pre-dose in UPDRS Part 3 motor score at 10, 20, 30, and 60 minutes 
and the average of the motor score at 10-60 following treatment of patients 
experiencing an OFF episode in the clinic. Change from pre-dose in the average 
UPDRS Part 3 score at 10 to 60 minutes is calculated as the mean of change of 
UPDRS Part III total score from pre-dose to each time point post-dose if UPDRS Part 
III total score is available for at least 2 time points post-dose. The scheduled post-
dose UPDRS Part III assessments are at 10, 20, 30, 60 minutes post-dose, 
respectively. If there is more than 2 time points post-dose with missing UPDRS Part 
III total score, the change of UPDRS Part III total score from pre-dose to 10 to 60 
minutes post-dose will be missing. A MMRM model as defined above will be used.  
 
• 
Time curve of the UPDRS response shown as change from pre-dose in UPDRS Part 3 
motor score to 10, 20, 30 and 60 minutes following treatment of patients 
experiencing an OFF episode in the clinic. A separate MMRM model will be fitted for 
each of the time points. 
• 
A ≥3, ≥6, and ≥11 point reduction in the UPDRS Part 3 motor score from pre-dose to 
post-dose, at 10 to 60 minutes following treatment in the clinic (cumulative and 
non-cumulative).  For the non-cumulative analysis, the proportions of patients with 
a reduction will be tabulated by treatment group, visit and time point.  For the 
cumulative analysis, the cumulative proportions of patients who achieved the first 
reduction before or at the time point in question will be tabulated by visit and time 
point.   
 
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• 
Resolution of an OFF to an ON state within 60 minutes after study drug is 
administered in the clinic and maintaining the ON at 60 minutes after study drug 
administration (per the examiner’s subjective assessment).  This endpoint will be 
based on the examiner’s subjective assessment.  The proportions of patients will be 
summarized descriptively for each CVT-301 treated patients. The missing values will 
be counted as non-resolved. 
 
• 
Change from baseline (3 consecutive days prior to TV/OV1) in patient-recorded total 
daily OFF time, assessed by the patient and recorded in the PD Diary for 3 
consecutive days prior to the visit.  Similar methods as for primary endpoint will be 
used.  However, the baseline daily OFF time will be used as a covariate in the MMRM 
model instead of the OFF-state baseline UPDRS part 3 score. Only valid diary days 
will be included in the diary summarizations. In addition, change from baseline in 
total daily ON time without dyskinesia, total daily ON time with non-troublesome 
dyskinesia, and total daily ON time with troublesome dyskinesia. 
 
• 
The PGI-C score. The proportions of patients who improved (much improved, 
improved or a little improved) will be tabulated by visit for CVT-301 treated 
patients.  This summary will be complemented by the distribution of each response 
category (much improved, improved, a little improved, no change, a little worse, 
worse, much worse) tabulated by the treatment group.    
• 
Changes from TV/OV1 in endpoints based on S&E ADL score, UPDRS Part 2 score, and 
PDQ-39 sub-scores.  An ANCOVA model with the treatment group and stratification 
variables as fixed factors and the TV/OV1 value as a covariate will be used to 
estimate the treatment differences.  Otherwise, the data will be presented with 
descriptive statistics only classified by treatment group and visit.  The observed 
cases will be used in the analysis and summaries. 
 
Sensitivity analyses of the exploratory efficacy data 
 
The following sensitivity analysis will be performed for the UPDRS Part 3 motor scores at 
30 minutes post-dose and daily OFF time exploratory efficacy endpoints. 
 
• 
MI analysis:  MI techniques based on Pattern Mixture Models (PMM) will be applied 
(Ratitch et al., 2011) as a further sensitivity analysis in the ITT population.  This 
methodology will structure data based on missing data patterns.  The method will 
be based on a missingness pattern having a monotone structure, i.e. if among the 
observations over time one data value is missing, all other values after this missing 
value will also be treated as missing.  For patients with intermittent missing values, 
before performing MI based on the PMM, it will be necessary to create a monotone 
missingness pattern.  Intermittent missing values will be imputed using the Markov 
Chain Monte Carlo (MCMC) methodology which assumes a multivariate normal 
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distribution over all variables included in the imputation model.  The MI procedure 
in SAS will be used for this purpose and this first MI step is planned to be repeated 
100 times, creating several different datasets with a monotone missing data 
structure.  Seed value of 201508 will be used in the MI procedure.  The imputation is 
based on the missing at random (MAR) assumption, i.e. the missing data are assumed 
to follow the same model as the other patients in their respective treatment arm 
that have complete data. 
 
After this, the remaining missing data can be imputed using a method for monotone 
missingness, also based on the MAR assumption.  Thus, for each of the created 
datasets with a monotone missing data pattern, the MI procedure in SAS will used to 
impute missing values based on a sequential procedure reflecting the monotone 
missing data pattern.  Patients with the first missing value occurring at visit at 
Month 1 will have their missing Month 1 value replaced by an imputed value from a 
regression model with baseline value and the stratification factors as explanatory 
variables.  In the next step, patients with their Month 3 value missing will have their 
missing Month 3 value replaced by an imputed value from a regression mode with 
baseline spirometry value, stratification factors and the Month 1 value as 
explanatory variables.  Similar procedure will be used to replace the missing values 
at Month 6, 9 and 12. 
 
The imputed datasets generated with the approach described above do contain only 
non-missing values and are used as input in the model for the exploratory efficacy 
endpoint.  MMRM models similar as described above will thus be run on each of the 
generated imputed datasets.  Finally, the MIANALYZE procedure in SAS will be 
applied to combine the results from these several datasets to derive an overall 
estimate of the within-group changes. 
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10. 
INTERIM ANALYSES 
Safety data will be reviewed by a Data Safety Monitoring Committee (DSMC) that will 
include relevant medical experts (including a neurologist and pulmonologist), an 
independent statistician, and additional representatives (as will be defined in the DSMC 
Charter).  Safety data, including but not limited to AEs, spirometry, vital signs, and ECG 
data will be reviewed.  The safety review will be documented in a DSMC Charter prior 
to the start of the study.  In the event that potential safety issues are identified, the 
committee may recommend modification of the study design or study termination, 
which will be communicated promptly with investigators, IRBs, IECs, and regulatory 
agencies, in accordance with legal and regulatory requirements.  There will be no 
prospective interim evaluation of efficacy endpoint data. 
 
Data summary, which will not affect study conduct, may be prepared to support 
regulatory submission. These analyses will be described in the Interim Analysis Charter. 
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11. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
There are no changes from the analyses planned in the protocol. 
 
 
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12. PROGRAMMING CONSIDERATIONS 
All tables, listings, figures (TLFs), and statistical analyses will be generated using SAS® 
for Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA) or higher. Computer-
generated table, listing and figure output produced by INC Research will adhere to the 
following specifications.   
12.1. GENERAL CONSIDERATIONS 
• 
One SAS program can create several outputs.  
• 
One output file can contain several outputs.  
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance 
12.2. TABLE, LISTING, AND FIGURE FORMAT 
12.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8  
• 
The data displays for all TLFs will have a 1.5-inch binding margin on top of a 
landscape oriented page and a minimum 1-inch margin on the other 3 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified. For spirometry 
graphs, separate colors will be used for ON (red circles) and OFF (blue triangles) 
State data. 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified.  
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. 
• 
Mixed case will be used for all titles, column headers, and programmer-supplied 
formats, as appropriate. 
12.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
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Civitas Therapeutics, Inc.   
Protocol No. CVT-301-005                 Confidential 
          
• 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
• 
The date and time (date and time output was generated) should appear along with 
program name and location as the last footer on each page. 
12.2.3. 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
The title is centered. The title and table designation are single spaced. A solid line 
spanning the margins will separate the display titles from the column headers. There 
will be 1 blank line between the last title and the solid line. 
12.2.4. 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above.  
• 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of patients in the analysis set. 
• 
The order of treatments in the tables will be Placebo first, followed by CVT-301 and 
a total column (if applicable in tables). 
12.2.5. 
Body of the Data Display 
12.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
 
12.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
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standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
X.XX 
Median 
XXX.X 
Minimum 
XXX, 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value is returned as >0.999 then present as >0.999. 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count, e.g., 7 (12.8%), 13 (5.4%). For a value that rounds 
down to 0.0, display it as “<0.1”. Unless otherwise noted, for all percentages, the 
number of patients in the analysis set for the treatment group who have an 
observation will be the denominator. Percentages after zero counts should not be 
displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
 
12.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of patient number, visit/collection 
day, and visit/collection time. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on patient listings as dashes (--JUL2000).  
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26).  
 
12.2.6. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
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• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date and time the program 
was run.  
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13. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 
03.010.00 and 03.013.00 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009.00 describes the quality control procedures that are 
performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs 
produce the proper clinical trial output by checking for their logic, efficiency and 
commenting and by review of the produced output. 
 
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14. 
INDEX OF TABLES 
Table 14.1.1.1 
Number of Subjects Enrolled and Study Termination  (All Available Population)  
Table 14.1.1.2 
Number of Subjects in Each Population by Study Center All Subjects 
 
Table 14.1.2.1 
Summary of Protocol Deviation  Randomized Set 
 
Table 14.1.3.1.1 
Demographic and Baseline Characteristics  (Safety Population)  
Table 14.1.3.1.2   
Demographic and Baseline Characteristics  (ITT Population) 
 
Table 14.1.3.1.3 
Demographic and Baseline Characteristics by Baseline PD Severity (ITT 
Population) 
 
Table 14.1.3.1.4 
Demographic and Baseline Characteristics by Baseline Dyskinesia  (ITT 
Population) 
 
Table 14.1.3.1.5 
Demographic and Baseline Characteristics by Baseline Daily Levodopa Dose (ITT 
Population) 
 
Table 14.1.3.1.6 
Demographic and Baseline Characteristics by PD Diary Mean Daily OFF Time 
during Screening (ITT Population) 
 
Table 14.1.3.1.7 
Demographic and Baseline Characteristics by Screening Spirometry  (ITT 
Population) 
 
Table 14.1.3.1.8 
Demographic and Baseline Characteristics by Age Group (ITT Population) 
 
Table 14.1.3.1.9 
Demographic and Baseline Characteristics by Gender (ITT Population) 
 
Table 14.1.3.2.1 
Parkinson’s Disease History (Safety Population)  
Table 14.1.3.2.2 
Parkinson’s Disease History (ITT Population) 
 
Table 14.1.3.2.3 
Parkinson’s Disease History by Baseline PD Severity (ITT Population) 
 
Table 14.1.3.2.4 
Parkinson’s Disease History by Baseline Dyskinesia  (ITT Population) 
 
Table 14.1.3.2.5 
Parkinson’s Disease History by Baseline Daily Levodopa Dose (ITT Population) 
 
Table 14.1.3.2.6 
Parkinson’s Disease History by PD Diary Mean Daily OFF Time during Screening 
(ITT Population) 
 
Table 14.1.3.2.7 
Parkinson’s Disease History by Screening Spirometry  (ITT Population) 
 
Table 14.1.3.2.8 
Parkinson’s Disease History by Age Group (ITT Population) 
 
Table 14.1.3.2.9 
Parkinson’s Disease History by Gender (ITT Population)  
Table 14.1.3.2.10 
Modified Hoehn and Yahr Staging in “ON” State (Safety Population) 
 
Table 14.1.3.2.11 
Modified Hoehn and Yahr Staging in “ON” State (ITT Population) 
Table 14.1.3.2.12   
Distribution of Average Daily OFF Time (Safety Population) 
 
Table 14.1.3.2.13 
Distribution of cumulative Average Daily OFF Time (Safety Population)  
Table 14.1.3.3 
Medical History  (Safety Population) 
 
Table 14.1.4.1 
Prior Medications  (Safety Population)  
Table 14.1.4.2 
Concomitant Medications  (Safety Population)  
Table 14.1.4.3 
Parkinson’s disease Treatment Medications at Baseline (ITT Population)  
Table 14.2.1.1 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score 
at 10 Minutes Post-dose by Visit (ITT Population) 
 
Table 14.2.1.2 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score 
at 20 Minutes Post-dose by Visit (ITT Population) 
 
Table 14.2.1.3.1 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score 
at 30 Minutes Post-dose by Visit (ITT Population) 
 
Table 14.2.1.3.2 
Sensitivity Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 
Minutes Post-dose by Visit (ITT Population) 
 
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Table 14.2.1.3.3 
Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 
3 Score at 30 Minutes Post-dose by Visit by Baseline PD Severity  (ITT 
Population) 
 
Table 14.2.1.3.4 
Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 
3 Score at 30 Minutes Post-dose by Visit by Baseline Dyskinesia (ITT Population)  
Table 14.2.1.3.5   
Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 
3 Score at 30 Minutes Post-dose by Visit by Baseline Daily Levodopa Dose  (ITT 
Population)  
Table 14.2.1.3.6  
Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 
3 Score at 30 Minutes Post-dose by Visit by PD Diary Mean Daily OFF Time during 
Screening  (ITT Population) 
 
Table 14.2.1.3.7 
Exploratory Efficacy Exploratory Efficacy Subgroup Analysis: Change from Pre-
dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Screening 
Spirometry  (ITT Population) 
 
Table 14.2.1.3.8 
Exploratory Efficacy Exploratory Efficacy Subgroup Analysis: Mean Change from 
Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Age 
Group (ITT Population)  
Table 14.2.1.3.9   
Exploratory Efficacy Exploratory Efficacy Subgroup Analysis: Mean Change from 
Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Gender  
(ITT Population) 
 
Table 14.2.1.4 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score 
at 60 Minutes Post-dose by Visit (ITT Population) 
 
Table 14.2.1.5 
 Exploratory Efficacy Analysis:  Change from Pre-dose in the Average UPDRS Part 
3 Score at 10 to 60 Minutes Post-dose by Visit (ITT Population)  
Table 14.2.2.1 
 Exploratory Efficacy Analysis: Change from Pre-dose in UPDRS Part 3 Score to 
10, 20, 30, 60 minutes Post-dose by Visit (ITT Population) 
 
Table 14.2.2.2 
 Exploratory Efficacy Analysis: Change from Pre-Dose to 10, 20, 30, 60 minutes 
Post-dose in UPDRS Part 3 Score by Visit and Timepoint  (ITT Population) 
  
Table 14.2.2.3 
 Exploratory Efficacy Analysis: Change from Pre-Dose to 10, 20, 30, 60 minutes 
Post-dose in UPDRS Part 3 Score by Timepoint and Visit  (ITT Population) 
  
Table 14.2.3.1 
Exploratory Efficacy Analysis Subjects with a >=3 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit (ITT Population)  
Table 14.2.3.2 
Exploratory Efficacy Analysis Subjects with a >=3 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit With Percentages Based on N  (ITT 
Population) 
  
Table 14.2.3.3 
Exploratory Efficacy Analysis Subjects with a >=6 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit (ITT Population)  
Table 14.2.3.4 
Exploratory Efficacy Analysis Subjects with a >=6 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit With Percentages Based on N  (ITT 
Population)   
Table 14.2.3.5   
Exploratory Efficacy Analysis Subjects with a >=11 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit (ITT Population)  
Table 14.2.3.6 
Exploratory Efficacy Analysis Subjects with a >=11 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit With Percentages Based on N  (ITT 
Population) 
  
Table 14.2.4.1 
 Exploratory Efficacy Analysis: Subjects Achieving Resolution of an OFF to an ON 
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State within 60 Minutes by Visit Worst Case Imputation [a] (ITT Population) 
 
Table 14.2.5.1.1    
Exploratory Efficacy Analysis: Mean of Total Daily OFF Time by Visit (ITT 
Population) 
 
Table 14.2.5.1.2    
Sensitivity Analysis: Mean of Total Daily OFF Time by Visit MI analysis with 
Missing At Random Assumption  (ITT Population 
Table 14.2.5.1.3 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Baseline PD Severity  (ITT Population)  
Table 14.2.5.1.4 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Baseline Dyskinesia (ITT Population) 
 
Table 14.2.5.1.5 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Baseline Daily Levodopa Dose (ITT Population)  
Table 14.2.5.1.6 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
PD Diary Mean Daily OFF Time during Screening (ITT Population) 
 
Table 14.2.5.1.7 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Screening Spirometry  (ITT Population)  
Table 14.2.5.1.8 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Age Group (ITT Population) 
 
Table 14.2.5.1.9 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Gender (ITT Population) 
 
Table 14.2.5.2 
Exploratory Efficacy Analysis: Mean of Total Daily ON Time without Dyskinesia 
by Visit (ITT Population) 
Table 14.2.5.3 
Exploratory Efficacy Analysis: Mean of Total Daily ON Time with non-
Troublesome Dyskinesia by Visit (ITT Population) 
Table 14.2.5.4 
Exploratory Efficacy Analysis: Mean of Total Daily ON Time with Troublesome 
Dyskinesia by Visit (ITT Population) 
Table 14.2.6.1 
Exploratory Efficacy Analysis: Subjects Global Impression of Change (PGI-C) by 
Visit  Worst Case Imputation [a] (ITT Population) 
 
Table 14.2.7.1 
Exploratory Efficacy Analysis:  UPDRS Part 2 Score at TV4/OV4 (ITT Population)   
Table 14.2.7.2   
Exploratory Efficacy Analysis:  UPDRS Part 2 Score at TV6/OV6  (ITT Population)   
Table 14.2.8.1 
Exploratory Efficacy Analysis:  Schwab and England (S&E) Activities of Daily 
Living (ADL) Score at TV4/OV4 (ITT Population)   
Table 14.2.8.2 
Exploratory Efficacy Analysis: Schwab and England (S&E) Activities of Daily 
Living (ADL) Score at TV6/OV6 (ITT Population)   
Table 14.2.9.1 
Exploratory Efficacy Analysis:  39 Item Parkinson's disease Questionnaire (PDQ-
39) Sub-scores and Summary Index Score at TV4/OV4 (ITT Population)   
Table 14.2.9.2 
Exploratory Efficacy Analysis: 39 Item Parkinson's disease Questionnaire (PDQ-
39) Sub-scores and Summary Index Score at TV6/OV6 (ITT Population)   
Table 14.3.1.1   
Extent of Exposure: Overall  (Safety Population)  
Table 14.3.1.2   
In-Clinic Study Drug Administration  (Safety Population)   
Table 14.3.1.3 
Distribution of Time of Study Drug Administration (Safety Population) 
  
Table 14.3.2.1   
Treatment-emergent adverse events -Overall Summary  (Safety Population) 
  
Table 14.3.2.2.1 
Treatment-emergent adverse events by System Organ Class and Preferred Term  
(Safety Population)  
Table 14.3.2.2.2   
Treatment-emergent adverse events by Preferred Term  (Safety Population)   
Table 14.3.2.3 
Drug-Related Treatment-emergent adverse events by System Organ Class, 
Preferred Term and Severity  (Safety Population) 
  
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Table 14.3.2.4 
Drug –Related Treatment-emergent adverse events by System Organ Class, 
Preferred Term and Relationship  (Safety Population) 
  
Table 14.3.2.5   
Drug-related Treatment-emergent adverse events by System Organ Class and 
Preferred Term  (Safety Population) 
  
Table 14.3.2.6 
Serious Treatment-emergent adverse events by System Organ Class and 
Preferred Term  (Safety Population) 
  
Table 14.3.2.7 
Listing of Serious Adverse Events 
  
Table 14.3.2.8 
Listing of Adverse Events Leading to Death 
  
Table 14.3.2.9 
Severe Treatment-emergent adverse events by System Organ Class and 
Preferred Term  (Safety Population) 
  
Table 14.3.2.10 
Listing of Severe Treatment-Emergent Adverse Events   
Table 14.3.2.11 
Treatment-emergent adverse events Leading to Study Drug Interruption by 
System Organ Class and Preferred Term  (Safety Population) 
  
Table 14.3.2.12   
Listing of Adverse Events Leading to Study Drug Interruption 
  
Table 14.3.2.13 
Treatment-emergent adverse events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term  (Safety Population) 
 
Table 14.3.2.14 
Listing of Adverse Events Leading to Study Drug Discontinuation   
Table 14.3.2.15 
Treatment-emergent adverse events Leading to Dose Reduction by System 
Organ Class and Preferred Term  (Safety Population) 
  
Table 14.3.2.16 
Listing of Adverse Events Leading to Dose Reduction 
  
Table 14.3.2.17 
Most Common Treatment-Emergent Adverse Events (Preferred Term Occurred in 
>10% of Over Patients) by System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.2.18 
Listing of Most Common Treatment-Emergent Adverse Events 
Table 14.3.2.19 
Time to first Onset of most Common Treatment-Emergent Adverse Events 
(Preferred Term Occurred in >10% of Over Patients) (Safety Population) 
Table 14.3.4.1 
Clinical Laboratory Results: PCS and PCSC Criteria 
  
Table 14.3.4.1.1.1 
Summary of Clinical Laboratory Results: Hematology (Safety Population) 
  
Table 14.3.4.1.1.2 
Summary of Clinical Laboratory Results: Hematology Abnormal Values (Safety 
Population) 
  
Table 14.3.4.1.1.3 
Summary of Clinical Laboratory Results: Hematology Abnormal Values –Shift 
from Baseline (Safety Population) 
  
Table 14.3.4.1.1.4 
Summary of Clinical Laboratory Results: Hematology PCS Values –Shift from 
Baseline (Safety Population) 
  
Table 14.3.4.1.1.5 
Summary of Clinical Laboratory Results: Hematology PCSC Values –Shift from 
Baseline (Safety Population) 
  
Table 14.3.4.1.1.6 
Clinical Laboratory Results – Hematology PCS and PCSC Values (Safety 
Population) 
  
Table 14.3.4.1.2.1 
Summary of Clinical Laboratory Results: Chemistry (Safety Population)   
Table 14.3.4.1.2.2 
Summary of Clinical Laboratory Results: Chemistry Abnormal Values (Safety 
Population) 
  
Table 14.3.4.1.2.3 
Summary of Clinical Laboratory Results: Chemistry Abnormal Values –Shift from 
Baseline (Safety Population) 
  
Table 14.3.4.1.2.4   
Summary of Clinical Laboratory Results: Chemistry PCS Values –Shift from 
Baseline (Safety Population) 
  
Table 14.3.4.1.2.5 
Summary of Clinical Laboratory Results: Chemistry PCSC Values –Shift from 
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Baseline (Safety Population) 
  
Table 14.3.4.1.2.6 
Clinical Laboratory Results – Chemistry PCS and PCSC Values  (Safety Population)
 
  
Table 14.3.4.2 
Vital Signs: PCS and PCSC Criteria 
  
Table 14.3.4.2.1 
Summary of Vital Signs: Actual Values and Change from Baseline across Visits  
(Safety Population)  
Table 14.3.4.2.2 
Summary of Vital Signs: Actual Values and Change from Pre-dose at TV1 (Safety 
Population) 
  
Table 14.3.4.2.3 
Summary of Standard Vital Signs: PCS and PCSC Values by Visit (Safety 
Population) 
  
Table 14.3.4.2.4 
Summary of Standard Vital Signs: PCS and PCSC Values by Scheduled Timepoint 
at TV1 (Safety Population) 
  
Table 14.3.4.2.5   
Standard Vital Signs: PCS and PCSC Values 
  
Table 14.3.4.2.6 
Summary of Vital Signs: Orthostatic Hypotension by Visit  (Safety Population) 
  
Table 14.3.4.2.7 
Summary of Vital Signs: Orthostatic Hypotension by Scheduled Timepoint at TV1  
(Safety Population)  
Table 14.3.4.2.8   
Orthostatic Vital Signs   
Table 14.3.4.3 
12-Lead ECG:PCS and PCSC Criteria 
  
Table 14.3.4.3.1 
Summary of 12-Lead ECG: Actual Values and Change across Visits  (Safety 
Population) 
  
Table 14.3.4.3.2 
Summary of 12-Lead ECG: PCS and PCSC Values  (Safety Population) 
  
Table 14.3.4.3.3 
12-Lead Electrocardiogram (ECG): PCS and PCSC Values   
Table 14.3.4.4 
Physical Examination  (Safety Population) 
  
Table 14.3.4.5.1.1 
Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1 and FVC by Visit  (Safety Population)   
Table 14.3.4.5.1.2 
Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1 and FVC by Visit  Using Subset of Assessments Meeting the ATS 
Quality Criteria (Safety Population) 
  
Table 14.3.4.5.1.3 
Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1 and FVC by Visit Excluding Patients with Co-efficient of 
Variation (CV) of FEV1 >7.5% (Safety Population) 
  
Table 14.3.4.5.1.4 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FEV1 by Visit  (Safety Population) 
Table 14.3.4.5.1.5 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FEV1 by Visit Using Subset of Assessments Meeting the ATS Quality Criteria 
(Safety Population) 
Table 14.3.4.5.1.6 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FEV1 by Visit Excluding Patients with Co-efficient of Variation (CV) of FEV1 
>7.5% (Safety Population) 
Table 14.3.4.5.1.7 
Sensitivity Analysis Using MMRM: Change from Baseline for FEV1 by Visit MI 
analysis with Missing At Random Assumption  (ITT Population) 
Table 14.3.4.5.1.8 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
Percentage Predicted FEV1 by Visit  (Safety Population) 
Table 14.3.4.5.1.9 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
Percentage Predicted FEV1 by Visit Using Subset of Assessments Meeting the ATS 
Quality Criteria (Safety Population) 
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Table 14.3.4.5.1.10 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
Percentage Predicted FEV1 by Visit Excluding Patients with Co-efficient of 
Variation (CV) of FEV1 >7.5% (Safety Population) 
Table 14.3.4.5.1.11 
Sensitivity Analysis Using MMRM: Change from Baseline for Percentage Predicted 
FEV1 by Visit MI analysis with Missing At Random Assumption  (ITT Population) 
Table 14.3.4.5.1.12 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FVC by Visit  (Safety Population) 
Table 14.3.4.5.1.13 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FVC by Visit Using Subset of Assessments Meeting the ATS Quality Criteria 
(Safety Population) 
Table 14.3.4.5.1.14 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FVC by Visit Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5% 
(Safety Population) 
Table 14.3.4.5.1.15 
Sensitivity Analysis Using MMRM: Change from Baseline for FVC by Visit MI 
analysis with Missing At Random Assumption  (ITT Population) 
Table 14.3.4.5.1.16 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
Percentage Predicted FVC by Visit  (Safety Population) 
Table 14.3.4.5.1.17 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
Percentage Predicted FVC by Visit  Using Subset of Assessments Meeting the ATS 
Quality Criteria (Safety Population) 
Table 14.3.4.5.1.18 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
Percentage Predicted FVC by Visit Excluding Patients with Co-efficient of 
Variation (CV) of FEV1 >7.5% (Safety Population) 
Table 14.3.4.5.1.19 
Sensitivity Analysis Using MMRM: Change from Baseline for Percentage Predicted 
FVC by Visit MI analysis with Missing At Random Assumption  (ITT Population) 
Table 14.3.4.5.2.1 
Summary of Spirometry:(Neurology Office): Actual Values and Change from 
Baseline for FEV1/FVC by Visit  (Safety Population) 
  
Table 14.3.4.5.2.2 
Summary of Spirometry:(Neurology Office): Actual Values and Change from 
Baseline for FEV1/FVC by Visit  Using Subset of Assessments Meeting the ATS 
Quality Criteria (Safety Population) 
  
Table 14.3.4.5.2.3 
Summary of Spirometry:(Neurology Office): Actual Values and Change from 
Baseline for FEV1/FVC by Visit  Excluding Patients with Co-efficient of Variation 
(CV) of FEV1 >7.5% (Safety Population)   
Table 14.3.4.5.2.4 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FEV1/FVC by Visit  (Safety Population) 
Table 14.3.4.5.2.5 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FEV1/FVC by Visit  Using Subset of Assessments Meeting the ATS Quality Criteria 
(Safety Population) 
Table 14.3.4.5.2.6 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for 
FEV1/FVC by Visit Excluding Patients with Co-efficient of Variation (CV) of FEV1 
>7.5% (Safety Population) 
Table 14.3.4.5.2.7 
Sensitivity Analysis Using MMRM: Change from Baseline for FEV1/FVC by Visit MI 
analysis with Missing At Random Assumption  (ITT Population) 
Table 14.3.4.5.3.1 
Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and 
<70% by Visit  (Safety Population)  
Table 14.3.4.5.3.2 
Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and 
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<70% by Visit Using Subset of Assessments Meeting the ATS Quality Criteria 
(Safety Population)  
Table 14.3.4.5.3.3 
Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and 
<70% by Visit Excluding Patients with Co-efficient of Variation (CV) of FEV1 
>7.5% (Safety Population)  
Table 14.3.4.5.4 
Spirometry(Neurology Office): 70% or Smaller FEV1/FVC Values and >=200 
Reduction from Pre-dose  
Table 14.3.4.5.5 
 Summary of Spirometry(Neurology Office): Measurements Meeting ATS Quality 
Criteria (Safety Population)  
Table 14.3.4.5.6 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and Change 
from Baseline for Calculated DLco Parameters by Visit  (Safety Population) 
  
Table 14.3.4.5.7 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and Change 
from Baseline for FEV1 and FVC by Visit  (Safety Population) 
  
Table 14.3.4.5.8 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and Change 
from Baseline for FEV1/FVC by Visit  (Safety Population) 
  
Table 14.3.4.5.9 
Summary of Spirometry (Pulmonary Function Facility): Summary of FEV1/FVC < 
60% and <70%by Visit (Safety Population)  
Table 14.3.4.5.10 
Spirometry(Pulmonary Function Facility):70% or Smaller FEV1/FVC Values by 
Visit  
Table 14.3.4.5.11 
Summary of Spirometry(Pulmonary Function Facility): Measurements Meeting 
ATS Quality Criteria  (Safety Population)  
Table 14.3.4.6.1 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) (Safety Population)
 
  
Table 14.3.4.6.2 
Shift from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) (Safety 
Population)  
Table 14.3.4.7 
Summary of Epworth Sleepiness Scale Total Score: Actual Values and Change 
from Baseline by Visit (Safety Population)  
Table 14.3.4.8 
Summary of Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
(QUIP) by Visit (Safety Population)  
Table 14.3.4.9.1 
MMRM Analysis of UPDRS Part 4: Change from Baseline in the UPDRS Part 4 Score 
at TV4 (Safety Population)  
Table 14.3.4.9.2 
 MMRM Analysis of UPDRS Part 4 Dyskinesias Score: Change from Baseline in the 
UPDRS Part 4 Score at TV4  (Safety Population)   
Table 14.3.4.9.3 
 MMRM Analysis of UPDRS Part 4 Fluctuations Score: Change from Baseline in the 
UPDRS Part 4 Score at TV4  (Safety Population)   
Table 14.3.4.9.4 
Summary of UPDRS Part 4: Actual Values and Change from Baseline by Visit  
(Safety Population) 
  
Table 14.3.4.9.5 
Summary of UPDRS Part 4 Dyskinesias Score: Actual Values and Change from 
Baseline by Visit  (Safety Population) 
  
Table 14.3.4.9.6 
Summary of UPDRS Part 4 Fluctuations Score: Actual Values and Change from 
Baseline by Visit  (Safety Population) 
  
Table 14.3.4.10 
Dyskinesia: Occurrence and Severity (In-clinic) by Visit  (ITT Population)   
 
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15. 
INDEX OF LISTINGS 
Listing 16.2.1 
 Patient Disposition 
  
Listing 16.2.2.1 
 Protocol Deviations 
  
Listing 16.2.3.1 
Inclusion Criteria not Met at Screening   
Listing 16.2.3.2 
Exclusion Criteria Met at Screening 
  
Listing 16.2.3.3 
 Analysis Populations 
  
Listing 16.2.4.1 
 Demographics   
Listing 16.2.4.2 
 Medical History  
Listing 16.2.4.3 
 Parkinson’s Disease History 
  
Listing 16.2.4.4 
 Smoking History 
  
Listing 16.2.4.5 
 ON and OFF Concordance Testing at Screening   
Listing 16.2.4.6 
 Modified Hoehn and Yahr Staging in “ON” State at Screening 
  
Listing 16.2.4.7 
 Mini Mental State Examination (MMSE) at Screening 
  
Listing 16.2.4.8 
 Parkinson’s Disease Diary Data at Screening: Derived Time 
  
Listing 16.2.4.9 
 Screening ON/OFF Log   
Listing 16.2.4.10 
 Randomization   
Listing 16.2.4.11.1 
 Prior and Concomitant Medications 
  
Listing 16.2.4.11.2 
 Parkinson’s disease Treatment Medications at Baseline   
Listing 16.2.4.12 
 Baseline Pulmonary Assessment Part 2 - Pulmonary History 
  
Listing 16.2.4.13 
 Baseline Pulmonary Assessment Part 3 - Assessments of Symptoms 
  
Listing 16.2.5.1.1 
 Study Drug Administration: in Clinic and at Home 
  
Listing 16.2.5.1.2 
 Study Drug Administration: Derived Variables (in Clinic)  
Listing 16.2.5.1.3 
 Study Drug Administration: Derived Variables (Overall)   
Listing 16.2.5.1.4 
 Study Drug Administration: Derived Variables (Overall by Visit)   
Listing 16.2.5.1.5 
 Listing of Study Drug Dose Change 
  
Listing 16.2.5.2 
 Study Drug Kit Dispensation 
  
Listing 16.2.5.3 
 Daily Levodopa Dose 
  
Listing 16.2.6.1.1 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 
  
Listing 16.2.6.1.2 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3: Derived 
Variables 
  
Listing 16.2.6.2.1 
 Clinic Assessment 
  
Listing 16.2.6.2.2 
 Parkinson’s Disease Diary Data   
Listing 16.2.6.2.3.1 
Parkinson’s Disease Diary Data – Derived Variable by Dairy Date   
Listing 16.2.6.2.3.2 
Parkinson’s Disease Diary Data – Derived Variable by Visit 
  
Listing 16.2.6.2.4 
Patient’s Global Impression of Change (PGI-C)   
Listing 16.2.6.2.5   
Impact of Parkinson’s OFF Episodes 
  
Listing 16.2.6.3.1 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 2   
Listing 16.2.6.3.2 
Listing of S&E Activities of Daily Living   
Listing 16.2.6.3.3 
39 Item Parkinson's Disease Questionnaire (PDQ-39) 
  
Listing 16.2.7.1 
Adverse Events   
Listing 16.2.8.1.1 
Clinical Laboratory Results - Hematology 
  
Listing 16.2.8.1.2 
Clinical Laboratory Results – Chemistry   
Listing 16.2.8.1.3 
Serum Pregnancy Test – Positive Only 
  
Listing 16.2.8.2.1 
Vital Signs 
  
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Listing 16.2.8.2.2 
12-Lead Electrocardiogram (ECG) 
  
Listing 16.2.8.2.3 
Physical Examination 
  
Listing 16.2.8.2.4.1 
Spirometry( Neurology Office)   
Listing 16.2.8.2.4.2 
Spirometry( Neurology Office) Measurements Not Meeting ATS Quality 
Criteria   
Listing 16.2.8.2.4.3 
Spirometry(Pulmonary Function Facility): DLco Parameters 
  
Listing 16.2.8.2.4.4 
 Spirometry(Pulmonary Function Facility): Spirometry/DLco Measurements 
Not Meeting ATS Quality Criteria 
  
Listing 16.2.8.2.5 
Columbia-Suicide Severity Rating Scale (C-SSRS)   
Listing 16.2.8.2.6 
Epworth Sleepiness Scale 
  
Listing 16.2.8.2.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP)   
Listing 16.2.8.2.8.1 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4 
  
Listing 16.2.8.2.8.2 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4: Derived 
Variables 
  
Listing 16.2.8.2.9.1 
 Telephone Contact 
  
Listing 16.2.8.2.9.2 
 Telephone Contact: Challenges with Inhaler or Capsules Data   
 
 
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16. 
INDEX OF FIGURES 
Not Applicable. 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Attachment 1 Table Mock-ups 
 
Table of Contents  
 
Table 14.1.1.1 Number of Subjects Enrolled and Study Termination  (All Available Population)............................................. 6 
Table 14.1.1.2 Number of Subjects in Each Population by Study Center All Subjects........................................................ 7 
Table 14.1.2.1    Summary of Protocol Deviation  Randomized Set.......................................................................... 9 
Table 14.1.3.1.1 Demographic and Baseline Characteristics  (Safety Population).......................................................... 10 
Table 14.1.3.1.2    Demographic and Baseline Characteristics  (ITT Population).......................................................... 12 
Table 14.1.3.1.3 Demographic and Baseline Characteristics by Baseline PD Severity (ITT Population)...................................... 12 
Table 14.1.3.1.4 Demographic and Baseline Characteristics by Baseline Dyskinesia  (ITT Population)...................................... 12 
Table 14.1.3.1.5 Demographic and Baseline Characteristics by Baseline Daily Levodopa Dose (ITT Population).............................. 12 
Table 14.1.3.1.6 Demographic and Baseline Characteristics by PD Diary Mean Daily OFF Time during Screening (ITT Population)............. 12 
Table 14.1.3.1.7 Demographic and Baseline Characteristics by Screening Spirometry  (ITT Population)..................................... 12 
Table 14.1.3.1.8 Demographic and Baseline Characteristics by Age Group (ITT Population)................................................. 12 
Table 14.1.3.1.9 Demographic and Baseline Characteristics by Gender (ITT Population).................................................... 13 
Table 14.1.3.2.1 Parkinson’s Disease History (Safety Population)........................................................................ 14 
Table 14.1.3.2.2 Parkinson’s Disease History (ITT Population)........................................................................... 16 
Table 14.1.3.2.3 Parkinson’s Disease History by Baseline PD Severity (ITT Population)................................................... 16 
Table 14.1.3.2.4 Parkinson’s Disease History by Baseline Dyskinesia  (ITT Population)................................................... 16 
Table 14.1.3.2.5 Parkinson’s Disease History by Baseline Daily Levodopa Dose (ITT Population)........................................... 16 
Table 14.1.3.2.6 Parkinson’s Disease History by PD Diary Mean Daily OFF Time during Screening (ITT Population).......................... 16 
Table 14.1.3.2.7 Parkinson’s Disease History by Screening Spirometry  (ITT Population).................................................. 17 
Table 14.1.3.2.8 Parkinson’s Disease History by Age Group (ITT Population).............................................................. 17 
Table 14.1.3.2.9 Parkinson’s Disease History by Gender (ITT Population)................................................................. 17 
Table 14.1.3.2.10 Modified Hoehn and Yahr Staging in “ON” State (Safety Population)..................................................... 18 
Table 14.1.3.2.11 Modified Hoehn and Yahr Staging in “ON” State (ITT Population)........................................................ 18 
Table 14.1.3.2.12    Distribution of Average Daily OFF Time at Baseline (Safety Population)............................................. 19 
Table 14.1.3.2.13    Distribution of Cumulative Average Daily OFF Time at Baseline (Safety Population).................................. 20 
Table 14.1.3.3 Medical History  (Safety Population)..................................................................................... 21 
Table 14.1.4.1 Prior Medications  (Safety Population)................................................................................... 22 
Table 14.1.4.2 Concomitant Medications  (Safety Population)............................................................................. 23 
Table 14.1.4.3    Parkinson’s disease Treatment Medications at Baseline (ITT Population)................................................ 24 
Table 14.2.1.1 Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 10 Minutes Post-dose by Visit (ITT 
Population) .......................................................................................................... 25 
Table 14.2.1.2 Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 20 Minutes Post-dose by Visit (ITT 
Population) .......................................................................................................... 26 
Table 14.2.1.3.1 Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit 
(ITT Population) ..................................................................................................... 26 
Table 14.2.1.3.2 Sensitivity Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit MI analysis 
with Missing At Random Assumption  (ITT Population) .................................................................. 27 
Table 14.2.1.3.3 Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Baseline PD 
Severity  (ITT Population) ........................................................................................... 28 
Table 14.2.1.3.4  Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by 
Visit by Baseline Dyskinesia (ITT Population) ........................................................................ 29 
Table 14.2.1.3.5     Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose 
by Visit by Baseline Daily Levodopa Dose  (ITT Population) ........................................................... 30 
Table 14.2.1.3.6  Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by 
Visit by PD Diary Mean Daily OFF Time during Screening  (ITT Population) ............................................. 31 
Table 14.2.1.3.7  Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by 
Visit by Screening Spirometry  (ITT Population) ...................................................................... 32 
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Program Name: xxxx.sas                                                           
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Table 14.2.1.3.8     Exploratory Efficacy Subgroup Analysis: Mean Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes 
Post-dose by Visit by Age Group (ITT Population) ..................................................................... 33 
Table 14.2.1.3.9     Exploratory Efficacy Subgroup Analysis: Mean Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes 
Post-dose by Visit by Gender  (ITT Population) ....................................................................... 34 
Table 14.2.1.4  Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 60 Minutes Post-dose by Visit (ITT 
Population) .......................................................................................................... 35 
Table 14.2.1.5 Exploratory Efficacy Analysis: Change from Pre-dose in the Average UPDRS Part 3 Score at 10 to 60 Minutes Post-dose 
by Visit (ITT Population) ............................................................................................ 35 
Table 14.2.2.1 Exploratory Efficacy Analysis: Change from Pre-dose in UPDRS Part 3 Score to 10, 20, 30, 60 minutes Post-dose by 
Visit (ITT Population) ............................................................................................... 36 
Table 14.2.2.2 Exploratory Efficacy Analysis: Change from Pre-Dose to 10, 20, 30, 60 minutes Post-dose in UPDRS Part 3 Score by 
Visit and Timepoint  (ITT Population) ................................................................................ 37 
Table 14.2.2.3  Exploratory Efficacy Analysis: Change from Pre-Dose to 10, 20, 30, 60 minutes Post-dose in UPDRS Part 3 Score by 
Timepoint and Visit  (ITT Population) ................................................................................ 38 
Table 14.2.3.1 Exploratory Efficacy Analysis: Subjects with a >=3 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score by 
Visit (ITT Population) ............................................................................................... 39 
Table 14.2.3.2 Additional Exploratory Efficacy Analysis: Subjects with a >=3 Reduction from Pre-dose to Post-dose in the UPDRS Part 
3 Score by Visit With Percentages Based on N  (ITT Population) ....................................................... 40 
Table 14.2.3.3    Exploratory Efficacy Analysis: Subjects with a >=6 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score 
by Visit (ITT Population) ............................................................................................ 40 
Table 14.2.3.4 Exploratory Efficacy Analysis: Subjects with a >=6 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score by 
Visit With Percentages Based on N  (ITT Population) .................................................................. 40 
Table 14.2.3.5    Exploratory Efficacy Analysis: Subjects with a >=11 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 
Score by Visit (ITT Population) ...................................................................................... 40 
Table 14.2.3.6    Exploratory Efficacy Analysis: Subjects with a >=11 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 
Score by Visit With Percentages Based on N  (ITT Population) ......................................................... 40 
Table 14.2.4.1 Exploratory Efficacy Analysis: Subjects Achieving Resolution of an OFF to an ON State within 60 Minutes by Visit 
Worst Case Imputation [a] (ITT Population) ........................................................................... 41 
Table 14.2.5.1.1    Exploratory Efficacy Analysis: Mean of Total Daily OFF Time by Visit (ITT Population)............................... 42 
Table 14.2.5.1.2 Sensitivity Analysis: Mean of Total Daily OFF Time by Visit MI analysis with Missing At Random Assumption  (ITT 
Population) .......................................................................................................... 43 
Table 14.2.5.1.3   Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Baseline PD Severity  (ITT 
Population) .......................................................................................................... 43 
Table 14.2.5.1.4   Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Baseline Dyskinesia (ITT 
Population) .......................................................................................................... 43 
Table 14.2.5.1.5   Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Baseline Daily Levodopa Dose 
(ITT Population) ..................................................................................................... 44 
Table 14.2.5.1.6   Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by PD Diary Mean Daily OFF Time 
during Screening  (ITT Population) ................................................................................... 44 
Table 14.2.5.1.7   Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Screening Spirometry  (ITT 
Population) .......................................................................................................... 44 
Table 14.2.5.1.8   Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Age Group (ITT Population).......... 44 
Table 14.2.5.1.9      Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Gender  (ITT Population)......... 44 
Table 14.2.5.2    Exploratory Efficacy Analysis: Mean of Total Daily ON Time without Dyskinesia by Visit (ITT Population)............... 45 
Table 14.2.5.3    Exploratory Efficacy Analysis: Mean of Total Daily ON Time with non-Troublesome Dyskinesia by Visit (ITT 
Population) .......................................................................................................... 45 
Table 14.2.5.4    Exploratory Efficacy Analysis: Mean of Total Daily ON Time with Troublesome Dyskinesia by Visit (ITT Population)...... 45 
Table 14.2.6.1 Exploratory Efficacy Analysis: Subjects Global Impression of Change (PGI-C) by Visit Worst Case Imputation [a] (ITT 
Population) .......................................................................................................... 46 
Table 14.2.7.1 Exploratory Efficacy Analysis: UPDRS Part 2 Score at TV4/OV4 (ITT Population)............................................ 47 
Table 14.2.7.2    Exploratory Efficacy Analysis: UPDRS Part 2 Score at TV6/OV6  (ITT Population)........................................ 48 
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Table 14.2.8.1 Exploratory Efficacy Analysis: Schwab and England (S&E) Activities of Daily Living (ADL) Score at TV4/OV4 (ITT 
Population) .......................................................................................................... 48 
Table 14.2.8.2 Exploratory Efficacy Analysis: Schwab and England (S&E) Activities of Daily Living (ADL) Score at TV6/OV6 (ITT 
Population) .......................................................................................................... 48 
Table 14.2.9.1 Exploratory Efficacy Analysis: 39 Item Parkinson's disease Questionnaire (PDQ-39) Sub-scores and Summary Index Score 
at TV4/OV4 (ITT Population) .......................................................................................... 48 
Table 14.2.9.2    Exploratory Efficacy Analysis: 39 Item Parkinson's disease Questionnaire (PDQ-39) Sub-scores and Summary Index 
Score at TV6/OV6 (ITT Population) .................................................................................... 48 
Table 14.3.1.1    Extent of Exposure: Overall for CVT-301 Group Only  (Safety Population)............................................... 49 
Table 14.3.1.2    In-Clinic Study Drug Administration  (Safety Population).............................................................. 52 
Table 14.3.1.3    Distribution of Time of Study Drug Administration for CVT-301 Group Only (Safety Population).......................... 53 
Table 14.3.2.1    Treatment-Emergent Adverse Events -Overall Summary  (Safety Population)............................................... 54 
Table 14.3.2.2.1 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  (Safety Population)........................ 55 
Table 14.3.2.2.2    Treatment-Emergent Adverse Events by Preferred Term  (Safety Population)............................................ 56 
Table 14.3.2.3 Drug-Related Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and Severity  (Safety 
Population) .......................................................................................................... 57 
Table 14.3.2.4 Drug –Related Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and Relationship  (Safety 
Population) .......................................................................................................... 58 
Table 14.3.2.5    Drug-related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  (Safety Population).......... 59 
Table 14.3.2.6 Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  (Safety Population).................. 59 
Table 14.3.2.7 Listing of Serious Adverse Events........................................................................................ 60 
Table 14.3.2.8 Listing of Adverse Events Leading to Death............................................................................... 61 
Table 14.3.2.9 Severe Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  (Safety Population)................... 61 
Table 14.3.2.10 Listing of Severe Treatment-Emergent Adverse Events..................................................................... 61 
Table 14.3.2.11    Treatment-Emergent Adverse Events Leading to Study Drug Interruption by System Organ Class and Preferred Term  
(Safety Population) .................................................................................................. 61 
Table 14.3.2.12    Listing of Adverse Events Leading to Study Drug Interruption......................................................... 61 
Table 14.3.2.13 Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System Organ Class and Preferred Term  
(Safety Population) .................................................................................................. 61 
Table 14.3.2.14 Listing of Adverse Events Leading to Study Drug Discontinuation......................................................... 62 
Table 14.3.2.15 Treatment-Emergent Adverse Events Leading to Dose Reduction by System Organ Class and Preferred Term  (Safety 
Population) .......................................................................................................... 62 
Table 14.3.2.16 Listing of Adverse Events Leading to Dose Reduction..................................................................... 62 
Table 14.3.2.17 Most Common Treatment-Emergent Adverse Events (Preferred Term Occurred in >10% of Over Patients) by System Organ 
Class and Preferred Term  (Safety Population) ........................................................................ 62 
Table 14.3.2.18 Listing of Most Common Treatment-Emergent Adverse Events................................................................ 62 
Table 14.3.2.19 Time to first Onset of Most Common Treatment-Emergent Adverse Events (Preferred Term Occurred in >10% of Over 
Patients)  (Safety Population) ....................................................................................... 63 
Table 14.3.4.1 Clinical Laboratory Results: PCS and PCSC Criteria....................................................................... 64 
Table 14.3.4.1.1.1 Summary of Clinical Laboratory Results: Hematology (Safety Population)............................................... 65 
Table 14.3.4.1.1.2 Summary of Clinical Laboratory Results: Hematology Abnormal Values (Safety Population)............................... 66 
Table 14.3.4.1.1.3 Summary of Clinical Laboratory Results: Hematology Abnormal Values –Shift from Baseline (Safety Population).......... 67 
Table 14.3.4.1.1.4 Summary of Clinical Laboratory Results: Hematology PCS Values –Shift from Baseline (Safety Population)............... 68 
Table 14.3.4.1.1.5 Summary of Clinical Laboratory Results: Hematology PCSC Values –Shift from Baseline (Safety Population).............. 69 
Table 14.3.4.1.1.6 Clinical Laboratory Results – Hematology PCS and PCSC Values (Safety Population)..................................... 70 
Table 14.3.4.1.2.1 Summary of Clinical Laboratory Results: Chemistry (Safety Population)................................................ 71 
Table 14.3.4.1.2.2 Summary of Clinical Laboratory Results: Chemistry Abnormal Values (Safety Population)................................ 71 
Table 14.3.4.1.2.3    Summary of Clinical Laboratory Results: Chemistry Abnormal Values –Shift from Baseline (Safety Population)........ 71 
Table 14.3.4.1.2.4    Summary of Clinical Laboratory Results: Chemistry PCS Values –Shift from Baseline (Safety Population)............. 71 
Table 14.3.4.1.2.5    Summary of Clinical Laboratory Results: Chemistry PCSC Values –Shift from Baseline (Safety Population)............ 72 
Table 14.3.4.1.2.6 Clinical Laboratory Results – Chemistry PCS and PCSC Values  (Safety Population)..................................... 72 
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Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2 Vital Signs: PCS and PCSC Criteria....................................................................................... 73 
Table 14.3.4.2.1 Summary of Vital Signs: Actual Values and Change from Baseline across Visits  (Safety Population)...................... 74 
Table 14.3.4.2.2 Summary of Vital Signs: Actual Values and Change from Pre-dose at dose at TV1 (Safety Population)...................... 75 
Table 14.3.4.2.3 Summary of Standard Vital Signs: PCS and PCSC Values by Visit (Safety Population)...................................... 76 
Table 14.3.4.2.4 Summary of Standard Vital Signs: PCS and PCSC Values by Scheduled Timepoint at TV1 (Safety Population)................. 77 
Table 14.3.4.2.5    Standard Vital Signs: PCS and PCSC Values........................................................................... 78 
Table 14.3.4.2.6 Summary of Vital Signs: Orthostatic Hypotension by Visit  (Safety Population).......................................... 79 
Table 14.3.4.2.7 Summary of Vital Signs: Orthostatic Hypotension by Scheduled Timepoint at TV1  (Safety Population)..................... 80 
Table 14.3.4.2.8  Orthostatic Vital Signs............................................................................................... 81 
Table 14.3.4.3 12-Lead ECG:PCS and PCSC Criteria........................................................................................ 82 
Table 14.3.4.3.1 Summary of 12-Lead ECG: Actual Values and Change across Visits  (Safety Population).................................... 83 
Table 14.3.4.3.2 Summary of 12-Lead ECG: PCS and PCSC Values  (Safety Population)....................................................... 84 
Table 14.3.4.3.3    12-Lead Electrocardiogram (ECG): PCS and PCSC Values................................................................ 85 
Table 14.3.4.4 Physical Examination  (Safety Population)................................................................................ 86 
Table 14.3.4.5.1.1 Summary of Spirometry (Neurology Office): Actual Values and Change from Baseline for FEV1 and FVC by Visit  
(Safety Population) .................................................................................................. 87 
Table 14.3.4.5.1.2 Summary of Spirometry (Neurology Office): Actual Values and Change from Baseline for FEV1 and FVC by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  (Safety Population) .................................... 88 
Table 14.3.4.5.1.3 Summary of Spirometry (Neurology Office): Actual Values and Change from Baseline for FEV1 and FVC by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  (Safety Population) ............................ 88 
Table 14.3.4.5.1.4 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1 by Visit (Safety Population)...... 89 
Table 14.3.4.5.1.5 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1 by Visit  Using Subset of 
Assessments Meeting the ATS Quality Criteria  (Safety Population) .................................................... 90 
Table 14.3.4.5.1.6 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1 by Visit  Excluding Patients 
with Co-efficient of Variation (CV) of FEV1 >7.5%  (Safety Population) ............................................... 90 
Table 14.3.4.5.1.7 Sensitivity Analysis Using MMRM: Change from Baseline for FEV1 by Visit MI analysis with Missing At Random 
Assumption  (Safety Population) ...................................................................................... 91 
Table 14.3.4.5.1.8 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FEV1 by Visit  
(Safety Population) .................................................................................................. 92 
Table 14.3.4.5.1.9 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FEV1 by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  (Safety Population) .................................... 92 
Table 14.3.4.5.1.10 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FEV1 by 
Visit  Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  (Safety Population) ..................... 92 
Table 14.3.4.5.1.11 Sensitivity Analysis Using MMRM: Change from Baseline for Percentage Predicted FEV1 by Visit  MI analysis with 
Missing At Random Assumption  (Safety Population) .................................................................... 92 
Table 14.3.4.5.1.12 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FVC by Visit  (Safety Population)..... 93 
Table 14.3.4.5.1.13 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FVC by Visit  Using Subset of 
Assessments Meeting the ATS Quality Criteria  (Safety Population) .................................................... 93 
Table 14.3.4.5.1.14 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FVC by Visit  Excluding Patients 
with Co-efficient of Variation (CV) of FEV1 >7.5%  (Safety Population) ............................................... 93 
Table 14.3.4.5.1.15 Sensitivity Analysis Using MMRM: Change from Baseline for FVC by Visit MI analysis with Missing At Random 
Assumption  (Safety Population) ...................................................................................... 94 
Table 14.3.4.5.1.16 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FVC by Visit  
(Safety Population) .................................................................................................. 94 
Table 14.3.4.5.1.17 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FVC by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  (Safety Population) .................................... 94 
Table 14.3.4.5.1.18 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FVC by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  (Safety Population) ............................ 95 
Table 14.3.4.5.1.19 Sensitivity Analysis Using MMRM: Change from Baseline for Percentage Predicted FVC by Visit MI analysis with 
Missing At Random Assumption  (Safety Population) .................................................................... 95 
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Program Name: xxxx.sas                                                           
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Table 14.3.4.5.2.1 Summary of Spirometry :( Neurology Office): Actual Values and Change from Baseline for FEV1/FVC by Visit  
(Safety Population) .................................................................................................. 96 
Table 14.3.4.5.2.2 Summary of Spirometry :( Neurology Office): Actual Values and Change from Baseline for FEV1/FVC by Visit  Using 
Subset of Assessments Meeting the ATS Quality Criteria  (Safety Population) .......................................... 97 
Table 14.3.4.5.2.3 Summary of Spirometry :( Neurology Office): Actual Values and Change from Baseline for FEV1/FVC by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  (Safety Population) ............................ 97 
Table 14.3.4.5.2.4 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1/FVC by Visit  (Safety 
Population) .......................................................................................................... 97 
Table 14.3.4.5.2.5 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1/FVC by Visit  Using Subset of 
Assessments Meeting the ATS Quality Criteria  (Safety Population) .................................................... 97 
Table 14.3.4.5.2.6 MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1/FVC by Visit  Excluding 
Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  (Safety Population) ...................................... 97 
Table 14.3.4.5.2.7 Sensitivity Analysis Using MMRM: Change from Baseline for FEV1/FVC by Visit MI analysis with Missing At Random 
Assumption  (Safety Population) ...................................................................................... 98 
Table 14.3.4.5.3.1 Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and <70% by Visit  (Safety Population)........... 99 
Table 14.3.4.5.3.2 Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and <70% by Visit  Using Subset of 
Assessments Meeting the ATS Quality Criteria  (Safety Population) ................................................... 100 
Table 14.3.4.5.3.3 Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and <70% by Visit  Excluding Patients with 
Co-efficient of Variation (CV) of FEV1 >7.5%  (Safety Population) ................................................... 100 
Table 14.3.4.5.4 Spirometry (Neurology Office): 70% or Smaller FEV1/FVC Values......................................................... 101 
Table 14.3.4.5.5 Summary of Spirometry (Neurology Office): Measurements Meeting ATS Quality Criteria  (Safety Population).............. 102 
Table 14.3.4.5.6 Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change from Baseline for Calculated DLco 
Parameters by Visit  (Safety Population) ............................................................................ 103 
Table 14.3.4.5.7 Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change from Baseline for FEV1 and FVC by 
Visit  (Safety Population) .......................................................................................... 104 
Table 14.3.4.5.8 Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change from Baseline for FEV1/FVC by Visit  
(Safety Population) ................................................................................................. 105 
Table 14.3.4.5.9 Summary of Spirometry (Pulmonary Function Facility): Summary of FEV1/FVC < 60% and <70% by Visit (Safety 
Population) ......................................................................................................... 106 
Table 14.3.4.5.10 Spirometry (Pulmonary Function Facility):70% or Smaller FEV1/FVC Values by Visit..................................... 107 
Table 14.3.4.5.11 Summary of Spirometry (Pulmonary Function Facility): Measurements Meeting ATS Quality Criteria  (Safety 
Population) ......................................................................................................... 108 
Table 14.3.4.6.1 Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) (Safety Population)........................................ 109 
Table 14.3.4.6.2 Shift from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) (Safety Population)............................ 110 
Table 14.3.4.7 Summary of Epworth Sleepiness Scale Total Score: Actual Values and Change from Baseline by Visit (Safety Population).... 111 
Table 14.3.4.8 Summary of Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP) by Visit (Safety Population).......... 112 
Table 14.3.4.9.1 MMRM Analysis of UPDRS Part 4: Change from Baseline in the UPDRS Part 4 Score by Visit (Safety Population)............ 114 
Table 14.3.4.9.2    MMRM Analysis of UPDRS Part 4 Dyskinesias Score: Change from Baseline in the UPDRS Part 4 Score by Visit  
(Safety Population) ................................................................................................. 115 
Table 14.3.4.9.3    MMRM Analysis of UPDRS Part 4 Fluctuations Score: Change from Baseline in the UPDRS Part 4 Score by Visit  
(Safety Population) ................................................................................................. 115 
Table 14.3.4.9.4 Summary of UPDRS Part 4: Actual Values and Change from Baseline by Visit  (Safety Population)......................... 116 
Table 14.3.4.9.5 Summary of UPDRS Part 4 Dyskinesias Score: Actual Values and Change from Baseline by Visit  (Safety Population)....... 117 
Table 14.3.4.9.6    Summary of UPDRS Part 4 Fluctuations Score: Actual Values and Change from Baseline by Visit  (Safety 
Population) ......................................................................................................... 117 
Table 14.3.4.10 Dyskinesia: Occurrence and Severity (In-clinic) by Visit  (ITT Population)............................................. 118 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.1.1 
Number of Subjects Enrolled and Study Termination  
(All Available Population) 
 
 
 
CVT-301 
 
 
 
O.C. 
n (%) 
002/003 
n (%) 
Naive 
n (%) 
Total 
n (%) 
Overall 
n (%) 
 
 
 
 
 
 
Screened 
 
 
 
 
xx 
Failed Screening [a] 
 
 
 
xx (xx.x) 
Randomized [a] 
xx 
xx 
xx 
xx 
xx (xx.x) 
Safety Population [b] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ITT Population [b] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Completed Study [b] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Withdrawn from Study [b] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reason for Withdrawal from Study [c] 
 
 
 
 
 
Adverse Event 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lack of Efficacy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subject Withdrew Consent 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Protocol Violation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lost to Follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Other  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
[a] Percentages are based on the number of screened subjects. 
[b] Percentages are based on the number of randomized subjects. 
[c] Percentages are based on the number of randomized and dosed subjects withdrawn from study. 
[d] Percentages are based on the number of subjects in safety population. 
Cross-reference: Listing 16.2.1, 16.2.3.3 
 
 
Page 73 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.1.2 
Number of Subjects in Each Population by Study Center 
All Subjects 
 
 
 
O.C. 
 
 
 
002/003 
 
 
 
Naive 
 
 
Randomized 
n (%) 
Safety 
n (%) 
ITT 
n (%) 
 
Randomized 
n (%) 
Safety 
n (%) 
ITT 
n (%) 
 
Randomized 
n (%) 
Safety 
n (%) 
ITT 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Overall 
xxx 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
Site 1 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
Site 2 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
Site 3 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
… 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. PP=Per-protocol; Percentages are based on the 
number of subjects in each population for each treatment group. 
 
Cross-reference: Listing 16.2.1, 16.2.3.3 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.1.2 
Number of Subjects in Each Population by Study Center  
All Subjects 
 
 
CVT-301 Total 
 
 
Overall 
 
 
 
Randomized 
n (%) 
Safety 
n (%) 
ITT 
n (%) 
 
Randomized 
n (%) 
Safety 
n (%) 
ITT 
n (%) 
 
 
 
 
 
 
 
 
 
 
Overall 
xxx 
xxx 
xxx 
 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
Site 1 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
Site 2 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
Site 3 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
… 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
xxx(xx.x) 
xxx(xx.x) 
xxx(xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. PP=Per-protocol; Percentages are based on the 
number of subjects in each population for each treatment group. 
 
Cross-reference: Listing 16.2.1, 16.2.3.3 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.2.1    
Summary of Protocol Deviation  
Randomized Set 
 
 
 
 
 
 
 
CVT-301 
 
 
 
O. C. 
N=xxx 
n (%) 
 
002/003 
N=xxx 
n (%) 
 
 
Naive 
N=xxx 
n (%) 
Total 
N=xxx 
n (%) 
Overall 
N=xxx 
n (%) 
 
 
 
 
 
 
 
 
 
Any Protocol Deviation 
xxx (xx.x) 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
xxx (xx.x) 
           xxx (xx.x) 
 
 
 
 
 
 
 
 
 
Any Minor Protocol Deviation 
xxx (xx.x) 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
xxx (xx.x) 
           xxx (xx.x) 
Any Major Protocol Deviation 
xxx (xx.x) 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
xxx (xx.x) 
           xxx (xx.x) 
Without Impact on Pulmonary Assessments 
xxx (xx.x) 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
xxx (xx.x) 
           xxx (xx.x) 
With Pulmonary Impact on Assessments 
xxx (xx.x) 
 
xxx (xx.x) 
 
 
xxx (xx.x) 
xxx (xx.x) 
           xxx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Percentages are based on the number of subjects in 
each treatment group.  
Cross-reference: Appendix 16.2.2.1 
 
Program Name: Lxxxxx.sas 
Table Generation: ddmonyyyy hh:mm 
 
 
 
Page 76 of 335


Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.1.1 
Demographic and Baseline Characteristics  
(Safety Population) 
 
 
 
 
 
CVT-301 
 
 
Characteristic 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naïve 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
Age (years)  
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Age (years) 
 
 
 
 
 
 
  <65 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  >=65 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Gender 
 
 
 
 
 
 
  Male 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Female 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
  Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Unknown 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Race 
 
 
 
 
 
 
  American Indian or Alaska Native  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Black or African American  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Hawaiian or other  
  Pacific Islander  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Unknown 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Other 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Height (cm) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
Weight (kg) 
... 
 
 
 
 
 
BMI ((kg/m^2) [a] 
... 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
[a] BMI was calculated as weight (kg) / [height (m)]^2. 
Cross-reference: Listing 16.2.4.1, 16.2.4.4, 16.2.4.7, 16.2.4.10 
Page 77 of 335


Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.1.1 
Demographic and Baseline Characteristics  
(Safety Population) 
 
 
 
 
 
CVT-301 
 
 
Characteristic 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
 Naïve 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
Country 
 
 
 
 
 
 
  United States 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Canada 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking History 
 
 
 
 
 
 
  Never 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Former 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Current 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Number of Years Smoked 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Number of Cigarettes/Day  
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
… 
 
 
 
 
 
MMSE Total Score 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
… 
 
 
 
 
 
Screening Spirometry  
 
 
 
 
 
 
FEV1 <60% or FEV1/FVC ratio <70% 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
FEV1 >=60% and FEV1/FVC ratio >=70% 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Baseline PD Severity 
 
 
 
 
 
 
Hoehn & Yahr scale < 2.5 points 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Hoehn & Yahr scale>= 2.5 points 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Randomization Strata 
 
 
 
 
 
 
Hoehn & Yahr scale < 2.5 points AND FEV1 <60% 
or FEV1/FVC ratio <70% 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Hoehn & Yahr scale < 2.5 points AND FEV1 
>=60% and FEV1/FVC ratio >=70% 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Hoehn & Yahr scale>= 2.5 points AND FEV1 <60% 
or FEV1/FVC ratio <70% 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Hoehn & Yahr scale>= 2.5 points AND FEV1 
>=60% and FEV1/FVC ratio >=70% 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
 [a] BMI was calculated as weight (kg) / [height (m)]^2. 
Cross-reference: Listing 16.2.4.1, 16.2.4.4, 16.2.4.7, 16.2.4.10 
Page 78 of 335


Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.1.2    
Demographic and Baseline Characteristics  
(ITT Population) 
 
Table 14.1.3.1.3 
Demographic and Baseline Characteristics 
by Baseline PD Severity 
(ITT Population) 
 
will have similar format as Table 14.1.2.1. Summarize for “Hoehn & Yahr scale < 2.5 points” and “Hoehn & Yahr scale >= 2.5 points” 
respectively. 
 
Table 14.1.3.1.4 
Demographic and Baseline Characteristics 
by Baseline Dyskinesia  
(ITT Population) 
 
will have similar format as Table 14.1.2.1. Summarize for “Dyskinetic before TV1” and “Non-dyskinetic before TV1” respectively. 
 
Table 14.1.3.1.5 
Demographic and Baseline Characteristics 
by Baseline Daily Levodopa Dose 
(ITT Population) 
 
will have similar format as Table 14.1.2.1. Summarize for “Baseline Daily Levodopa Dose<=Median of Baseline Daily Levodopa Dose” and 
“Baseline Daily Levodopa Dose>=Median of Baseline Daily Levodopa Dose” respectively. 
 
Table 14.1.3.1.6 
Demographic and Baseline Characteristics 
by PD Diary Mean Daily OFF Time during Screening 
(ITT Population) 
 
will have similar format as Table 14.1.2.1. Summarize for “PD Diary Mean Daily OFF Time during Screening < 4.5 Hours” and “PD Diary 
Mean Daily OFF Time during Screening >=4.5 Hours” respectively. 
 
Table 14.1.3.1.7 
Demographic and Baseline Characteristics 
by Screening Spirometry  
(ITT Population) 
 
will have similar format as Table 14.1.2.1. Summarize for “FEV1 <60% or FEV1/FVC ratio <70%” and “FEV1 ≥60% and FEV1/FVC ratio ≥70%” 
respectively. 
 
Table 14.1.3.1.8 
Demographic and Baseline Characteristics 
by Age Group 
(ITT Population) 
 
will have similar format as Table 14.1.3.1.1 Summarize for “Non-elderly (<65 years)” and “Elderly (≥65 years) patients” respectively. 
Page 79 of 335


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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table 14.1.3.1.9 
Demographic and Baseline Characteristics 
by Gender 
(ITT Population) 
 
will have similar format as Table 14.1.3.1.1 Summarize for “Female” and “Male” respectively. 
 
 
 
 
 
Page 80 of 335


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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.2.1 
Parkinson’s Disease History 
(Safety Population) 
 
 
 
 
 
CVT-301 
 
 
 
Statistic 
O. C. 
(N=xx) 
002/003 
 (N=xx) 
Naïve 
(N=xx) 
Total 
 (N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
Time Since Diagnosis of Parkinson’s Disease (months) 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Duration of Levodopa Treatment (months) 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Duration since Onset of Fluctuation (Wearing Off) 
 Episodes (months) 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Average Daily Levodopa Dose (mg) 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
Baseline  Average # of Daily Levodopa Doses 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
Screening UPDRS III Total Score (ON State) 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
Screening UPDRS III Total Score (OFF State) 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
Difference from OFF to ON State in Screening 
 UPDRS III Total Score 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
Percent Difference from OFF to ON in Screening  
UPDRS III Total Score (%)[a] 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Average Number of Daily OFF Episodes Experienced 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
Patients who Changed the Timing of Their Usual 
 Levodopa Medication 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Patients who Took an Extra Dose of Levodopa  
or other PD Medication 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
[a] % was calculated as OFF-ON/OFF * 100%’. 
[b]The patients who have recorded at least 1 hour of dyskinesia (either ON with non-troublesome dyskinesia or ON with troublesome 
Cross-reference: Listing 16.2.4.3, 16.2.4.8, 16.2.4.9, 16.2.5.3, 16.2.6.1.1, 16.2.8.2.4.1 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.2.1 
Parkinson’s Disease History 
(Safety Population) 
 
 
 
 
CVT-301 
 
 
 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
 Naïve 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
Screening PD Diary 
 
 
 
 
 
 
  Mean Daily OFF Time (hours)  
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
… 
 
 
 
 
 
Mean Daily OFF Time during Screening< 4.5 Hours 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Mean Daily OFF Time during Screening>= 4.5 Hours 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
  Mean Daily ON Time Without Dyskinesia    (hours) 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
  Mean Daily ON Time With  
  Non-troublesome Dyskinesia (hours) 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
  Mean Daily ON Time With  
  Troublesome Dyskinesia (hours) 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
Baseline Dyskinesia 
 
 
 
 
 
 
  Dyskinetic before TV1/OV1[b] 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Non-dyskinetic before TV1 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Missing 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Screening Spirometry data (ON) 
 
 
 
 
 
 
   FEV1 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
 
 
   FVC 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   FEV1/FVC 
n 
xx 
xx 
xx 
xx 
xx 
 
mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Screening Spirometry data (OFF) 
 
 
 
 
 
 
   FEV1 
 
 
 
 
 
 
   FVC 
 
 
 
 
 
 
   FEV1/FVC 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
[a] % was calculated as OFF-ON/OFF * 100%. 
[b]The patients who have recorded at least 1 hour of dyskinesia (either ON with non-troublesome dyskinesia or ON with troublesome 
dyskinesia) on at least 2 days before TV1/OV1 will be classified as dyskinetic. 
 
Cross-reference: Listing 16.2.4.3, 16.2.4.8, 16.2.4.9, 16.2.5.3, 16.2.6.1.1, 16.2.8.2.4.1 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table 14.1.3.2.2 
Parkinson’s Disease History 
(ITT Population) 
 
will have similar format as Table 14.1.3.2.1. 
 
Table 14.1.3.2.3 
Parkinson’s Disease History 
by Baseline PD Severity 
(ITT Population) 
 
will have similar format as Table 14.1.3.2.1, but to summarize for “Hoehn & Yahr scale < 2.5 points” and “Hoehn & Yahr scale >= 2.5 
points” respectively. No need to summarize “Baseline PD Severity”. 
 
Table 14.1.3.2.4 
Parkinson’s Disease History 
by Baseline Dyskinesia  
(ITT Population) 
 
will have similar format as Table 14.1.3.2.1, but to summarize for “Dyskinetic before Visit 3” and “Non-dyskinetic before Visit 3” 
respectively. No need to summarize “Baseline Dyskinesia”. 
 
Table 14.1.3.2.5 
Parkinson’s Disease History 
by Baseline Daily Levodopa Dose 
(ITT Population) 
 
will have similar format as Table 14.1.3.2.1. Summarize for “Baseline Daily Levodopa Dose<=Median of Baseline Daily Levodopa Dose” and 
“Baseline Daily Levodopa Dose>=Median of Baseline Daily Levodopa Dose ” respectively. 
 
Table 14.1.3.2.6 
Parkinson’s Disease History 
by PD Diary Mean Daily OFF Time during Screening 
(ITT Population) 
 
will have similar format as Table 14.1.3.2.11, but to summarize for “PD Diary Mean Daily OFF Time during Screening <4.5 Hours” and “PD 
Diary Mean Daily OFF Time during Screening >=4.5 Hours”. 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.2.7 
Parkinson’s Disease History 
by Screening Spirometry  
(ITT Population) 
 
will have similar format as Table 14.1.3.2.1. Summarize for “FEV1 <60% or FEV1/FVC ratio <70%” and “FEV1 ≥60% and FEV1/FVC ratio ≥70%” 
respectively. 
 
Table 14.1.3.2.8 
Parkinson’s Disease History 
by Age Group 
(ITT Population) 
 
will have similar format as Table 14.1.3.2.1. Summarize for “Non-elderly (<65 years)” and “Elderly (≥65 years) patients” respectively. 
 
Table 14.1.3.2.9 
Parkinson’s Disease History 
by Gender 
(ITT Population) 
 
will have similar format as Table 14.1.3.2.1. Summarize for “Female” and “Male” respectively. 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.2.10 
Modified Hoehn and Yahr Staging in “ON” State 
(Safety Population) 
 
 
 
CVT-301 
 
 
 
O. C. 
(N=xx) 
n (%) 
002/003 
(N=xx) 
n (%) 
Naive 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
Overall 
(N=xx) 
n (%) 
 
 
 
 
 
 
Modified Hoehn and Yahr  
 
 
 
 
 
  Stage 0 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Stage 1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Stage 1.5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Stage 2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Stage 2.5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Stage 3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Stage 4 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Stage 5 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Cross-reference: Listing 16.2.4.6 
 
 
Table 14.1.3.2.11 
Modified Hoehn and Yahr Staging in “ON” State 
(ITT Population) 
will have similar format as Table 14.1.3.2.11. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.2.12    
Distribution of Average Daily OFF Time at Baseline 
(Safety Population) 
 
 
 
 
CVT-301 
 
 
Time Interval/OFF Hours (%) 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
Average Total Daily OFF Time (Hours) 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Average Daily OFF Hours (%) 
 
 
 
 
 
00:00 -< 00:30 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
00:30 -< 01:00 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
01:00 -< 01:30 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
01:30 -< 02:00 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
... 
 
 
 
 
 
 
 
 
 
 
 
Continue with 30 mins interval until 23:30 -< 
24:00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Total daily OFF time is calculated as the average of total OFF time collected three days prior to TV1/OV1and is normalized to 16 awake 
hours per day. Average daily OFF Hours at each interval will be calculated similarly. The percentage is based on Total Daily OFF Time.  
Cross-reference: Listing 16.2.6.2.2 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.3.2.13    
Distribution of Cumulative Average Daily OFF Time at Baseline 
(Safety Population) 
 
 
 
 
CVT-301 
 
 
Time Interval/OFF Hours (%) 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
Average Total Daily OFF Time (Hours) 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
Cumulative Average Daily OFF Hours (%) 
 
 
 
 
 
00:00 -< 00:30 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
00:00 -< 01:00 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
00:00 -< 01:30 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
00:00 -< 02:00 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
... 
 
 
 
 
 
 
 
 
 
 
 
Continue with 30 mins interval until 00:00 -< 24:00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Total daily OFF time is calculated as the average of total OFF time collected three days prior to TV1/OV1and is normalized to 16 awake 
hours per day.  Cumulative Average daily OFF Hours are calculated similarly. The percentage is based on Total Daily OFF Time.  
Cross-reference: Listing 16.2.6.2.2 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table 14.1.3.3 
Medical History  
(Safety Population) 
 
 
 
 
CVT-301 
 
 
System Organ Class   
  Preferred Term [a] 
O. C. 
(N=xx) 
Subjects Events 
n  (%)     n 
002/003 
(N=xx) 
Subjects Events 
n  (%)     n 
Naïve 
(N=xx) 
Subjects Events 
n  (%)     n 
Total 
(N=xx) 
Subjects Events 
n  (%)     n 
Overall 
(N=xx) 
Subjects Events 
n  (%)     n 
 
 
 
 
 
 
Any Medical History 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
System Organ Class 1 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term 1 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term 2 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
System Organ Class 2 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term 1 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term 2 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
 [a] Medical history data were coded into system organ class and preferred term by using MedDRA version 17.0. 
 
Cross-reference: Listing 16.2.4.2 
 
 
Programming note: The table will be sorted by total descending frequency of SOC and then, within a SOC, by total descending frequency 
of PT. 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.4.1 
Prior Medications  
(Safety Population) 
 
 
 
 
CVT-301 
 
 
ATC Level 1 
  ATC Level 2 
    Preferred Term 
[a] 
O. C. 
(N=xx) 
Subjects   Meds 
    n  (%)       n 
002/003 
(N=xx) 
Subjects   Meds 
   n  (%)       n 
Naive 
(N=xx) 
Subjects   Meds 
   n  (%)       n 
Total 
(N=xx) 
Subjects   Medi 
   n  (%)       n 
Overall 
(N=xx) 
Subjects   Meds 
   n  (%)       n 
 
 
 
 
 
 
Any Medications 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
ATC Level 1 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  ATC Level 2 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  ATC Level 2 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
ATC Level 1 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  ATC Level 2 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  ATC Level 2 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Meds = Medications; O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were 
previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Data from “Prior and Concomitant Medications” CRF page were summarized in this table. The medications with a stop date before the 
first date of study drug dosing will be considered prior medications. 
[a] Medications were coded into ATC and preferred term using the WHO Drug Dictionary,Q1March2014. 
 
Cross-reference: Listing 16.2.4.11.1 
 
Programming note: The table will be sorted by total descending frequency of ATC1 and ATC2 and then, within a ATC2, by total descending 
frequency of PT. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.4.2 
Concomitant Medications  
(Safety Population) 
 
Will have same format as Table 14.1.4.1 
 
Note: Meds = Medications; O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were 
previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Data from “Prior and Concomitant Medications” CRF page were summarized in this table. The medications with start date or stop date on 
or after the first date of study drug dosing will be considered concomitant medications. 
[a] Medications were coded into ATC and preferred term using the WHO Drug Dictionary, Q1March2014. 
 
Cross-reference: Listing 16.2.4.11.2 
Page 90 of 335


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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.1.4.3    
Parkinson’s disease Treatment Medications at Baseline 
(ITT Population) 
 
 
 
 
CVT-301 
 
 
  ATC Level 4 
    Preferred Term 
[a] 
O. C. 
(N=xx) 
Subjects   Meds 
    n  (%)       n 
002/003 
(N=xx) 
Subjects   Meds 
   n  (%)       n 
Naive 
(N=xx) 
Subjects   Meds 
   n  (%)       n 
Total 
(N=xx) 
Subjects   Meds 
   n  (%)       n 
Overall 
(N=xx) 
Subjects   Meds 
   n  (%)       n 
 
 
 
 
 
 
Any Medications 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
  ATC Level 4 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  ATC Level 4 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
  ATC Level 4 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  ATC Level 4 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
    Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Meds = Medications; O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were 
previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
 [a] Medications were coded into ATC and preferred term using the WHO Drug Dictionary, Q1March2014.The medications which start with 
ATC code N04 are considered as baseline PD treatment medications. 
Cross-reference: Listing 16.2.4.11.2 
 
 
Programming note: The table will be sorted by total descending frequency of ATC and then, within a ATC, by total descending frequency 
of PT. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.1.1 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 10 Minutes Post-dose by Visit 
(ITT Population) 
 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
  Screening Spirometry 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV2 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS  Part 3 total scores at 10 minutes at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5 or TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) as fixed factors; the baseline UPDRS part 3 score will be included as a covariate, assuming an unstructured 
covariance matrix. 
 
Cross-reference: Listing 16.2.6.1.2 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.1.2 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 20 Minutes Post-dose by Visit 
(ITT Population) 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS  Part 3 total scores at 20 minutes at each post-baseline visit (TV2, TV3,TV4, TV5 or 
TV6) as the dependent variable, and includes visit ((TV2, TV3,TV4, TV5 or TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) as fixed factors; the baseline UPDRS part 3 score will be included as a covariate, assuming an unstructured 
covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
Table 14.2.1.3.1 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit 
(ITT Population) 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS  Part 3 total scores at 30 minutes at each post-baseline visit (TV2, TV3,TV4, TV5 or 
TV6) as the dependent variable, and includes visit (TV2, TV3,TV4, TV5 or TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) as fixed factors; the baseline UPDRS part 3 score will be included as a covariate, assuming an unstructured 
covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
will have similar format as Table 14.2.1.1.1. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.1.3.2 
Sensitivity Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit 
MI analysis with Missing At Random Assumption  
(ITT Population) 
 
Visit/Statistic((Number of Datasets = 100) 
CVT-301 
(N=xx) 
 
 
TV2 
 
MI Mean (SE)  
xx.x(xx.xx) 
MI Median  
xx.x 
MI Minimum, MI Maximum  
xx, xx 
 
 
TV3 
 
TV4 
 
TV5 
 
TV6 
 
TV3 
 
Note: TV = Treatment Visit;  
The non-monotone missing values will be imputed using the Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate 
normal distribution over all variables included in the imputation model. The monotone missing values are imputed using pattern mixture 
model assuming missing at random. MMRM model uses the change from pre-dose in UPDRS Part 3 total scores at 30 minutes at each post-
baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, visit (TV2, TV3, TV4, TV5, TV6), the stratification variables 
(baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio 
<70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; the Baseline UPDRS part 3 score will be included as a covariate, 
assuming an unstructured covariance matrix. The MIANALYZE procedure in SAS will be applied to combine the results from these datasets 
to derive an overall estimate at each visi 
Cross-reference: Listing 16.2.6.1.2 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.1.3.3 
Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Baseline PD Severity  
(ITT Population) 
 
Hoehn & Yahr scale < 2.5 points 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
Overall p-value   
 
 
 
  Screening Spirometry 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV2 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS Part 3 total scores at 30 minutes at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5, TV6), the stratification variable (screening spirometry 
([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; the baseline 
UPDRS part 3 score will be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
 
Programming Note: Do separate analysis for “Hoehn & Yahr scale < 2.5 points” and “Hoehn & Yahr scale >= 2.5 points”, and do not 
include baseline PD severity in MMRM model. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.1.3.4 
 Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Baseline 
Dyskinesia 
(ITT Population) 
 
Dyskinetic before TV1 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
  Screening Spirometry 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV2 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS Part 3 total scores at 30 minutes at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; the Baseline UPDRS part 3 score will 
be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
 
Programming Note: Do separate analysis for Dyskinetic before TV1/OV1versus Non-Dyskinetic before TV1 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.1.3.5    
 Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Baseline 
Daily Levodopa Dose  
(ITT Population) 
 
Baseline Daily Levodopa Dose<=Median of Baseline Daily Levodopa Dose 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
  Screening Spirometry 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV2 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS Part 3 total scores at 30 minutes at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; the Baseline UPDRS part 3 score will 
be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
 
Programming Note: Do separate analysis for “Baseline Daily Levodopa Dose<=Median of Baseline Daily Levodopa Dose” and “Baseline Daily 
Levodopa Dose>=Median of Baseline Daily Levodopa Dose” respectively. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
 
Table 14.2.1.3.6 
 Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by PD Diary 
Mean Daily OFF Time during Screening  
(ITT Population) 
 
PD Diary Mean Daily OFF Time during Screening <4.5 Hours 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
  Screening Spirometry 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV2 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS Part 3 total scores at 30 minutes at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; the Baseline UPDRS part 3 score will 
be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
 
Programming Note: Do separate analysis for “PD Diary Mean Daily OFF Time during Screening<4.5 Hours” and “PD Diary Mean Daily OFF Time 
during Screening>=4.5 Hours”. 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.1.3.7 
 Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Screening 
Spirometry  
(ITT Population) 
 
FEV1 <60% or FEV1/FVC ratio <70% 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV2 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS Part 3 total scores at 30 minutes at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)) and the interaction between the treatment group and visit as fixed factors; the Baseline UPDRS part 3 score 
will be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
 
Programming Note: Do separate analysis for FEV1 <60% or FEV1/FVC ratio <70% and FEV1 ≥60% and FEV1/FVC ratio ≥70% 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table 14.2.1.3.8    
 Exploratory Efficacy Subgroup Analysis: Mean Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Age 
Group 
(ITT Population) 
 
Non-elderly (<65 years) 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
  Screening Spirometry 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV2 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS Part 3 total scores at 30 minutes at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; the Baseline UPDRS part 3 score will 
be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
 
Programming Note: Do separate analysis for ‘Non-elderly (<65 years)’ and ‘Elderly (>=65 years)‘ respectively. 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.1.3.9    
 Exploratory Efficacy Subgroup Analysis: Mean Change from Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by 
Gender  
(ITT Population) 
 
Male 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
  Screening Spirometry 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV2 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS Part 3 total scores at 30 minutes at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; the Baseline UPDRS part 3 score will 
be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
 
Programming Note: Do separate analysis for ‘Male’ and ‘Female’ respectively. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
 
Table 14.2.1.4  
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 60 Minutes Post-dose by Visit 
(ITT Population) 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS  Part 3 total scores at 60 minutes at each post-baseline visit (TV2, TV3,TV4, TV5 or 
TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5 or TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) as fixed factors; the baseline UPDRS part 3 score will be included as a covariate, assuming an unstructured 
covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
Table 14.2.1.5 
Exploratory Efficacy Analysis: Change from Pre-dose in the Average UPDRS Part 3 Score at 10 to 60 Minutes Post-dose by Visit 
(ITT Population) 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose to the average of the 4 post-dose UPDRS Part 3 total scores (10,20,30 and 60 minutes) at each 
post-baseline visit (TV2, TV3,TV4, TV5 or TV6) as the dependent variable, and includes visit (TV2, TV3,TV4, TV5 or TV6), the 
stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital 
capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; the baseline UPDRS part 3 score will be 
included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.6.1.2 
 
will have similar format as Table 14.2.1.1.1. 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.2.1 
Exploratory Efficacy Analysis: Change from Pre-dose in UPDRS Part 3 Score to 10, 20, 30, 60 minutes Post-dose by Visit 
(ITT Population) 
 
Timeponit 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
 
10 mins Post-dose 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
 
  Screening Spirometry 
 
0.xxx 
 
 
  Treatment  
 
0.xxx 
 
 
  Visit 
 
0.xxx 
 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
 
 
TV2 
n 
xx 
 
 
 
LS Mean 
xx.x 
 
 
 
SE (LS Mean) 
xx.xx 
 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
TV3 
... 
 
 
 
TV4 
... 
 
 
 
TV5 
 
 
 
 
TV6 
 
 
 
 
 
 
 
 
20 mins Post-dose 
 
... 
 
 
 
 
 
 
 
30 mins Post-dose 
 
... 
 
 
 
 
 
 
 
60 mins Post-dose 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from pre-dose in UPDRS Part 3 score to 10, 20, 30, or 60 minutes at each post-baseline visit (TV2, TV3, 
TV4, TV5, TV6) as the dependent variable, and includes visit (TV2, TV3, TV4, TV5, TV6) the stratification variables (baseline Hoehn 
and Yahr stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 
≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; baseline UPDRS part 3 score will be included as a covariate, assuming an unstructured 
covariance matrix. A separate MMRM model will be fitted for each of the time points. 
 
 
Cross-reference: Listing 16.2.6.1.2 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
 
Table 14.2.2.2 
Exploratory Efficacy Analysis: Change from Pre-Dose to 10, 20, 30, 60 minutes Post-dose in UPDRS Part 3 Score by Visit and Timepoint  
(ITT Population) 
 
Timepoint 
Visit 
Statistic 
CVT-301 
(N=xx) 
 
 
 
 
Pre-dose 
TV2 
Actual value 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
SEM 
xx.x 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
 
 
 
 
TV3 
... 
 
 
TV4 
... 
 
 
… 
 
 
 10 mins post-dose 
TV2 
Actual value 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
SEM 
xx.x 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
 
 
 
 
 
Change from Pre-dose 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
SEM 
xx.x 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
TV3 
... 
 
 
TV4 
... 
 
 
 
 
 
 
… 
 
 
 
 
 
 
  20 mins Post-dose 
 
 
 
  30 mins Post-dose 
 
 
 
  60 mins Post-dose 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
Cross-reference: Listing 16.2.6.1.2 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.2.3 
 Exploratory Efficacy Analysis: Change from Pre-Dose to 10, 20, 30, 60 minutes Post-dose in UPDRS Part 3 Score by Timepoint and Visit  
(ITT Population) 
 
Visit 
 
 Timepoint 
Statistic 
CVT-301 
(N=xx) 
 
 
 
 
TV2 
  Pre-dose 
Actual value 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
SEM 
xx.x 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
 
 
 
 
  10 mins Post-dose 
Actual value 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
SEM 
xx.x 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
 
 
 
 
 
Change from Pre-dose 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
SEM 
xx.x 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
 
 
 
 
 
... 
 
 
  20 mins Post-dose 
 
 
 
  30 mins Post-dose 
 
 
 
  60 mins Post-dose 
 
 
 
 
 
 
Continue with TV3, TV4, TV5, TV6 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
Cross-reference: Listing 16.2.6.1.2 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.2.3.1 
Exploratory Efficacy Analysis: Subjects with a >=3 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score by Visit 
(ITT Population) 
 
 
Visit/Time Point 
CVT-301 
(N=xx) 
n (%) 
TV2 
 
  Any Time Post-dose 
 
n* 
xx 
Cumulative number of subjects having achieved the response 
xx (xx.x) 
 
 
  10 mins Post-dose 
 
n* 
xx 
Number of subjects achieving the first response 
xx (xx.x) 
 
 
  20 mins Post-dose 
xx (xx.x) 
n* 
xx 
Number of subjects achieving the first response 
xx (xx.x) 
Cumulative number of subjects having achieved the response[a] 
xx (xx.x) 
 
 
  30 mins Post-dose 
xx (xx.x) 
n* 
xx 
Number of subjects achieving the first response 
xx (xx.x) 
Cumulative number of subjects having achieved the response 
xx (xx.x) 
 
 
  60 mins Post-dose  
xx (xx.x) 
n* 
xx 
Number of subjects achieving the first response 
xx (xx.x) 
Cumulative number of subjects having achieved the response 
xx (xx.x) 
 
 
TV3 … 
 
TV4 … 
 
TV5 … 
 
TV6 … 
 
 
 
Note: TV = Treatment Visit; ; Percentages are based on n*, the number of subjects with UPDRS Part 3 performed at any time post-dose 
and pre-dose. 
[a]Cumulative numbers of subjects refer to the subjects who achieved the first reduction before or at the time point. 
 
Cross-reference: Listing 16.2.6.1.2 
 
 
 
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Program Name: xxxx.sas                                                           
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Table below will use the table 14.2.3.1 template except that percentages are based on N 
 
Table 14.2.3.2 
Additional Exploratory Efficacy Analysis: Subjects with a >=3 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score by Visit 
With Percentages Based on N 
 (ITT Population) 
 
 
Note: Percentages are based on the header count N. 
Cross-reference: Listing 16.2.6.1.2 
 
 
Table 14.2.3.3    
Exploratory Efficacy Analysis: Subjects with a >=6 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score by Visit 
(ITT Population) 
 
 
Table 14.2.3.4 
Exploratory Efficacy Analysis: Subjects with a >=6 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score by Visit 
With Percentages Based on N 
 (ITT Population) 
 
Note: TV = Treatment Visit; Percentages are based on the header count N. 
Cross-reference: Listing 16.2.6.1.2 
 
 
Table 14.2.3.5    
Exploratory Efficacy Analysis: Subjects with a >=11 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score by Visit 
(ITT Population) 
 
 
Table 14.2.3.6    
Exploratory Efficacy Analysis: Subjects with a >=11 Reduction from Pre-dose to Post-dose in the UPDRS Part 3 Score by Visit 
With Percentages Based on N 
 (ITT Population) 
 
 
Note: TV = Treatment Visit; Percentages are based on the header count N. 
Cross-reference: Listing 16.2.6.1.2 
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Program Name: xxxx.sas                                                           
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Table 14.2.4.1 
Exploratory Efficacy Analysis: Subjects Achieving Resolution of an OFF to an ON State within 60 Minutes by Visit 
Worst Case Imputation [a] 
(ITT Population) 
 
Visit/ 
 Category 
Statistic 
 
CVT-301 
(N=xx) 
 
 
 
 
TV2 
 
 
 
  Turned ON within 60 Minutes  
 
 
 
    Yes 
n (%) 
 
xx (xx.x) 
    No 
n (%) 
 
xx (xx.x) 
 
 
 
 
  Turned ON within 60 Minutes (Observed) 
 
 
 
    Yes 
n (%) 
 
xx (xx.x) 
    No 
n (%) 
 
xx (xx.x) 
    Missing  
n (%) 
 
xx (xx.x) 
 
 
 
 
TV3 
 
 
 
TV4 
 
 
 
TV5 
 
 
 
TV6 
 
 
 
Note: TV = Treatment Visit;  
[a] The patient who achieved resolution of an OFF to an ON state within 60 minutes after study drug is administered in the clinic and 
maintaining the ON at 60 minutes after study drug administration will be counted as Yes. The missing values will be counted as non-
resolved. 
Cross-reference: Listing 16.2.6.2.1 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
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Table 14.2.5.1.1    
Exploratory Efficacy Analysis: Mean of Total Daily OFF Time by Visit 
(ITT Population) 
 
Visit 
Statistic 
O.C. 
(N=xx) 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
 
0.xxx 
 
  Screening Spirometry 
 
 
0.xxx 
 
  Treatment  
 
 
0.xxx 
 
  Visit 
 
 
0.xxx 
 
  Treatment-by-Visit Interaction 
 
 
0.xxx 
 
  Baseline Daily OFF time 
 
 
0.xxx 
 
 
 
 
 
TV2/OV2 
n 
xx 
xx 
 
 
LS Mean 
xx.x 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
LS Mean Difference (CVT-301 – O.C.) 
 
xx.x 
 
 
95% CI (LS Mean Difference) 
 
(xx.x, xx.x) 
 
 
p-value (LS Mean Difference) 
 
0.xxx 
 
TV3/OV3 
 
 
 
 
... 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit; MMRM model uses the total daily OFF time at each post-baseline visit (TV2, 
TV3,TV4, TV5 or TV6) as the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), 
the stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5) and screening spirometry ([FEV1] <60% or FEV1/forced 
vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit 
as fixed factors. The total daily OFF time at baseline will be included as a covariate, assuming an unstructured covariance matrix.  
 
Cross-reference: Listing 16.2.6.2.3.2 
 
 
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Program Name: xxxx.sas                                                           
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Table below will use format Table 14.2.1.3.2 except for two treatment group. 
 
Table 14.2.5.1.2 
Sensitivity Analysis: Mean of Total Daily OFF Time by Visit 
MI analysis with Missing At Random Assumption  
(ITT Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit; 
The non-monotone missing values will be imputed using the Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate 
normal distribution over all variables included in the imputation model. The monotone missing values are imputed using pattern mixture 
model assuming missing at random. MMRM model uses the total daily OFF time at each post-baseline visit (TV2, TV3,TV4, TV5 or TV6) as 
the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification 
variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] 
ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors.  The 
total daily OFF time at baseline will be included as a covariate, assuming an unstructured covariance matrix. The MIANALYZE procedure 
in SAS will be applied to combine the results from these datasets to derive an overall estimate at each visit. 
 
Cross-reference: Listing 16.2.6.2.3.2 
 
 
Table below will use the table 14.2.5.1.1 template except will be performed for “Hoehn & Yahr scale < 2.5 points” and “Hoehn & Yahr 
scale >= 2.5 points” and removed ‘baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)’ in the model. Footnote revised. 
 
Table 14.2.5.1.3 
  Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Baseline PD Severity  
(ITT Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit; MMRM model uses the total daily OFF time at each post-baseline visit (TV2, 
TV3,TV4, TV5 or TV6) as the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), 
the stratification variables (screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors. The total daily OFF time at baseline 
will be included as a covariate, assuming an unstructured covariance matrix.  
 
Cross-reference: Listing 16.2.6.2.3.2 
 
Table below will use the table 14.2.5.1.1 template and footnote except will be performed for “Dyskinetic before TV1” and “Non-
dyskinetic before TV1” 
 
 
Table 14.2.5.1.4 
  Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Baseline Dyskinesia 
(ITT Population) 
 
 
Table below will use the table 14.2.5.1.1 template and footnote except will be performed for “Baseline Daily Levodopa Dose<=Median of 
Baseline Daily Levodopa Dose” and “Baseline Daily Levodopa Dose>=Median of Baseline Daily Levodopa Dose”. 
 
 
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Program Name: xxxx.sas                                                           
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Table 14.2.5.1.5 
  Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Baseline Daily Levodopa Dose 
(ITT Population) 
 
 
Table below will use the table 14.2.5.1.1 template and footnote except will be performed for “PD Diary Mean Daily OFF Time during 
Screening < 4.5 Hours” and “PD Diary Mean Daily OFF Time during Screening >=4.5 Hours”. 
 
 
Table 14.2.5.1.6 
  Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by PD Diary Mean Daily OFF Time during Screening  
(ITT Population) 
 
 
Table below will use the table 14.2.5.1.1 template and footnote except will be performed for “FEV1 <60% or FEV1/FVC ratio <70%” and 
“FEV1 ≥60% and FEV1/FVC ratio ≥70%”removed ‘screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus 
FEV1 ≥60% and FEV1/FVC ratio ≥70%’ in the model. Footnote revised. 
 
Table 14.2.5.1.7 
  Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Screening Spirometry  
(ITT Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit; MMRM model uses the total daily OFF time at each post-baseline visit (TV2, 
TV3,TV4, TV5 or TV6) as the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), 
the stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)) and the interaction between the treatment group and 
visit as fixed factors. The total daily OFF time at baseline will be included as a covariate, assuming an unstructured covariance 
matrix. 
  
Cross-reference: Listing 16.2.6.2.3.2 
 
Table below will use the table 14.2.5.1.1 template and footnote except will be performed for “Non-elderly (<65 years)” and “Elderly 
(≥65 years) patients”. 
 
Table 14.2.5.1.8 
  Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Age Group 
(ITT Population) 
 
Table below will use the table 14.2.5.1.1 template and footnote except will be performed for “Female” and “Male”. 
 
Table 14.2.5.1.9    
  Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by Gender  
(ITT Population) 
 
Table below will use the table 14.2.5.1.1 template. 
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Program Name: xxxx.sas                                                           
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Table 14.2.5.2    
Exploratory Efficacy Analysis: Mean of Total Daily ON Time without Dyskinesia by Visit 
(ITT Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit;  MMRM model uses the total daily ON time without dyskinesia at each post-
baseline visit (TV2, TV3,TV4, TV5 or TV6) as the dependent variable, and includes visit (TV2, TV3,TV4, TV5 or TV6), the stratification 
variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] 
ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; the total daily ON time without dyskinesia at baseline will be 
included as a covariate, assuming an unstructured covariance matrix.  
 
Cross-reference: Listing 16.2.6.2.3.2 
 
Table 14.2.5.3    
Exploratory Efficacy Analysis: Mean of Total Daily ON Time with non-Troublesome Dyskinesia by Visit 
(ITT Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit; MMRM model uses the total daily ON time with non-troublesome dyskinesia at each 
post-baseline visit (TV2, TV3,TV4, TV5 or TV6) as the dependent variable, and includes visit (TV2, TV3,TV4, TV5 or TV6), the 
stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital 
capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; the total daily ON time with non-troublesome 
dyskinesia at baseline will be included as a covariate, assuming an unstructured covariance matrix.  
 
Cross-reference: Listing 16.2.6.2.3.2 
 
Table 14.2.5.4    
Exploratory Efficacy Analysis: Mean of Total Daily ON Time with Troublesome Dyskinesia by Visit 
(ITT Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit;  MMRM model uses the total daily ON time with troublesome dyskinesia at each 
post-baseline visit (TV2, TV3,TV4, TV5 or TV6) as the dependent variable, and includes visit (TV2, TV3,TV4, TV5 or TV6), the 
stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)  and screening spirometry ([FEV1] <60% or FEV1/forced vital 
capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; the total daily ON time with troublesome 
dyskinesia at baseline will be included as a covariate, assuming an unstructured covariance matrix.  
 
Cross-reference: Listing 16.2.6.2.3.2 
 
 
will have similar format as Table 14.2.5.1.1. 
  
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
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Table 14.2.6.1 
Exploratory Efficacy Analysis: Subjects Global Impression of Change (PGI-C) by Visit 
Worst Case Imputation [a] 
(ITT Population) 
 
Visit/Statistic 
 
CVT-301 
(N=xx) 
n (%) 
 
 
 
TV4/OV4 
 
 
n 
 
xx 
Much Improved 
 
xx (xx.x) 
Improved 
 
xx (xx.x) 
A little Improved 
 
xx (xx.x) 
No Change 
 
xx (xx.x) 
A Little Worse 
 
xx (xx.x) 
Worse 
 
xx (xx.x) 
Much Worse 
 
xx (xx.x) 
 
 
 
Improved [b] 
 
 
  Yes 
 
xx (xx.x) 
  No  
 
xx (xx.x) 
 
 
 
Improved (Observed) 
 
 
  Yes 
 
xx (xx.x) 
  No  
 
xx (xx.x) 
  Missing 
 
xx (xx.x) 
 
 
 
TV6/OV6 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit; Percentages are based on n, the number of subjects with PGI-C performed at each 
visit. 
[a] The missing values will be counted as No. 
[b] The patient who had PGI-C response of much improved, improved or a little improved will be counted as Yes. 
 
Cross-reference: Listing 16.2.6.2.4 
 
 
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Program Name: xxxx.sas                                                           
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Table 14.2.7.1 
Exploratory Efficacy Analysis: UPDRS Part 2 Score at TV4/OV4 
(ITT Population) 
 
Visit 
Statistic 
O. C. 
(N=xx)  
CVT-301 
(N=xx) 
 
 
 
 
Baseline 
Actual Value 
 
 
 
n 
xx 
xx 
 
Mean  
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
 
TV4/OV4 
Actual value 
 
 
 
n 
xx 
xx 
 
Mean  
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
 
 
Change from Baseline 
 
 
 
n 
xx 
xx 
 
Mean  
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
 
 
LS Mean 
xx.xx 
xx.xx 
 
SE (LS Mean) 
xx.xxx 
xx.xxx 
 
95% CI (LS Mean) 
(xx.xx, xx.xx) 
(xx.xx, xx.xx) 
 
 
 
 
 
LS Mean Difference (CVT-301 – O. C.) 
 
xx.xx 
 
95% CI (LS Mean Difference) 
 
(xx.xx, xx.xx) 
 
p-value (LS Mean Difference) 
 
0.xxx 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit; Baseline is defined as the assessments performed at TV1/OV1. If the TV1/OV1 
assessment is missing, the last non-missing screening assessment will be used as baseline.  An ANCOVA model with the treatment group 
and stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5) and screening spirometry ([FEV1] <60% or FEV1/forced 
vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors and the baseline value as a covariate will 
be used to estimate the treatment differences. 
 
Cross-reference: Listing 16.2.6.3.1 
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Program Name: xxxx.sas                                                           
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Table below s will use the table 14.2.7.1 template. 
 
Table 14.2.7.2    
Exploratory Efficacy Analysis: UPDRS Part 2 Score at TV6/OV6  
(ITT Population) 
 
Table below s will use the table 14.2.7.1 template with revised cross-reference 
 
Table 14.2.8.1 
Exploratory Efficacy Analysis: Schwab and England (S&E) Activities of Daily Living (ADL) Score at TV4/OV4 
(ITT Population) 
 
Table 14.2.8.2 
Exploratory Efficacy Analysis: Schwab and England (S&E) Activities of Daily Living (ADL) Score at TV6/OV6 
(ITT Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit; Baseline is defined as the assessments performed at TV1/OV1. If the TV1/OV1 
assessment is missing, the last non-missing screening assessment will be used as baseline. An ANCOVA model with the treatment group 
and stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced 
vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors and the baseline value as a covariate will 
be used to estimate the treatment differences. 
 
Cross-reference: Listing 16.2.6.3.2 
 
 
Table below s will use the table 14.2.7.1 template with revised cross-reference 
 
Table 14.2.9.1 
Exploratory Efficacy Analysis: 39 Item Parkinson's disease Questionnaire (PDQ-39) Sub-scores and Summary Index Score at TV4/OV4 
(ITT Population) 
 
 
Table 14.2.9.2    
Exploratory Efficacy Analysis: 39 Item Parkinson's disease Questionnaire (PDQ-39) Sub-scores and Summary Index Score at TV6/OV6 
(ITT Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit; Baseline is defined as the assessments performed at TV1/OV1. If the TV1/OV1 
assessment is missing, the last non-missing screening assessment will be used as baseline. An ANCOVA model with the treatment group 
and stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced 
vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors and the baseline value as a covariate will 
be used to estimate the treatment differences. 
 
Cross-reference: Listing 16.2.6.3.2 
 
 
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Program Name: xxxx.sas                                                           
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Table 14.3.1.1    
Extent of Exposure: Overall for CVT-301 Group Only  
(Safety Population) 
 
 
 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Subjects with Dose Change 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Increase 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Decrease 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Duration of Exposure (days) [a] 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
Summed Total 
xxx 
xxx 
xxx 
 
 
 
 
 
Total Number of Capsules Taken (Overall) 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
TV1-<TV2 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
TV2-<TV3 
 
 
 
 
TV3-<TV4 
 
 
 
 
TV4-<TV5 
... 
 
 
 
TV5-TV6 
... 
 
 
 
Total Number of Doses Taken (Overall) 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
TV1-<TV2 
... 
 
 
 
TV2-<TV3 
... 
 
 
 
TV3-<TV4 
... 
 
 
 
TV4-<TV5 
 
 
 
 
TV5-TV6 
 
 
 
 
 
 
 
 
 
Average Daily Doses (Overall) 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
TV1-<TV2 
... 
 
 
 
TV2-<TV3 
... 
 
 
 
TV3-<TV4 
... 
 
 
 
TV4-<TV5 
 
 
 
 
TV5-TV6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Average Daily Number of Capsules (Overall) 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
TV1-<TV2 
 
 
 
 
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Program Name: xxxx.sas                                                           
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TV2-<TV3 
 
 
 
 
TV3-<TV4 
 
 
 
 
TV4-<TV5 
 
 
 
 
TV5-TV6 
 
 
 
 
Note: TV = Treatment Visit; Total column is for all CVT-301 treated patients, 002/003 column is for the patients who were previously 
enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Data presented is self-reported by 
study participants and is subject to limitations of self-report measures.  
[a] Duration of exposure (days) is calculated as documented last dose date-first dose date +1. 
Cross-reference: Listing 16.2.5.1.3, 16.2.5.1.4, 16.2.5.1.5 
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Program Name: xxxx.sas                                                           
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Table 14.3.1.1    
Extent of Exposure: Overall for CVT-301 Group Only 
(Safety Population) 
 
 
 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Proportion of Days with >5 Doses per Day 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Days with 5 Doses per Day 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Days with 4 Doses per Day 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Days with 3 Doses per Day 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Days with 2 Doses per Day 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Days with 1 Dose per Day 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Days with 0 Dose per Day 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Patients using >5 Doses/day at least once 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Patients using 5 Doses/day at least once 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Patients using 4 Doses/day at least once 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Patients using 3 Doses/day at least once 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Patients using 2 Doses/day at least once 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
... 
 
 
 
Proportion of Patients using 1 Dose/day at least once 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
Proportion of Patients using 0 Dose/day at least once 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
Note: TV = Treatment Visit; Total column is for all CVT-301 treated patients, 002/003 column is for the patients who were previously 
enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
 Data presented is self-reported by study participants and is subject to limitations of self-report measures.  
[b] Duration of exposure (days) is calculated as documented last dose date-first dose date +1. 
Cross-reference: Listing 16.2.5.1.1, 16.2.5.1.3 
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Program Name: xxxx.sas                                                           
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Table 14.3.1.2    
In-Clinic Study Drug Administration  
(Safety Population) 
 
Visit 
Parameter 
Statistic 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
TV1 
Standard Morning Dose of LD-containing Medications 
to in-clinic OFF (mins) 
n 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
<= 180 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 180 to <= 210 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 210 to <= 240 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 240 to <= 270 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 270 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
In-clinic OFF to Start of Study Drug Inhalation (mins)  
n 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
 
 
... 
 
 
 
 
<= 10 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 10 to <= 15 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 15 to <= 20 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 20 to <= 25 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 25 to <= 30 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
> 30 mins 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
Standard Morning Dose of LD-containing Medications  
to Start of Study Drug Inhalation (mins) 
n 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
 
Duration of Study Drug Inhalation (mins) 
n 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
 
 
... 
 
 
 
TV2 
... 
 
 
 
 
TV3 
... 
 
 
 
 
... 
 
 
 
 
 
Note: TV = Treatment Visit; Total column is for all CVT-301 treated patients, 002/003 column is for the patients who were previously 
enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Percentages are based on the number of subjects with results for each parameter at each treatment visit within each treatment group or 
Overall. 
 
Cross-reference: Listing 16.2.5.1.2 
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Program Name: xxxx.sas                                                           
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Table 14.3.1.3    
Distribution of Time of Study Drug Administration for CVT-301 Group Only 
(Safety Population) 
 
Time Interval 
Statistic 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Total Study Medication Intakes 
n 
xx 
xx 
xx 
 
 
 
 
 
00:00 -< 00:30 
n (%) 
xx (%) 
xx (%) 
xx (%) 
00:30 -< 01:00 
n (%) 
xx (%) 
xx (%) 
xx (%) 
01:00 -< 01:30 
n (%) 
xx (%) 
xx (%) 
xx (%) 
01:30 -< 02:00 
n (%) 
xx (%) 
xx (%) 
xx (%) 
... 
 
 
 
 
 
 
 
 
 
Continue with 30 mins interval until 23:30 -< 24:00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Total column is for all CVT-301 treated patients, 002/003 column is for the patients who were previously enrolled in the CVT-
301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. The percentage is based on the total # of study medication 
intakes. 
Cross-reference: Listing 16.2.5.1.1 
 
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Program Name: xxxx.sas                                                           
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Table 14.3.2.1    
Treatment-Emergent Adverse Events -Overall Summary  
(Safety Population) 
 
 
 
 
CVT- 301 
 
 
 
O. C. 
(N=xx) 
Subjects Events 
n  (%)  n 
002/003 
(N=xx) 
Subjects Events 
n  (%)  n 
Naive 
(N=xx) 
Subjects Events 
n  (%)  n 
Total 
(N=xx) 
Subjects Events 
n  (%)  n 
Overall 
(N=xx) 
Subjects Events 
n  (%)  n 
 
 
 
 
 
 
Any TEAEs 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
Drug-related TEAEs [a] 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
Severe TEAEs 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
Serious TEAEs 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
TEAEs Leading to Study  
Drug Interruption 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
TEAEs Leading to Study  
Drug Discontinuation 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
TEAEs Leading to Dose 
Reduction 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
TEAEs Leading to Death 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
xx (xx.x)  xx (xx.x) 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Treatment-emergent adverse events (TEAEs) are defined 
as all AEs that start after the patient receives the first dose of study drug. 
[a] Adverse events are considered drug-related if the event is classified as possibly, probably, or definitely related  
to study drug. 
 
Cross-reference: Listing 16.2.7.1 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
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Table 14.3.2.2.1 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  
(Safety Population) 
 
 
 
 
CVT- 301 
 
 
System Organ Class   
  Preferred Term [a] 
O. C. 
 (N=xx) 
Subjects Events 
n  (%)  n 
002/003 
(N=xx) 
Subjects Events 
n  (%)  n 
Naive 
(N=xx) 
Subjects Events 
n  (%)  n 
Total 
(N=xx) 
Subjects Events 
n  (%)  n 
Overall 
(N=xx) 
Subjects Events 
n  (%)  n 
 
 
 
 
 
 
Any TEAEs 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
System Organ Class  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
System Organ Class  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  ... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Treatment-Emergent Adverse Events (TEAEs) are defined 
as all AEs that start after the patient receives the first dose of study drug. 
[a] Adverse events were coded into system organ class and preferred term using MedDRA version 17.0.  
 
Cross-reference: Listing 16.2.7.1 
 
 
Programming note: The table will be sorted by total descending frequency of SOC and then, within a SOC, by total descending frequency 
of PT. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.2.2.2    
Treatment-Emergent Adverse Events by Preferred Term  
(Safety Population) 
 
 
 
 
CVT- 301 
 
 
  Preferred Term [a] 
O. C. 
 (N=xx) 
Subjects Events 
n  (%)  n 
002/003 
 (N=xx) 
Subjects Events 
n  (%)  n 
Naive 
 (N=xx) 
Subjects Events 
n  (%)  n 
Total 
 (N=xx) 
Subjects Events 
n  (%)  n 
Overall 
(N=xx) 
Subjects Events 
n  (%)  n 
 
 
 
 
 
 
Any TEAEs 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
  Preferred Term 1  
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term 2 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term 3 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  Preferred Term 4 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
  ... 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
xx (xx.x)  xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Treatment-Emergent Adverse Events (TEAEs) are defined 
as all AEs that start after the patient receives the first dose of study drug  
[a] Adverse events were coded into system organ class and preferred term using MedDRA version 17.0.  
 
Cross-reference: Listing 16.2.7.1 
 
 
Programming note: The table will be sorted by total descending frequency of PT. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table 14.3.2.3 
Drug-Related Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and Severity  
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
System Organ Class   
   Preferred Term [a] 
Severity 
O. C. 
(N=xx) 
n  (%) 
002/003 
(N=xx) 
n  (%) 
Naive 
(N=xx) 
n  (%) 
Total 
(N=xx) 
n  (%) 
Overall 
(N=xx) 
n  (%) 
 
 
 
 
 
 
 
All TEAEs 
Total 
xx  
xx  
xx  
xx  
xx  
 
Mild 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
Moderate 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
Severe 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
 
System Organ Class  
Total 
xx  
xx  
xx  
xx  
xx  
 
Mild 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
Moderate 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
Severe 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
 
  Preferred Term  
... 
 
 
 
 
 
  Preferred Term  
 
 
 
 
 
 
... 
 
 
 
 
 
 
System Organ Class  
 
 
 
 
 
 
  Preferred Term  
 
 
 
 
 
 
  Preferred Term  
 
 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Treatment-Emergent Adverse Events (TEAEs) are defined 
as all AEs that start after the patient receives the first dose of study drug. Adverse events are considered drug-related if the event 
is classified as possibly, probably, or definitely related to study drug. The percentages are calculated based on the total number of 
TEAEs. 
[a] Adverse events were coded into system organ class and preferred term using MedDRA version 17.0.  
 
 
Cross-reference: Listing 16.2.7.1 
 
 
Programming note: The table will be sorted by total descending frequency of SOC then PT in total row, total column. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.2.4 
Drug –Related Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and Relationship  
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
System Organ Class 
   Preferred Term [a] 
Maximal 
Severity [b] 
O. C. 
(N=xx) 
n  (%) 
002/003 
(N=xx) 
n  (%) 
Naive 
(N=xx) 
n  (%) 
Total 
(N=xx) 
n  (%) 
Overall 
(N=xx) 
n  (%) 
 
 
 
 
 
 
 
All TEAEs 
Total 
xx     
xx   
xx     
xx     
xx     
 
Possibly Related 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
Probably Related 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
Definitely Related 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
 
System Organ Class  
Total 
xx     
xx   
xx     
xx     
xx     
 
Possibly Related 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
Probably Related 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
Definitely Related 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
 
  Preferred Term  
...  
 
 
 
 
 
  Preferred Term  
 
 
 
 
 
 
... 
 
 
 
 
 
 
System Organ Class  
 
 
 
 
 
 
  Preferred Term  
 
 
 
 
 
 
  Preferred Term  
 
 
 
 
 
 
  ... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Treatment-Emergent Adverse Events (TEAEs) are defined 
as all AEs that start after the patient receives the first dose of study drug. Adverse events are considered drug-related if the event 
is classified as possibly, probably, or definitely related to study drug. The percentages are calculated based on the total number of 
TEAEs.  
[a] Adverse events were coded into system organ class and preferred term using MedDRA version 17.0.  
 
Cross-reference: Listing 16.2.7.1 
 
Programming note: The table will be sorted by Definitely Not Related descending frequency of SOC then PT in total row, total column. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table below s will have same format as T14.3.2.4.1 and note: 
 
 
Table below s will have same format as 14.3.2.2.1and note: 
 
Table 14.3.2.5    
Drug-related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  
(Safety Population) 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Treatment-Emergent Adverse Events (TEAEs) are defined 
as all AEs that start after the patient receives the first dose of study drug Adverse events are considered drug-related if the event 
is classified as possibly, probably, or definitely related to study drug.   
[a] Adverse events were coded into system organ class and preferred term using MedDRA version 17.0.  
 
Cross-reference: Listing 16.2.7.1 
 
Table 14.3.2.6 
Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  
(Safety Population) 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Treatment-Emergent Adverse Events (TEAEs) are defined 
as all AEs that start after the patient receives the first dose of study drug 
[a] Adverse events were coded into system organ class and preferred term using MedDRA version 17.0. 
 
Cross-reference: Listing 16.2.7.1, Table 14.3.2.7 
  
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.2.7 
Listing of Serious Adverse Events 
 
Treatment Group: O. C. 
Treatment 
Group: O. 
C.
 
Su
bject 
ID 
System Organ Class/  
Preferred Term/  
Verbatim Term [a] 
AE Start  
Date  
and Time/ 
Study Day  
[b] 
AE Stop Date and Time 
I: Intensity 
R: Relationship 
   to Study   
   Medication 
A: Action Taken 
Outcome 
SAE? If Yes, Specify [c] 
 
 
 
 
 
 
 
xxxx-xxx 
xxxxxxxxxx/ 
xxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
hh:mm/ 
-xx 
 
ddmonyyyy 
Hh:mm 
I: xxxxxxxx 
R: xxxxxxxx 
A: xxxxxxxxx 
Resolved 
Yes: 1 
 
xxxxxxxxxx/ 
xxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
hh:mm/ 
xx# 
Ongoing 
I: xxxxxxxx 
R: xxxxxxxx 
A: xxxxxxxxx 
Unknown 
No 
xxxx-xxx 
xxxxxxxxxx/ 
xxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
hh:mm/ 
-xx 
 
ddmonyyyy 
Hh:mm 
I: xxxxxxxx 
R: xxxxxxxx 
A: xxxxxxxxx 
Resolved 
Yes: 2 
... 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve)  
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. TEAE=Treatment-emergent AE. SAE=Serious AE. 
[a] Adverse events were coded into system organ class and preferred term using MedDRA version 17.0.  
[b] TEAEs were flagged with a #. The AEs occurred on the clinic visit were flagged with *. Study day is relative to date of first 
study medication (date of first dose = Day 1). 
[c] 1 = The event is fatal or life-threatening, 2 = The event is permanently disabling (incapacitating or interfering 
with the ability to resume usual life patterns), 3 = The event results in unplanned in subject hospitalization or  
prolongation of existing hospitalization, 4 = The event is a congenital anomaly, 5 = The event requires medical  
intervention of any kind in order to prevent any of the aforementioned outcomes. 
 
Cross-reference: Listing 16.2.7.1 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table below s will have same format as T14.3.2.7 
Table 14.3.2.8 
Listing of Adverse Events Leading to Death 
 
 
Table below s will have same format as T14.3.2.2.1and revised Cross-reference 
Table 14.3.2.9 
Severe Treatment-Emergent Adverse Events by System Organ Class and Preferred Term  
(Safety Population) 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Treatment-Emergent Adverse Events (TEAEs) are defined 
as all AEs that start after the patient receives the first dose of study drug Adverse events are considered drug-related if the event 
is classified as possibly, probably, or definitely related to study drug.   
[a] Adverse events were coded into system organ class and preferred term using MedDRA version 17.0.  
 
Cross-reference: Listing 16.2.7.1, table 14.3.2.10 
 
 
Table below s will have same format as T14.3.2.7 
 
Table 14.3.2.10 
Listing of Severe Treatment-Emergent Adverse Events 
(Safety Population) 
 
 
Table below s will have same format as T14.3.2.2.1and revised Cross-reference 
Table 14.3.2.11    
Treatment-Emergent Adverse Events Leading to Study Drug Interruption by System Organ Class and Preferred Term  
(Safety Population) 
Cross-reference: Listing 16.2.7.1, table 14.3.2.12 
 
 
 
Table below s will have same format as T14.3.2.7 
 
Table 14.3.2.12    
Listing of Adverse Events Leading to Study Drug Interruption 
 
 
Table below s will have same format as T14.3.2.2.1and revised Cross-reference 
Table 14.3.2.13 
Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation by System Organ Class and Preferred Term  
(Safety Population) 
Cross-reference: Listing 16.2.7.1, table 14.3.2.14 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table below  will have same format as T14.3.2.7 
 
Table 14.3.2.14 
Listing of Adverse Events Leading to Study Drug Discontinuation 
 
 
 
Table below  will have same format as T14.3.2.2.1and revised Cross-reference 
Table 14.3.2.15 
Treatment-Emergent Adverse Events Leading to Dose Reduction by System Organ Class and Preferred Term  
(Safety Population) 
Cross-reference: Listing 16.2.7.1, table 14.3.2.16 
 
 
 
 
Table below  will have same format as T14.3.2.7 
 
Table 14.3.2.16 
Listing of Adverse Events Leading to Dose Reduction  
 
 
 
Table 14.3.2.17 
Most Common Treatment-Emergent Adverse Events (Preferred Term Occurred in >10% of Over Patients) by System Organ Class and Preferred 
Term  
(Safety Population) 
 
Cross-reference: Listing 16.2.7.1, table 14.3.2.18 
 
Table 14.3.2.18 
Listing of Most Common Treatment-Emergent Adverse Events 
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.2.19 
Time to first Onset of Most Common Treatment-Emergent Adverse Events (Preferred Term Occurred in >10% of Over Patients)  
(Safety Population) 
 
 
 
 
CTV-301 
 
 
Parameter 
O.C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
0 -< 30 Days 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
30 -< 90 Days 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
90 -< 180 Days 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
180 -< 270 Days 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
>= 270 Days 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. TEAE=Treatment-emergent AE. Percentages are based on 
the number of subjects at each treatment group or Overall. Most common TEAEs is defined any AE preferred term occurred in greater than 
10% of overall patients.  Time to first onset of most common TEAE is calculated as onset of first common TEAE-first dose date (or date 
of OV1) +1).  
 
Cross-reference: Listing 16.2.7.1 
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Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.1 
Clinical Laboratory Results: PCS and PCSC Criteria 
 
Laboratory Parameter (Units) 
 
Criteria for PCS Values (Actual values) 
Criteria for PCSC values (Changes from baseline values) 
 
 
High  
Low  
% Increase  
% Decrease  
Hemoglobin  (g/L) 
 
> 10 above ULN  
>20 below LLN  
NA  
25%  
Hematocrit   (1) 
 
>0.04 above ULN  
>0.05 below LLN  
NA  
25%  
WBC (GI/L) 
 
>5 above ULN  
>1 below LLN  
100%  
50%  
Neutrophils (GI/L) 
 
NA  
<0.5xLLN  
100%  
50%  
Neutrophils (% ) 
 
NA  
<0.5xLLN  
100%  
50%  
Lymphocytes (GI/L) 
 
NA  
<0.5xLLN  
100%  
50%  
Lymphocytes (% ) 
 
NA  
<0.5xLLN  
100%  
50%  
Total bilirubin (μmol/L) 
 
>1.5xULN  
NA  
300%  
NA  
Total protein (g/L) 
 
>15 above ULN  
>15 below LLN  
200%  
60%  
Albumin (g/L)  
 
>5 above ULN  
>5 below LLN  
NA  
60%  
AST (U/L) 
 
>3xULN  
NA  
300%  
NA  
ALT (U/L) 
 
>3xULN  
NA  
300%  
NA  
Alkaline Phosphatase (U/L) 
 
>3xULN  
NA  
300%  
NA  
GGT (U/L) 
 
>3xULN  
NA  
300%  
NA  
Creatinine (μmol/L) 
 
>1.5xULN  
NA  
200%  
NA  
Urea (mmol/L) 
 
>2.5xULN  
NA  
300%  
NA  
Uric Acid (μmol/L) 
 
>3xULN  
NA  
300%  
NA  
Sodium (mmol/L) 
 
>5 above ULN  
>5 below LLN  
10%  
10%  
Potassium (mmol/L) 
 
>1 above ULN  
>0.5 below LLN  
25%  
20%  
Carbon dioxide (mmol/L) 
 
>40  
<16  
25%  
25%  
Calcium (mmol/L) 
 
>2.99  
<1.78  
30%  
30%  
Glucose (fasting)* (mmol/L) 
 
>11.1  
<2.8  
300%  
40%  
Note:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gamma glutamyl transferase; LLN = lower limit of normal 
range; NA = not applicable; PCS = potentially clinically significant; PCSC = potentially clinically significant changes;  
Baseline is defined as the assessments performed at TV1/OV1. If the TV1/OV1 assessment is missing, the last non-missing screening 
assessment will be used as baseline. * fasting defined as >=4 hr from prior meal. 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.1.1.1 
Summary of Clinical Laboratory Results: Hematology 
(Safety Population) 
 
 
 
 
 
 
CVT- 301 
 
 
Test (unit) 
Visit 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
 
Test 1 (unit) 
Baseline 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV3/OV3 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Change from Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV4/OV4 
… 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Test 2 (unit) 
Baseline 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Baseline is defined as the TV1/OV1 assessment. If the 
TV1/OV1 assessment is missing, the last non-missing screening assessment will be used as baseline. 
 
Cross-reference: Listing 16.2.8.1.1 
 
Programming Note: Sort by test alphabetically. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.1.1.2 
Summary of Clinical Laboratory Results: Hematology Abnormal Values 
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
Test (unit) 
Visit  
  Assessment 
O. C. 
(N=xx) 
n  (%) 
002/003 
(N=xx) 
n  (%) 
Naive 
(N=xx) 
n  (%) 
Total 
(N=xx) 
n  (%) 
Overall 
(N=xx) 
n  (%) 
 
 
 
 
 
 
 
Test 1 (unit) 
SV1 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Normal 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Abnormal: Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Abnormal: High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCS Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCS High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCSC Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCSC High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
 
 
SV2 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Normal 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Abnormal: Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Abnormal: High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV3/OV3 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Followup 
 
 
 
 
 
 
... 
 
 
 
 
 
Test 2 (unit) 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit;  O.C. column is for the patients in Observational Cohort, 002/003 column is for the 
patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Percentages are based on n, the number of subjects with the test performed at each visit. 
      PCS = potentially clinically significant values. PCSC = potentially clinically significant changes. 
 
Cross-reference: Listing 16.2.8.1.1, Table 14.3.4.1.1.6 
 
Programming Note: Sort by tests alphabetically.  
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.1.1.3 
Summary of Clinical Laboratory Results: Hematology Abnormal Values –Shift from Baseline 
(Safety Population) 
 
Test 1 
 
 
Baseline 
Treatment 
Visit  
  Assessment 
Normal 
n  (%) 
Abnormal: Low 
n  (%) 
Abnormal: High 
n  (%) 
Total 
n  (%) 
 
 
 
 
 
 
O. C. 
TV3/OV3 
 
 
 
 
 
  Normal 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Abnormal: Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Abnormal: High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Total 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
… 
 
 
 
 
 
Followup 
 
 
 
 
 
... 
 
 
 
 
CVT-301 (002/003) 
 
 
 
 
 
CVT-301 (Naïve) 
 
 
 
 
 
CVT-301 Total 
 
 
 
 
 
Overall 
 
 
 
 
 
 
 
 
 
 
 
Continue with other 
tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Percentages are based on the number of subjects with 
the test performed at both baseline and the visit. 
 
 
Cross-reference: Listing 16.2.8.1.1, Table 14.3.4.1.1.6 
 
Programming Note: Sort by tests alphabetically.  
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.1.1.4 
Summary of Clinical Laboratory Results: Hematology PCS Values –Shift from Baseline 
(Safety Population) 
 
Test 1 
 
 
Baseline 
Treatment 
Visit  
  Assessment 
Not PCS 
n  (%) 
PCS: Low 
n  (%) 
PCS: High 
n  (%) 
Total 
n  (%) 
 
 
 
 
 
 
O. C. 
TV3/OV3 
 
 
 
 
 
Not PCS 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
PCS: Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
PCS: High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 Total 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
 
Followup 
 
 
 
 
 
... 
 
 
 
 
CVT-301 (002/003) 
 
 
 
 
 
CVT-301 (Naïve) 
 
 
 
 
 
CVT-301 Total 
 
 
 
 
 
Overall 
 
 
 
 
 
 
 
 
 
 
 
Continue with other 
tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Percentages are based on the number of subjects with 
the test performed at both baseline and the visit. 
      PCS = potentially clinically significant values.  
 
Cross-reference: Listing 16.2.8.1.1, Table 14.3.4.1.1.6 
 
Programming Note: Sort by tests alphabetically.  
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.1.1.5 
Summary of Clinical Laboratory Results: Hematology PCSC Values –Shift from Baseline 
(Safety Population) 
 
Test 1 
 
 
 
 
 
 
Treatment 
Visit  
  Assessment 
Normal 
(N=xx) 
n  (%) 
Abnormal: Low 
(N=xx) 
n  (%) 
Abnormal: High 
(N=xx) 
n  (%) 
Total 
(N=xx) 
n  (%) 
 
 
 
 
 
 
O. C. 
TV4 
 
 
 
 
 
  Normal 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Abnormal: Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Abnormal: High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  Total 
 
 
 
 
 
 
 
 
 
 
 
Followup 
 
 
 
 
 
... 
 
 
 
 
CVT-301 (002/003) 
 
 
 
 
 
CVT-301(Naïve) 
 
 
 
 
 
CVT-301 Total 
 
 
 
 
 
Overall 
 
 
 
 
 
 
 
 
 
 
 
Continue with other 
tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Percentages are based on the number of subjects with 
the test performed at both baseline and the visit. 
      PCSC = potentially clinically significant changes. 
 
Cross-reference: Listing 16.2.8.1.1, Table 14.3.4.1.1.6 
 
Programming Note: Sort by tests alphabetically.  
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.1.1.6 
Clinical Laboratory Results – Hematology PCS and PCSC Values 
(Safety Population) 
 
Treatment Group: O. C. 
Patient  
ID 
Visit 
Date and Time  
of Sample 
Test Name  
(unit)  
Normal  
Range  
Result 
[a] 
 
 
 
 
 
 
xxxx-xxx 
Screening 
ddmonyyyy hh:mm 
xxxxxxx (xxx) 
xxxx-xxx 
Xx H** 
 
 
 
xxxxxxx (xxx) 
xxxx-xxx 
xx L* 
 
 
 
... 
 
 
 
TV3 
ddmonyyyy hh:mm 
xxxxxxx (xxx) 
xxxx-xxx 
Xx L** 
 
 
 
xxxxxxx (xxx) 
xxxx-xxx 
xx H* 
 
 
 
... 
 
 
 
OV3 
 
 
 
 
 
 
 
 
 
 
 
Followup 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
... 
 
 
 
 
 
Programmer note: Please display all values for the parameter if there is at least one PCS or PCSC 
for the parameter 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients.  
L* = potentially clinically significant (PCS) low value, H* = PCS high value, 
      L** = potentially clinically significant change (PCSC) low, H** = PCSC high. 
 
Cross-reference: Listing 16.2.8.1.1 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table below will have same format as T14.3.4.1.1.1 
 
Table 14.3.4.1.2.1 
Summary of Clinical Laboratory Results: Chemistry 
(Safety Population) 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Baseline is defined as the TV1/OV1 assessment. If the 
TV1/OV1 assessment is missing, the last non-missing screening assessment will be used as baseline. 
 
Cross-reference: Listing 16.2.8.1.2 
 
 
Table below will have same format as T14.3.4.1.1.2 with revised cross reference 
 
Table 14.3.4.1.2.2 
Summary of Clinical Laboratory Results: Chemistry Abnormal Values 
(Safety Population) 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. Percentages are based on n, the number of subjects 
with the test performed at each visit. 
 
Cross-reference: Listing 16.2.8.1.2, Table 14.3.4.1.2.6 
 
 
Table below will have same format as T14.3.4.1.1.3 with revised cross reference 
 
Table 14.3.4.1.2.3    
Summary of Clinical Laboratory Results: Chemistry Abnormal Values –Shift from Baseline 
(Safety Population) 
 
Cross-reference: Listing 16.2.8.1.2, Table 14.3.4.1.2.6 
 
 
 
Table below will have same format as T14.3.4.1.1.4with revised cross reference 
 
Table 14.3.4.1.2.4    
Summary of Clinical Laboratory Results: Chemistry PCS Values –Shift from Baseline 
(Safety Population) 
 
 
Cross-reference: Listing 16.2.8.1.2, Table 14.3.4.1.2.6 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
 
Table below will have same format as T14.3.4.1.1.5with revised cross reference 
 
Table 14.3.4.1.2.5    
Summary of Clinical Laboratory Results: Chemistry PCSC Values –Shift from Baseline 
(Safety Population) 
 
Cross-reference: Listing 16.2.8.1.2, Table 14.3.4.1.2.6 
 
 
Table below will have same format as T14.3.4.1.1.6 with revised cross reference 
 
Table 14.3.4.1.2.6 
Clinical Laboratory Results – Chemistry PCS and PCSC Values  
(Safety Population) 
 
Cross-reference: Listing 16.2.8.1.2 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2 
Vital Signs: PCS and PCSC Criteria 
 
Vital Sign Parameters (Units) 
 
Criteria for PCS Values (Actual 
values) 
Criteria for PCSC values (Change from Baseline or pre-dose 
values *) 
 
 
High  
Low  
Increase  
Decrease  
Pulse rate(bpm) 
 
>120  
<40  
2x  
0.5x  
Respiration Rate (brpm) 
 
>32  
<8  
1.5x  
NA  
SBP (Supine) (mmHg) 
 
>200  
<85  
1.6x  
0.2x  
DBP (Supine) (mmHg) 
 
>120  
<40  
1.2x  
0.2x  
Note: bpm = beats per minute; brpm = breaths per minute; NA = not applicable; SBP = Systolic Blood Pressure; DBP = Diastolic Blood  
pressure; PCS = potentially clinically significant; PCSC = potentially clinically significant change. 
* Baseline values will be used for pre-dose and pre-dose values assessment at each treatment visits. Pre-dose values will be used for 
corresponding post-dose values assessment.  
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2.1 
Summary of Vital Signs: Actual Values and Change from Baseline across Visits  
(Safety Population) 
 
 
 
 
 
 
CVT- 301 
 
 
Parameter (unit) 
Visit 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
 
Standard Systolic  
Blood Pressure (unit) 
Baseline 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV2/OV2 Pre-dose 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Change from Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV3/OV3 Pre-dose 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Followup 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Diastolic  
Blood Pressure (unit) 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. The baseline is defined as the TV1/OV1 pre-dose value. 
If TV1/OV1 pre-dose value is missing, the last non-missing screening assessment will be used as baseline. 
 
 
Cross-reference: Listing 16.2.8.2.1 
 
Programming Note: Repeat for Standard Diastolic Blood Pressure, Standard Heart Rate, Standard Respiratory Rate, Upright Systolic Blood 
Pressure, Upright Diastolic Blood Pressure, Upright Heart Rate, Respiration Rate 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2.2 
Summary of Vital Signs: Actual Values and Change from Pre-dose at dose at TV1 
(Safety Population) 
 
Parameter (unit) 
Time Point 
Statistic 
CVT-301 
(N=xx) 
 
 
 
 
Standard Systolic  
Blood Pressure (unit) 
Pre-dose 
Actual value 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
 
 
 
 
 
 
 
 
10 mins Post-dose 
Actual value 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
 
 
 
 
 
Change from Pre-dose 
 
 
 
n 
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.xx 
 
 
Median 
xx.x 
 
 
Min, Max 
xx, xx 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard Diastolic  
Blood Pressure (unit) 
 
 
 
... 
 
 
 
 
 
 
 
Cross-reference: Listing 16.2.8.2.1 
 
Programming Note: Repeat for Standard Diastolic Blood Pressure, Standard Heart Rate, Standard Respiratory Rate, Upright Systolic Blood 
Pressure, Upright Diastolic Blood Pressure, Upright Heart Rate, Respiration Rate 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2.3 
Summary of Standard Vital Signs: PCS and PCSC Values by Visit 
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
Parameter (unit) 
Visit  
  Assessment 
O. C. 
(N=xx)  
n  (%) 
002/003 
(N=xx) 
n  (%) 
Naive 
(N=xx) 
n  (%) 
Total 
(N=xx) 
n  (%) 
Overall 
(N=xx) 
n  (%) 
 
 
 
 
 
 
 
Standard Systolic  
Blood Pressure (unit) 
SV1 
  n 
xx 
xx 
xx 
xx 
xx 
 
  PCS Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCS High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCSC Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCSC High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
 
 
SV2 
  n 
xx 
xx 
xx 
xx 
xx 
 
  PCS Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCS High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCSC Low 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCSC High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
 
 
TV1/OV1 Pre-dose 
  n 
xx 
xx 
xx 
xx 
xx 
 
... 
 
 
 
 
 
 
TV2/OV2 Pre-dose 
 
 
 
 
 
 
... 
 
 
 
 
 
 
TV3/OV3 Pre-dose 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
Followup 
 
 
 
 
 
 
... 
 
 
 
 
 
Standard Diastolic  
Blood Pressure (unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; O.C. column is for the patients in Observational Cohort, 002/003 column is for the 
patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Percentages are based on n, the number of subjects with the test performed at each visit.  
PCS = potentially clinically significant values, PCSC = potentially clinically significant changes. 
 
Cross-reference: Listing 16.2.8.2.1, Table 14.3.4.2.5 
 
Programming Note: Repeat for Standard Diastolic Blood Pressure, Standard Heart Rate, Standard Respiratory Rate. Only visits with any 
PCS or PCSC values are included. 
 
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Page x of y 
Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2.4 
Summary of Standard Vital Signs: PCS and PCSC Values by Scheduled Timepoint at TV1 
(Safety Population) 
 
Parameter (unit) 
Timepoint 
  Assessment 
CVT- 301 
(N=xx) 
n  (%) 
 
 
 
Standard Systolic  
Blood Pressure (unit) 
Pre-dose 
  n 
xx 
 
  PCS Low 
xx (xx.x)   
 
  PCS High 
xx (xx.x)   
 
  PCSC Low 
xx (xx.x)   
 
  PCSC High 
xx (xx.x)   
 
 
 
 
10 mins post-dose 
  n 
xx 
 
  PCS Low 
xx (xx.x)   
 
  PCS High 
xx (xx.x)   
 
  PCSC Low 
xx (xx.x)   
 
  PCSC High 
xx (xx.x)   
 
 
 
 
20 mins post-dose 
  n 
xx 
 
... 
 
 
30 mins post-dose 
 
 
... 
 
 
60 mins post-dose 
 
 
... 
 
Standard Diastolic  
Blood Pressure (unit) 
 
 
 
 
 
... 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Percentages are based on n, the number of subjects with the test performed at each visit.  
PCS = potentially clinically significant values, PCSC = potentially clinically significant changes. 
 
Cross-reference: Listing 16.2.8.2.1, Table 14.3.4.2.5 
 
Programming Note: Repeat for Standard Diastolic Blood Pressure, Standard Heart Rate, Standard Respiratory Rate. Only visits with any 
PCS or PCSC values are included. 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2.5    
Standard Vital Signs: PCS and PCSC Values 
 
Treatment Group: O. C. 
 
Patient 
ID 
Visit 
 
Time Point 
Date 
Performed 
Time 
Performed 
Position 
Blood Pressure 
(mmHg) 
Heart Rate 
(Beats/Min) 
 
SBP 
DBP 
Respiratory Rate 
(Breaths/Min) 
 
 
  
 
 
 
 
 
 
 
xxxx-xxx 
Screening 
 
 
ddmonyyyy 
hh:mm 
SUPINE/SEMI-
SUPINE 
xx 
xx 
xx 
xx 
 
 
  
 
hh:mm 
STANDING 
xx 
Xx H 
xx 
xx 
 
TV3/OV3 
 Pre-dose 
ddmonyyyy 
hh:mm 
SUPINE/SEMI-
SUPINE 
xx L** 
xx 
xx 
xx 
 
 
  
 
hh:mm 
STANDING 
xx L* 
xx 
xx 
xx 
 
 
 ... 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
... 
  
 
 
 
 
 
 
 
xxxx-xxx 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
CVT-301 (002/003) 
 
  
 
 
 
 
 
 
 
CVT-301(Naïve) 
 
  
 
 
 
 
 
 
 
CVT-301 Total 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Programmer note: Please display all related values if there is one Orthostatic Hypertension Data 
 
... 
 
  
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit;  O.C. column is for the patients in Observational Cohort, 002/003 column is for the 
patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. L* = 
potentially clinically significant (PCS) low value, H* = PCS high value, 
L** = potentially clinically significant change (PCSC) low, H** = PCSC high. 
 
Cross-reference: Listing 16.2.8.2.1 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2.6 
Summary of Vital Signs: Orthostatic Hypotension by Visit  
(Safety Population) 
 
 
 
 
CVT- 301 
 
 
Visit  
O. C. 
(N=xx) 
n  (%) 
002/003 
(N=xx) 
n  (%) 
Naive 
(N=xx) 
n  (%) 
Total 
(N=xx) 
n  (%) 
Overall 
(N=xx) 
n  (%) 
 
 
 
 
 
 
SV1 
  n 
xx 
xx 
xx 
xx 
xx 
  Yes  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
  No 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
SV2 
  n 
xx 
xx 
xx 
xx 
xx 
  Yes  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
  No 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
TV1/OV1 Pre-dose   
  n 
xx 
xx 
xx 
xx 
xx 
  Yes  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
  No 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
 
 
 
 
 
TV2/OV2 Pre-dose 
 
 
 
 
 
... 
 
 
 
 
 
TV3/OV3 Pre-dose 
 
 
 
 
 
... 
 
 
 
 
 
… 
 
 
 
 
 
... 
 
 
 
 
 
Followup 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit;  O.C. column is for the patients in Observational Cohort, 002/003 column is for the 
patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Percentages are based on n, the number of subjects with the test performed at each visit.  
Orthostatic hypotension is defined as a reduction in SBP of 20 mmHg or more, and/or a reduction in DBP of 10 mmHg  
or more, for the standing measurement compared to the semi-supine measurement. 
 
Cross-reference: Listing 16.2.8.2.1 and Table 14.3.4.2.8 
 
 
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Page x of y 
Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2.7 
Summary of Vital Signs: Orthostatic Hypotension by Scheduled Timepoint at TV1  
(Safety Population) 
 
Timepoint 
CVT- 301 
(N=xx) 
n  (%) 
 
 
Pre-dose 
  n 
xx 
  Yes  
xx (xx.x)   
  No 
xx (xx.x)   
 
 
10 mins post-dose 
  n 
xx 
  Yes  
xx (xx.x)   
  No 
xx (xx.x)   
 
 
20 mins post-dose 
  n 
xx 
  Yes  
xx (xx.x)   
  No 
xx (xx.x)   
 
 
30 mins post-dose 
 
... 
 
60 mins post-dose 
 
... 
 
 
 
 
 
Percentages are based on n, the number of subjects with the test performed at each visit.  
Orthostatic hypotension is defined as a reduction in SBP of 20 mmHg or more, and/or a reduction in DBP of 10 mmHg  
or more, for the standing measurement compared to the semi-supine measurement. 
 
Cross-reference: Listing 16.2.8.2.1 and Table 14.3.4.2.8 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.2.8  
Orthostatic Vital Signs 
 
Treatment Group: O. C. 
Patient 
ID 
Visit 
 
Time Point 
Date 
Performed 
Time 
Performed 
Position 
Blood Pressure 
(mmHg) 
Heart Rate 
(Beats/Min) 
 
SBP 
DBP 
Respiratory Rate 
(Breaths/Min) 
 
 
  
 
 
 
 
 
 
 
xxxx-xxx 
Screening 
 
 
ddmonyyyy 
hh:mm 
SUPINE/SEMI-
SUPINE 
xx 
xx 
xx 
xx 
 
 
  
 
hh:mm 
STANDING * 
xx 
xx 
xx 
xx 
 
Visit 3 
 Pre-dose 
ddmonyyyy 
hh:mm 
SUPINE/SEMI-
SUPINE 
xx 
xx 
xx 
xx 
 
  
hh:mm 
STANDING * 
xx 
xx 
xx 
xx 
 
 
 ... 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
  
 
 
 
 
 
 
 
CVT-301 (002/003) 
 
  
 
 
 
 
 
 
 
CVT-301(Naïve) 
 
  
 
 
 
 
 
 
 
CVT-301 Total 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Programmer note: Please display all related values if there is one Orthostatic Hypertension Data 
 
... 
 
  
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV=Treatment Visit; FU= Follow-up; UNS= unscheduled; O.C. column is for the patients in Observational 
Cohort, 002/003 column is for the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the 
CVT-301 naive patients. 
* denotes orthostatic hypotension that is defined as a reduction in SBP of 20 mmHg or more, and/or a reduction in  
DBP of 10 mmHg or more, for the standing measurement compared to the Semi-supine measurement. 
Cross-reference: Listing 16.2.8.2.1 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.3 
12-Lead ECG:PCS and PCSC Criteria 
 
ECG Parameters(Units)  Criteria for PCS Values (Actual values) Criteria for PCSC values (Change from Baseline or pre-dose values *) 
 
High  
Low  
Increase  
Decrease  
PR interval (msec)   
>300  
NA  
>25% for baseline >=200  
>50% for baseline <200  
NA  
QRS interval (msec) 
>200  
NA  
>25% for baseline >=100  
>50% for baseline <100  
NA  
QTcB (msec) 
>500  
NA  
>15% for baseline >=440  
>30% for baseline <440  
NA  
QTcF (msec) 
>500  
NA  
>15% for baseline >=440  
>30% for baseline <440  
NA  
Heart Rate (bpm) 
>120  
<35  
NA  
NA  
Note: bpm = beats per minute; msec = Micro Second; NA = not applicable; SBP = Systolic Blood Pressure; DBP = Diastolic Blood  
Pressure; PCS = potentially clinically significant; PCSC = potentially clinically significant change. 
* Baseline values will be used for pre-dose and pre-dose values assessment at each treatment visits. Pre-dose values will be used for 
corresponding post-dose values assessment. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table 14.3.4.3.1 
Summary of 12-Lead ECG: Actual Values and Change across Visits  
(Safety Population) 
 
 
 
 
 
 
CVT- 301 
 
 
Parameter (unit) 
Visit 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
 
PR Interval (unit) 
Baseline 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV1/OV1 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Change from Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV3/OV3 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. The baseline is defined as the TV1/OV1 pre-dose value. 
If TV1/OV1 pre-dose value is missing, the last non-missing screening assessment will be used as baseline. 
 
Cross-reference: Listing 16.2.8.2.2 
 
Programming Note: Repeat for other ECG parameters. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.3.2 
Summary of 12-Lead ECG: PCS and PCSC Values  
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
Parameter (unit) 
Visit  
  Assessment 
O. C. 
(N=xx) 
n  (%) 
002/003 
 (N=xx) 
n  (%) 
Naive 
 (N=xx) 
n  (%) 
Total 
 (N=xx) 
n  (%) 
Overall 
(N=xx) 
n  (%) 
 
 
 
 
 
 
 
PR Interval (unit) 
TV1/OV1  
  n 
xx 
xx 
xx 
xx 
xx 
 
  PCS High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
  PCSC High 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV3/OV3 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients.  Percentages are based on n, the number of subjects 
with the test performed at each visit.  
PCS = potentially clinically significant values, PCSC = potentially clinically significant changes. 
 
Cross-reference: Listing 16.2.8.2.2, Table 14.3.4.3.3    
 
Programming Note: For PCS repeat for other applicable ECG parameters (QRS Interval, QTcB, QTcF, Heart Rate). For Heart Rate, both PCS 
Low and PCS High will be assessed. 
For PCSC repeat for other applicable ECG parameters (QRS Interval, QTcB, QTcF). PCSC Low values will not be assessed. 
Only visits with any PCS or PCSC values are included. 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.3.3    
12-Lead Electrocardiogram (ECG): PCS and PCSC Values 
 
Treatment Group: O. C. 
Patient  
ID 
Visit 
Time Point 
Date and Time 
Of Assessment  
Test (Unit) 
Result  
 
 
 
 
 
 
 
xxxx-xxx 
SV1 
 
 
ddmonyyyy hh:mm  
 
 
 
OV3 
Pre-dose 
ddmonyyyy hh:mm  
xxx (xxx) 
xx H* 
 
 
 
+5mins 
 
 
xx L** 
 
 
 
+20mins 
 
 
 
 
 
 
+30mins 
 
 
 
 
 
... 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
... 
 
 
 
 
 
 
CVT-301 (002/003) 
 
 
 
 
 
 
CVT-301(Naïve) 
 
 
 
 
 
 
CVT-301 Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programmer note: Please display all values for the parameter if there is at least one PCS or PCSC for the parameter 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; OV = Observational Cohort; O.C. column is for the patients in Observational Cohort, 
002/003 is for the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive 
patients. 
Note: L* = potentially clinically significant (PCS) low value, H* = PCS high value, 
      L** = potentially clinically significant change (PCSC) low, H** = PCSC high. 
 
Cross-reference: Listing 16.2.8.2.2    
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.4 
Physical Examination  
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
Visit 
Assessment 
O. C. 
(N=xx) 
n  (%) 
002/003 
(N=xx) 
n  (%) 
Naive 
(N=xx) 
n  (%) 
Total 
(N=xx) 
n  (%) 
Overall 
(N=xx) 
n  (%) 
 
 
 
 
 
 
 
Screening 
Any Clinically Significant Abnormal Findings  
 
 
 
 
 
 
Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
Missing 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV1/OV1 
Any Clinically Significant Abnormal Findings  
That Are New or Have Worsened  
 
 
 
 
 
 
Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
Missing 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
TV2/OV2 
 
 
 
 
 
 
TV3/OV3 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; OV = Observational Cohort; O.C. column is for the patients in Observational Cohort, 
002/003 column is for the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 
naive patients. 
Cross-reference: Listing 16.2.8.2.3 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.5.1.1 
Summary of Spirometry (Neurology Office): Actual Values and Change from Baseline for FEV1 and FVC by Visit  
(Safety Population) 
 
 
 
 
 
 
CVT- 301 
 
 
Parameter (unit) 
Visit 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
 Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
 
FEV1 (unit) 
Screening (ON 
state) 
Actual value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening (OFF 
state) 
Actual value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV1/OV1 Arrival 
Actual value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
Actual value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV2/OV2 Arrival 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Change from Baseline 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Percent Change from 
Baseline (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV3/OV3 Arrival 
... 
 
 
 
 
 
 
TV4/OV4 Arrival 
... 
 
 
 
 
 
 
TV5/OV5 Arrival 
 
 
 
 
 
 
 
TV6/OV6 Arrival 
 
 
 
 
 
 
 
… 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
FVC, Percentage Predicted FEV1, 
Percentage Predicted FVC 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; OV = Observational Visit; O.C. column is for the patients in Observational Cohort, 
002/003 column is for the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 
naive patients. Screening is the latest assessment during screening period. Baseline is defined as the TV1/OV1 arrival value. If the 
TV1/OV1 arrival value is missing, the last available value in ON state before the first dose of study drug is used. 
 
Cross-reference: Listing 16.2.8.2.4.1 
 
Programming Note: Repeat for Percentage predicted FEV1, FVC, Percentage predicted FVC. No need to summarize percent change for 
Predicted FEV1 and Predicted FVC. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.5.1.2 
Summary of Spirometry (Neurology Office): Actual Values and Change from Baseline for FEV1 and FVC by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  
(Safety Population) 
 
Table 14.3.4.5.1.3 
Summary of Spirometry (Neurology Office): Actual Values and Change from Baseline for FEV1 and FVC by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  
(Safety Population) 
 
Note: SV = Screening Visit; TV = Treatment Visit; OV = Observational Visit; O.C. column is for the patients in Observational Cohort, 
002/003 column is for the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 
naive patients. Screening is the latest assessment during screening period. Baseline is defined as the TV1/OV1 arrival value. If the 
TV1/OV1 arrival value is missing, the last available value in ON state before the first dose of study drug is used. The CV will be 
calculated for each patient as standard deviation divided by the mean. The screening visit FEV1 data (assessed in ON state) and 
arrival values at subsequent visits will be used for the calculation. 
 
Cross-reference: Listing 16.2.8.2.4.1 
 
Programming Note: Repeat for Percentage predicted FEV1, FVC, Percentage predicted FVC. No need to summarize percent change for 
Predicted FEV1 and Predicted FVC. 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.5.1.4 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1 by Visit 
(Safety Population) 
 
Visit 
Statistic 
O. C. 
(N=xx) 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
 
0.xxx 
 
  Screening Spirometry 
 
 
0.xxx 
 
  Treatment  
 
 
0.xxx 
 
  Visit 
 
 
0.xxx 
 
  Treatment-by-Visit Interaction 
 
 
0.xxx 
 
  Baseline Spirometry 
 
 
0.xxx 
 
 
 
 
 
TV2/OV2 
n 
xx 
xx 
 
 
LS Mean 
xx.x 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
LS Mean Difference (CVT-301 – O. C.) 
 
xx.x 
 
 
95% CI (LS Mean Difference) 
 
(xx.x, xx.x) 
 
 
p-value (LS Mean Difference) 
 
0.xxx 
 
 
 
 
 
 
TV3/OV3  
 
 
 
 
TV4/OV4  
 
 
 
 
TV5/OV5  
 
 
 
 
TV6/OV6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the Change from baseline for FEV1 at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, and 
includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors. Baseline FEV1 will be included as a 
covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.5.1.5 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1 by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  
(Safety Population) 
 
Table 14.3.4.5.1.6 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1 by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. The CV will be 
calculated for each patient as standard deviation divided by the mean. The screening visit FEV1 data (assessed in ON state) and 
arrival values at subsequent visits will be used for the calculation. 
MMRM model uses the Change from baseline for FEV1 at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, and 
includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors. Baseline FEV1 will be included as a 
covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table 14.3.4.5.1.7 
Sensitivity Analysis Using MMRM: Change from Baseline for FEV1 by Visit 
MI analysis with Missing At Random Assumption  
(Safety Population) 
 
Visit/Statistic 
O. C. 
(N=xx) 
CVT-301 
(N=xx) 
 
 
 
TV2/OV2  
 
 
MI mean (SE) 
xx.xx(x.xxx) 
xx.xx(x.xxx) 
MI Treatment Difference in Mean Change from Baseline (SE) 
 
xx.xx(x.xxx) 
95% CI (MI Treatment Difference) 
 
(xx.xx, xx.xx) 
P-Value 
 
0.xxx 
 
 
 
TV3/OV3  
 
 
TV4/OV4  
 
 
TV5/OV5  
 
 
TV6/OV6  
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
The non-monotone missing values will be imputed using the Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate 
normal distribution over all variables included in the imputation model. The monotone missing values are imputed using pattern mixture 
model assuming missing At Random. MMRM model uses the Change from baseline for FEV1 at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the 
stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital 
capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as 
fixed factors. Baseline FEV1 will be included as a covariate, assuming an unstructured covariance matrix. The MIANALYZE procedure in 
SAS will be applied to combine the results from these datasets to derive an overall estimate of the treatment difference at each 
visit. 
 
Cross-reference: Listing 16.2.8.2.4.1 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.5.1.8 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FEV1 by Visit  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the Change from baseline for percentage predicted FEV1 at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the 
dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables 
(baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% 
versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline 
Percentage predicted FEV1 will be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
 
 
Table 14.3.4.5.1.9 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FEV1 by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the Change from baseline for percentage predicted FEV1 at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the 
dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables 
(baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% 
versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline 
Percentage predicted FEV1 will be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
 
 
Table 14.3.4.5.1.10 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FEV1 by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. The CV will be 
calculated for each patient as standard deviation divided by the mean. The screening visit FEV1 data (assessed in ON state) and 
arrival values at subsequent visits will be used for the calculation. 
MMRM model uses the Change from baseline for percentage predicted FEV1 at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the 
dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables 
(baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% 
versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline 
Percentage predicted FEV1 will be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
 
Table 14.3.4.5.1.11 
Sensitivity Analysis Using MMRM: Change from Baseline for Percentage Predicted FEV1 by Visit  
MI analysis with Missing At Random Assumption  
(Safety Population) 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
The non-monotone missing values will be imputed using the Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate 
normal distribution over all variables included in the imputation model. The monotone missing values are imputed using pattern mixture 
model assuming missing At Random. MMRM model uses the change from baseline for percentage predicted FEV1 at each post-baseline visit 
(TV2, TV3, TV4, TV5, TV6) as the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, 
TV6), the stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or 
FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group 
and visit as fixed factors. Baseline percentage predicted FEV1 will be included as a covariate, assuming an unstructured covariance 
matrix. The MIANALYZE procedure in SAS will be applied to combine the results from these datasets to derive an overall estimate of the 
treatment difference at each visit. 
 
Cross-reference: Listing 16.2.8.2.4.1 
 
Table 14.3.4.5.1.12 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FVC by Visit  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the Change from Baseline for FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, and 
includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline FVC will be included as a 
covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
 
Table 14.3.4.5.1.13 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FVC by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the Change from Baseline for FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, and 
includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline FVC will be included as a 
covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
Table 14.3.4.5.1.14 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FVC by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  
(Safety Population) 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. The CV will be 
calculated for each patient as standard deviation divided by the mean. The screening visit FEV1 data (assessed in ON state) and 
arrival values at subsequent visits will be used for the calculation. 
MMRM model uses the Change from Baseline for FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, and 
includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and Yahr 
stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline FVC will be included as a 
covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
Table 14.3.4.5.1.15 
Sensitivity Analysis Using MMRM: Change from Baseline for FVC by Visit 
MI analysis with Missing At Random Assumption  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
The non-monotone missing values will be imputed using the Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate 
normal distribution over all variables included in the imputation model. The monotone missing values are imputed using pattern mixture 
model assuming missing At Random. MMRM model uses the change from baseline for FVC at each post-baseline visit (TV2, TV3, TV4, TV5, 
TV6) as the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the 
stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital 
capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as 
fixed factors. Baseline FVC will be included as a covariate, assuming an unstructured covariance matrix. The MIANALYZE procedure in 
SAS will be applied to combine the results from these datasets to derive an overall estimate of the treatment difference at each 
visit. 
Cross-reference: Listing 16.2.8.2.4.1 
Table 14.3.4.5.1.16 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FVC by Visit  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the change from baseline for percentage predicted FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the 
dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables 
(baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% 
versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline 
percentage predicted FVC will be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
Will use format for 14.3.4.5.1.2 
Table 14.3.4.5.1.17 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FVC by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the change from baseline for percentage predicted FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the 
dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables 
(baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline 
percentage predicted FVC will be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
Will use format for 14.3.4.5.1.2 
Table 14.3.4.5.1.18 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for Percentage Predicted FVC by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. The CV will be 
calculated for each patient as standard deviation divided by the mean. The screening visit FEV1 data (assessed in ON state) and 
arrival values at subsequent visits will be used for the calculation. 
MMRM model uses the change from baseline for percentage predicted FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the 
dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables 
(baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% 
versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline 
percentage predicted FVC will be included as a covariate, assuming an unstructured covariance matrix. 
Cross-reference: Listing 16.2.8.2.4.1 
Will use format for 14.3.4.5.1.2 
 
Table 14.3.4.5.1.19 
Sensitivity Analysis Using MMRM: Change from Baseline for Percentage Predicted FVC by Visit 
MI analysis with Missing At Random Assumption  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
The non-monotone missing values will be imputed using the Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate 
normal distribution over all variables included in the imputation model. The monotone missing values are imputed using pattern mixture 
model assuming missing At Random. MMRM model uses the change from Baseline for percentage predicted FVC at each post-baseline visit 
(TV2, TV3, TV4, TV5, TV6) as the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, 
TV6), the stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or 
FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group 
and visit as fixed factors. Baseline percentage predicted FVC will be included as a covariate, assuming an unstructured covariance 
matrix. The MIANALYZE procedure in SAS will be applied to combine the results from these datasets to derive an overall estimate of the 
treatment difference at each visit. 
 
Cross-reference: Listing 16.2.8.2.4.1 
Will use format for Table 14.3.4.5.1.2 and Table 14.3.4.5.1.3 respectively. 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
Table 14.3.4.5.2.1 
Summary of Spirometry :( Neurology Office): Actual Values and Change from Baseline for FEV1/FVC by Visit  
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
Visit  
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
Screening (ON state) 
Actual value 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Screening (OFF state) 
... 
 
 
 
 
 
 
 
 
 
 
 
 
TV1/OV1 Arrival 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV2/OV2 Arrival 
Actual value 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Change from Baseline 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Percent Change from Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
TV3/OV3 Arrival 
 
 
 
 
 
 
TV4/OV4 Arrival 
 
 
 
 
 
 
TV5/OV5 Arrival 
 
 
 
 
 
 
TV6/OV6 Arrival 
 
 
 
 
 
 
 
 
 
 
 
 
 
SV = Screening Visit; TV = Treatment Visit; OV = Observational Cohort; O.C. column is for the patients in Observational Cohort, 
002/003 column is for the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 
naive patients. Screening is the latest assessment during screening period. Baseline is defined as the TV1/OV1 arrival value. If the 
TV1/OV1 arrival value is missing, the last available value in ON state before the first dose of study drug is used. 
 
Cross-reference: Listing 16.2.8.2.4.1 
 
 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Table 14.3.4.5.2.2 
Summary of Spirometry :( Neurology Office): Actual Values and Change from Baseline for FEV1/FVC by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  
(Safety Population) 
 
 
Table 14.3.4.5.2.3 
Summary of Spirometry :( Neurology Office): Actual Values and Change from Baseline for FEV1/FVC by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  
(Safety Population) 
 
 
 
Table 14.3.4.5.2.4 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1/FVC by Visit  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the change from baseline for FEV1/FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, 
and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and 
Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline FEV1/FVC will be included 
as a covariate, assuming an unstructured covariance matrix. 
 
Will use format for table 14.3.4.5.1.2 
 
Table 14.3.4.5.2.5 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1/FVC by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. 
MMRM model uses the change from baseline for FEV1/FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, 
and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and 
Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline FEV1/FVC will be included 
as a covariate, assuming an unstructured covariance matrix. 
 
Will use format for table 14.3.4.5.1.2 
 
Table 14.3.4.5.2.6 
MMRM Analysis of Spirometry Data (Neurology Office): Change from Baseline for FEV1/FVC by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  
(Safety Population) 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort. The CV will be 
calculated for each patient as standard deviation divided by the mean. The screening visit FEV1 data (assessed in ON state) and 
arrival values at subsequent visits will be used for the calculation. 
MMRM model uses the change from baseline for FEV1/FVC at each post-baseline visit (TV2, TV3, TV4, TV5, TV6) as the dependent variable, 
and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the stratification variables (baseline Hoehn and 
Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and 
FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as fixed factors; Baseline FEV1/FVC will be included 
as a covariate, assuming an unstructured covariance matrix. 
 
Will use format for table 14.3.4.5.1.2 
 
 
Table 14.3.4.5.2.7 
Sensitivity Analysis Using MMRM: Change from Baseline for FEV1/FVC by Visit 
MI analysis with Missing At Random Assumption  
(Safety Population) 
 
Note: TV = Treatment Visit; OV = Observational Visit 
The non-monotone missing values will be imputed using the Markov Chain Monte Carlo (MCMC) methodology which assumes a multivariate 
normal distribution over all variables included in the imputation model. The monotone missing values are imputed using pattern mixture 
model assuming missing At Random. MMRM model uses the change from baseline for FEV1/FVC at each post-baseline visit (TV2, TV3, TV4, 
TV5, TV6) as the dependent variable, and includes the treatment group (CVT-301 or O.C.), visit (TV2, TV3, TV4, TV5, TV6), the 
stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening spirometry ([FEV1] <60% or FEV1/forced vital 
capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) and the interaction between the treatment group and visit as 
fixed factors. Baseline FEV1/FVC will be included as a covariate, assuming an unstructured covariance matrix. The MIANALYZE procedure 
in SAS will be applied to combine the results from these datasets to derive an overall estimate of the treatment difference at each 
visit. 
 
Cross-reference: Listing 16.2.8.2.4.1 
 
Will use format for table 14.3.4.5.1.3 
 
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Protocol No. CVT-301-005                                    Confidential                                         
 
 
Program Name: xxxx.sas                                                           
Table Generation: ddmomyyyy 
 
 
 
Table 14.3.4.5.3.1 
Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and <70% by Visit  
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
Category/Visit  
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
FEV1/FVC < 60% 
 
 
 
 
 
 
Screening (ON state) 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Screening (OFF state) 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
TV1/OV1 Arrival 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Baseline 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
TV2/OV2 Arrival 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x) 
xx (xx.x)  
   ... 
 
 
 
 
 
 
FEV1/FVC < 70% 
 
 
 
 
 
 
Screening (ON state) 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x) 
xx (xx.x)  
Screening (OFF state) 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x) 
xx (xx.x)  
TV1/OV1 Arrival 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x) 
xx (xx.x)  
Baseline 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x) 
xx (xx.x)  
TV2/OV2 Arrival 
n (%) 
xx (xx.x)   
xx (xx.x)  
xx (xx.x)  
xx (xx.x) 
xx (xx.x)  
   … 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; OV = Observational Visit; O.C. column is for the patients in Observational Cohort, 
002/003 column is for the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 
naive patients. Screening is the latest assessment during screening period. Baseline is defined as the TV1/OV1 arrival value. If the 
TV1/OV1 arrival value is missing, the last available value in ON state before the first dose of study drug is used. 
 
Cross-reference: Listing 16.2.8.2.4.1, Table 14.3.4.5.8 
 
 
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Program Name: xxxx.sas                                                           
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Table 14.3.4.5.3.2 
Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and <70% by Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria  
(Safety Population) 
 
Table 14.3.4.5.3.3 
Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and <70% by Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5%  
(Safety Population) 
 
Note: SV = Screening Visit; TV = Treatment Visit; OV = Observational Visit; O.C. column is for the patients in Observational Cohort, 
002/003 column is for the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 
naive patients. Screening is the latest assessment during screening period. Baseline is defined as the TV1/OV1 arrival value. If the 
TV1/OV1 arrival value is missing, the last available value in ON state before the first dose of study drug is used. The CV will be 
calculated for each patient as standard deviation divided by the mean. The screening visit FEV1 data (assessed in ON state) and 
arrival values at subsequent visits will be used for the calculation. 
Cross-reference: Listing 16.2.8.2.4.1, Table 14.3.4.5.8 
 
 
 
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Program Name: xxxx.sas                                                           
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Table 14.3.4.5.4 
Spirometry (Neurology Office): 70% or Smaller FEV1/FVC Values  
 
Treatment Group: CVT-301 (002/003) 
Patient  
ID 
Visit 
 
Time  
Point 
Motor  
State 
Date and Time  
of Assessment  
Test (Unit) 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx@ 
TV2 
 
Pre-dose 
ON 
ddmonyyyy hh:mm 
xxx (xxx) 
Xx* 
 
 
 
TV3 
 
Pre-dose 
ON 
ddmonyyyy hh:mm # 
xxx (xxx) 
Xx $ 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
Programmer note: please display all FEV1, FVC and FEV1/FVC from all timepoint if any criteria meet. 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
Note: TV = Treatment Visit;  
# indicates spirometry measurement not meeting ATS quality criteria. * indicates imputed values. $ indicates manual data @ indicates 
patients with Co-efficient of Variation (CV) of FEV1 >7.5% 
Data with 70% or smaller FEV1/FVC Values at each timepoint/visit are included. 
 
Cross-reference: Listing 16.2.8.2.4.1 
 
 
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Program Name: xxxx.sas                                                           
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Table 14.3.4.5.5 
Summary of Spirometry (Neurology Office): Measurements Meeting ATS Quality Criteria  
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
State 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
Overall 
 
 
 
 
 
 
Total Number of Spirometry Measurements 
n 
xx 
xxx 
xxx 
xxx 
xx 
 
 
 
 
 
 
 
Total Number (Percent) of Measurements 
Meeting ATS Quality Criteria [a] 
 
n (%) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
Total Number (Percent) of Measurements  
Not Meeting ATS Quality Criteria [a] 
 
n (%) 
xx (xx.x) 
xx (xx.x 
xx (xx.x 
xx (xx.x 
xx (xx.x 
 
 
 
 
 
 
 
Reason for Not Meeting ATS Quality Criteria [b] 
 
 
 
 
 
 
Acceptable Effort of ANY and Repeatable Effort of 0 
n (%) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
Acceptable Effort of 3 and Repeatable Effort of 0 n (%) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
Acceptable Effort of 2 and Repeatable Effort of 0 n (%) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
Acceptable Effort of 1 and Repeatable Effort of 0 n (%) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
Acceptable Effort of 0 and Repeatable Effort of 0 n (%) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
Acceptable Effort of 2 and Repeatable Effort of 2 
n (%) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
       Other 
n (%) 
xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) 
 
 
 
 
 
 
 
Proportion of Measurements Meeting ATS 
Quality Criteria at Subject Level[c] 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
ON State 
 
 
 
 
 
 
 
 
 
 
 
 
 
    ... 
 
 
 
 
 
 
 
 
 
 
 
 
 
OFF State 
 
 
 
 
 
 
 
 
 
 
 
 
 
    ... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: O.C. column is for the patients in Observational Cohort, 002/003 column is for the patients who were previously enrolled in the 
CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
[a] Percent is based on the total number of spirometry measurements. 
[b] Percent is based on the total number of spirometry measurements not meeting ATS quality criteria. 
[c] For each subject, the proportion is calculated as spirometry measurements meeting ATS criteria divided by total the count of 
records with unique assessment date/time and non-missing ATS Quality Criteria Flag. 
Cross-reference: Listing 16.2.8.2.4.1, Listing 16.2.8.2.4.3 
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Table 14.3.4.5.6 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change from Baseline for Calculated DLco Parameters by Visit  
(Safety Population) 
 
 
 
 
 
 
CVT-301 
 
 
Parameter (unit) 
Visit 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
 
DLco predicted (unit) 
Baseline 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV2/OV2 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Change from Baseline 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Percent Change from Baseline (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV4/OV4 
... 
 
 
 
 
 
 
TV5/OV5 
 
 
 
 
 
 
 
TV6/OV6 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
Continue with all Applicable Calculated Parameters 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
The baseline is defined as the DLco results taken after SV2 and before randomization. 
 
Cross-reference: Listing 16.2.8.2.4.4 
 
 
 
 
 
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Table 14.3.4.5.7 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change from Baseline for FEV1 and FVC by Visit  
(Safety Population) 
 
 
 
 
 
 
CVT- 301 
 
 
Parameter (unit) 
Visit 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
 
FEV1 (unit) 
Baseline 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV2/OV2 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Change from Baseline 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Percent Change from Baseline (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV4/OV4 
... 
 
 
 
 
 
 
TV5/OV5 
 
 
 
 
 
 
 
TV6/OV6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with all Applicable Parameters  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
 
The baseline is defined as the DLco results taken after SV2 and before randomization. 
 
Cross-reference: Listing 16.2.8.2.4.4 
 
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Table 14.3.4.5.8 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change from Baseline for FEV1/FVC by Visit  
(Safety Population) 
 
 
 
 
 
 
CVT- 301 
 
 
Parameter (unit) 
Visit 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
 
FEV1/FVC(unit) 
Baseline 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
TV2/OV2 
Actual value 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Change from Baseline 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Percent Change from Baseline (%) 
 
 
 
 
 
 
TV4/OV4 
 
 
 
 
 
 
 
TV5/OV5 
... 
 
 
 
 
 
 
TV6/OV6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit; O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
The baseline is defined as the DLco results taken after SV2 and before randomization. 
 
Cross-reference: Listing 16.2.8.2.4.4 
 
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Program Name: xxxx.sas                                                           
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Table 14.3.4.5.9 
Summary of Spirometry (Pulmonary Function Facility): Summary of FEV1/FVC < 60% and <70% by Visit 
(Safety Population) 
 
 
 
 
 
 
CVT- 301 
 
 
Category/Visit  
Statistic 
O. C. 
(N=xx) 
 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
FEV1/FVC < 60% 
 
 
 
 
 
 
 
Baseline 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
TV2/OV2 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
TV4/OV4 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
TV5/OV5 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
TV6/OV6 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
   ... 
 
 
 
 
 
 
FEV1/FVC < 70% 
 
 
 
 
 
 
 
Baseline 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
TV2/OV2 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
TV4/OV4 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
TV5/OV5 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
TV6/OV6 
n (%) 
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Visit. O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
The baseline is defined as the DLco results taken after SV2 and before randomization. 
 
Cross-reference: Listing 16.2.8.2.4.4, Table 14.3.4.5.19 
 
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Program Name: xxxx.sas                                                           
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Table 14.3.4.5.10 
Spirometry (Pulmonary Function Facility):70% or Smaller FEV1/FVC Values by Visit 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
 
Time  
Point 
Motor  
State 
Date and Time  
of Assessment  
Test (Unit) 
Result 
Change from 
Baseline 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV2/OV2 
 
Pre-dose 
ON 
ddmonyyyy hh:mm 
xxx (xxx) 
xx 
 
 
TV3/OV3 
 
Pre-dose 
ON 
ddmonyyyy hh:mm # 
xxx (xxx) 
Xx $ 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
Programmer note: please display all FEV1, FVC and FEV1/FVC from all timepoint if any criteria meet. 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
Note: TV = Treatment Visit; OV = Observational Visit;  
# indicates spirometry measurement not meeting ATS quality criteria. * indicates imputed values. $ indicates manual data.  
Data with 70% or smaller FEV1/FVC Values are included. 
 
Cross-reference: Listing 16.2.8.2.4.4 
 
 
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Table 14.3.4.5.11 
Summary of Spirometry (Pulmonary Function Facility): Measurements Meeting ATS Quality Criteria  
(Safety Population) 
 
 
 
CVT-301 
 
 
State 
Statistic 
O.C. 
(N=5) 
002/003 
(N=7) 
Naive 
(N=8) 
Total 
(N=20) 
Overall 
(N=xx) 
 
 
Overall 
  Total Number of Spirometry/DLCO Measurements 
n 
xx 
xx 
xx 
xx 
 
 
 
  Total Number (Percent) of Spirometry Measurements  
     Meeting ATS Quality Criteria [a] 
n (%) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
  Total Number (Percent) of Spirometry Measurements  
     Not Meeting ATS Quality Criteria [b] 
n (%) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
 
 
  Total Number (Percent) of DLCO Measurements  
     Meeting ATS Quality Criteria [a] 
n (%) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
  Total Number (Percent) of DLCO Measurements  
     Not Meeting ATS Quality Criteria [b] 
n (%) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
xx ( xx) 
 
 
  Proportion of  Spirometry Measurements Meeting  
     ATS Quality Criteria at Subject Level[c] 
n 
xx 
xx 
xx 
xx 
xx 
Mean 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
SD 
0.xxxxx 
0.xxxxx 
0.xxxxx 
0.xxxxx 
0.xxxxx 
Median 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
0.xxxx 
Min, Max 0.xxx, x.xxx 
0.xxx, x.xxx 0.xxx, x.xxx 0.xxx, x.xxx 0.xxx, x.xxx 
  Proportion of  DLCO Measurements Meeting  
     ATS Quality Criteria at Subject Level[c] 
n 
xx 
xx 
xx 
xx 
Mean 
   0.xxxx 
   0.xxxx 
   0.xxxx 
   0.xxxx 
… 
Note: TV = Treatment Visit; OV = Observational Visit; O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
 [a] Percent is based on the total number of DLco measurements. 
[b] Percent is based on the total number of DLco measurements not meeting ATS quality criteria. 
[c] For each subject, the proportion is calculated as Dlco measurements meeting ATS criteria divided by total the count of records 
with unique assessment date/time and non-missing ATS Quality Criteria Flag. 
Cross-reference: Listing 16.2.8.2.4.4, Listing 16.2.8.2.4.6 
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Table 14.3.4.6.1 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) 
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
 
Section 
   Item 
Visit 
  Assessment 
O. C. 
(N=xx) 
n (%) 
002/003 
(N=xx) 
n (%) 
Naive 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
Overall 
(N=xx) 
n (%) 
Baseline (TV1/OV1) 
 
 
 
 
 
 
  Any Suicidal Ideation or Behavior 
 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
  Any Suicidal Ideation 
 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
  Any Suicidal Behavior 
 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
Post Baseline 
 
 
 
 
 
 
  Any Suicidal Ideation or Behavior 
 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
  Any Suicidal Ideation 
 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
  Any Suicidal Behavior 
 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suicidal Ideation 
 
 
 
 
 
 
Wish to be Dead 
TV1/OV1 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  Missing 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
TV2/OV2 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  Missing 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
TV3/OV3 
... 
 
 
 
 
 
TV4/OV4 
... 
 
 
 
 
 
TV5/OV5 
... 
 
 
 
 
 
TV6/OV6 
 
 
 
 
 
   Non-Specific Active Suicidal Thoughts 
 
 
 
 
 
 
 
 
 
 
 
 
 
   ... 
 
 
 
 
 
 
Intensity of Ideation  
 
 
 
 
 
 
 
 
 
 
 
 
 
Suicidal Behavior 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV2/OV2... 
 
 
 
 
 
 
...  
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Cohort; O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Percentages are based on n, the number of subjects assessed at each visit. 
 
Cross-reference: Listing 16.2.8.2.5 
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Table 14.3.4.6.2 
Shift from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) 
(Safety Population) 
 
 
TV1/OV1 n (%) 
 
Baseline 
No Suicidal Behavior or Ideation 
Suicidal Ideation 
Suicidal Behavior 
Missing 
Total 
  
O. C. 
 (N=xx) 
No Suicidal Ideation 
 or Behavior 
  xx  (xx.x) 
xx (xx.x) 
xx  (xx.%) 
xx  (xx.%) xx  (xx.x) 
 
Suicidal Ideation 
  xx  (xx.x) 
xx (xx.x) 
xx  (xx.%) 
xx  (xx.%) xx  (xx.x) 
 
Suicidal Behavior 
  xx  (xx.x) 
xx (xx.x) 
xx  (xx.%) 
xx  (xx.%) xx  (xx.x) 
 
Missing 
  xx  (xx.x) 
xx (xx.x) 
xx  (xx.%) 
xx  (xx.%) xx  (xx.x) 
 
 
 
 
 
 
 
CVT-301 
(002/003) 
(N=xx) 
No Suicidal Ideation 
 or Behavior 
  xxx  (xx.x) 
xxx  (xx.x) 
xxx  (xx.%) 
xx  (xx.%) xx  (xx.x) 
 
Suicidal Ideation 
  xx  (xx.x) 
xx (xx.x) 
xx  (xx.%) 
xx  (xx.%) xx  (xx.x) 
 
Suicidal Behavior 
  xx  (xx.x) 
xx (xx.x) 
xx  (xx.%) 
xx  (xx.%) xx  (xx.x) 
 
Missing 
  xx  (xx.x) 
xx (xx.x) 
xx  (xx.%) 
xx  (xx.%) xx  (xx.x) 
Continue with CVT-301 (Naïve), CVT-301 Total and Overall 
Continued with TV2/OV2 TV3/OV3, TV4/OV4, … 
Note: O.C. rows is for the patients in Observational Cohort, 002/003 rows is for the patients who were previously enrolled in the CVT-
301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Percentages are based on N, the number of subjects in each treatment group. 
 
Cross-reference: Listing 16.2.8.2.5 
 
 
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Table 14.3.4.7 
Summary of Epworth Sleepiness Scale Total Score: Actual Values and Change from Baseline by Visit 
(Safety Population) 
 
 
 
 
 
CVT- 301 
 
 
Visit  
Statistic 
O. C. 
(N=xx) 
002/003 
 (N=xx) 
Naive 
 (N=xx) 
Total 
 (N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
Baseline 
Actual value 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
TV4/OV4 
Actual value 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Change from Baseline 
 
 
 
 
 
 
n 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
xx, xx 
TV6/OV6 
... 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Cohort; O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Baseline is the last non-missing assessment before the first dose of study drug. 
 
Cross-reference: Listing 16.2.8.2.6 
 
 
 
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Table 14.3.4.8 
Summary of Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP) by Visit 
(Safety Population) 
 
 
 
 
 
CVT-301 
 
 
 
Section 
   Item 
Visit 
  Assessment 
O. C. 
(N=xx) 
n (%) 
002/003 
(N=xx) 
n (%) 
Naive 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
Overall 
(N=xx) 
n (%) 
 
 
 
 
 
 
 
  Any Impulse or Other Compulsive Behaviors 
TV1/OV1 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
 
TV4/OV4 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
... 
 
 
 
 
 
 
TV6/OV6 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
  Any Impulse Behaviors 
TV1/OV1 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
 
TV4/OV4 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
... 
 
 
 
 
 
 
TV6/OV6 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
  Any Other Compulsive Behaviors 
TV1/OV1 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
 
TV4/OV4 
 
 
 
 
 
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  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
 
TV6/OV6 
 
 
 
 
 
 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
Impulse Control Disorders 
 
 
 
 
 
 
    Compulsive Gambling  
TV1/OV1 
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
 
 
 
 
 
 
 
TV4/OV4   
  n 
xx 
xx 
xx 
xx 
xx 
 
  Yes 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
  No 
xx (xx.x)  
xx (xx.x)   
xx (xx.x)   
xx (xx.x)   
xx (xx.x)  
 
... 
 
 
 
 
 
    Compulsive Sexual Behavior  
... 
 
 
 
 
 
    Compulsive Buying  
 
 
 
 
 
 
    Compulsive Eating  
 
 
 
 
 
 
 
 
 
 
 
 
 
Other Compulsive Behaviors 
 
 
 
 
 
 
    Hobbyism 
 
 
 
 
 
 
    Punding  
 
 
 
 
 
 
    Walkabout  
 
 
 
 
 
 
 
 
 
 
 
 
 
Compulsive Medication Use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Cohort; O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Percentages are based on n, the number of subjects assessed at each visit. 
 
Cross-reference: Listing 16.2.8.2.7 
 
 
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Table 14.3.4.9.1 
MMRM Analysis of UPDRS Part 4: Change from Baseline in the UPDRS Part 4 Score by Visit 
(Safety Population) 
 
Visit 
Statistic 
CVT-301 
(N=xx) 
p-value 
 
 
 
 
Overall 
 
Overall p-value   
  Baseline Hoehn and Yahr stage 
 
0.xxx 
 
  Screening Spirometry 
 
0.xxx 
 
  Visit 
 
0.xxx 
 
  Baseline UPDRS Part 3 Score 
 
0.xxx 
 
 
 
 
TV4 
n 
xx 
 
 
LS Mean 
xx.x 
 
 
SE (LS Mean) 
xx.xx 
 
 
95% CI (LS Mean) 
(xx.x, xx.x) 
 
 
 
 
 
TV6 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from baseline in UPDRS  Part 4 total scores at each post-baseline visit (TV4, TV6) as the dependent 
variable, and includes visit (TV4 or TV6), the stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening 
spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; 
The baseline UPDRS part 4 score will be included as a covariate, assuming an unstructured covariance matrix. 
 
Cross-reference: Listing 16.2.8.2.8.2 
 
 
 
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Tables below will have similar format as Table 14.3.4.9.1 
 
 
 
Table 14.3.4.9.2    
MMRM Analysis of UPDRS Part 4 Dyskinesias Score: Change from Baseline in the UPDRS Part 4 Score by Visit  
(Safety Population) 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from baseline in UPDRS  Part 4 Dyskinesias scores at each post-baseline visit (TV4, TV6) as the dependent 
variable, and includes visit (TV4 or TV6), the stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening 
spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; 
The baseline UPDRS part 4 score will be included as a covariate, assuming an unstructured covariance matrix. 
 
Cross-reference: Listing 16.2.8.2.8.2 
 
 
Table 14.3.4.9.3    
MMRM Analysis of UPDRS Part 4 Fluctuations Score: Change from Baseline in the UPDRS Part 4 Score by Visit  
(Safety Population) 
 
Note: TV = Treatment Visit;  
MMRM model uses the change from baseline in UPDRS  Part 4 Fluctuations scores at each post-baseline visit (TV4, TV6) as the dependent 
variable, and includes visit (TV4 or TV6), the stratification variables (baseline Hoehn and Yahr stage (<2.5 versus ≥2.5)and screening 
spirometry ([FEV1] <60% or FEV1/forced vital capacity [FVC] ratio <70% versus FEV1 ≥60% and FEV1/FVC ratio ≥70%)) as fixed factors; 
The baseline UPDRS part 4 score will be included as a covariate, assuming an unstructured covariance matrix. 
 
Cross-reference: Listing 16.2.8.2.8.2 
 
 
 
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Table 14.3.4.9.4 
Summary of UPDRS Part 4: Actual Values and Change from Baseline by Visit  
(Safety Population) 
 
Visit  
Statistic 
002/003 
 (N=xx) 
Naive 
 (N=xx) 
Total 
 (N=xx) 
 
 
 
 
 
Baseline 
Actual value 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
TV4/OV4 
Actual value 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
 
Change from Baseline 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean  
xx.x 
xx.x 
xx.x 
 
SD 
xx.xx 
xx.xx 
xx.xx 
 
Median 
xx.x 
xx.x 
xx.x 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
 
TV6/OV6 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Cohort; Total column is for all CVT-301 treated patients, 002/003 column is for the 
patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
Baseline is the last non-missing assessment before the first dose of study drug. 
 
Cross-reference: Listing 16.2.8.2.6 
 
 
 
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Table below will have similar format as Table 14.3.4.9.4 
 
 
Table 14.3.4.9.5 
Summary of UPDRS Part 4 Dyskinesias Score: Actual Values and Change from Baseline by Visit  
(Safety Population) 
 
Table 14.3.4.9.6    
Summary of UPDRS Part 4 Fluctuations Score: Actual Values and Change from Baseline by Visit  
(Safety Population) 
 
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Table 14.3.4.10 
Dyskinesia: Occurrence and Severity (In-clinic) by Visit  
(ITT Population) 
 
 
 
 
 
CVT-301 
 
 
 
Visit 
Statistic 
O. C. 
(N=xx) 
002/003 
(N=xx) 
Naive 
(N=xx) 
Total 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
 
 
 
TV2/OV2 
Dyskinesia  
 
 
 
 
 
 
 
  Yes (Percentages based on N) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
  No (Percentages based on N) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
Severity of Dyskinesia 
 
 
 
 
 
 
 
  Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
  Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
  Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
  Unknown 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
TV3/OV3 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; OV = Observational Cohort;  O.C. column is for the patients in Observational Cohort, 002/003 column is for 
the patients who were previously enrolled in the CVT-301-002 or CVT-301-003 studies and Naïve is for the CVT-301 naive patients. 
[a] The data for which a subject was dyskinetic already before the study drug administration was excluded from summary. 
 
Cross-reference: Listing 16.2.6.2.1 
 
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Attachment 2 Listing Mock-ups 
 
Table of Contents  
 
Listing 16.2.1   Patient Disposition..................................................................................................... 3 
Listing 16.2.2.1 Protocol Deviations..................................................................................................... 4 
Listing 16.2.3.1 Inclusion Criteria not Met at Screening................................................................................. 5 
Listing 16.2.3.2 Exclusion Criteria Met at Screening..................................................................................... 7 
Listing 16.2.4.1    Demographics........................................................................................................ 10 
Listing 16.2.4.2 Medical History........................................................................................................ 11 
Listing 16.2.4.3 Parkinson’s Disease History............................................................................................ 12 
Listing 16.2.4.4    Smoking History..................................................................................................... 13 
Listing 16.2.4.5    ON and OFF Concordance Testing at Screening......................................................................... 14 
Listing 16.2.4.6    Modified Hoehn and Yahr Staging in “ON” State at Screening.......................................................... 15 
Listing 16.2.4.7    Mini Mental State Examination (MMSE) at Screening................................................................... 16 
Listing 16.2.4.8    Parkinson’s Disease Diary Data at Screening: Derived Time........................................................... 17 
Listing 16.2.4.9    Screening ON/OFF Log................................................................................................ 18 
Listing 16.2.4.10 Randomization......................................................................................................... 19 
Listing 16.2.4.11.1 Prior and Concomitant Medications................................................................................... 20 
Listing 16.2.4.11.2 Parkinson’s disease Treatment Medications at Baseline............................................................... 21 
Listing 16.2.4.12 Baseline Pulmonary Assessment Part 2 - Pulmonary History.............................................................. 22 
Listing 16.2.4.13 Baseline Pulmonary Assessment Part 3 - Assessments of Symptoms........................................................ 24 
Listing 16.2.5.1.1 Study Drug Administration: in Clinic and at Home..................................................................... 25 
Listing 16.2.5.1.2    Study Drug Administration: Derived Variables (in Clinic).......................................................... 26 
Listing 16.2.5.1.3 Study Drug Administration: Derived Variables (Overall)............................................................... 27 
Listing 16.2.5.1.4 Study Drug Administration: Derived Variables (Overall by Visit)...................................................... 28 
Listing 16.2.5.1.5 Listing of Study Drug Dose Change.................................................................................... 29 
Listing 16.2.5.2    Study Drug Kit Dispensation......................................................................................... 30 
Listing 16.2.5.3 Daily Levodopa Dose.................................................................................................... 31 
Listing 16.2.6.1.1 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3.............................................................. 32 
Listing 16.2.6.1.2 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3: Derived Variables........................................... 35 
Listing 16.2.6.2.1 Clinic Assessment.................................................................................................... 36 
Listing 16.2.6.2.2    Parkinson’s Disease Diary Data.................................................................................... 37 
Listing 16.2.6.2.3.1 Parkinson’s Disease Diary Data – Derived Variable by Dairy Date.................................................... 38 
Listing 16.2.6.2.3.2 Parkinson’s Disease Diary Data – Derived Variable by Visit......................................................... 39 
Listing 16.2.6.2.4 Patient’s Global Impression of Change (PGI-C)........................................................................ 40 
Listing 16.2.6.2.5    Impact of Parkinson’s OFF Episodes................................................................................ 41 
Listing 16.2.6.3.1 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 2.............................................................. 44 
Listing 16.2.6.3.2 Listing of S&E Activities of Daily Living............................................................................ 45 
Listing 16.2.6.3.3 39 Item Parkinson's Disease Questionnaire (PDQ-39)................................................................... 46 
Listing 16.2.7.1    Adverse Events...................................................................................................... 50 
Listing 16.2.8.1.1 Clinical Laboratory Results - Hematology............................................................................. 51 
Listing 16.2.8.1.2 Clinical Laboratory Results – Chemistry.............................................................................. 51 
Listing 16.2.8.1.3 Serum Pregnancy Test – Positive Only................................................................................. 52 
Listing 16.2.8.2.1 Vital Signs.......................................................................................................... 53 
Listing 16.2.8.2.2 12-Lead Electrocardiogram (ECG)...................................................................................... 54 
Listing 16.2.8.2.3 Physical Examination................................................................................................. 55 
Listing 16.2.8.2.4.1 Spirometry( Neurology Office)...................................................................................... 56 
Listing 16.2.8.2.4.2 Spirometry( Neurology Office) Measurements Not Meeting ATS Quality Criteria........................................ 57 
Listing 16.2.8.2.4.3 Spirometry(Pulmonary Function Facility): DLco Parameters........................................................... 58 
Listing 16.2.8.2.4.4    Spirometry(Pulmonary Function Facility): Spirometry/DLco Measurements Not Meeting ATS Quality Criteria.......... 59 
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Listing 16.2.8.2.5 Columbia-Suicide Severity Rating Scale (C-SSRS)...................................................................... 60 
Listing 16.2.8.2.6 Epworth Sleepiness Scale............................................................................................. 64 
Listing 16.2.8.2.7 Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP)............................................... 65 
Listing 16.2.8.2.8.1    Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4......................................................... 68 
Listing 16.2.8.2.8.1    Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4......................................................... 68 
Listing 16.2.8.2.8.2 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4: Derived Variables......................................... 69 
Listing 16.2.8.2.9.1 Telephone Contact.................................................................................................. 70 
Listing 16.2.8.2.9.2 Telephone Contact: Challenges with Inhaler or Capsules Data........................................................ 71 
 
 
 
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Listing 16.2.1   
Patient Disposition 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Date of First 
Dose 
Date of 
Last Dose 
Date of Completion/ 
Withdrawal (Study Day) 
[a] 
Completed 
Study? 
Primary Reason 
for Withdrawal 
 
Screen 
Failure/Date 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy ddmonyyyy 
Yes 
 
 
 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy ddmonyyyy 
No 
Adverse Event: AE #x 
 
Yes 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy ddmonyyyy 
No 
Lack of Efficacy 
 
 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy ddmonyyyy 
No 
Patient Withdrew Consent 
 
No 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy ddmonyyyy 
No 
Protocol Violation: 
xxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
Note: [a] Study Day = Date of Completion/Withdrawal – Date of first Dose + 1. 
 
 
 
 
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Listing 16.2.2.1 
Protocol Deviations 
 
Treatment Group: Observational Cohort 
Patient ID 
Deviation Type 
Deviation Description 
Created Date 
Major  
Deviation 
Affect Pulmonary 
Assessments 
 
 
 
 
 
 
xxxx-xxx 
xxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
ddmonyyyy 
 
 
 
 
xxxxxxxxxxxxxxxxxx 
ddmonyyyy 
 
 
xxxx-xxx 
xxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
ddmonyyyy 
Yes 
Yes 
 
xxxxxxxxxxx 
xxxxxxxxxxxxxxxxxx 
ddmonyyyy 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
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Listing 16.2.3.1 
Inclusion Criteria not Met at Screening 
 
Inclusion Criteria: 
 
1. 
Has signed and dated an IRB/IEC-approved informed consent form before any protocol-specific screening procedures are performed. 
2. 
Is a male or female aged 30 to 80 years, inclusive.  Women of child-bearing potential must use protocol-defined contraceptive 
measures (see Section 11.1.5) and must have a negative serum human chorionic gonadotropin (hCG) test at screening.  These patients 
must be willing to remain on their current form of contraception for the duration of the study. 
3. 
Patients who have idiopathic PD (i.e., not induced by drugs or other diseases) as defined by fulfilling Steps 1 and 2 of the United 
Kingdom (UK) Brain Bank criteria, diagnosed after the age of 30 years. 
4. 
Patients who are classified as Stage 1 to 3 (in the ON state) on the modified Hoehn and Yahr scale for staging of PD severity. 
5. 
Patients who have experienced motor fluctuations for a minimum of 2 hours of average daily OFF time per waking day (excluding early 
morning OFF time) by self-report and confirmed by the PD Diary (on 3 consecutive days) during the screening period. 
6. 
Patients must be stable on oral LD-containing therapy for at least 2 weeks prior to SV1 with a LD/DDI-containing regimen, which must 
include doses at least 4 times during the waking day and a total daily LD dose of ≤1600 mg (exclusive of PRN LD-containing 
medications).   
7. 
Patients should be stable on other PD medications for at least 4 weeks prior to SV1. 
8. 
Patients must have a ≥25% difference between UPDRS Part 3 scores recorded in their ON and OFF states at screening. 
9. 
Patients must understand (with or without caregiver assistance) their daily medication regimen and must agree that they will not 
change their daily medication doses during the study. 
10. 
Patients must have normal cognition as confirmed by a score of ≥25 on the Mini Mental State Examination (MMSE). 
11. 
Patients must be able to perform a spirometry maneuver in the ON and OFF states and must have a screening FEV1 ≥50% of predicted, 
and a FEV1/FVC ratio >60% of predicted in the ON state at screening.  (A pulmonologist will review the spirometry 
tracings/morphology of any patient with FEV1 <60% or FEV1/FVC <70% in order to determine eligibility.  Patients with an FEV1/FVC 
<70% will complete spirometry before and after the administration of a bronchodilator in a pulmonary function laboratory.  Testing 
will be performed in accordance with the 2005 ATS/European Respiratory Society (ERS) criteria prior to randomization.  The results 
of the bronchodilator challenge will be reviewed by a pulmonologist prior to potential randomization.)  
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
Listing 16.2.3.1 
Inclusion Criteria not Met at Screening 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Any Criterion  
Violation  
at SV1 
Criterion Not Met at SV1 
Patient Has >= 2 Hours of OFF 
Time during the Waking Day 
Confirmed by Diary. 
Criterion Not Met at SV2 
 
Criterion Number 
Comment 
 
Criterion Number 
Comment 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
Yes 
 
x 
xxxxxxx 
x 
 
x 
xxxxxxx 
 
 
 
x 
xxxxxxx 
x 
 
x 
xxxxxxx 
xxxx-xxx 
 
 
x 
xxxxxxx 
x 
 
x 
xxxxxxx 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.3.2 
Exclusion Criteria Met at Screening 
 
Exclusion Criteria 
 
1. 
Patients who have dyskinesia of a severity that would significantly interfere with their ability to participate or perform study 
procedures. 
2. 
Pregnant or lactating females or females wishing to become pregnant. 
3. 
Patients who have any known contraindication to the use of LD, including a history of malignant melanoma or a history of narrow-
angle glaucoma.   
4. 
Patients who have had previous surgery for PD (including but not limited to deep brain stimulation or cell transplantation) or plan 
to have stereotactic surgery during the study period. 
5. 
Patients with a history of psychotic symptoms requiring treatment, or suicidal ideation or attempt within the prior 12 months 
(stable regimens [for at least 4 weeks prior to SV1] of anti-depressant medications and certain low-dose atypical antipsychotic 
medications are permitted).   
6. 
Patients who have cancer with the exception of the following:  basal cell carcinoma or successfully treated squamous cell carcinoma 
of the skin; cervical carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively treated and with no evidence 
of disease recurrence for at least 3 years. 
7. 
Patients taking certain prohibited medications (see Section 9.4.2). 
8. 
Patients with a history of drug or alcohol abuse within the prior 12 months.  
9. 
Patients with chronic obstructive pulmonary disease (COPD), asthma, or other chronic respiratory disease within the last 5 years (or 
if a patient is receiving treatment for any of these conditions). 
10. 
Patients with any contraindication to performing routine spirometry or who are unable to perform a spirometry maneuver (see Appendix 
14 for a list of contraindications). 
11. 
Patients with a current history of symptomatic orthostatic hypotension despite adequate treatment.   
12. 
Patients with any condition that in the investigator’s opinion would make patients unable to comply with study procedures or make 
them unsuitable for participation in the study.   
13. 
Patients who have any clinically significant abnormality or finding from examination, tests, or history that may compromise patient 
safety.  Potential issues of concern should be raised to the medical monitor during eligibility review. 
14. 
Patients who have participated in any prior CVT-301 study, regardless of treatment group assignment. 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.3.2    
Exclusion Criteria Met at Screening 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Any Criterion  
Violation  
at SV1 
Criterion Met at SV1 
Patient Has >= 2 Hours of 
OFF time during the Waking 
Day Confirmed by Diary. 
Criterion Met at SV2 
 
Criterion Number 
Comment 
 
Criterion Number 
Comment 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
Yes 
 
x 
xxxxxxx 
x 
 
x 
xxxxxxx 
 
 
 
x 
xxxxxxx 
x 
 
x 
xxxxxxx 
xxxx-xxx 
 
 
x 
xxxxxxx 
x 
 
x 
xxxxxxx 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.3.3 
Analysis Populations 
 
Treatment Group: Observational Cohort 
Patient ID 
Safety  
Population 
ITT  
Population 
 
 
Completed Visit 
TV1/OV1 
TV2/OV2 
TV3/OV3 
TV4/OV4 
TV5/OV5 
TV6/OV6 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
No 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
Listing 16.2.4.1    
Demographics 
 
Treatment Group: Observational Cohort 
Patient ID 
Date of  
Informed 
Consent 
Date of  
Birth 
Age 
(years) 
[a] 
Sex 
Race 
Ethnicity 
Height  
(cm) 
Weight  
(kg) 
BMI  
(kg/m^2) 
[b] 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy 
xx 
Male 
White 
Hispanic or Latino 
xxx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy 
xx 
Male 
Black or African 
American 
Not Hispanic or 
Latino 
xxx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy 
xx 
Female 
Other: xxxxx 
Hispanic or Latino 
xxx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
ddmonyyyy 
xx 
Female 
Asian 
Unknown 
xxx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
  
[a] Age was calculated as the difference between date of birth and date of Informed Consent, in years.   
[b] BMI was calculated as weight (kg) / [height (m)]^2. 
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.2 
Medical History 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Body System 
Description 
System Organ Class/  
Preferred Term [a] 
Start Date 
 
Stop Date 
 
 
 
 
 
 
xxxx-xxx 
HEENT 
xxxxxxxxxxxx 
xxxxxxxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
ddmonyyyy 
 
Dermatological  
xxxxxxxxxxxx 
xxxxxxxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
Ongoing 
 
Psychiatric 
xxxxxxxxxxxx 
xxxxxxxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
Ongoing 
 
Neurological 
xxxxxxxxxxxx 
xxxxxxxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
Ongoing 
 
... 
 
 
ddmonyyyy 
Ongoing 
 
Other: xxxxxx 
 
 
Unknown 
Unknown 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
  
[a] Medical history data were coded into system organ class and preferred term by using MedDRA version 17.0.  
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.3 
Parkinson’s Disease History 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Date of 
Diagnosis 
Start Date  
of Levodopa 
Treatment 
Date of Onset of  
Motor Fluctuation 
(Wearing Off) Episodes 
 
 
 
 
 
 
xxxx-xxx 
monyyyy 
monyyyy 
monyyyy 
 
 
 
 
 
 
xxxx-xxx 
monyyyy 
monyyyy 
monyyyy 
 
 
 
 
 
 
xxxx-xxx 
monyyyy 
monyyyy 
monyyyy 
 
 
 
 
 
 
xxxx-xxx 
monyyyy 
monyyyy 
monyyyy 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.4    
Smoking History 
 
Treatment Group: Observational Cohort 
Patient  
ID 
 
 
 
 
Age 
Quitted  
If Former or Current Smoker, 
Ever Smoked 
Cigarettes 
Age 
Started 
Current 
Smoker 
Smoking  
Status 
Average Number of Cigarettes 
per Day 
Number of Years 
Smoked 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
Yes 
25 
No 
Former 
xx 
xx 
xx 
 
xxxx-xxx 
Yes 
26 
Yes 
Current xx 
xx 
xx 
 
xxxx-xxx 
No 
 
 
Never 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
Number of Years Smoked = (Age-Age Started+1)(Current Smoker) OR =(Age Quitted-Age Started+1)(Former Smoker).    
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.5    
ON and OFF Concordance Testing at Screening 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of  
Assessment 
Has the Patient Been Tested for Competence in self-rating with at least 75% concordance with the ratings 
of the examiner?  
 
 
 
 
xxxx-
xxx 
SV1 
ddmonyyyy 
Yes 
 
SV2 
Not Done 
 
 
 
 
 
xxxx-
xxx 
UNS 
ddmonyyyy 
No 
 
SV1 
ddmonyyyy 
Yes 
... 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
Note: SV = Screening Visit; UNS = Unscheduled;  
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.6    
Modified Hoehn and Yahr Staging in “ON” State at Screening 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Date of 
Assessment 
Stage in “ON” 
State [a] 
 
 
 
xxxx-xxx 
ddmonyyyy 
0 = No signs of disease 
 
 
 
xxxx-xxx 
ddmonyyyy 
1 = Unilateral disease 
 
 
 
xxxx-xxx 
Not Done, xxxxxx 
 
... 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
[a] 0 = No signs of disease, 1 = Unilateral disease, 1.5 = Unilateral plus axial involvement,  
    2 = Bilateral disease, without impairment of balance, 2.5 = Mild bilateral disease, with recovery on pull test,  
    3 = Mild to moderate bilateral disease; some postural instability; physical independent,  
    4 = Severe disability; still able to walk or stand unassisted, 5 = Wheelchair-bound or bedridden unless aided.  
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.7    
Mini Mental State Examination (MMSE) at Screening 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of  
Assessment 
Q1 
Q2 
Q3 
Q4 
Q5 
Q6 
Q7 
Q8 
Q9 
Q10 
Q11 
Total 
Score [a] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
SV1 
ddmonyyyy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
SV2 
ddmonyyyy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
Not Done, 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV= Screening Visit; UNS=Unscheduled Visit;  
[a] >=25 points = normal, 21-24 points = mild cognitive impairment, 10-20 points = moderate cognitive impairment, 
    0-9 points = severe cognitive impairment. 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.8    
Parkinson’s Disease Diary Data at Screening: Derived Time 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Mean OFF 
Time 
(hours) 
Mean Daily 
ON Time Without 
Dyskinesia 
(hours) 
Mean Daily 
ON Time With 
Non- 
troublesome 
Dyskinesia 
(hours) 
Mean Daily 
ON Time With Troublesome 
Dyskinesia 
(hours) 
Dyskinetic 
Before 
TV1 [a] 
 
 
 
 
 
 
xxxx-xxx 
xx.x 
xx.x 
xx.x 
xx.x 
Yes 
 
 
 
 
 
 
xxxx-xxx 
xx.x 
xx.x 
xx.x 
xx.x 
No 
 
 
 
 
 
 
xxxx-xxx 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
xxxx-xxx 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; All diary data were normalized to 16 awake hours per day. 
[a] Patients who have recorded at least 1 hour of dyskinesia (either ON with non-troublesome dyskinesia or ON with troublesome   
dyskinesia) on at least 2 days before TV1 are classified as dyskinetic. 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.9    
Screening ON/OFF Log 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Date of  
Assessment 
 
Time of Start  
of OFF Episode 
Changed the Timing of 
 Usual LD Medication? 
Take an Extra Dose of LD/ 
Other Parkinson’s Medication? 
Daily  
Number of  
OFF Episodes 
 Experienced 
 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
 
hh:mm a.m. 
Yes 
Yes 
xx 
 
 
 
hh:mm a.m. 
No 
No 
 
 
ddmonyyyy 
 
hh:mm p.m. 
No 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.10 
Randomization 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Date of 
Randomization 
Kit Number 
 
Baseline Disease 
Severity [a] 
Screening Spirometry 
Country 
Site 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
NA 
 
Low 
FEV1 <60% or FEV1/FVC ratio <70% 
US 
xx 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
NA 
 
High 
FEV1 ≥60% and FEV1/FVC ratio ≥70% 
US 
xx 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
NA 
 
High 
FEV1 ≥60% and FEV1/FVC ratio ≥70% 
Canada 
xx 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
  
[a] Low = Hoehn and Yahr Stage < 2.5, High = Hoehn and Yahr Stage >= 2.5. 
[b] Patients who have recorded at least 1 hour of dyskinesia (either ON with non-troublesome dyskinesia or ON with troublesome  
dyskinesia) on at least 2 days before Visit 3 are classified as dyskinetic. 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.11.1 
Prior and Concomitant Medications 
 
 
Treatment Group: Observational Cohort 
Patient  
ID 
ATC Level 1/ 
  ATC Level 2 [a] 
Preferred Term [a]/  
 Medication Name 
Start/  
Stop Date 
P/C 
[b] 
Dose  
(Unit) 
 
Frequency 
 
Route 
Indication 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
xxxxxxxx/   
xxxxxxxxxxxx 
xxxxxxxx/   
xxxxxxxxxxxx 
Ddmonyyyy/ddmonyyyy 
P 
xxxxx (xxx) 
xxx 
xxxxx 
 
Medical History: x 
 
xxxxxxxx/   
xxxxxxxxxxxx 
xxxxxxxx/   
xxxxxxxxxxxx 
ddmonyyyy/ 
ddmonyyyy 
 
C 
xxxxx (xxx) 
xxx 
xxxxx 
 
Adverse Event: x 
 
 
xxxxxxxx/   
xxxxxxxxxxxx 
ddmonyyyy/ Ongoing 
 
C 
xxxxx (xxx) 
Other: xxx 
xxxxx 
 
... 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
  
[a] Medications were coded into ATC and preferred term using the WHO Drug Dictionary Q1March2014. 
[b] P=Prior, C=Concomitant. 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.11.2 
Parkinson’s disease Treatment Medications at Baseline 
 
 
Treatment Group: Observational Cohort 
Patient  
ID 
ATC Level 1/ 
  ATC Level 2 [a] 
Preferred Term [a]/  
 Medication Name 
Start/  
Stop Date 
P/C 
[b] 
Dose  
(Unit) 
 
Frequency 
 
Route 
Indication 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
xxxxxxxx/   
xxxxxxxxxxxx 
xxxxxxxx/   
xxxxxxxxxxxx 
ddmonyyyy/ddmonyyyy 
P 
xxxxx (xxx) 
xxx 
xxxxx 
 
Medical History: x 
 
xxxxxxxx/   
xxxxxxxxxxxx 
xxxxxxxx/   
xxxxxxxxxxxx 
ddmonyyyy/ddmonyyyy 
C 
xxxxx (xxx) 
xxx 
xxxxx 
 
Adverse Event: x 
 
 
xxxxxxxx/   
xxxxxxxxxxxx 
ddmonyyyy/ Ongoing 
 
C 
xxxxx (xxx) 
Other: xxx 
xxxxx 
 
... 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
[a] Medications were coded into ATC and preferred term using the WHO Drug Dictionary, Q1March2014. The medications which start with 
ATC code N04 are considered as baseline PD treatment medications. 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
Listing 16.2.4.12 
Baseline Pulmonary Assessment Part 2 - Pulmonary History 
 
Part 2: Pulmonary History 
A. Asthma Questions: 
1. Have you ever been told by an MD or other health care provider that you have asthma?/Details 
  2. If yes, how old were you when you were diagnosed with asthma?(years) 
  3. Do you still have asthma? 
  4. If no, at what age did your asthma resolve? 
  5. If yes, do you take medicine for asthma? 
  6. Which medicine(s) do you take for asthma? 
  7. What things cause your asthma to worsen or asthma attacks to occur? 
B. COPD Questions: 
1. Have you ever been told by an MD or other health care provider that you have smoker’s cough, COPD, emphysema, or chronic           
bronchitis? 
2. If yes, how old were you when you were diagnosed with this condition? 
3. What has/have been your primary occupation(s)?  
4. Have you worked in jobs with significant dust exposure?  
5. If yes, for how many years?  
6. Do you currently take medicines for COPD?  
7. If yes, which medicine(s) for COPD do you take?  
C. Other Lung or Airway Disease: 
1. Do you have any condition that may have affected your breathing or lung health, such as congenital conditions of the chest wall 
or spine (for example, scoliosis) or other conditions, such as sleep apnea?  
2. Have you ever sustained any chest or lung injuries or trauma that have had a long-term impact on your breathing?  
3. Have you had any medical issues affecting your heart, such as a heart attack or congestive heart failure, that have caused you to 
have shortness of breath or limited your ability to exercise?  
4. Have you ever needed to be put on a mechanical ventilator or respirator for any reason?/If yes, was this needed for  
5. Have there been any other illnesses, chronic conditions, injuries or anything you can think of in your past, even as a child, that 
may have had a lasting impact on your lungs or respiratory health?  
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.12 
Baseline Pulmonary Assessment Part 2 - Pulmonary History 
 
Treatment Group: Observational Cohort 
Patient  
ID 
A. Asthma  Questions 
B. COPD Questions 
C. Other Lung or Airway Disease 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
No 
 
 
 
 
 
 
Yes 
xx 
xxx 
No 
 
No 
 
Yes 
No 
xx 
Yes./xxx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
Yes/xxx 
xxx 
No 
xx 
xx 
xxx 
xxx 
No 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: The actual listing started with new page 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.4.13 
Baseline Pulmonary Assessment Part 3 - Assessments of Symptoms 
 
1. Shortness of breath or breathlessness? / If yes, when does this seem to occur?  
2. Chest Tightness? / If yes, when does this seem to occur?  
3. Chest Pain? / If yes, when does this seem to occur?  
4. Persistent Cough? / If yes, when does this seem to occur?  
5. Sputum Production/If yes, when does this seem to occur?  
6. Episodes of coughing up blood or blood in your sputum?/ If yes, when does this seem to occur?  
 
 
Listing 16.2.4.13 
Baseline Pulmonary Assessment Part 3 - Assessments of Symptoms 
Treatment Group: Observational Cohort 
Patient  
ID 
Assessments of Symptoms 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
 
xxxx-xxx 
Yes,xxx 
No 
Yes,xxx 
No 
Yes,xxx 
Yes,xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
No 
Yes,xxx 
Yes,xxx 
Yes,xxx 
No 
No 
... 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
Programming note: The actual listing started with new page 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.5.1.1 
Study Drug Administration: in Clinic and at Home 
 
Treatment Group: CVT-301 (002/003) 
Patient 
ID 
Dosing 
Category 
Visit 
Start 
Date/Time 
 of Treatment 
End Date/Time  
of Treatment (Time 
0) 
Capsules 
Administered 
Time 
Intervals 
Doses/Day 
Any 
Reinhalations/Which 
Capsules 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
In Clinic 
TV1 
ddmonyyyyhh:mm ddmonyyyyhh:mm 
x 
00:00 -< 
00:30 
x 
No 
 
At Home 
TV1-
<TV2 
ddmonyyyyhh:mm ddmonyyyyhh:mm 
x 
00:30 -< 
01:00 
x 
 
 
 
TV2-
<TV2 
ddmonyyyyhh:mm ddmonyyyyhh:mm 
x 
01:00 -< 
01:30 
x 
Yes/1st 
 
 
TV3-
<TV4 
ddmonyyyyhh:mm ddmonyyyyhh:mm 
x 
01:30 -< 
02:00 
x 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
Note: TV=Treatment;  
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.5.1.2    
Study Drug Administration: Derived Variables (in Clinic) 
 
Treatment Group: CVT-301 (002/003) 
Patient 
ID 
Visit 
Standard Morning Dose of LD-
Containing Medications to In-
clinic OFF (mins) 
In-clinic OFF to Start of 
Study Drug Inhalation 
(mins) 
Standard Morning Dose of LD-containing 
Medications to Start of Study Drug 
Inhalation (mins) 
Duration of 
Study 
Drug 
Inhalation 
 
 
 
 
 
 
xxxx-
xxx 
TV1 
xx 
xx 
xx 
x 
 
TV2 
xx 
xx 
xx 
x 
 
TV3 
xx 
xx 
xx 
x 
 
TV4 
xx 
xx 
xx 
x 
 
 
 
 
 
x 
xxxx-
xxx 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV=Treatment Visit;  
 
Page 211 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.5.1.3 
Study Drug Administration: Derived Variables (Overall) 
 
Treatment Group: CVT-301 (002/003) 
Patient 
ID 
Duration of 
Exposure (days) [a] 
Total # of 
Capsules Taken 
Average Daily 
Capsules 
Total # of 
Doses Taken 
Average Daily 
Dose(s) 
 
 
 
 
 
 
xxxx-xxx 
xx 
xx 
xx 
xx 
2 
 
xx 
xx 
xx 
xx 
3 
 
xx 
xx 
xx 
xx 
5 
 
xx 
xx 
xx 
xx 
4 
 
xx 
xx 
xx 
xx 
5 
 
xx 
xx 
xx 
xx 
4 
 
xx 
xx 
xx 
xx 
5 
xxxx-xxx 
 
 
 
 
 
... 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
 
 [a] Duration of exposure (days) is calculated as documented last dose date-first dose date +1. 
 
 
 
Page 212 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.5.1.4 
Study Drug Administration: Derived Variables (Overall by Visit) 
 
Treatment Group: CVT-301 (002/003) 
Patient 
ID 
Visit 
Total # of 
Capsules Taken 
Average Daily 
Capsules 
Total # of 
Doses Taken 
Average Daily 
Dose(s) 
 
 
 
 
 
 
xxxx-xxx 
TV1-<TV2 
xx 
xx 
xx 
2 
 
TV2-<TV3 
xx 
xx 
xx 
3 
 
TV3-<TV4 
xx 
xx 
xx 
5 
 
 
xx 
xx 
xx 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
... 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
 
Note: TV = Treatment Visit;   
 
Page 213 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.5.1.5 
Listing of Study Drug Dose Change 
 
Treatment Group: CVT-301 (002/003) 
Patient 
ID 
Type of change 
Reason for 
Change 
Date of Change 
Old Dose Level 
(# capsules per 
treatment) 
New Dose Level 
(# capsules per 
treatment) 
Was Medical Monitor 
Contacted? 
 
 
 
 
 
 
 
xxxx-xxx 
Increase 
xxxxx 
 
ddmmmyyyy 
1 
2 
Yes 
xxxx-xxx 
Decrease 
xxxxxxxxxx 
ddmmmyyyy 
2 
1 
No 
xxxx-xxx 
Decrease 
xxxxxxxxxx 
 
ddmmmyyyy 
2 
1 
Yes 
... 
 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
Page 214 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
Listing 16.2.5.2    
Study Drug Kit Dispensation 
 
Patient  
ID 
Visit  
Treatment 
Kit Number 
Dispensed 
Date Dispensed 
 
 
 
 
 
xxxx-xxx 
TV1 
Observational Cohort 
xxxx 
ddmonyyyy 
 
TV2 
Observational Cohort 
xxxx 
ddmonyyyy 
 
TV3 
Observational Cohort 
xxxx 
ddmonyyyy 
 
Other: xxxx 
Observational Cohort 
xxxx 
ddmonyyyy 
 
 
 
 
 
xxxx-xxx 
 
CVT DL1 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV=Treatment Visit; UNS= Unscheduled;  
 
Page 215 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.5.3 
Daily Levodopa Dose 
 
Treatment Group: Observational Cohort 
Patient ID 
Visit  
How many times 
Total Levodopa daily dose 
 
 
 
 
xxxx-xxx 
SV1 
xx 
 
 
TV1 
xx 
xxxx 
 
TV2 
xx 
xxxx 
 
TV3 
xx 
xxxx 
 
... 
 
xxxx 
 
 
 
 
xxxx-xxx 
 
 
 
... 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; UNS= Unscheduled;  
 
 
 
Page 216 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
 
Listing 16.2.6.1.1 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 
 
Treatment Group: CVT-301 (002/003) 
 
Tremor at Rest 
Action 
or 
Postural 
Tremor 
Rigidity 
Patient 
ID 
Visit 
Time 
Point 
Date and Time 
of Assessment 
Speech 
Facial 
Exp. 
Face RUE LUE RLE LLE RUE 
LUE Neck RUE LUE RLE LLE 
 
xxx-xxx 
SV1 - OFF 
16APR2013 14:10 
1 
1 
0 
0 
0 
0 
0 
0 
0 
3 
3 
1 
1 
1 
SV1 - ON 
16APR2013 16:20 
1 
1 
0 
0 
0 
0 
0 
0 
0 
3 
1 
0 
0 
0 
 
xxx-xxx 
SV1 - OFF 
16APR2013 15:35 
2 
2 
0 
0 
0 
0 
2 
1 
1 
1 
1 
1 
0 
0 
SV1 - ON 
16APR2013 14:10 
1 
1 
0 
0 
0 
0 
2 
1 
1 
1 
0 
0 
1 
0 
 
SV2 
Not Done, not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV1 
Pre-dose 
14MAY2013 11:20 
2 
2 
0 
0 
0 
0 
0 
1 
1 
2 
1 
1 
0 
0 
+10 mins 
14MAY2013 11:37 
0 
1 
0 
0 
0 
0 
0 
0 
0 
2 
0 
0 
0 
0 
+20 mins 
14MAY2013 11:47 
1 
0 
0 
0 
0 
0 
0 
0 
0 
1 
0 
0 
0 
0 
+30 mins 
14MAY2013 11:57 
0 
1 
0 
0 
0 
0 
0 
0 
0 
2 
0 
0 
0 
0 
+60 mins 
14MAY2013 12:27 
2 
1 
0 
0 
0 
0 
0 
0 
1 
2 
1 
0 
0 
0 
 
TV2 
Pre-dose 
21MAY2013 11:43 
2 
1 
0 
0 
0 
0 
0 
0 
0 
3 
1 
1 
0 
0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
*indicates imputed item score. 18=Speech, 19=Facial Expression, 20=Tremor at Rest, 21=Action or Postural Tremor of hands, 22=Rigidity, 
23=Finger Taps, 24=Hand Movements, 25=Rapid Alternating Movements of Hands, 26=Leg Agility, 27=Arising from Chair, 28=Posture, 
29=Gait, 30=Postural Stability, 31=Body Bradykinesia and Hypokinesia.  
 
 
Page 217 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.1.1    
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 
 
Treatment Group: CVT-301 (002/003) 
 
Finger Taps 
Hand 
Movements 
Rapid 
Alternating 
Movements 
of Hands 
Leg Agility 
 
Patient 
ID 
Visit 
Time 
Point 
Date and Time 
of Assessment 
Right 
Left 
Right Left 
Right 
Left 
Right 
Left 
Arising 
from 
Chair 
 
xxx-xxx 
SV1 - OFF 
16APR2013 14:10 
4 
2 
2 
2 
3 
2 
1 
1 
4 
SV1 - ON 
16APR2013 16:20 
1 
1 
1 
1 
1 
1 
0 
0 
0 
 
xxx-xxx 
SV1 - OFF 
16APR2013 15:35 
2 
1 
1 
0 
1 
0 
1 
1 
0 
SV1 - ON 
16APR2013 14:10 
2 
1 
0 
0 
0 
0 
0 
0 
0 
 
SV2 
Not Done, not applicable 
 
 
 
 
 
 
 
 
 
 
TV1 
Pre-dose 
14MAY2013 11:20 
2 
2 
2 
1 
1 
1 
0 
1 
0 
+10 mins 
14MAY2013 11:37 
1 
1 
0 
1 
1 
1 
0 
0 
0 
+20 mins 
14MAY2013 11:47 
0 
1 
1 
1 
0 
0 
0 
2 
0 
+30 mins 
14MAY2013 11:57 
0 
0 
1 
1 
0 
1 
0 
0 
0 
+60 mins 
14MAY2013 12:27 
1 
2 
1 
1 
1 
1 
1 
2 
0 
 
TV2 
Pre-dose 
21MAY2013 11:43 
1 
2 
1 
1 
0 
1 
1 
2 
0 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
*indicates imputed item score. 18=Speech, 19=Facial Expression, 20=Tremor at Rest, 21=Action or Postural Tremor of hands, 22=Rigidity, 
23=Finger Taps, 24=Hand Movements, 25=Rapid Alternating Movements of Hands, 26=Leg Agility, 27=Arising from Chair, 28=Posture, 
29=Gait, 30=Postural Stability, 31=Body Bradykinesia and Hypokinesia.  
 
 
Page 218 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.1.1    
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 
 
Treatment Group: CVT-301 (002/003) 
Patient 
ID 
Visit 
Time 
Point 
Date and Time 
of Assessment 
Posture 
Gait 
Postural 
Stability 
Bradykinesia/ 
Hypokinesia 
UPDRS III 
Total Score 
 
xxxx-xxx 
SV1 - OFF 
16APR2013 14:10 
1 
2 
0 
3 
38 
SV1 - ON 
16APR2013 16:20 
1 
1 
0 
2 
16 
 
xxx-xxx 
SV1 - OFF 
16APR2013 15:35 
2 
1 
1 
2 
24* 
SV1 - ON 
16APR2013 14:10 
2 
1 
0 
1 
15 
 
SV2 
Not Done, not applicable 
 
 
 
 
 
 
TV1 
Pre-dose 
14MAY2013 11:20 
1 
1 
0 
2 
24 
+10 mins 
14MAY2013 11:37 
1 
1 
0 
1 
11 
+20 mins 
14MAY2013 11:47 
1 
1 
0 
1 
10 
+30 mins 
14MAY2013 11:57 
1 
1 
0 
1 
9 
+60 mins 
14MAY2013 12:27 
2 
1 
0 
1 
21 
 
TV2 
Pre-dose 
21MAY2013 11:43 
2 
1 
0 
2 
22 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
*indicates imputed item score. 18=Speech, 19=Facial Expression, 20=Tremor at Rest, 21=Action or Postural Tremor of hands, 22=Rigidity, 
23=Finger Taps, 24=Hand Movements, 25=Rapid Alternating Movements of Hands, 26=Leg Agility, 27=Arising from Chair, 28=Posture, 
29=Gait, 30=Postural Stability, 31=Body Bradykinesia and Hypokinesia.  
 
Page 219 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.1.2 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3: Derived Variables 
 
Treatment Group: CVT-301 (002/003) 
Patient 
ID 
Visit 
Time 
Point 
UPDRS III 
Total 
Score 
Change from 
Pre-dose 
Mean Change 
from Pre-dose 
at 10 to 60 
mins 
Post-dose 
>=3 Reduction 
from Pre-dose 
>=6 Reduction 
from Pre-dose 
>=11 
Reduction 
from Pre-
dose 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV2 
Pre-dose 
xx 
 
xx 
 
 
 
 
 
+10mins 
xx 
xx 
 
 
 
 
 
 
+20mins 
xx 
xx 
 
 
Y 
 
 
 
+30mins 
xx 
xx 
 
Y  
 
Y 
 
 
+60mins 
xx 
xx 
 
Y 
 
 
 
TV3 
Pre-dose 
xx 
 
xx 
 
 
 
 
 
+10mins 
xx 
xx 
 
 
 
 
 
 
+20mins 
xx 
xx 
 
 
 
 
 
 
+30mins 
xx 
xx 
 
 
 
 
 
 
+60mins 
xx 
xx 
 
 
 
 
 
TV4 
Pre-dose 
xx 
 
xx 
 
 
 
 
 
+10mins 
xx 
xx 
 
 
 
 
 
 
+20mins 
xx 
xx 
 
 
 
 
 
 
+30mins 
xx 
xx 
 
 
 
 
 
 
+60mins 
xx 
xx 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; ET = Early Termination;  
 
 
Page 220 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.2.1 
Clinic Assessment 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Visit 
Date of 
Assessment 
Time of Standard 
Morning Dose of LD-
Containing 
Medications 
Motor 
State at 
Arrival 
Time 
Patient 
Turned OFF 
Turned ON 
within the 
60-min Post 
Dose Period? 
Was Patient ON at 
60-min Post 
Inhaled 
Treatment? 
Experience 
Dyskinesia 
 
Maximum 
Severity 
 
 
 
 
 
 
 
 
 
 
 
xxxx-
xxx 
SV1 
ddmonyyyy 
hh:mm 
 
 
 
 
 
 
 
SV2 
Not Done, 
xxxx 
 
 
 
 
 
 
 
 
TV1 
ddmonyyyy 
hh:mm 
OFF 
hh:mm 
Yes 
No 
Yes 
xxx 
 
… 
ddmonyyyy 
hh:mm 
OFF 
hh:mm 
Yes 
Yes 
No 
 
 
 
 
 
 
 
 
 
 
 
xxxx-
xxx 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; FU = Follow up; ET = Early Termination; UNS = Unscheduled;  
 
 
Page 221 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.2.2    
Parkinson’s Disease Diary Data 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Week 
Date of Assessment 
Time of  
Assessment 
Asleep 
OFF 
ON without 
Dyskinesia 
ON with Non-troublesome 
Dyskinesia 
ON with Troublesome 
Dyskinesia 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
SV 
ddmonyyyy 
hh:mm 
 
 
 
 
 
 
TV3 
Not Done, xxxx 
 
 
 
 
 
 
 
TV4 
ddmonyyyy 
hh:mm 
1 
0 
0 
0 
0 
 
… 
ddmonyyyy 
hh:mm 
1 
0 
0 
0 
0 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; FU = Follow up; ET = Early Termination; UNS = Unscheduled;  
 
Page 222 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.2.3.1 
Parkinson’s Disease Diary Data – Derived Variable by Dairy Date 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Visit 
Date of 
Assessment 
Daily Awake 
Time (Hrs) 
Daily OFF Time (Hrs)/ 
% of OFF time 
Daily 
ON Time 
Without 
Dyskinesia 
(hours) 
 
Daily ON Time 
With 
Non- 
troublesome 
Dyskinesia 
(hours) 
Daily 
ON Time With 
Troublesome Dyskinesia 
(hours) 
  
 
 
 
 
 
 
  
 
  
xxxx-
xxx 
SV 
ddmonyyyy 
x.x 
x.x 
x.x 
 
x.x 
x.x 
  
 
TV2 
ddmonyyyy 
x.x 
x.x 
x.x 
 
x.x 
 
  
 
TV3 
ddmonyyyy 
x.x 
x.x 
x.x 
 
x.x 
x.x 
  
 
TV4 
ddmonyyyy 
x.x 
x.x 
x.x 
 
x.x 
x.x 
  
 
 
 
 
 
 
  
 
  
xxxx-
xxx 
 
 
 
 
 
  
 
 
 
... 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
Note: SV = Screening Visit; TV = Treatment Visit; FU = Follow up; ET = Early Termination; UNS = Unscheduled;  
 
 
 
Page 223 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.2.3.2 
Parkinson’s Disease Diary Data – Derived Variable by Visit 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Visit 
Date of 
Assessment 
Daily 
Awake 
Time 
(Hrs) 
Mean Daily OFF 
Time (Hrs)/ % 
of OFF time 
Mean Daily 
ON Time 
Without 
Dyskinesia 
(hours) 
 
Mean Daily 
ON Time 
With 
Non- 
troublesome 
Dyskinesia 
(hours) 
Mean Daily 
ON Time With 
Troublesome 
Dyskinesia 
(hours) 
Baseline Daily OFF 
Time/ Category at 
Screening 
  
 
 
 
 
 
 
  
 
 
  
xxxx-
xxx 
SV 
ddmonyyyy 
x.x 
x.x 
x.x 
 
x.x 
x.x 
x.x /<4.5 hours 
  
 
TV2 
ddmonyyyy 
x.x 
x.x 
x.x 
 
x.x 
 
 
  
 
TV3 
ddmonyyyy 
x.x 
x.x 
x.x 
 
x.x 
x.x 
 
  
 
TV4 
ddmonyyyy 
x.x 
x.x 
x.x 
 
x.x 
x.x 
 
  
 
 
 
 
 
 
  
 
 
  
xxxx-
xxx 
 
 
 
 
 
  
 
 
 
 
... 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
  
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
  
Note: SV = Screening Visit; TV = Treatment Visit; FU = Follow up; ET = Early Termination; UNS = Unscheduled;  
 
Page 224 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.2.4 
Patient’s Global Impression of Change (PGI-C) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date and Time  
of Assessment 
Response  
[a] 
 
 
 
 
xxxx-xxx 
TV4 
ddmonyyyyhh:mm 
x 
xxxx-xxx 
TV4 
Ddmonyyyyhh:mm 
x 
 
 
 
 
xxxx-xxx 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  [a] 1 = Much Improved, 2 = Improved, 3 = A little Improved, 4 = No change, 5 = A little worse, 6 = Worse,  
    7 = Much worse. 
 
 
 
Page 225 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.2.5    
Impact of Parkinson’s OFF Episodes 
 
Time Spend in OFF Time: 
1. Over the last week, on average… how many hours in the day are you typically awake? 
2. Over the last week, on average… how many of your awake hours are typically in an OFF state? 
3. Over the last week, on average… how many OFF episodes do you experience in a typical day? 
4. Over the last week, on average… what is the typical duration of each OFF episode? 
 
Functional Impact of OFF time 
1. Over the last week, on average, when you experience an OFF episode, did it stop you from doing things? 
 
Impact of OFF Time on Activities of Daily Living 
a. Motor and Physical 
  1. Had difficulty with housework or cooking? 
  2. Had difficult with work tasks like typing? 
  3. Had difficulty getting around in public? 
  4. Been confined to the house more than you would like? 
  5. Had difficulty washing/dressing yourself? 
  6. Felt Pain? 
  7. Had difficulty walking safely? 
b. Social and Cognitive 
  1. Felt depressed? 
  2. Felt anxious? 
  3. Had problems with concentration? 
  4. Felt memory was bad? 
  5. Felt unable to communicate properly? 
  6. Had trouble mentally changing from one task to another? 
c. Any other things you would like to share about your off time 
 
Impact of OFF Time on Well-being and quality of Life 
1. Over the last week, on average, how do OFF periods affect your overall feeling of health and well-being? 
 
Impact of OFF Time on Disability 
1. Over the last week, on an average day when you are in an ON state, you would rate your disability: 
2. Over the last week, on an average day when experiencing OFF time, you would rate your disability: 
 
 
Page 226 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.2.5 
Impact of Parkinson’s OFF Episodes 
 
Treatment Group: Observational Cohort 
 
 
 
 
Impact of OFF Time on Activities of Daily Living 
Patient 
ID 
Visit 
Date of 
Assessment 
Time Spend in OFF Time 
Motor and Physical 
Social and Cognitive 
1 
2 
3 
4 
1 
2 
3 
4 
5 
6 
7 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
Programming note: The actual listing started with new page 
 
Page 227 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.2.5 
Impact of Parkinson’s OFF Episodes 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Visit 
Date of 
Assessment 
 
 
 
Impact of OFF Time on Disability 
 
Functional Impact 
 of OFF time 
 
Impact of OFF Time on 
 Well-being 
 and Quality of Life 
Any other things you  
would like to share 
 about your OFF time 
1 
 
 
1 
2 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
x 
 
x 
x 
x 
xxxx 
xxxx-xxx 
TV1 
 
x 
 
x 
x 
x 
xxxxx 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 228 of 335


Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.3.1 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 2 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Visit 
Date Of 
Assessment 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Total 
Score 
Change 
from 
Baseline 
xxxx-
xxx 
TV1 
ddmonyyyy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
TV4 
Not Done, 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-
xxx 
TV1 
ddmonyyyy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
TV4 
ddmonyyyy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; ET = Early Termination;  
5=Speech, 6=Salivation, 7=Swallowing, 8=Handwriting, 9=Cutting food and handling utensils, 10=Dressing, 11=Hygiene, 12=Turning in bed 
and adjusting bed clothes, 13=Falling(unrelated to freezing), 14=Freezing when walking, 15=Walking, 16=Tremor(Symptomatic complaint of 
tremor in any part of body), 17=Sensory complaints related to parkinsonism. 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.3.2 
Listing of S&E Activities of Daily Living 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of Assessment 
Rating Description of ADL capability 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
x 
 
TV4 
ddmonyyyy 
x 
xxxx-xxx 
TV1 
ddmonyyyy 
x 
 
TV4 
Not Done, xxxxxxxx 
 
 
 
 
 
xxxx-xxx 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; ET = Early Termination;  
 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
 
Listing 16.2.6.3.3 
39 Item Parkinson's Disease Questionnaire (PDQ-39) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date and  
Time of  
Assessment 
Mobility 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Dimension 
Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyyhh:mm 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
TV4 
Not Done, xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
The assessments on TV1 were taken prior to study medication application. 
 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.3.3 
39 Item Parkinson's Disease Questionnaire (PDQ-39) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date and  
Time of  
Assessment 
Activities of Daily Living 
Emotional Well-being 
11 
12 
13 
14 
15 
16 
Dimension 
Score 
17 
18 
19 
20 
21 
22 
Dimension 
Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyyhh:mm 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
TV4 
Not Done, xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
The assessments on TV1 were taken prior to study medication application. 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.3.3 
39 Item Parkinson's Disease Questionnaire (PDQ-39) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date and  
Time of  
Assessment 
Stigma 
Social Support 
Cognitions 
23 
24 
25 
26 
Dimension 
Score 
27 
28 
29 
Dimension 
Score 
30 
31 
32 
33 
Dimension 
Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyyhh:mm 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
TV4 
Not Done, xxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
The assessments on TV1 were taken prior to study medication application. 
 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.6.3.3 
39 Item Parkinson's Disease Questionnaire (PDQ-39) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date and  
Time of  
Assessment 
Communication 
Bodily Discomfort 
 
Summary Index Score 
34 
35 
36 
Dimension 
Score 
37 
38 
39 
Dimension 
Score 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyyhh:mm 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
TV4 
Not Done, xxxxx 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
The assessments on TV1 were taken prior to study medication application. 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.7.1    
Adverse Events 
 
Treatment Group: Observational Cohort 
Patient  
ID 
System Organ Class/  
Preferred Term/  
Verbatim Term [a] 
AE Start  
Date  
and Time/ 
Study Day  
[b] 
AE Stop Date 
and Time 
I: Intensity 
R: Relationship 
   to Study   
   Medication 
A: Action Taken 
Outcome 
SAE? If Yes, 
Specify [c] 
 
 
 
 
 
 
 
xxxx-xxx 
xxxxxxxxxx/ 
xxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
hh:mm/ 
-xx 
 
ddmonyyyy 
Hh:mm 
I: xxxxxxxx 
R: xxxxxxxx 
A: xxxxxxxxx 
Resolved 
Yes: 1 
 
xxxxxxxxxx/ 
xxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
hh:mm/ 
xx# 
Ongoing 
I: xxxxxxxx 
R: xxxxxxxx 
A: xxxxxxxxx 
Unknown 
No 
xxxx-xxx 
xxxxxxxxxx/ 
xxxxxxxxx/ 
xxxxxxxxx 
ddmonyyyy 
hh:mm/ 
-xx 
 
ddmonyyyy 
Hh:mm 
I: xxxxxxxx 
R: xxxxxxxx 
A: xxxxxxxxx 
Resolved 
Yes: 2 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Notes: TEAE=Treatment-emergent AE. SAE=Serious AE.[a] Adverse events were coded into system organ class and preferred term using 
MedDRA version 17.0. 
[b] TEAEs were flagged with a #. The AEs occurred on the clinic visit were flagged with *.Study day is relative to date of first study 
medication (date of first dose = Day 1). 
[c] 1 = The event is fatal or life-threatening, 2 = The event is permanently disabling (incapacitating or interfering 
with the ability to resume usual life patterns), 3 = The event results in unplanned inpatient hospitalization or  
prolongation of existing hospitalization, 4 = The event is a congenital anomaly, 5 = The event requires medical  
intervention of any kind in order to prevent any of the aforementioned outcomes. 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.1.1 
Clinical Laboratory Results - Hematology 
 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date and Time  
of Sample 
Test1 
unit 
Test2 
unit 
Test3 
unit 
... 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
SV1 
ddmonyyyyhh:mm 
xx H*  
xx L*  
xx 
 
 
 
 
TV1 
ddmonyyyyhh:mm 
xx 
xx 
xx 
 
 
 
 
TV4 
Not Done, xxxxx 
xx H** 
xx H** 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV=Treatment Visit; FU= Follow-up; UNS= unscheduled;  
L = Low, H = High, L* = potentially clinically significant (PCS) low value, H* = PCS high value, 
L** = potentially clinically significant change (PCSC) low, H** = PCSC high. 
 
 
Below listing will has similar structure as Listing 16.2.8.1.1 
Listing 16.2.8.1.2 
Clinical Laboratory Results – Chemistry  
 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.1.3 
Serum Pregnancy Test – Positive Only 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date and Time  
of Sample 
Result 
 
 
 
 
xxxx-xxx 
SV1 
ddmonyyyyhh:mm 
Positive 
 
TV1 
ddmonyyyyhh:mm 
Positive 
 
 
 
 
xxxx-xxx 
SV1 
 
 
 
... 
 
 
xxxx-xxx 
SV1 
 
 
 
... 
 
 
... 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV=Treatment Visit; FU= Follow-up; UNS= unscheduled; At home pregnancy tests and an extra serum pregnancy 
test at TV2 visit will be performed for the CVT treated patients in Belgium and Germany.  
 
 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.1 
Vital Signs 
 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
 
Time Point 
Date and Time 
Of Assessment  
 
Blood Pressure 
(mmHg) 
Heart Rate 
(beats per minute) 
Respiration Rate 
(breaths per minute) 
Position 
SBP 
DBP 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
SV1 
 
ddmonyyyyhh:mm 
Standing  
xx 
xx 
xx 
xx 
 
 
 
 
Supine/Semi-
Supine 
 
 
 
 
 
TV1 
Pre-dose 
ddmonyyyyhh:mm 
 
xx  
xx 
xx 
xx 
 
 
+5mins 
 
 
xx H* 
xx L** 
xx 
xx 
 
 
... 
Not Done, xxxxx 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV=Treatment Visit; FU= Follow-up; UNS= unscheduled;  
L* = potentially clinically significant (PCS) low value, H* = PCS high value, 
      L** = potentially clinically significant change (PCSC) low, H** = PCSC high. 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
 
Listing 16.2.8.2.2 
12-Lead Electrocardiogram (ECG) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Time Point 
Date and Time 
Of Assessment  
Heart 
Rate 
(bpm) 
RR 
(ms) 
PR 
(ms) 
QRS 
(ms) 
QT 
(ms) 
QTcB 
(ms) 
QTcF 
(ms) 
Result 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
SV1 
 
ddmonyyyyhh:mm 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Normal 
 
TV1 
Pre-dose 
ddmonyyyyhh:mm 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Normal 
 
 
+5mins 
Not Done 
xx 
xx 
xx L** 
xx 
xx H** 
Xx  
xx 
Abnormal CS 
 
 
+20mins 
 
 
 
 
 
 
 
 
Abnormal NCS 
 
 
+30mins 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV=Treatment Visit; FU= Follow-up; UNS= unscheduled;  
L* = potentially clinically significant (PCS) low value, H* = PCS high value, 
For PR interval, H1= PCSC high, >25% for baseline >=200; H2= PCSC high, >25% for baseline >=200; For QRS interval, H1= PCSC high, >25% 
for baseline >=100; H2= PCSC high, >25% for baseline >=100; For QTcB and QTcF, H1**=PCSC high, >15% for baseline >=440  
; H2**=PCSC high, >30% for baseline <440; H3**=PCSC high, Increase>30; H4**=PCSC high, Increase>60, H5**=PCSC high Change>30 and 
Value>500, H6**=PCSC high, Change>60 and Value>500  
  
 
 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.3 
Physical Examination 
 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of  
Assessment  
Any Clinically Significant 
Abnormal Findings  
That 
Are New or Have Worsened? 
Findings 
 
 
 
 
 
xxxx-xxx 
SV1 
ddmonyyyy 
Yes 
New or Worsened Clinically Significant 
 
SV2 
Not Done 
 
 
 
TV1 
ddmonyyyy 
... 
 
 
… 
 
 
 
xxxx-xxx 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SV = Screening Visit; TV=Treatment Visit; FU= Follow-up; UNS= unscheduled;  
[a] BMI was calculated as weight (kg) / [height (m)]^2. 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.4.1 
Spirometry( Neurology Office) 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Visit 
Time 
Point 
Motor 
State 
Date and Time 
of Assessment 
FEV1 
(Liter) 
FEV1 
(% Predicted) 
FVC 
(Liter) 
FVC 
(% Predicted) 
FEV1/FVC 
(%) 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx@ 
Screening 
 
ON 
ddmonyyyyhh:mm 
xx 
xx 
xx 
xx 
xx 
 
TV1 
Arrival 
ON 
ddmonyyyyhh:mm # 
xx 
xx 
xx 
xx 
xx 
 
 
Pre-dose 
 
ddmonyyyyhh:mm 
xx 
xx 
xx 
xx 
xx 
 
 
+15mins 
 
ddmonyyyyhh:mm 
Xx * 
Xx $ 
xx 
xx 
xx 
 
 
... 
 
Not Done, xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit;   # indicates spirometry measurement not meeting ATS quality criteria. * indicates 
imputed values. $ indicates manual data  @ indicates patients with Co-efficient of Variation (CV) of FEV1 >7.5% 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
Listing 16.2.8.2.4.2 
Spirometry( Neurology Office) Measurements Not Meeting ATS Quality Criteria 
 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Time  
Point 
Motor  
State 
Date and Time  
of Assessment  
Acceptable Efforts 
Repeatable Efforts 
 
 
 
 
 
 
 
xxxx-xxx@ 
SV 
 
ON 
ddmonyyyyhh:mm # 
x 
x 
 
TV1 
Arrival 
ON 
ddmonyyyyhh:mm # 
x 
x 
 
 
Pre-dose 
 
ddmonyyyyhh:mm # 
x 
x 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
... 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  # indicates spirometry measurement not meeting ATS quality criteria. @ indicates patients with Co-
efficient of Variation (CV) of FEV1 >7.5% 
 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
Listing 16.2.8.2.4.3 
Spirometry(Pulmonary Function Facility): DLco Parameters 
 
Treatment Group: Observational Cohort 
Patient 
ID 
Visit 
Time 
Point 
Motor 
State 
Date and Time 
of Assessment 
1/20/21 2 3 4(13)/7(15) 5(14)/8(16) 6/9 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx@ 
Screening  
ON 
ddmonyyyyhh:mm 
 
 
 
xx 
xx 
xx 
xx xx 
 
TV1 
Arrival ON 
ddmonyyyyhh:mm 
# 
 
 
 
xx 
xx 
xx 
xx xx 
 
 
Pre-
dose 
 
ddmonyyyyhh:mm 
 
 
 
xx 
xx 
xx 
xx xx 
 
 
+15mins  
ddmonyyyyhh:mm 
 
 
 
Xx * 
Xx $ 
xx 
xx xx 
 
 
... 
 
Not Done, xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit;   # indicates spirometry measurement not meeting ATS quality criteria. $ indicates 
manual data  @ indicates patients with Co-efficient of Variation (CV) of FEV1 >7.5%; 1=DLCO (mL/min/mmHg), 2=IVC (L), 3=VA (L), 4=Pre 
Original FEV1 (L), 5=Pre Original FVC (L), 6=Pre FEV1/FVC (%),7=Post Original FEV1, 8=Post Original FVC, 9=Post  FEV1/FVC (%),10=SVC 
(L), 13=Percentage Predicted Pre-FEV1 (%),14=Percentage Predicted Pre-FVC (%),   15=Percentage Predicted Post-FEV1 (%) ,   
16=Percentage Predicted Post-FVC (%), 20=Percentage Predicted DLCO (%) 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
Listing 16.2.8.2.4.4    
Spirometry(Pulmonary Function Facility): Spirometry/DLco Measurements Not Meeting ATS Quality Criteria 
 
 
Will have same format as L16.2.8.2.4.3 and removed the irrelevant columns (Motor State, Repeatable Efforts and Acceptable Efforts) 
 
 
 # indicates DLco measurement not meeting ATS quality criteria. 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
 
Listing 16.2.8.2.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
 
Suicide Ideation: 
1.Wish to be Dead 
2.Non-Specific Suicidal Thought 
3.Suicidal Ideation-No Intent 
4.Ideation With Intent, No Plan 
5.Ideation With Plan/Intent 
 
Intensity of Ideation: 
1.Most Severe Ideation 
2.Most Severe Ideation, Description 
3.Most Severe Ideation, Frequency 
4.Most Severe Ideation, Duration 
5.Most Severe Ideation, Control 
6.Most Severe Ideation, Deterrents 
7.Most Severe Ideation, Reasons 
 
Suicidal Behavior: 
1.Actual Attempt 
2.Number of Actual Attempts 
3.Non-suicidal Self-injurious Behavior 
4.Interrupted Attempt 
5.Number of Interrupted Attempts 
6.Aborted Attempt 
7.Number of Aborted Attempts 
8.Preparatory Acts/Behavior 
9.Suicidal Behavior 
10.Completed Suicide 
 
Actual Attempts: 
1.Most Recent Attempt Date 
2.Most Recent Attempt Damage 
3.Most Recent Attempt Potential 
4.Most Lethal Attempt Date 
5.Most Lethal Attempt Damage 
6.Most Lethal Attempt Potential 
7.First Attempt Date 
8.First Attempt Damage 
9.First Attempt Potential 
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of 
Assessment 
Suicide Ideation 
Intensity of Ideation 
1 
2 
3 
4 
5 
1 
2 
3 
4 
5 
6 
7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
TV4 
Not Done, xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
Programming note: The actual listing started with new page 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of 
Assessment 
Suicidal Behavior 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
 
 
 
 
 
 
 
 
 
 
 
TV4 
Not Done, xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.5 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of 
Assessment 
Actual Attempts 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
 
 
 
 
 
 
 
 
 
 
TV4 
Not Done, xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  
 
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.6 
Epworth Sleepiness Scale 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of 
Assessment 
1 
2 
3 
4 
5 
6 
7 
8 
Total  
Score 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
TV4 
Not Done, xxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;  1 = Sitting and reading, 2 = Watching TV, 3 = Sitting inactive in a public place, 4 = As a passenger in a 
car for an hour  
without a break, 5 = Lying down to rest in the afternoon when circumstances permit, 6 = Sitting and talking to someone, 
      7 = Sitting quietly after a lunch without alcohol, 8 = In a car, while stopped for a few minutes in traffic. 
 
 
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Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of 
Assessment 
Impulse control disorders 
1. 
Gambling 
1. 
Sex 
1. 
Buying 
1.  
Eating 
2. 
Gambling 
2. 
Sex 
2. 
Buying 
2. 
Eating 
3. 
Gambling 
3. 
Sex 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
Yes 
No 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
 
TV4 
Not Done, 
xxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;   
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of 
Assessment 
Impulse control disorders 
3. 
Buying 
3.  
Eating 
4. 
Gambling 
4. 
Sex 
4. 
Buying 
4. 
Eating 
5. 
Gambling 
5. 
Sex 
5. 
Buying 
5. 
Eating 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
 
TV4 
Not Done, 
xxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;   
 
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Civitas Therapeutics, Inc.   
 
 
 
Page x of y 
Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP) 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Visit 
Date of 
Assessment 
Other compulsive behaviors 
Compulsive medication use 
1A 
1B 
1C 
2 
3 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
 
TV4 
Not Done, 
xxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: TV = Treatment Visit;   
 
 
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Civitas Therapeutics, Inc.   
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.8.1    
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4 
 
Dyskinesias: 
32. Duration: What proportion of the waking day are dyskinesias present? 
33. Disability: How disabling are the dyskinesias?  
34. Painful Dyskinesias: How painful are the dyskinesias?  
35. Presence of Early Morning Dystonia. 
 
Clinical Fluctuations: 
36. Are “off” periods predictable?  
37. Are “off” periods unpredictable?  
38. Do “off” periods come on suddenly, within a few seconds?  
39. What proportion of the waking day is the patient “off” on average?  
 
Other Complications: 
40. Does the patient have anorexia, nausea, or vomiting?  
41. Any sleep disturbances, such as insomnia or hypersomnolence?  
42. Does the patient have symptomatic orthostasis?  
Listing 16.2.8.2.8.1    
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4 
 
 
Treatment Group: Observational Cohort 
 
 
 
Dyskinesias 
Clinical Fluctuations 
Other Complications 
Patient  
ID 
Visit 
Date Of Assessment 
32 
33 
34 
35 
36 
37 
38 
39 
40 
41 
42 
xxxx-xxx 
TV1 
ddmonyyyy 
x 
x 
x 
x 
x 
x 
x 
x 
x* 
x 
x 
 
TV4 
Not Done, xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxx-xxx 
TV1 
ddmonyyyy 
x 
x 
x 
x 
x 
x* 
x 
x 
x 
x 
x 
 
TV4 
ddmonyyyy 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x* 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Note: SV = Screening Visit; TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.8.2 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4: Derived Variables 
 
Treatment Group: Observational Cohort 
Patient ID 
Score Category 
Visit 
Change from  
Baseline 
Percent change from 
Baseline 
 
 
 
 
 
xxxx-xxx 
Total Score 
TV1 
 
 
 
 
TV4 
xx 
xx.xx 
 
Dyskinesias 
TV1 
 
 
 
 
TV4 
xx 
xx.xx 
 
Clinical Fluctuations 
TV1 
 
 
 
 
TV4 
xx 
xx.xx 
xxxx-xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: SV = Screening Visit; TV = Treatment Visit; ET = Early Termination; UNS = Unscheduled;  
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.9.1 
Telephone Contact 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Date of Contact 
Any Changes to  
PD Medications? 
Any Challenges with 
Inhaler or Capsules? 
Any Challenges 
with Diary? 
Any Adverse Events 
Noted? 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
Yes 
No 
No 
Yes 
 
ddmonyyyy 
Yes 
Yes, xxxxxxxxxx 
Yes, xxxxxxxxxx 
Yes 
 
... 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
 
 
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Protocol No. CVT-301-005                                    Confidential 
 
Program Name: xxxx.sas                                                           
Listing Generation: ddmomyyyy 
 
Listing 16.2.8.2.9.2 
Telephone Contact: Challenges with Inhaler or Capsules Data 
 
Treatment Group: Observational Cohort 
Patient  
ID 
Date of Contact 
Any Changes to  
PD Medications? 
Any Challenges with 
Inhaler or Capsules? 
Any Challenges 
with Diary? 
Any Adverse Events 
Noted? 
 
 
 
 
 
 
xxxx-xxx 
ddmonyyyy 
No 
Yes, xxxxxxxxxx 
No 
Yes 
 
ddmonyyyy 
Yes 
Yes, xxxxxxxxxx 
Yes, xxxxxxxxxx 
Yes 
 
... 
 
 
 
 
xxxx-xxx 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
Continue with CVT-301 (002/003), CVT-301 (Naïve) 
 
 
 
 
 
 
 
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Study No. CVT-301-005 
Summary of SAP Changes From final Version 1.0 (22-Dec-2015) to Version 2.0 (13Jan2017) 
SAP final version 1.0 (22-Dec-2015) 
SAP final version 2.0 (13Jan2017) 
Cover page: 
 
CVT-301-005 
A Phase 3, Randomized Study Investigating the Safety of 
CVT-301 (Levodopa Inhalation Powder) in Parkinson’s 
Disease Patients With Motor Response Fluctuations (OFF 
Phenomena) Compared to an Observational Cohort 
Control (SUPPORT-PD™) 
 
Protocol Version and Date: Version 3.0 19-Aug-2015; 
SAP version and date: Final version 1.0, 22-Dec-2015 
Cover page: 
 
CVT-301-005 
A Phase 3, Randomized Study Investigating the Safety of 
CVT-301 (Levodopa Inhalation Powder) in Parkinson’s 
Disease Patients With Motor Response Fluctuations (OFF 
Phenomena) Compared to an Observational Cohort 
Control  
 
Protocol Version and Date: Version 4.0, 07-Mar-2016 
SAP version and date: Final version 2.0, 13-Jan-2017 
3.5 Determination of Sample Size 
 
Approximately 250 CVT-301 treatment patients and 115 
control patients will be enrolled in this study.  It is assumed 
that the drop-out rate will be approximately 25%. 
 
3.5 Determination of Sample Size 
 
Approximately 350 CVT-301 treatment patients and 175 
control patients will be enrolled in this study. 
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The primary objective of this study will be to characterize the 
pulmonary safety within the CVT-301-treated patients and the 
differences between the groups will be estimated as a 
secondary objective.  However, for the secondary comparison 
of FEV1 change between the CVT-301 treatment group and 
the randomized observational cohort, the standard deviation 
of FEV1 change from baseline is expected to be 0.281 L, 
based on data from 
.  Assuming that there 
is no difference in the changes from baseli
Study CVT-301-003
ne between the 
CVT-301-treated patients and the observational cohort, the 
study has the following power for the comparison between 
the 2 groups.  The upper limit of the 95% confidence interval 
for the difference between the 2 groups in change from 
baseline in FEV1 will be less than 0.121 L with 90% power, 
assuming 188 and 86 patients completing the study in the 
CVT-301 
treatment 
group 
and 
observational 
cohort, 
respectively.  The sample size calculation was performed 
using nQuery Advisor, Version 7.0. 
 
3.6 Treatment Assignment & Blinding 
 
Add sentence below: 
Randomization can occur before the baseline DLco has been 
performed. Note: Patients who were enrolled from the 
 and 
 studies under an earlier version of 
this protocol (Version 2) were assigned only to the CVT-301 
301-002
CVT-
CVT-301-003
treatment group. 
5.2 
Safety population  
The Safety Population will include all randomized 
5.2 
Safety population  
The Safety Population will include all randomized 
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patients who received at least 1 dose of inhaled CVT-301 
and patients from the Observational Cohort.  Patients 
will be analyzed according to study treatment that they 
received.  The Safety Population will be used for all 
analyses of safety endpoints and summaries of patient 
demographics and baseline characteristics. 
patients who received at least 1 dose of inhaled CVT-301 
and patients from the Observational Cohort who came 
in for treatment visit 1.  Patients will be analyzed 
according to study treatment that they received.  The 
Safety Population will be used for all analyses of safety 
endpoints and summaries of patient demographics and 
baseline characteristics. 
 
6.2 Key Definitions 
 
 DLCO predicted  
DLCO predicted will be calculated by Miller equation. 
 
 
(Miller A, Thornton JC, Warshaw R, Anderson H, 
Teirstein AS, Selikoff IJ. Single breath diffusing capacity
in a representative of Michigan, a large industrial state.
Am Rev Resp Dis 1983; 127: 270-277). 
• Men  predicted DLCO = 12.9113 - (0.229 x 
age) + (0.418 x height in)  
• Women predicted DLCO = 2.2382 - (0.1111 x 
age) + (0.4068 x height in)  
Where age is the age at the time of assessment taken, 
6.2 Key Definitions 
 
 DLCO predicted  
DLCO predicted will be calculated by Miller equation. 
(Miller A, Thornton JC, Warshaw R, Anderson H, 
Teirstein AS, Selikoff IJ. Single breath diffusing capacity 
in a representative of Michigan, a large industrial state. 
Am Rev Resp Dis 1983; 127: 270-277). 
• Men  predicted DLCO = 12.9113 - (0.229 x 
age) + (0.418 x height in)  
• Women predicted DLCO = 2.2382 - (0.1111 x 
age) + (0.4068 x height in)  
Where age is the age at baseline, height is measured in 
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height is measured in inches. 
inches. 
8.1 Spirometry 
Spirometry will be performed by trained and qualified 
staff at each study site.  Spirometry data obtained in the 
study site will reviewed by a central spirometry 
laboratory (Biomedical Systems, Inc.) which will provide 
a quality over read of all evaluations based on 
acceptability and repeatability metrics in accordance 
with ATS criteria.  FEV1, FVC and FEV1/FVC ratio will be 
recorded from the single “best test” (based on effort 
with highest summed FEV1 and FVC).  Variables will 
include the absolute FEV1, FVC, and FEV1/FVC ratio and 
FEV1 and FVC expressed as % of predicted value. 
 
FEV1, FVC, FEV1/FVC ratio and DLco will be summarized 
descriptively by treatment group and overall. For 
screening data, the summary will be presented for each 
motor status, ON or OFF, separately. For other visits, 
data in ON or OFF state will be combined for summary. 
The following will be summarized: 
 
• 
Change from baseline to other visits Arrival values 
for each parameter. The baseline is defined as the 
8.1 Spirometry 
Spirometry will be performed by trained and qualified 
staff at each study site.  Spirometry data obtained in the 
study site will reviewed by a central spirometry 
laboratory (Biomedical Systems, Inc.) which will provide 
a quality over read of all evaluations based on 
acceptability and repeatability metrics in accordance 
with ATS criteria.  FEV1, FVC and FEV1/FVC ratio will be 
recorded from the single “best test” (based on effort 
with highest summed FEV1 and FVC).  Variables will 
include the absolute FEV1, FVC, and FEV1/FVC ratio and 
FEV1 and FVC expressed as % of predicted value. 
The variables from pulmonary laboratory will include 
the FEV1, FVC, FEV1/FVC ratio, DLCO, IVC, SVC and 
VA.  FEV1 and FVC expressed as % of predicted 
value, predicted DLCO, hemoglobin (Hb) adjusted 
predicted DLCO, and DLCO expressed as % of these 
predicted values will be calculated per the method in 
section 6.2.  The following analysis will be 
performed: 
All the parameters collected at the pulmonary 
laboratory as well as the % of predicted DLCO and % 
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TV/OV1 Arrival value. If the TV/OV1 Arrival value 
is missing, the last available value in ON state 
before the first dose of study drug will be used. 
• 
Number and percentage of patients with FEV1/FVC < 
60% and <70% by Visit  
• Spirometry data will also be provided to indicate 
whether specific determinations met American 
Thoracic Society (ATS) quality criteria. The 
proportion of spirometry data measurements 
meeting or not meeting ATS quality criteria will 
be summarized by treatment group and overall. 
The summary will also be performed for ON 
state measurements, OFF state measurements, 
and all measurements, separately. The reasons 
for not meeting ATS quality criteria will be 
classified as not meeting the criteria for 
acceptability, not meeting the criteria for 
repeatability 
or 
as 
other/unknown 
and 
summarized. 
 
The spirometry analyses will be repeated for the subset of 
assessments meeting the ATS quality criteria. 
Another subset analysis will be performed by excluding the  
spirometry  data from … 
In addition to the descriptive statistics, the changes in the 
of Hb adjusted predicted DLCO will be summarized 
descriptively by treatment group and overall.  
• 
Change from baseline to other visits for each 
parameter.  The summary for FEV1 will also be 
provided by smoker status. 
• 
Number and percentage of patients with FEV1/FVC < 
60% and <70% by Visit  
• 
DLCO data will also be provided to indicate whether 
specific determinations met American Thoracic Society 
(ATS) 
quality 
criteria. 
The 
proportion 
of 
DLCO/spirometry data measurements meeting or not 
meeting ATS quality criteria will be summarized by 
treatment group and overall.  
• 
Categories of changes (<-50%, -50% -<-40%, -40% -
<-30%, , -30% -<-20%, , -20% -<-10%, -10% -<-10%, 
10% -<20% , 20% -<30% , 30% -<40% , 40% -<50%, 
>=50%) from baseline for FEV1, FEV, FEV1/FVC 
ratio and DLCO  by visit. The summary for FEV1 
will also be provided by smoker status. 
 
The descriptive summaries will be repeated for the 
subset of assessments meeting the ATS quality criteria. 
Another subset analysis will be performed by excluding 
the DLCO data from … 
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spirometry values within … 
Sensitivity analyses of the spirometry data 
 
The following sensitivity analysis will be performed for 
the primary endpoint. 
In addition to the descriptive statistics, the changes in the 
FEV1, FEV1/FVC ratio, and DLCO values within … 
Sensitivity analyses of the spirometry data 
 
The following sensitivity analysis will be performed for 
the FEV1, FVC/FEV1 and DLCO assessments. 
 
The following summary will be performed on the 
neurology sites data. 
• 
Change from baseline to other visits for each 
parameter. The baseline is defined as the TV/OV1 
Arrival value. If the TV/OV1 Arrival value is missing, 
the last available value in ON state before the first 
dose of study drug will be used. The summary for 
FEV1 will also be provided by smoker status. 
• 
Number and percentage of patients with 
FEV1/FVC < 60% and <70% by visit  
• 
Spirometry data will also be provided to 
indicate 
whether 
specific 
determinations 
met 
American Thoracic Society (ATS) quality criteria. The 
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proportion of DLCO/spirometry data measurements 
meeting or not meeting ATS quality criteria will be 
summarized by treatment group and overall. The 
summary will also be performed for ON state 
measurements, OFF state measurements, and all 
measurements, separately. The reasons for not 
meeting ATS quality criteria will be summarized, as 
data allow. 
• 
Categories of changes (<-50%, -50% -<-40%, -
40% -<-30%, , -30% -<-20%, , -20% -<-10%, -10% -<-
10%, 10% -<20% , 20% -<30% , 30% -<40% , 40% -
<50%, 
>=50%) 
from 
baseline 
for 
FEV1, 
FEV, 
FEV1/FVC ratio and DLCO  by visit. The summary for 
FEV1 will also be provided by smoker status. 
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Document 
Type: 
Template 
Document ID: 
 
Issue Date:          02 APR 2012 
Effective Date:  30 APR 2012       
 
 
Sponsor Name: 
Civitas Therapeutics, Inc. 
Protocol Number and Title: 
 
CVT-301-005 
A Phase 3, Randomized Study Investigating the 
Safety of CVT-301 (Levodopa Inhalation 
Powder) in Parkinson’s Disease Patients With 
Motor Response Fluctuations (OFF Phenomena) 
Compared to an Observational Cohort Control  
  
Protocol Version and Date: 
Version 4.0, 07-Mar-2016 
INC Research Project Code: 
 
Author(s): 
 
 
  
  
SAP Version: 
 Final Version 2.0 
SAP Version Date:  
13-Jan-2017 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to Civitas Therapeutics, 
Inc. Acceptance of this document constitutes agreement by the recipient that no information 
contained herein will be published or disclosed without prior written authorization from an 
official of Civitas Therapeutics, Inc. However, this document may be disclosed to appropriate 
Institutional Review Board and Ethics Committees or duly authorized representatives of a 
national regulatory authority under the condition that they are requested to keep it confidential. 
In the event of an actual or suspected breach of this obligation, INC Research should be notified 
promptly. 
 
 
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1003805 
Acorda Therapeutics, Inc. 
CVT • 301·005 
Ftnal Version 2.0 
Version: 
Final Version 2.0 
Statistical Analysis Plan 
Version Date: 
13-Jan-2017 
I confirm that I have revtewed this document and agree with the content. 
APPROVALS 
IHC Research 
• :nc 
Researctf 
--....--
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INC Re$earch 0 LLC 


TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ..................................................................... 14 
2. 
PURPOSE ....................................................................................................... 17 
2.1. 
Responsibilities ................................................................................................................... 17 
2.2. 
Timings of Analyses ............................................................................................................ 17 
3. 
STUDY OBJECTIVES AND STUDY DESIGN ...................................................... 18 
3.1. 
Primary Objective .............................................................................................................. 18 
3.2. 
Secondary Objectives ......................................................................................................... 18 
3.3. 
Exploratory Efficacy Objectives ........................................................................................ 18 
3.4. 
Patient Selection ................................................................................................................ 19 
3.4.1. 
Inclusion Criteria ......................................................................................................... 20 
3.4.2. 
Exclusion Criteria ........................................................................................................ 21 
3.5. 
Determination of Sample Size ........................................................................................... 22 
3.6. 
Treatment Assignment & Blinding..................................................................................... 23 
3.7. 
Administration of Study Medication .................................................................................. 23 
3.8. 
Study Procedures and Flowchart ...................................................................................... 24 
4. 
ENDPOINTS .................................................................................................... 27 
4.1. 
Primary Endpoint ................................................................................................................ 27 
4.2. 
Secondary Endpoints .......................................................................................................... 27 
4.3. 
Exploratory EffiCacy Endpoints ......................................................................................... 28 
5. 
ANALYSIS SETS .............................................................................................. 32 
5.1. 
All Available Population (AAP) .......................................................................................... 32 
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5.2. 
Safety Population ............................................................................................................... 32 
5.3. 
Intent-to-Treat Population (ITT) ....................................................................................... 32 
5.4. 
Protocol Deviations ............................................................................................................ 32 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ......................................... 34 
6.1. 
General Methods ................................................................................................................. 34 
6.2. 
Key Definitions.................................................................................................................... 35 
6.3. 
Missing Data......................................................................................................................... 37 
6.4. 
Visit Windows ...................................................................................................................... 38 
6.5. 
Pooling of Sites ................................................................................................................... 39 
6.6. 
Subgroups ............................................................................................................................ 39 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION .... 40 
7.1. 
Patient Disposition and Withdrawals ................................................................................ 40 
7.2. 
Demographic and Other Baseline Characteristics ........................................................... 40 
7.3. 
Medical History ................................................................................................................... 42 
7.4. 
Medication ........................................................................................................................... 42 
8. 
SAFETY .......................................................................................................... 44 
8.1. 
Spirometry .......................................................................................................................... 44 
8.2. 
Extent of Exposure ............................................................................................................. 47 
8.3. 
Treatment Compliance ...................................................................................................... 48 
8.4. 
Adverse Events ................................................................................................................... 48 
8.5. 
Laboratory Evaluations ...................................................................................................... 49 
8.6. 
Vital Signs ............................................................................................................................ 51 
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8.7. 
Electrocardiogram .............................................................................................................. 52 
8.8. 
Physical Examination ......................................................................................................... 53 
8.9. 
Columbia-Suicidality Severity Rating Scale ...................................................................... 54 
8.10. 
Epworth Sleepiness Scale ................................................................................................... 54 
8.11. 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease ................... 54 
8.12. 
UPDRS Part 4 ....................................................................................................................... 55 
8.13. 
examiner-rated dyskinesia ................................................................................................ 55 
9. 
EXPLORATORY EFFICACY ............................................................................. 56 
9.1. 
Exploratory Efficacy Endpoint and Analysis ..................................................................... 56 
10. 
INTERIM ANALYSES .................................................................................... 59 
11. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL .................................. 60 
12. 
PROGRAMMING CONSIDERATIONS ............................................................. 61 
12.1. 
General Considerations ...................................................................................................... 61 
12.2. 
Table, Listing, and Figure Format .................................................................................... 61 
12.2.1. 
General ........................................................................................................................ 61 
12.2.2. 
Headers ....................................................................................................................... 61 
12.2.3. 
Display Titles ............................................................................................................... 62 
12.2.4. 
Column Headers .......................................................................................................... 62 
12.2.5. 
Body of the Data Display ............................................................................................. 62 
12.2.6. 
Footnotes .................................................................................................................... 63 
13. 
QUALITY CONTROL.................................................................................... 65 
14. 
INDEX OF TABLES ...................................................................................... 66 
 
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15. 
INDEX OF LISTINGS .................................................................................... 74 
16. 
INDEX OF FIGURES ..................................................................................... 76 
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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AAP 
All Available Population 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical  
ATS 
American Thoracic Society  
BMI 
Body Mass Index 
BMS 
Biomedical Systems  
BP 
Blood Pressure 
CI 
confidence interval  
CMH 
Cochran-Mantel-Haenszel 
COPD 
Chronic Obstructive Pulmonary Disease 
CRO 
Contract Research Organization 
C-SSRS 
Columbia-Suicidality Severity Rating Scale 
DBP 
diastolic  blood pressure 
DDI 
Dopamine Decarboxylase Inhibitor 
DL 
Dose Level 
DLCO 
Carbon Monoxide Diffusion Capacity 
DSMC 
Data Safety Monitoring Committee 
ECG 
Electrocardiogram 
ERS 
European Respiratory Society 
ET 
Early Termination 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
Hb 
hemoglobin 
HR 
Heart Rate 
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Abbreviation 
Description 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat  
IWRS 
Interactive Web Response System 
LD 
Levodopa 
LS 
least square 
MAR 
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMSE 
Mini Mental State Examination  
MMRM 
Mixed Model for Repeated Measures 
PCS 
potentially clinically significant values  
PCSC 
potentially clinically significant changes 
PD 
Parkinson’s Disease  
PDQ-39 
39-Item Parkinson’s Disease Questionnaire  
PGI-C 
Patient Global Impression of Change 
PMM 
Pattern Mixture Models 
PRN 
As needed 
PT 
Preferred Term  
QUIP 
Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s Disease 
QTcB 
QT interval corrected using Bazett’s formula 
QTcF 
QT interval corrected using Fridericia’s formula 
RR 
Respiratory Rate 
S&E 
Schwab and England 
SAP 
Statistical Analysis Plan 
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Abbreviation 
Description 
SBP 
systolic blood pressure 
SD 
Standard Deviation  
SEM 
Standard Error of the Mean 
SI 
International System of Units  
SOC 
System Organ Class  
SV 
Screening Visit 
TEAE 
Treatment-Emergent Adverse Event 
TLF 
tables, listings, figure 
TV 
Treatment Visit 
UPDRS 
Unified Parkinson’s Disease Rating Scale  
WHO-DD 
World Health Organization Drug Dictionary  
 
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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives. 
This SAP describes the statistical analysis as it is foreseen at the time of planning the 
study.  The SAP will serve as a compliment to the study protocol and supersedes it in 
case of differences.  In case of major differences between the study protocol and SAP 
(e.g. changes in the analysis related to the primary endpoint) protocol amendment will 
be considered.  The SAP may be updated during the conduct of the study and will be 
finalized before database lock. However, because this is an open-label study, the 
analyses defined after the first patient has been randomized to the study will be 
considered as exploratory. 
2.1. 
RESPONSIBILITIES 
INC Research will perform the statistical analyses and are responsible for the production 
and quality control of all tables, figures and listings. Acorda (or its designee) will review 
and approve all statistical work done by INC Research as agreed between INC Research 
and Acorda. 
2.2. 
TIMINGS OF ANALYSES 
The primary analysis of safety and efficacy is planned after all patients complete the 
final study visit or terminate early from the study, and database is cleaned and locked. 
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3. 
STUDY OBJECTIVES AND STUDY DESIGN 
3.1. 
PRIMARY OBJECTIVE 
To characterize the pulmonary safety, as assessed by spirometry (forced expiratory 
volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/ FVC ratio), over a 
12-month period within the CVT-301-treated patients. 
3.2. 
SECONDARY OBJECTIVES 
• 
To characterize the pulmonary safety, as assessed by spirometry (FEV1, FVC and 
FEV1/FVC ratio), over a 12-month period in the observational (‘standard of care’) 
cohort. 
 
• 
To estimate the difference between the CVT-301-treated patients and the 
observational cohort on measures of pulmonary safety. 
 
• 
To characterize the effects of CVT-301 on safety over a 12-month period:  safety 
will be assessed by adverse event (AE) reports, physical examination, standard and 
orthostatic vital signs (blood pressure [BP], heart rate [HR], and respiratory rate 
[RR]), clinical laboratory tests, 12-lead electrocardiograms (ECGs), the Parkinson’s 
Disease Impulsive-Compulsive Disorders Questionnaire (QUIP), the Epworth 
Sleepiness Scale, and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
 
• 
To evaluate the effect of CVT-301 on mean change from baseline in the UPDRS 
Part 4 measures of motor fluctuations (dyskinesias [Q32-35] and wearing off 
[Q36-39]) measured at baseline and at 6 and 12 months after the initiation of CVT-
301 treatment. 
 
• 
To characterize the occurrence and severity of examiner-rated dyskinesia following 
treatment of patients experiencing an OFF episode in the clinic over a 12-month 
period. 
 
• 
To describe the effects of CVT-301 on Carbon Monoxide Diffusion Capacity (DLCO) 
over a 12-month period. 
 
3.3. 
EXPLORATORY EFFICACY OBJECTIVES 
The following exploratory objectives related to the efficacy endpoints will primarily be 
assessed for the CVT-301-treated patients.    The same objectives will be explored for 
the pool of CVT-301-naïve patients and patients who were previously enrolled in the 
 or 
 studies, if feasible. 
CVT-301-003
CVT-301-002
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• 
Change from pre-dose in UPDRS Part 3 motor score at 10, 20, 30, and 60 minutes 
following treatment of patients experiencing an OFF episode. 
• 
Time curves of the UPDRS response at 10, 20, 30 and 60 minutes will be evaluated 
descriptively 
• 
Change from pre-dose in the average UPDRS Part 3 motor score at 10 to 60 minutes 
following treatment of patients experiencing an OFF episode. 
• 
Proportion of patients with a ≥ 3, ≥ 6, and ≥ 11 point reduction in the UPDRS Part 3 
motor score from pre-dose to post-dose, at 10, 20, 30, and 60 minutes. 
• 
Proportion of patients achieving resolution of an OFF to an ON state within 60 
minutes after study drug is administered in the clinic, maintaining the ON state at 
60 minutes after study drug administration (per the examiner’s subjective 
assessment). 
• 
Total daily OFF time, total daily ON time without dyskinesia, total daily ON time 
with non-troublesome dyskinesia, and total daily ON time with troublesome 
dyskinesia, assessed by the patient and recorded in the patient diary. 
• 
Change from baseline in 39-Item Parkinson’s Disease Questionnaire (PDQ-39). 
• 
Proportion of patients who improved based on the Patient Global Impression of 
Change (PGI-C) rating scale. 
• 
Change from baseline in Schwab and England (S&E) Activities of Daily Living (ADL). 
• 
Change from baseline in UPDRS Part 2 score. 
3.4. 
PATIENT SELECTION 
The study population for this study is PD patients experiencing motor fluctuations (OFF 
episodes) that meet the following inclusion criteria and do not meet any of the 
following exclusion criteria. 
Patients may have been previously enrolled in the
 or 
 studies, 
or may be CVT-301-naïve i.e. no previous exposure to CVT-301.  Patients previously 
enrolled in the 
 and 
 studies must have completed all of the 
CVT-301 study visits without any safety issues that would preclude participation in this 
study according to the investigator.  Patients who withdrew from either of the CVT-301 
studies prior to completion, for any reason, will not be eligible. 
CVT-301-003
CVT-301-003
CVT-301-002
 CVT-301-002
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3.4.1. 
Inclusion Criteria 
In order to be eligible to enter the study, patients must meet all of the following 
criteria:  
 
• 
Has signed and dated an IRB/IEC-approved informed consent form before any 
protocol-specific screening procedures are performed. 
 
• 
Is a male or female aged 30 to 85 years, inclusive.  Women of child-bearing 
potential must use protocol-defined contraceptive measures (see 
) 
and must have a negative serum human chorionic gonadotropin (hCG) test at 
screening.  These patients must be willing to remain on their current form of 
contraception for the duration of the study. 
 
• 
Patients who have idiopathic PD (i.e., not induced by drugs or other diseases) as 
defined by fulfilling Steps 1 and 2 of the UK Brain Bank criteria, diagnosed after 
the age of 30 years. 
 
• 
Patients who are classified as Stage 1 to 3 (in the ON state) on the modified 
Hoehn and Yahr scale for staging of PD severity. 
 
• 
Patients who have experienced motor fluctuations for a minimum of 2 hours of 
average daily OFF time per waking day (excluding early morning OFF time) by 
self-report and confirmed by the PD Diary (on 3 consecutive days) during the 
screening period. 
 
• 
Patients who are on a LD-containing therapy, not including Rytary (or 
equivalent), must be stable on oral LD-containing therapy for at least 2 weeks 
prior to SV1 with a LD/dopamine decarboxylase inhibitor (DDI)-containing 
regimen.  
 
• 
Patients who are on a LD containing therapy, when including Rytary (or 
equivalent), should be on a stable dose for at least 6 weeks prior to SV1 
 
• 
The frequency of L-dopa administrations must be at least 3 times during the 
waking day and a total daily LD dose of ≤1600 mg (exclusive of PRN LD-
containing medications).   
 
• 
Patients should be stable on other PD medications for at least 4 weeks prior to 
SV1.   
 
Section 11.1.5
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• 
Patients must have a ≥ 25% difference between UPDRS Part 3 scores recorded in 
their ON and OFF states at screening. 
 
• 
Patients must have normal cognition as confirmed by a score of ≥ 25 on the 
MMSE. 
 
• 
Patients must be able to perform a spirometry maneuver in the ON and OFF 
states, and must have a screening FEV1 ≥ 50% of predicted and an FEV1/FVC 
ratio >60% in the ON state at screening.  (A pulmonologist will review the 
spirometry tracings/morphology of any patient with an FEV1 that is ≥ 50% to 
<60% of predicted or an FEV1/FVC ratio that is >60% to <70% in order to 
determine potential eligibility.  All CVT-301-naïve patients with an FEV1/FVC 
ratio of >60% to <70% will be required to undergo a bronchodilator challenge and 
the results must be reviewed prior to entry into the study.  Patients with an 
FEV1/FVC ratio that is >60% to <70% will complete spirometry before and after 
the administration of a bronchodilator in a pulmonary function 
laboratory.  Testing will be performed in accordance with the 2005 
ATS/European Respiratory Society [ERS] criteria prior to randomization.  The 
results of the bronchodilator challenge will be reviewed by a pulmonologist prior 
to potential randomization.) 
 
3.4.2. 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria at screening will not be enrolled 
in the study:  
 
• 
Patients who have dyskinesia of a severity that would significantly interfere with 
their ability to participate or perform study procedures. 
 
• 
Pregnant or lactating females or females wishing to become pregnant. 
 
• 
Patients who have any known contraindication to the use of LD, including a 
history of malignant melanoma or a history of narrow-angle glaucoma.   
 
• 
Patients who have had previous surgery for PD (including but not limited to deep 
brain stimulation [DBS] or cell transplantation). 
 
• 
Patients with a history of psychotic symptoms requiring treatment, or suicide 
ideation or attempt within the prior 12 months (stable regimens [for at least 4 
weeks prior to SV1] of anti-depressant and certain low-dose atypical 
antipsychotic medications are permitted, in case they are indicated to treat 
symptoms other than psychotic symptoms). 
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• 
Patients who have cancer with the exception of the following:  basal cell 
carcinoma or successfully treated squamous cell carcinoma of the skin; cervical 
carcinoma in situ; prostatic carcinoma in situ; or other malignancies curatively 
treated and with no evidence of disease recurrence for at least 3 years. 
 
• 
Patients taking certain prohibited medications (see 
). 
 
• 
Patients with a history of drug or alcohol abuse within the prior 12 months. 
 
• 
Patients with chronic obstructive pulmonary disease (COPD), asthma, or other 
chronic respiratory disease within the last 5 years. 
 
• 
Patients with any contraindication to performing routine spirometry or who are 
unable to perform a spirometry maneuver (see 
 for a list of 
contraindications).  
 
• 
Patients with a current history of symptomatic orthostatic hypotension despite 
adequate treatment.   
 
• 
Patients with any condition that in the investigator’s opinion would make 
patients unsuitable or interfere with their participation in the study.  Potential 
issues of concern should be raised to the medical monitor during eligibility 
review. 
 
• 
Patients who have any clinically significant abnormality or finding from 
examination, tests, or history that may compromise patient safety. 
 
• 
Patients who have been treated with an investigational drug within 4 weeks or 5 
half-lives (whichever is longer) prior to the beginning of the screening 
period  (this includes investigational formulations of marketed products). 
 
• 
Prior exposure to CVT-301. 
 
3.5. 
DETERMINATION OF SAMPLE SIZE 
Approximately 350 CVT-301 treatment patients and 175 control patients will be enrolled 
in this study.  It is assumed that the drop-out rate will be approximately 25%. 
 
The primary objective of this study will be to characterize the pulmonary safety within 
the CVT-301-treated patients and the differences between the groups will be estimated 
as a secondary objective.  However, for the secondary comparison of FEV1 change 
Appendix 20
Section 9.4.2
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between the CVT-301 treatment group and the randomized observational cohort, the 
standard deviation of FEV1 change from baseline is expected to be 0.281 L, based on 
data from 
.  Assuming that there is no difference in the changes from 
baseline between the CVT-301-treated patients and the observational cohort, the study 
has the following power for the comparison between the 2 groups.  The upper limit of 
the 95% confidence interval for the difference between the 2 groups in change from 
baseline in FEV1 will be less than 0.121 L with 90% power, assuming 188 and 86 patients 
completing the study in the CVT-301 treatment group and observational cohort, 
respectively.  The sample size calculation was performed using nQuery Advisor, Version 
7.0. 
 
3.6. 
TREATMENT ASSIGNMENT & BLINDING 
This study is a 12-month, open-label, randomized, multicenter study which will evaluate 
the safety and effects of CVT-301 for the treatment of up to 5 OFF episodes per day in 
PD patients experiencing motor fluctuations (OFF episodes) and will include a 
concurrent observational cohort of PD patients managed using the usual standards of 
care.  Patients may have been previously enrolled in the 
 or 
 
studies, or may be CVT-301-naïve.  Patients who were previously enrolled in the 
-
 and 
 studies will be assigned to the CVT-301 treatment group (CVT-
301 at a target nominal respirable dose of 50 mg LD fine particle dose [FPD]), in this 
study.  Patients who are CVT-301-naïve will be randomized in a 2:1 ratio to the CVT-301 
treatment group (CVT-301 at a target nominal respirable dose of 50 mg LD FPD) or the 
observational cohort. Randomization can occur before the baseline DLCO has been 
performed. Note: Patients who were enrolled from the 
 and 
 
studies under an earlier version of this protocol (Version 2) were assigned only to the 
CVT-301 treatment group. Randomization will be stratified by the patient’s Hoehn and 
Yahr stage (<2.5 versus ≥2.5) to balance the severity of disease across each group and 
by screening spirometry (FEV1 <60% of predicted or FEV1/FVC ratio <70% versus FEV1 
≥60% of predicted and FEV1/FVC ratio ≥70%).  
 
Following completion of SV2 and prior to randomization, the patients’ eligibility criteria 
will be reviewed by delegated staff. Upon confirmation of eligibility, the site will 
randomize an eligible patient using the Interactive Web Response System (IWRS).  The 
study is an open-label study, so patients and clinical staff will not be blinded to study 
group assignment. 
 
3.7. 
ADMINISTRATION OF STUDY MEDICATION 
Prior to the self-administration of inhaled study treatment, study staff will ensure that 
patients are adequately trained on the use of the inhaler according to the Instructions 
for Use (IFU).  The IFU will be provided to each patient and will be part of the 
permanent study record. 
CVT-301-002
301-002
CVT
CVT-301-002
CVT-301-003
CVT-301-003
CVT-301-003
Study CVT-301-003
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Since this is an open-label study, the patient, investigator, and study site personnel, the 
Sponsor, representatives of the Contract Research Organization (CRO) involved in 
monitoring, data management, or other aspects of the study, and Core Laboratories will 
be not blinded to the inhaled study treatment. 
 
During inhaler training, patients will be instructed to use the inhalation system in 
accordance with the IFU which includes a breath hold of 5 seconds following each 
capsule inhalation.  For the purposes of timing study assessments in the clinic, “Time 0” 
(T0) is defined as the time of completion of inhalation of the last capsule of inhaled 
study treatment administered (i.e., beginning of the final breath hold).  In the event 
that a capsule needs to be reinhaled, T0 is at the end of the reinhalation 
administration. 
 
During the treatment period, patients will self-administer inhaled study treatment 
(CVT-301 DL1, CVT-301 DL2) up to 5 times daily to treat OFF episodes during their 
waking day. 
 
3.8. 
STUDY PROCEDURES AND FLOWCHART 
This study has 3 periods: screening period, treatment period, and follow-up period; and 
a total of 9 planned visits: 2 screening visits, 6 treatment visits, and 1 follow-up visit.  
For each patient, the planned treatment period will be approximately 52 weeks, and 
maximum anticipated study duration, including screening and follow-up, will be 
approximately 62 weeks. 
The screening period, which takes place within 35 days prior to Day 1 of the treatment 
period, will have 2 separate visits:  SV1 and SV2 must be separated by at least 4 days.  
The screening period may be extended an additional 7 days if repeat screening 
assessments are required. 
Before patients return to the clinic for TV/OV1, they will be randomized to treatment.  
The treatment period includes 6 separate in-clinic visits over approximately 52 weeks.  
The first dose of study drug will be given in the clinic at TV/OV1.  The subsequent visits 
during the treatment period take place as follows: 
• 
TV/OV2: Week 4; 28±5 days after TV/OV1. 
• 
TV/OV3: Week 12; 84±14 days after TV/OV1. 
• 
TV/OV4: Week 24; 168±14 days after TV/OV1. 
• 
TV/OV5: Week 36; 252±14 days after TV/OV1. 
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• 
TV/OV6: Week 52; 364±14 days after TV/OV1. 
Patients who terminate the study early will complete TV/OV6 and return for the Follow-
up DLCO visit 4-5 weeks after TV/OV6. 
Refer to 
 to 
 for tables of study assessments at each visit. 
15
Protocol Appendices 1
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In Clinic Assessments  
SV1 
SV2 
TV/OV1  
TV/OV2 
TV/OV3 
TV/OV4 
TV/OV5 
TV/OV6 
ON 
OFF 
ON 
OFF 
ON* 
ON 
ON 
ON 
ON 
ON 
MMSE 
x 
  
  
  
  
  
  
  
  
  
UPDRS Part 1 
  
  
  
  
  
  
  
  
  
  
UPDRS Part 2 
  
  
  
  
x 
  
  
x 
  
x 
UPDRS Part 3 
x 
x 
  
  
  
x** 
x** 
x** 
x** 
x** 
UPDRS Part 4 
  
  
  
  
x 
  
  
x*** 
  
x*** 
C-SSRS 
  
  
  
  
x 
x 
x 
x 
x 
x 
Epworth Sleep Scale 
  
  
  
  
x 
  
  
x 
  
x 
QUIP 
  
  
  
  
x 
  
  
x 
  
x 
PDQ-39 
  
  
  
  
x 
  
  
x 
  
x 
PGI-C 
  
  
  
  
  
  
  
x*** 
  
x*** 
S&E ADL 
  
  
  
  
x 
  
  
x 
  
x 
At home for patients 
PD Diary (only treatment after screening) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ON/OFF logs (both groups) 
x 
x 
  
  
  
  
  
  
  
  
Inhaled dosing (CVT-301 only) 
  
  
  
  
x 
x 
x 
x 
x 
x 
 
 
*      For the CVT 301 arm these assessments are performed pre-dose 
**    Performed pre-dose, 10, 20, 30, and 60 min post dose (only performed in CVT 301 arm) 
***  CVT 301 arm only 
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4. 
ENDPOINTS 
4.1. 
PRIMARY ENDPOINT 
The primary endpoints related to the primary objective of the study are the pulmonary 
safety measures, FEV1, FVC and FEV1/ FVC ratio, assessed over a 12 month period. 
FEV1, FVC and FEV1/FVC ratio will be recorded from the single “best test” (based on 
effort with highest summed FEV1 and FVC).  Variables will include the absolute FEV1, 
FVC, and FEV1/FVC ratio and FEV1 and FVC expressed as % of predicted value. Changes 
from baseline (TV/OV1) for each variable will be calculated at each subsequent visit.  
Percent Predicted = 100 * (Observed) / Predicted, where predicted is calculated and 
provided to INC by Biomedical Systems (BMS). 
4.2. 
SECONDARY ENDPOINTS 
The following endpoints related to the secondary objectives will be calculated. 
 
• 
Standard safety endpoints; for definitions see Section 8 of this SAP  
o Adverse Event (AE) reports 
o Physical examination 
o Standard and orthostatic vital signs (BP, HR and RR) 
o Clinical laboratory tests (hematology, clinical chemistry, and additional 
laboratory parameters) 
o 12-lead ECGs (HR, PR, QRS, QT, QT interval corrected using Bazett’s formula 
[QTcB] and QT interval corrected using Fridericia’s formula [QTcF]) 
o Parkinson’s Disease Impulsive-Compulsive Disorders Questionnaire (QUIP)  
o Epworth Sleepiness Scale 
o Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
• 
Change from TV/OV1 (baseline) in the UPDRS Part 4 sum scores of dyskinesias 
(UPDRS items 32-35) and wearing-off (UPDRS items 36-39).  The dyskinesia score will 
be calculated as the sum of the individual items 32-35 and the wearing-off score as 
sum of 36-39.  Missing individual items will not be imputed and the sum score will be 
missing in case of 1 or more missing items. 
 
• 
Occurrence and severity of examiner-rated dyskinesia following treatment of 
patients experiencing an OFF episode in the clinic.  The occurrence will be based on 
the examiner’s subjective assessment and no further derivation will be performed.  
Among the patients with reported dyskinesia, the severity will be classified as mild, 
moderate, severe or missing based on the examiner’s subjective assessment and no 
further derivation will be performed.  Only observed cases will be used for this 
endpoint and the visits with missing data will not be included in the analysis. 
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• 
Carbon Monoxide Diffusion Capacity (DLCO) assessed over a 12 month period within 
the CVT 301 treated and the observational (‘standard of care’) cohorts. Variables 
will include the absolute DLCO values and DLCO expressed as % of predicted value. 
 
4.3. 
EXPLORATORY EFFICACY ENDPOINTS  
The following endpoints related to the exploratory efficacy objectives will be 
calculated. 
• 
Change from pre-dose in UPDRS Part 3 motor score at 10, 20, 30, and 60 minutes 
following treatment of patients experiencing an OFF episode.  
 
o The UPDRS Part 3 total score will be calculated as the sum of the individual 
items of the UPDRS Part 3 questionnaire (UPDRS items 18-31) separately at 
each time point, i.e. the scores will range from 0 to 108.  Missing individual 
items will be imputed using the 2 non-missing values at time points adjacent 
to the missing item on the same date.  The maximum of the 2 adjacent 
values will be assigned as the score for the missing item.  However, pre-dose 
values will not be assigned as post-dose values and if one of the adjacent 
values for a post-dose value is a pre-dose value, only 1 adjacent value will be 
used.  The total score for UPDRS Part 3 assessments will be calculated after 
imputation of the missing item(s).  Missing items at screening will not be 
imputed.  If a pre-dose value is missing, the pre-dose value at the prior visit 
will be used.  A missing TV/OV1 pre-dose value will be imputed using the last 
screening value in OFF state. 
 
• 
Time curve of the UPDRS response shown as change from pre-dose in UPDRS Part 3 
motor score to 10, 20, 30 and 60 minutes following treatment of patients 
experiencing an OFF episode in the clinic. The UPDRS Part 3 scores will be derived 
as described above.   
 
• 
Change from pre-dose in the average UPDRS Part 3 score at 10 to 60 minutes 
following treatment of patients experiencing an OFF episode in the clinic. The 
change from pre-dose to the average of the 4 UPDRS Part 3 total scores (assessments 
scheduled at 10, 20, 30 and 60 minutes) will be used as the response variable in the 
statistical analysis.   
 
• 
A ≥3, ≥6, and ≥11 point reduction in the UPDRS Part 3 motor score from pre-dose to 
post-dose, at 10 to 60 minutes following treatment in the clinic (cumulative and 
non-cumulative).  The non-missing UPDRS Part 3 motor scores at each time point 
(10, 20, 30 and 60 minutes post-dose) are classified as a reduction of ≥3 points or 
not, reduction of ≥6 points or not and reduction of ≥11 points or not.  Furthermore, 
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for the purpose of the cumulative analysis, the time point (10, 20, 30 and 60 
minutes post-dose) when the reduction of ≥3, ≥6 or ≥11 points occurs for the first 
time will be defined.  The categorical scheduled time point is used in this analysis.  
The missing assessment regarding single items will be managed similarly as describe 
above. The missing values regarding visits will be managed by considering the 
missing visits as non-responses. 
 
• 
Proportion of patients achieving resolution of an OFF to an ON state within 60 
minutes after study drug is administered in the clinic and maintaining the ON at 60 
minutes after study drug administration (per the examiner’s subjective assessment).  
This endpoint will be based on the examiner’s subjective assessment. In case the 
assessment of turning on within 60 minutes is missing but the assessment of 
maintaining the ON at 60 minutes has been done, the patient will be classified based 
on the available assessment. In case the assessment of maintenance of ON at 60 
minutes is missing, the patient will be classified as having missing data. 
 
• 
Change from baseline (3 consecutive days prior to TV1, or in case of missing data, 
the last 3 recorded days before TV1) in patient-recorded total daily OFF time, 
assessed by the patient and recorded in the PD Diary for 3 consecutive days prior to 
in-clinic visits (or in case of missing data, the last 3 recorded days before the visit).  
The validity of the PD diary entries will be checked prior to including a diary day in 
the summary calculations. Only valid diary days will be included in the diary 
summarizations. Change from baseline in total daily ON time without dyskinesia, 
total daily ON time with non-troublesome dyskinesia, and total daily ON time with 
troublesome dyskinesia will be calculated similarly. 
 
o A day will be considered as being valid if at least 80% of the entries during 
the day have been completed per instructions.  That is, for each half hour 
period, only one entry among the responses (Asleep, OFF, ON without 
dyskinesia, ON with non-troublesome dyskinesia, or ON with troublesome 
dyskinesia) has been checked.  The entry will not be used if no responses are 
checked or more than one response is checked.  However, if the proportion 
of entries rejected due to multiple checked responses is large, sensitivity 
analysis will be performed by using the worst case out of the entries that had 
been checked.  The worst case will be defined in the following order: OFF, 
ON with troublesome dyskinesia, ON with non-troublesome dyskinesia, ON 
without dyskinesia, Asleep.  In case there are duplicate entries (i.e., 
multiple entries recorded with same date and time interval), the worst entry 
will be used for the date and time interval in question.  The worst entry will 
be selected in the order defined above. 
 
o All diary data will be normalized to 16 awake hours per day.  The daily OFF 
time will be extrapolated to a 16 hour period by determining the percentage 
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of OFF time among accurately recorded entries, excluding Asleep time and 
missing/non-valid recordings, and by multiplying this percentage by 16 hours.  
 
 
Off Time / (Total time recorded – Asleep Time – missing time interval) 
x 16 
 
o The mean daily OFF time prior to each visit will be calculated as mean value 
of the valid days documented in the patient’s diary prior to that visit.  In 
case there are gaps within the 3 days preceding the visit, the last 3 recorded 
days before the visit will be used regardless of the gaps.  If there are more 
than 3 valid days, only the last 3 days will be used.  If there are only 1 or 2 
valid days, the average of these days will be used. 
• 
Change from TV/OV1 (baseline) in PDQ-39 sub-scores (mobility score, activities of 
daily living, bodily discomfort score, emotional wellbeing score, social support 
score, communication score, cognitive impairment score, and stigma score) and 
summary index score. The questionnaire provides scores on eight dimensions as 
outlined below: 
 
o mobility (10 items, #1 to 10)  
o activities of daily living (6 items, #11 to 16)  
o emotional well-being (6 items, #17 to 22)  
o stigma (4 items, #23 to 26)  
o social support (3 items, #27 to 29)  
o cognitions (4 items, #30 to 33)  
o communication (3 items, #34 to 36)  
o bodily discomfort (3 items, #37 to 39) 
 
Items are scored from 0 (never) to 4 (always).  Dimension scores are obtained by 
dividing the sum of the item scores by the maximum possible score for any given 
dimension and expressing this as a percentage.  For example: 
 
o mobility = (sum of scores of #1 to 10)/(4 x 10) x 100 
o activities of daily living = (sum of scores of #11 to 16)/(4 x 6) x 100 
 
For social support, if the response indicates that a patient does not have a spouse or 
partner for #28, social support can be calculated as [(sum of scores of #27 and 
29)/(4 x 2) x 100]. 
 
A summary index is then calculated as the sum of the total score of the dimensions 
divided by the number of dimensions, i.e. (sum of dimension scores / 8).  If any item 
score is missing, the relevant dimension score and the summary index will be 
missing. 
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• 
The PGI-C score.  The non-missing values will be categorized as improvements (much 
improved, improved, a little improved) or non-improvements (no change, a little 
worse, worse, much worse). 
• 
Change from TV/OV1 (baseline) Schwab and England (S&E) Activities of Daily Living 
(ADL). No further derivation will be done for the S&E scores. 
• 
Change from TV/OV1 (baseline) in the UPDRS Part 2 score.  The UPDRS Part 2 score 
will be calculated as the sum of the individual items of the UPDRS Part 2 
questionnaire (UPDRS items 5-17).  Missing individual items will not be imputed and 
the sum score will be missing in case of 1 or more missing items.  
 
 
 
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5. 
ANALYSIS SETS 
5.1. 
ALL AVAILABLE POPULATION (AAP) 
The AAP will include all patients who have consented for the study, including screening 
failures.  Unless specified otherwise, the AAP will be used for patient listings and for 
the summary of patient disposition. 
 
5.2. 
SAFETY POPULATION  
The Safety Population will include all randomized patients who received at least 1 dose 
of inhaled CVT-301 and patients from the Observational Cohort who came in for 
treatment visit 1.  Patients will be analyzed according to study treatment that they 
received.  The Safety Population will be used for all analyses of safety endpoints and 
summaries of patient demographics and baseline characteristics.  
 
5.3. 
INTENT-TO-TREAT POPULATION (ITT) 
The ITT population will include all patients from the safety population. Patients will be 
analyzed according to randomized treatment. The ITT Population will be used for all 
analyses of exploratory efficacy endpoints.   
 
5.4. 
PROTOCOL DEVIATIONS 
A protocol deviation is any significant finding indicating that the study investigator or 
patient failed to adhere to the protocol requirements (e.g., drug noncompliance, failure 
to return for defined number of visits or within an acceptable visit window for 
completion of study assessments). The deviation may necessitate premature 
termination of the patient from the visit assessments, or from the study. 
 
The deviations will be classified during a review process with the Sponsor and other 
study personnel (as appropriate) before database lock. The deviations will be classified 
as minor or major with/without impact on pulmonary assessments during the review 
process.  All decisions regarding major deviations will also be discussed between the 
Sponsor, other study personnel (as appropriate), and the study statistician prior to 
commencing the final analysis on the locked database. The following deviations will be 
identified, but do not necessarily represent a complete list of potential deviations: 
• 
Administration of PD medications after the usual morning dose of PD medication 
and before study drug administration 
• 
Incorrect study drug administered at a visit 
• 
Drug non-compliance including but not limited to unapproved dose modification 
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• 
Failure to return for defined study visits or within an acceptable visit window for 
completion of study assessments 
The number of subjects with minor, major with/without impact on pulmonary 
assessments protocol deviations will be summarized by treatment groups and overall. 
All protocol deviations will be listed. 
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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
All patient data will be included in listings.  All patients entered into the database will 
be included in patient data listings.  The listings will be generally sorted by Patient ID 
(and by visit and by time point, if applicable), unless specified otherwise.  
 
All applicable data will be summarized by treatment group (Observational Cohort or 
CVT-301) and overall in tables, unless specified otherwise. The CVT-301 group will be 
broken down into CVT-301-naïve patients and patients who were previously enrolled in 
the 
 or 
 studies.  Where appropriate, data will be summarized 
by visit and/or time point in addition to treatment group.  Unscheduled or repeat 
assessments will not be included in summary tables, but will be included in listings. 
 
For the Observational Cohort, the “start of treatment” will be defined as attendance of 
TV/OV1, unless specified otherwise. Baseline will be defined as the assessments 
performed at TV/OV1. In case of missing data, the last non-missing screening 
assessment will be used as the baseline value. 
 
Continuous variables will be summarized using the number of observations (n), mean, 
SD, median, minimum, and maximum.  Standard error of the mean (SEM) will also be 
provided for summaries of UPDRS and other exploratory efficacy endpoints, if relevant.  
The same number of decimal places as in the raw data will be presented when reporting 
minimum and maximum, 1 more decimal place than in the raw data will be presented 
when reporting mean and median, and 2 more decimal places than in the raw data will 
be presented when reporting SD and SEM.  
 
Descriptive statistics for categorical/qualitative data will include frequency counts and 
percentages.  The total number of patients in the treatment group overall (N) will be 
used as the denominator for percent calculations, unless stated otherwise in the table 
shell.  All percentages will be presented with one decimal point, unless specified 
otherwise.  Percentages equal to 100 will be presented as 100% and percentages will not 
be presented for zero frequencies.  
Significance testing will be 2-tailed using α = 0.05, unless otherwise specified.  All 
analyses and summaries will be produced using SAS® version 9.3 (or higher). 
Deviations from the statistical plan will be reported in the clinical study report, 
including the rationale for use. 
 
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6.2. 
KEY DEFINITIONS 
Age 
 
Age, as an integer, will be calculated using the date of birth and the date of informed 
consent. 
 
Age = int ((date of informed consent- date of birth)/365.25) 
 
Body Mass Index (BMI) 
 
BMI will be calculated as follows and rounded to 1 decimal place: 
 
BMI (kg/m2) = weight (kg) / [height (m)]2 
 
Parkinson’s Disease History 
 
The following parameters will be calculated for the PD history: 
 
Time since diagnosis of PD (months) =  
Date of Screening Visit 1 (M/Y) - Date of diagnosis (M/Y) 
 
Duration of levodopa treatment (months) =  
Date of Screening Visit 1 (M/Y) - Start date of levodopa treatment (M/Y) 
 
Time since onset of wearing off episodes (months) =  
Date of Screening Visit 1 (M/Y) - Date of onset of wearing off episodes (M/Y) 
 
If the month is missing, the first month of the year will be used. 
 
Change from pre-dose to post-dose   
 
The change from pre-dose to post-dose within each visit will be calculated for each 
post-dose assessment as: 
 
Change from Pre-dose to Post-dose = Post-dose value – Pre-dose value 
 
Percent change from pre-dose to post-dose  
 
The percent change from pre-dose to post-dose within each visit will be calculated for 
each post-dose assessment as: 
 
Percent Change from Pre-dose to Post-dose =  
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(Post-dose value – Pre-dose value)*100/Pre-dose value 
 
Baseline 
 
For CVT-301 patients, baseline is defined as the last non-missing assessment before the 
first dose of study drug, unless specified otherwise. For the Observational Cohort, 
baseline is defined as TV/OV1, or, in the case of missing data, the last non-missing 
assessment before TV/OV1, unless specified otherwise. However, for all patients who 
were included in the 
 or 
 studies, TV/OV1 of the 
 
study will be used as baseline. 
 
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Change from baseline  
 
The change from baseline will be calculated for each post-baseline assessment as: 
 
Change from Baseline = Post-baseline value – Baseline value 
 
Percent change from baseline  
 
The percent change from baseline will be calculated for specified post-baseline 
assessments as: 
 
Percent Change from Baseline = 
(Post-baseline value – Baseline value)*100/Baseline value 
 
DLCO predicted and DLCO predicted, adjusted for hemoglobin (Hb) 
 
DLCO predicted  
DLCO predicted will be calculated by Miller equation. 
 
Anderson H, Teirstein AS, Selikoff IJ. Single breath diffusing capacity in a representative of 
Michigan, a large industrial state. Am Rev Resp Dis 1983; 127: 270-277). 
(Miller A, Thornton JC, Warshaw R,
• 
Men  predicted DLCO = 12.9113 - (0.229 x age) + (0.418 x height in)  
• 
Women predicted DLCO = 2.2382 - (0.1111 x age) + (0.4068 x height in)  
Where age is the age at baseline, height is measured in inches. 
 
DLCO Predicted, adjusted for Hb  
DLCO predicted adjusted for Hb is calculated using the Cotes method, according to the 
2005 ATS/ERS guidelines for DLCO. 
 
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• 
DLCO predicted, adjusted for Hb in adult men:  
DLCO predicted for Hb = DLCO predicted 1.7* Hb / (10.22 + Hb) 
 
• 
DLCO predicted, adjusted for Hb in adult women: 
DLCO predicted for Hb = DLCO predicted 1.7 *Hb / (9.38 + Hb) 
Where DLCOpredicted is the DLCO calculated from Miller equation; Hb = hemoglobin, 
measured in g/dL. The Hb closest to the date/time of DLCO taken will be used.  
Percent predicted of FEV1 and FVC 
The percent predicted of FEV1 and FVC will be calculated using the following equation. 
Percent Predicted = 100 * (Observed) / Predicted 
where observed value is the value provided by TechEd, and the predicted value is the 
predicted value that provided by BMS and is the values closest to the date of observed 
value taken. The details are listed in table below. 
DLCOpredicted, percent predicted of 
FEV1 and FVC  
Value selection for Hb, predicted FEV1 and FVC 
Screening  (prior to randomization) 
From TV/OV1 or the value closest to the date of DLCO 
assessment if the value at TV/OV1 is missing 
TV/OV3, within 2 weeks  prior to 3 
From TV/OV3 or the value closest to the date of DLCO 
assessment if the value at TV/OV3 is missing 
TV/OV4, within 2 weeks  prior to 6 
From TV/OV4 or the value closest to the date of DLCO 
assessment if the value at TV/OV4 is missing 
TV/OV5, within 2 weeks  prior to 9 
From TV/OV5 or the value closest to the date of DLCO 
assessment if the value at TV/OV5 is missing 
TV/OV6, within 2 weeks  prior to 12 
From TV/OV6 or the value closest to the date of DLCO 
assessment if the value at TV/OV6 is missing 
4 to 5 weeks after TV/OV6 
The latest non-missing Hb that closest to the date of 
DLCO assessment taken. 
6.3. 
MISSING DATA 
Several different methods to handle the missing data will be used. 
 
• 
For calculation of the UPDRS part 3 scores, the missing single UPDRS items will be 
imputed as described in Section 4.3. 
 
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• 
For the primary analysis of spirometry and selected explorative efficacy endpoints, 
likelihood-based modeling approach will be used to handle incomplete data.  For 
this purpose, Mixed Model for Repeated Measures (MMRM) will be applied, see 
Section 8.1. 
 
• 
Sensitivity analysis for spirometry and selected explorative efficacy endpoints will 
be conducted using the Multiple Imputation (MI) approach, i.e. by replacing each 
missing value with a set of plausible values that represent the uncertainty about the 
right value to impute, see Section 8.1. 
 
• 
For the binary explorative efficacy endpoints, sensitivity analyses will be conducted 
using worst case imputation, where visits with missing data are counted as non-
resolved (primary method), see Section 9.1.  
 
• 
For AEs, the overall incidence of TEAEs, normalized for duration of exposure will be 
calculated to account for the shorter follow-up time in patients who discontinue the 
study prematurely, see Section 8.4. 
 
The Safety and ITT populations will be used for the analysis of the primary, secondary 
and exploratory endpoints. The patients with no post-baseline data will not contribute 
to the analyses performed with the MMRM approach, but they do contribute to the 
sensitivity analyses using the MI approach.  Due to this, no additional population, like a 
modified ITT population including only the patients with post-baseline will be defined.  
 
6.4. 
VISIT WINDOWS 
The visits recorded in database will be used for all analyses.  There is no plan to  
re-assign visits based on actual visit dates. 
 
For the patients who discontinue the study prematurely, a set of assessments is 
scheduled to be performed at the Early Termination (ET) visit (PDQ-39, UPDRS Part 2, 
UPDRS Part 4, S&E ADL score and safety assessments). CVT 301 treated patients will also 
perform the UPDRS Part 3 assessments at 10, 20, 30, and 60 minutes post dose as well 
as the PGI-C. The following rules will be used to analyze the data collected at the ET 
visit: 
 
• 
For the PDQ-39, PGI-C, UPDRS Part 2, UPDRS Part 3, UPDRS Part 4 and S&E ADL 
score, the data from the ET visit will be re-assigned to TV/OV6 in case there is no 
TV/OV6 assessment. 
 
• 
In case there are PD diary assessments performed during the three days before the 
ET visit, these assessments will be re-assigned to the first visit at which the PD diary 
assessments were scheduled but are missing due to the premature withdrawal. 
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• 
The safety assessment assessments performed at the ET visit will be re-assigned to 
the first time point at which the corresponding safety assessments were scheduled 
but are missing due to the premature withdrawal. 
 
• 
Any other data collected at the ET visit will not be used. 
 
6.5. 
POOLING OF SITES 
Not applicable. 
 
6.6. 
SUBGROUPS 
At least the following subgroup analyses have been pre-planned.  The subgroup analyses 
will be performed for selected efficacy endpoints (at least the Change from pre-dose in 
UPDRS Part 3 motor score at 30 minutes post-dose and the mean daily OFF time).  
Selected baseline data will be presented for the subgroups as well. 
• 
Patients with baseline PD severity < 2.5 points on the Hoehn & Yahr scale versus 
patients with baseline PD severity ≥ 2.5 points on the Hoehn & Yahr scale 
• 
Patients who are dyskinetic before TV/OV1 versus non-dyskinetic patients. The 
classification will be done based on the Parkinson’s disease diary data. The 
patients who have recorded at least 1 hour of dyskinesia (either ON with non-
troublesome dyskinesia or ON with troublesome dyskinesia) on at least 2 days 
before TV/OV1 will be classified as dyskinetic 
• 
Patient with the baseline daily levodopa dose less than or equal to the median 
versus the patients with the baseline daily levodopa dose higher than the median 
• 
Patients who have less than 4.5 hours of PD diary mean daily OFF time before 
TV/OV1 versus patients who have 4.5 hours or more of OFF time 
• 
Patients with FEV1 <60% of predicted or FEV1/FVC ratio <70% at baseline versus 
patients with FEV1 ≥60% of predicted and FEV1/FVC ratio ≥70% 
• 
Non-elderly (<65 years) versus elderly (≥65 years) patients 
• 
Female versus male patients. 
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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
PATIENT DISPOSITION AND WITHDRAWALS 
The patient disposition table will summarize the following and will be presented for 
each treatment group, as applicable, and overall.  The percentages will be calculated 
based on the number of randomized patients, unless otherwise specified). The 
randomized set will include all randomized patients as well as those from 
 
and 
 studies who were assigned to the CVT 301 treatment group. 
 
• 
The number of patients screened (i.e. the number of patients in the AAP 
population) 
• 
The number of patients who failed screening 
• 
The number (%) of patients randomized into the study (% calculated from the 
AAP population) 
• 
The number (%) of patients in the different study populations (Safety and ITT 
populations) 
• 
The number (%) of patients who completed the study (based on end-of-study 
case record page) 
• 
The number (%) of patients who withdrew from the study and associated reasons 
(% calculated from the Safety population) 
 
 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographics and baseline characteristics will be summarized descriptively for the 
Safety population by treatment group and overall. The following variables will be 
summarized: 
 
• 
Demographics (age (continuous), age categorized as <65 years versus ≥65 years, 
gender, ethnicity, race, height, weight, BMI, country)  
• 
Smoking history (current, former, never, Number of Years Smoked and Number 
of Cigarettes/Day) 
• 
Cognitive status (MMSE)  
• 
Average number of daily OFF episodes experienced from the Screening ON/OFF 
Log. The screening ON/OFF log data collected on 3 days prior to TV/OV1 will be 
used as baseline. If the data are only available on 1 or 2 days prior to TV/OV1, 
the available data will be used as baseline. If there is no data prior to TV/OV1, 
the data collected on 3 days prior to SV2 will be used as baseline.  
 
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• 
Proportion of patients who changed the timing of their usual levodopa 
medication and proportion of patients who took an extra dose of levodopa or 
other PD medication from the Screening ON/OFF Log. The screening ON/OFF log 
data collected on 3 days prior to TV/OV1 will be used as baseline. If the data are 
only available on 1 or 2 days prior to TV/OV1, the available data will be used as 
baseline. If there is no data prior to TV/OV1, the data collected on 3 days prior 
to SV2 will be used as baseline. 
• 
Average daily OFF time, ON time Without Dyskinesia, ON time with troublesome 
and non-troublesome dyskinesia (from PD diary before TV/OV1) 
• 
Proportion of patients with total daily OFF time <4.5 hours or ≥4.5 hours (from 
PD diary before TV/OV1) 
• 
Distribution of average daily OFF time in 30-minute intervals (00:00 – 00:30, 
00:30 – 01:00, …). The percentage based on the total daily OFF time will also be 
presented and is calculated as the average of total OFF time collected three 
days prior to TV1 and is normalized to 16 awake hours per day. 
• 
PD history (time since diagnosis of PD, duration of levodopa treatment, time 
since onset of wearing off episodes) 
• 
Total daily levodopa dose, number of levodopa doses per day 
• 
PD disease severity (Modified Hoehn and Yahr Staging in “ON” State) 
• 
UPDRS Part 3 Motor score in ON/OFF (from screening assessment); the change 
from OFF to ON state in UPDRS part 3 Motor score at the Screening will also be 
classified as ≥6 points, or ≥11 points reduction.  
• 
Baseline Dyskinesia (Dyskinetic before TV/OV1, Non-dyskinetic before TV/OV1). 
The classification will be done based on the Parkinson’s disease diary data. The 
patients who have recorded at least 1 hour of dyskinesia (either ON with non-
troublesome dyskinesia or ON with troublesome dyskinesia) on at least 2 days 
before TV will be classified as dyskinetic. 
• 
Proportion of patients with FEV1 <60% of predicted or FEV1/FVC ratio <70% at 
baseline versus FEV1 ≥60% of predicted and FEV1/FVC ratio ≥70% (based on the 
randomization strata). 
• 
Screening  spirometry data: FEV1, FVC, and FEV1/FVC ratio, presented for each 
motor status, ON or OFF, separately. 
 
Demographics and PD disease data will also be summarized by subgroups (Patients with 
baseline PD severity < 2.5 points on the Hoehn & Yahr scale versus ≥ 2.5 points; Patients 
who are dyskinetic before TV/OV1 versus non-dyskinetic; Patient with the baseline  less 
than or equal to the median versus above median; Patients who have less than 4.5 hours 
of PD diary mean daily OFF time before TV/OV1 versus 4.5 hours or more; Patients with 
FEV1 <60% of predicted or FEV1/FVC ratio <70% at baseline versus FEV1 ≥60% of 
predicted and FEV1/FVC ratio ≥70%, Non-elderly (<65 years) versus elderly (≥65 years) 
patients, Female versus Male patients). 
 
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7.3. 
MEDICAL HISTORY  
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 17.0. The medical history data will be summarized with frequencies 
and percentages of patients with at least one medical history item, and patient 
frequencies and percentages on the system organ class (SOC) and preferred term (PT) 
levels. The events will also be summarized. The table, using the Safety population, will 
be sorted by overall descending frequency of SOC and then, within a SOC, by overall 
descending frequency of PT. 
7.4. 
MEDICATION 
All medications will be classified using the Anatomical Therapeutic Chemical (ATC) 
classification codes and preferred drug names from the World Health Organization Drug 
Dictionary (WHO-DD), Q1March2014.  
 
For the medications recorded on CRF page “Prior and Concomitant Medications”, 
medications with a stop date before the first date of study drug dosing or TV/OV1 for 
the observational cohort will be considered prior medications. Medications with start 
date or stop date on or after the first date of study drug dosing will be considered 
concomitant medications. 
 
Tables will be generated for the Safety Population. Summaries of baseline PD treatment 
medications (medications which start with ATC code N04) will be presented in tabular 
form using the ATC Level 4 and preferred term. Other prior medications and 
concomitant medications will be presented in tabular form using the ATC Level 1, ATC 
Level 2, and PT. Frequencies and percentages will be presented by treatment group and 
overall. The counts of medications will also be summarized. The tables will be sorted by 
overall descending frequency of ATC Level(s) and then, within an ATC Level, by overall 
descending frequency of PT. 
If the medication start date is incomplete, then it will be imputed as follows for the 
purpose of determining concomitance only:  
• 
If the start date is completely missing, the start date will be equal to the first 
dose date. However, if the stop date is not missing and is before the first dose 
date, then the stop date will be used instead.  
• 
If the start day is missing, the first day of the month will be used.  
• 
If the start day and month are missing, then the first day of the first month 
(January) will be used. 
 
If the medication stop date is partial, then it will be imputed as follows for the purpose 
of determining concomitance only:  
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• 
If the stop date is completely missing and the medication is not ongoing, the 
stop date will be equal to the last dose date or date of completion/withdrawal, 
whichever is the latest.  
• 
If the stop day is missing, the last day of the month will be used.  
• 
If the stop day and month are missing, then the last day of the last month 
(December) will be used. 
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8. 
SAFETY 
The population used for safety analyses will be the Safety Population.  The analyses are 
outlined below. 
8.1. 
SPIROMETRY 
Spirometry will be performed by trained and qualified staff at each study site.  
Spirometry data obtained in the study site will reviewed by a central spirometry 
laboratory (Biomedical Systems, Inc.) which will provide a quality over read of all 
evaluations based on acceptability and repeatability metrics in accordance with ATS 
criteria.  FEV1, FVC and FEV1/FVC ratio will be recorded from the single “best test” 
(based on effort with highest summed FEV1 and FVC).  Variables will include the 
absolute FEV1, FVC, and FEV1/FVC ratio and FEV1 and FVC expressed as % of predicted 
value. 
The variables from pulmonary laboratory will include the FEV1, FVC, FEV1/FVC ratio, 
DLCO, IVC, SVC and VA.  FEV1 and FVC expressed as % of predicted value, predicted 
DLCO, hemoglobin (Hb) adjusted predicted DLCO, and DLCO expressed as % of these 
predicted values will be calculated per the method in section 6.2.  The following 
analysis will be performed: 
All the parameters collected at the pulmonary laboratory as well as the % of predicted 
DLCO and % of Hb adjusted predicted DLCO DLCO will be summarized descriptively by 
treatment group and overall.  
• 
Change from baseline to other visits for each parameter.  The summary for FEV1 
will also be provided by smoker status. 
• 
Number and percentage of patients with FEV1/FVC < 60% and <70% by Visit  
• 
DLCO data will also be provided to indicate whether specific determinations met 
American 
Thoracic 
Society 
(ATS) 
quality 
criteria. 
The 
proportion 
of 
DLCO/spirometry data measurements meeting or not meeting ATS quality 
criteria will be summarized by treatment group and overall.  
• 
Categories of changes (<-50%, -50% -<-40%, -40% -<-30%, , -30% -<-20%, , -20% -<-
10%, -10% -<-10%, 10% -<20% , 20% -<30% , 30% -<40% , 40% -<50%, >=50%) from 
baseline for FEV1, FEV, FEV1/FVC ratio and DLCO  by visit. The summary for 
FEV1 will also be provided by smoker status. 
 
The descriptive summaries will be repeated for the subset of assessments meeting the 
ATS quality criteria. 
 
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Another subset analysis will be performed by excluding the DLCO data from patients 
with a very high intra-individual variability. For the purpose of this analysis, all patients 
who have a co-efficient of variation (CV) value >7.5% for FEV1 will be excluded. The CV 
will be calculated for each patient as standard deviation divided by the mean. The 
screening visit FEV1 data (assessed in ON state) and arrival values at subsequent visits 
will be used for the calculation. 
 
In addition to the descriptive statistics, the changes in the FEV1, FEV1/FVC ratio, and 
DLCO values within each treatment group and differences between the treatment 
groups will be estimated with MMRM. The model will include the treatment group (CVT-
301 or observational cohort), visit (visits at 1, 3, 6, 9, and 12 months), the stratification 
variables (Hoehn and Yahr stage and screening FEV1 and/or FEV1/FVC) and the 
interaction between the treatment group and visit as fixed factors. The baseline 
spirometry value will be included as a covariate. An unstructured covariance structure 
will be applied for MMRM.  In case the model will not converge with the unstructured 
covariance structure, the heterogeneous compound symmetry (CSH) or the 
heterogeneous Toeplitz structure (TOEPH) will be used instead.  If the unstructured 
covariance structure will be used, the denominator degrees of freedom will be 
computed using the Kenward-Roger method. In case of other covariance structures, the 
BETWITHIN option will be used for the denominator degrees of freedom. The least 
square (LS) mean, standard error, and LS mean difference between CVT-301 and 
observational cohort at each visit; along with the 95% confidence interval (CI) will be 
provided in a table. Treatment difference will be assessed with a 2-sided alpha level of 
0.05, unless specified otherwise.  
 
The SAS code planned for the analysis is outlined below. 
 
proc mixed data=&data; 
class pdsevbl fev1bl trta avisit usubjid; 
model chg=base pdsevbl fev1bl trta avisit trta*avisit / ddfm=kr; 
repeated avisit / subject=usubjid(trtp) type=un; 
lsmeans trtp*avisit / cl; 
estimate 'CVT vs OBS Month 1'  
        trta 1 -1 trta*avisit 1 0 0 0 0 -1 0 0 0 0 / cl; 
estimate 'CVT vs OBS Month 3'  
        trta 1 -1 trta*avisit 0 1 0 0 0 0 -1 0 0 0 / cl; 
estimate 'CVT vs OBS Month 6'  
        trta 1 -1 trta*avisit 0 0 1 0 0 0 0 -1 0 0 / cl; 
estimate 'CVT vs OBS Month 9'  
        trta 1 -1 trta*avisit 0 0 0 1 0 0 0 0 -1 0 / cl; 
estimate 'CVT vs OBS Month 12'  
        trta 1 -1 trta*avisit 0 0 0 0 1 0 0 0 0 -1 / cl; 
run; 
 
The Safety population will be used for the primary analysis. 
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Sensitivity analyses of the spirometry data 
 
The following sensitivity analysis will be performed for the FEV1, FVC/FEV1 and DLCO 
assessments. 
 
• 
MI analysis:  MI techniques based on Pattern Mixture Models (PMM) will be applied 
(
) as a further sensitivity analysis in the Safety population.  This 
methodology will structure data based on missing data patterns.  The method will 
be based on a missingness pattern having a monotone structure, i.e. if among the 
observations over time one data value is missing, all other values after this missing 
value will also be treated as missing.  For patients with intermittent missing values, 
before performing MI based on the PMM, it will be necessary to create a monotone 
missingness pattern.  Intermittent missing values will be imputed using the Markov 
Chain Monte Carlo (MCMC) methodology which assumes a multivariate normal 
distribution over all variables included in the imputation model.  The MI procedure 
in SAS will be used for this purpose and this first MI step is planned to be repeated 
100 times, creating several different datasets with a monotone missing data 
structure.  Seed value of 201508 will be used in the MI procedure.  The imputation is 
based on the missing at random (MAR) assumption, i.e. the missing data are assumed 
to follow the same model as the other patients in their respective treatment arm 
that have complete data. 
 
After this, the remaining missing data can be imputed using a method for monotone 
missingness, also based on the MAR assumption.  Thus, for each of the created 
datasets with a monotone missing data pattern, the MI procedure in SAS will used to 
impute missing values based on a sequential procedure reflecting the monotone 
missing data pattern.  Patients with the first missing value occurring at visit at 
Month 1 will have their missing Month 1 value replaced by an imputed value from a 
regression model with treatment group, baseline spirometry value and the 
stratification factors as explanatory variables.  In the next step, patients with their 
Month 3 value missing will have their missing Month 3 value replaced by an imputed 
value from a regression model with treatment group, baseline spirometry value, 
stratification factors and the Month 1 value as explanatory variables.  Similar 
procedure will be used to replace the missing values at Month 6, 9 and 12. 
 
The imputed datasets generated with the approach described above do contain only 
non-missing values and are used as input in the model for the primary endpoint.  
MMRM models similar as described above will thus be run on each of the generated 
imputed datasets and the difference between the treatment groups will be 
estimated. The MMRM model will be similar to the primary analysis. Finally, the 
MIANALYZE procedure in SAS will be applied to combine the results from these 
several datasets to derive an overall estimate of the within-group changes and 
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treatment differences.  Estimates and corresponding 95% confidence intervals will 
be calculated. 
The following summary will be performed on the neurology sites data. 
• 
Change from baseline to other visits for each parameter. The baseline is defined 
as the TV/OV1 Arrival value. If the TV/OV1 Arrival value is missing, the last 
available value in ON state before the first dose of study drug will be used. The 
summary for FEV1 will also be provided by smoker status. 
• 
Number and percentage of patients with FEV1/FVC < 60% and <70% by visit  
• 
Spirometry data will also be provided to indicate whether specific 
determinations met American Thoracic Society (ATS) quality criteria. The 
proportion of DLCO/spirometry data measurements meeting or not meeting ATS 
quality criteria will be summarized by treatment group and overall. The 
summary will also be performed for ON state measurements, OFF state 
measurements, and all measurements, separately. The reasons for not meeting 
ATS quality criteria will be summarized, as data allow. 
• 
Categories of changes (<-50%, -50% -<-40%, -40% -<-30%, , -30% -<-20%, , -20% -<-
10%, -10% -<-10%, 10% -<20% , 20% -<30% , 30% -<40% , 40% -<50%, >=50%) from 
baseline for FEV1, FEV, FEV1/FVC ratio and DLCO  by visit. The summary for 
FEV1 will also be provided by smoker status. 
8.2. 
EXTENT OF EXPOSURE 
The following information will be summarized for CVT-301 treated subjects: 
• 
The number of patients with dose change 
• 
Duration of exposure (days) 
• 
Total exposure to study treatment, expressed as person years (sum of exposure 
to study treatment over all CVT – 301 treated patients) 
• 
Total number of doses and capsules taken, by visit and overall. Average number 
of daily doses and number of capsules, by visit and overall 
• 
Proportion of days with 5, 4, 3, 2, 1 or 0 doses administered 
• 
Proportion of patients using 5, 4, 3, 2, 1 or 0 doses/day at least once 
 
In addition, these in-clinic data will be summarized by treatment group and visit: 
 
• 
Standard morning dose of LD-containing medications to in-clinic OFF (mins) 
• 
In-clinic OFF to start of study drug inhalation (mins)  
• 
Standard morning dose of LD-containing medications to start of study drug 
inhalation (mins) 
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• 
Duration of study drug inhalation (mins), calculated as (Completion time of last 
inhalation – Time of start of first capsule inhalation). 
 
Furthermore, the distribution of time of intake of study medication (00:00 – 00:30, 
00:30 – 01:00, …) as percentage of the total number of study medication intakes will be 
displayed during the whole treatment period.  This data will be collected on the Inhaled 
Dosing Log. 
 
All study drug data will be listed.  A listing will also be provided to show how many 
times each patient will take study drug and the capsules taken for each day. 
 
8.3. 
TREATMENT COMPLIANCE  
Patients will be instructed to administer inhaled study drug up to 5 times each day 
during the treatment period. In-clinic administration of study drug will be supervised by 
study personnel, and at-home diary data will be reviewed to ensure patient compliance. 
Since there are no fixed scheduled doses for each day, compliance will not be 
calculated for this study; alternatively, study drug use will be evaluated based on the 
inhaled medication treatment log by summarizing the proportion of days with >5, 5, 4, 
3, 2, 1 or 0 doses administered.  
8.4. 
ADVERSE EVENTS 
All AEs will be coded using the MedDRA version 17.0.  
 
Treatment-emergent adverse events (TEAEs) are defined as all AEs that start after the 
patient receives the first dose of study drug.  For the observational cohort, TEAE will 
be defined as events that occur during/after TV/OV1. Events will be classified as drug-
related if the AE is classified as possibly, probably, or definitely related to study drug. 
 
Events with a missing start time, but with a start date equal to the date of first dose of 
study drug will be considered treatment-emergent.  If the AE start date is incomplete, 
then it will be imputed as follows for the purpose of determining TEAE:  
 
• 
If the start date is completely missing, the start date will be equal to the first 
dose date.  However, if the stop date is not missing and is before the first dose 
date, then the stop date will be used instead.  
• 
If the start day is missing, the first day of the month will be used.  
• 
If the start day and month are missing, then the first day of the first month 
(January) will be used. 
The original date and time will be shown on all listings of AEs.  Listings will be provided 
for all AEs, serious AEs, AEs leading to study drug discontinuation, AEs leading to dose 
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reduction, and deaths. 
 
TEAEs will be summarized by SOC and PT for each treatment group and overall total.  
TEAEs with onset after the treatment period are attributed to the treatment group and 
dose level during the treatment period.  Both event and patient counts, where 
applicable, will be summarized.  The counts will be complemented by percentages will 
be calculated for the patient counts unless otherwise specified. In addition, the 
incidence of TEAEs, normalized for duration of exposure will be presented (number of 
TEAEs divided by the total exposure to CVT 301 or observation, measured as patient 
years). 
• 
An overall summary of the number and percentage of patients reporting TEAEs 
and the number of TEAE events, drug-related TEAEs, severe TEAEs, serious 
TEAEs, TEAEs leading to dose interruption, TEAEs leading to study drug 
discontinuation, TEAEs leading to dose reduction and TEAEs leading to death 
• 
TEAEs by SOC and PT, both as event and patient counts 
• 
TEAEs by PT, both as event and patient counts  
• 
Drug-related TEAEs by SOC and PT, both as event and patient counts 
• 
Severe TEAEs by SOC and PT, both as event and patient counts 
• 
Drug-related TEAEs by SOC, PT and severity, as event counts; percentages will 
be calculated for the event count out of total number of events 
• 
Drug-related TEAEs by SOC, PT and relationship, as event counts; percentages 
will be calculated for the event count out of total number of events 
• 
Serious TEAEs by SOC and PT, both as event and patient counts 
• 
TEAEs leading to study drug interruption, both as event and patient counts  
• 
TEAEs leading to study drug withdrawal, both as event and patient counts  
• 
TEAEs leading to dose reduction, both as event and patient counts 
• 
Most common AEs, both as event and patient counts, most common TEAEs is 
defined any AE preferred term occurred in greater than 10% total patients. 
• 
Time to first onset of most common AEs, classified as 0-1 months, >1-3 months, 
>3-6 months, >6-9 months and after 9 months, where the date of TEAE onset will 
be used as the time point for classification.   
The tables will be sorted by overall descending frequency of SOC and then, within a 
SOC, by overall descending frequency of PT based on the patient count for the Total 
column.  If only event count is presented, the sorting will be done based on the event 
count. 
 
8.5. 
LABORATORY EVALUATIONS 
Laboratory samples for hematology and clinical chemistry will be analyzed by a central 
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laboratory (located in the United Kingdom for EU sites and the United States for US 
sites) to ensure consistent interpretation of results.  In the event of an unexplained 
clinically significant abnormal laboratory test value, the test should be repeated 
immediately and followed up until it has returned to the normal range and/or an 
adequate explanation of the abnormality is found. 
 
All parameters will be converted to consistent units according to the International 
System of Units (SI) before summarization.  The following will be summarized by 
treatment group and overall: 
 
• 
Actual values and change from baseline, if applicable, at each visit for each 
parameter (for handling of data from the ET visit, see Section 6.4) 
• 
Number and percentage of patients with normal or “abnormal” (i.e., out of 
reference range) labs at each visit for each parameter 
• 
Number and percentage of patients with potentially clinically significant (PCS) 
lab values at each visit for each parameter 
• 
Number and percentage of patients with potentially clinically significant changes 
(PCSC) in lab values at each post-baseline visit for each parameter 
PCS and PCSC will be identified for specific laboratory parameters as outlined in the 
following table. 
 
 
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Laboratory 
Parameter 
Units 
Criteria for PCS Values (Actual 
values) 
Criteria for PCSC values 
(Changes from baseline 
values) 
 
 
High  
Low  
% increase  
% decrease  
Hemoglobin  
g/L  
> 10 above ULN  
>20 below LLN  
NA  
25%  
Hematocrit  
L/L 
>0.04 above ULN  
>0.05 below LLN  NA  
25%  
WBC  
GI/L  
>5 above ULN  
>1 below LLN  
100%  
50%  
Neutrophils  
GI/L  
NA  
<0.5xLLN  
100%  
50%  
Neutrophils  
%  
NA  
<0.5xLLN  
100%  
50%  
Lymphocytes  
GI/L  
NA  
<0.5xLLN  
100%  
50%  
Lymphocytes  
%  
NA  
<0.5xLLN  
100%  
50%  
Total bilirubin  
μmol/L  
>1.5xULN  
NA  
300%  
NA  
Total protein  
g/L  
>15 above ULN  
>15 below LLN  
200%  
60%  
Albumin  
g/L  
>5 above ULN  
>5 below LLN  
NA  
60%  
AST  
U/L  
>3xULN  
NA  
300%  
NA  
ALT  
U/L  
>3xULN  
NA  
300%  
NA  
Alkaline 
Phosphatase  
U/L  
>3xULN  
NA  
300%  
NA  
GGT  
U/L  
>3xULN  
NA  
300%  
NA  
Creatinine  
μmol/L  
>1.5xULN  
NA  
200%  
NA  
Urea  
mmol/L  
>2.5xULN  
NA  
300%  
NA  
Uric Acid  
μmol/L  
>3xULN  
NA  
300%  
NA  
Sodium  
mmol/L  
>5 above ULN  
>5 below LLN  
10%  
10%  
Potassium  
mmol/L  
>1 above ULN  
>0.5 below LLN  
25%  
20%  
Carbon dioxide  
mmol/L  
>40  
<16  
25%  
25%  
Calcium  
mmol/L  
>2.99  
<1.78  
30%  
30%  
Glucose (fasting)* 
mmol/L  
>11.1  
<2.8  
300%  
40%  
ULN = Upper limit of normal range, LLN = Lower limit of normal range 
Baseline is defined as the visit 3 assessment. If the visit 3 assessment is missing, the last non-
missing screening assessment will be used as baseline. * fasting defined as ≥4 hr from prior meal 
The tables showing the normal/abnormal values, PCS values and PCSCs will be done 
both as summaries of all data and as shift tables (i.e., classified by the baseline status). 
 
Values which fall outside the central laboratory normal range will be flagged as “L” – 
below normal range, or “H” – above normal range, on the data listings. PCS and PCSC 
values will also be flagged. All repeated values will be presented on the data listings but 
not included in the summaries showing data by visit.  
 
8.6. 
VITAL SIGNS  
Standard vital sign measurements will include RR, systolic and diastolic BP (SBP, DBP), 
and HR.  At SV1 (or SV2) and each of the subsequent study visits, and in the event of a 
clinically significant finding that could be suggestive of symptomatic orthostatic 
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hypotension (e.g., dizziness, lightheadedness, or other AE), orthostatic vital signs will 
be performed.  Orthostatic vital sign measurements will include SBP, DBP, and HR.  
 
The following will be summarized: 
• 
Change from baseline to other visit for each parameter. The baseline is defined 
as the TV/OV1. If TV/OV1 is missing, the last non-missing screening assessment 
will be used as baseline. 
• 
Actual values and change from pre-dose to post-dose time points at TV/OV1 by 
time point for each parameter for CVT-301 treated patients 
• 
Number and percentage of patients with PCS values at each applicable visit and 
time point for each standard vital sign parameter 
• 
Number and percentage of patients with PCSC values at each applicable visit and 
time point for each standard vital sign parameter 
• 
Number and percentage of patients with Orthostatic hypotension at each 
applicable visit  
PCS and PCSC for standard vital sign will be identified as outlined in the following table. 
 
Vital Sign 
Units 
Criteria for PCS Values 
(Actual values) 
Criteria for PCSC values 
(Change from Baseline or 
pre-dose values *) 
 
 
High  
Low  
increase  
decrease  
Pulse rate 
bpm  
>120  
<40  
100 
50  
Respiration Rate  
brpm  
>32  
<8  
50  
NA  
Systolic Blood 
Pressure (supine)  
mmHg  
>200  
<85  
60  
20  
Diastolic Blood 
pressure (supine)  
mmHg  
>120  
<40  
 
0.2x  
*Pre-dose values will be used for corresponding post-dose values assessment at TV/OV1.  
Otherwise baseline values are used. 
 
Orthostatic hypotension will be defined as a reduction in SBP of 20 mmHg or more, 
and/or a reduction in DBP of 10 mmHg or more, for the standing measurement 
compared to the supine/semi-supine measurement. 
 
8.7. 
ELECTROCARDIOGRAM 
Standard 12-lead ECGs will be obtained after the patient has rested in a supine position 
for at least 5 minutes.  Electrocardiograms will be measured using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, QT interval corrected using 
Bazett’s formula (QTcB) and QT interval corrected using Fridericia’s formula (QTcF).   
 
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The following will be summarized: 
• 
Change from baseline to other visit for each parameter. The baseline is defined 
as the TV/OV1 value. If TV/OV1 value is missing, the last non-missing screening 
assessment will be used as baseline. 
• 
Number and percentage of patients with PCS values at each applicable visit for 
each parameter 
• 
Number and percentage of patients with PCSC values at each applicable visit for 
each parameter 
PCS and PCSC will be identified as outlined in the following table. 
 
ECG 
Units 
Criteria for PCS Values 
(Actual values) 
Criteria for PCSC values (Change from 
Baseline) 
 
 
High  
Low  
increase  
decrease  
PR interval  
msec  
>300  
NA  
>25% for baseline ≥200  
>50% for baseline <200  
NA  
QRS interval  msec  
>200  
NA  
>25% for baseline ≥100  
>50% for baseline <100  
NA  
QTcB  
msec  
>500  
NA  
>15% for baseline ≥440  
>30% for baseline <440 
>30 msec increase 
>60 msec increase  
Change>30 and value>500  
Change>60 and value>500 
NA  
QTcF  
msec  
>500  
NA  
>15% for baseline ≥440  
>30% for baseline <440 
>30 msec increase 
>60 msec increase 
>Change>30 and value>500  
Change>60 and value>500 
NA  
Heart Rate  
bpm  
>120  
<35  
NA  
NA  
 
 
8.8. 
PHYSICAL EXAMINATION 
A complete physical examination (head, eyes, ears, nose, and throat [HEENT], heart, 
lungs, abdomen, skin, cervical and axillary lymph nodes, neurological, and 
musculoskeletal systems) will be performed at screening.  Genital, rectal, and breast 
examination may be excluded if not clinically indicated. 
 
The following will be summarized: 
 
• 
Total number and percentage of patients reporting abnormal clinically 
significant physical examination results 
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8.9. 
COLUMBIA-SUICIDALITY SEVERITY RATING SCALE 
The C-SSRS is a measure of suicidal ideation and behavior.  The rating scale has 4 
general categories: suicidal ideation, intensity of ideation, suicidal behavior, and actual 
attempts.  All C-SSRS data will be listed.  The frequency and percentage of patients 
with each response for suicidal ideation, intensity of ideation, and suicidal behavior 
items will be summarized as appropriate by treatment group and overall.  
 
A shift from baseline table will be constructed to assess any changes in the subjects’ 
suicidal ideation and behavior during the treatment period. 
 
8.10. EPWORTH SLEEPINESS SCALE 
The Epworth Sleepiness Scale is used to determine the level of daytime sleepiness.  
There are 8 situations listed for which patients rate their likelihood of dozing or 
sleeping (0=would never doze or sleep, 1=slight chance of dozing or sleeping, 
2=moderate chance of dozing or sleeping, and 3=high chance of dozing or sleeping).  
The total score is the sum of 8 item scores and can range between 0 and 24.  In case of 
missing item scores, the missing value will be replaced by the average of non-missing 
scores at the same visit from the same patient.  In case all item scores are missing, the 
total score will be set as missing.  The higher total score indicates the higher level of 
daytime sleepiness.  A score of 10 or more is considered sleepy, and a score of 18 or 
more is very sleepy.  
 
All Epworth Sleepiness Scale data will be listed.  The total score and change from 
baseline will be summarized by treatment group and overall (for handling of data from 
the ET visit, see Section 6.4). 
 
8.11. QUESTIONNAIRE FOR IMPULSIVE-COMPULSIVE DISORDERS IN 
PARKINSON’S DISEASE 
The QUIP is an instrument used to measure the extent of impulsive and compulsive 
behaviors in PD patients.  The QUIP has 3 sections: Section 1 assesses any impulsive 
control disorder (gambling, sexual, buying, and eating disorders); Section 2 assesses 
other compulsive behaviors (punding, hobbyism, and walkabout); and Section 3 assesses 
compulsive medication use.  
 
The frequency and percentage of patients with positive response for each of the item 
within each section will be summarized by visit treatment group and overall.  The 
assessment of positive response for each item will be based on the table below. 
 
 
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Section and Item 
Number of items with positive response 
A. Impulse Control Disorders  
 
Compulsive gambling  
any 2 of the 5 gambling items  
Compulsive sexual behavior  
any 1 of the 5 sexual behavior items  
Compulsive buying  
any 1 of the 5 buying items  
Compulsive eating  
any 2 of the 5 eating items  
B. Other Compulsive Behaviors  
 
Hobbyism 
 item #1A  
Punding  
 item #1B  
Walkabout  
 item #1C  
C. Compulsive Medication Use  
items #1 and #4  
 
8.12. UPDRS PART 4 
Changes from baseline to the subsequent visits in UPDRS Part 4 sum scores (dyskinesia 
sum score, wearing-off sum score) will be analyzed using a similar MMRM as for the 
UPDRS Part 3 scores (described below) to estimate the within-group changes. 
Otherwise, the data will be presented with descriptive statistics only classified by visit 
for CVT treated patients.  The observed cases will be used in the analysis and 
summaries. 
 
8.13. EXAMINER-RATED DYSKINESIA 
The occurrence and severity will be tabulated by treatment group and visit.  The 
observed cases will be used in the summaries.  No formal statistical methods will be 
used. 
 
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9. 
EXPLORATORY EFFICACY 
9.1. 
EXPLORATORY EFFICACY ENDPOINT AND ANALYSIS 
The ITT population will be used for the exploratory efficacy analysis. Patients will be 
analyzed according to randomized treatment.  The within group changes from baseline 
in continuous efficacy variables will be estimated using an MMRM. No between group 
differences will be calculated, unless otherwise specified. The model will include visit 
and the stratification variables (Hoehn and Yahr stage and screening FEV1 and/or 
FEV1/FVC) as fixed factors.  The baseline value will be used as a covariate.  For 
variables which do not have a pretreatment baseline assessment, OFF-state baseline 
UPDRS Part 3 score will be used as the baseline covariate.  An unstructured covariance 
structure will be applied for the MMRM.  In case the model will not converge with the 
unstructured covariance structure, compound symmetry will be used instead. For all 
patients, categorical data will be evaluated descriptively.  Each visit will be evaluated 
separately for the categorical endpoints. The exploratory efficacy endpoints and 
associated analyses are as follows. For the detailed definition of the endpoints, see 
Section 4.3. 
 
• 
Change from pre-dose in UPDRS Part 3 motor score at 10, 20, 30, and 60 minutes 
and the average of the motor score at 10-60 following treatment of patients 
experiencing an OFF episode in the clinic. Change from pre-dose in the average 
UPDRS Part 3 score at 10 to 60 minutes is calculated as the mean of change of 
UPDRS Part III total score from pre-dose to each time point post-dose if UPDRS Part 
III total score is available for at least 2 time points post-dose. The scheduled post-
dose UPDRS Part III assessments are at 10, 20, 30, 60 minutes post-dose, 
respectively. If there is more than 2 time points post-dose with missing UPDRS Part 
III total score, the change of UPDRS Part III total score from pre-dose to 10 to 60 
minutes post-dose will be missing. A MMRM model as defined above will be used.  
 
• 
Time curve of the UPDRS response shown as change from pre-dose in UPDRS Part 3 
motor score to 10, 20, 30 and 60 minutes following treatment of patients 
experiencing an OFF episode in the clinic. A separate MMRM model will be fitted for 
each of the time points. 
• 
A ≥3, ≥6, and ≥11 point reduction in the UPDRS Part 3 motor score from pre-dose to 
post-dose, at 10 to 60 minutes following treatment in the clinic (cumulative and 
non-cumulative).  For the non-cumulative analysis, the proportions of patients with 
a reduction will be tabulated by treatment group, visit and time point.  For the 
cumulative analysis, the cumulative proportions of patients who achieved the first 
reduction before or at the time point in question will be tabulated by visit and time 
point.   
 
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• 
Resolution of an OFF to an ON state within 60 minutes after study drug is 
administered in the clinic and maintaining the ON at 60 minutes after study drug 
administration (per the examiner’s subjective assessment).  This endpoint will be 
based on the examiner’s subjective assessment.  The proportions of patients will be 
summarized descriptively for each CVT-301 treated patients. The missing values will 
be counted as non-resolved. 
 
• 
Change from baseline (3 consecutive days prior to TV1) in patient-recorded total 
daily OFF time, assessed by the patient and recorded in the PD Diary for 3 
consecutive days prior to the visit.  Similar methods as for primary endpoint will be 
used.  However, the baseline daily OFF time will be used as a covariate in the MMRM 
model instead of the OFF-state baseline UPDRS part 3 score. Only valid diary days 
will be included in the diary summarizations. In addition, change from baseline in 
total daily ON time without dyskinesia, total daily ON time with non-troublesome 
dyskinesia, and total daily ON time with troublesome dyskinesia. 
 
• 
The PGI-C score. The proportions of patients who improved (much improved, 
improved or a little improved) will be tabulated by visit for CVT-301 treated 
patients.  This summary will be complemented by the distribution of each response 
category (much improved, improved, a little improved, no change, a little worse, 
worse, much worse) tabulated by the treatment group.    
• 
Changes from TV/OV1 in endpoints based on S&E ADL score, UPDRS Part 2 score, and 
PDQ-39 sub-scores.  An ANCOVA model with the treatment group and stratification 
variables as fixed factors and the TV/OV1 value as a covariate will be used to 
estimate the treatment differences.  Otherwise, the data will be presented with 
descriptive statistics only classified by treatment group and visit.  The observed 
cases will be used in the analysis and summaries. 
 
Sensitivity analyses of the exploratory efficacy data 
 
The following sensitivity analysis will be performed for the UPDRS Part 3 motor scores at 
30 minutes post-dose and daily OFF time exploratory efficacy endpoints. 
 
• 
MI analysis:  MI techniques based on Pattern Mixture Models (PMM) will be applied 
(
) as a further sensitivity analysis in the ITT population.  This 
methodology will structure data based on missing data patterns.  The method will 
be based on a missingness pattern having a monotone structure, i.e. if among the 
observations over time one data value is missing, all other values after this missing 
value will also be treated as missing.  For patients with intermittent missing values, 
before performing MI based on the PMM, it will be necessary to create a monotone 
missingness pattern.  Intermittent missing values will be imputed using the Markov 
Chain Monte Carlo (MCMC) methodology which assumes a multivariate normal 
Ratitch et al., 2011
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distribution over all variables included in the imputation model.  The MI procedure 
in SAS will be used for this purpose and this first MI step is planned to be repeated 
100 times, creating several different datasets with a monotone missing data 
structure.  Seed value of 201508 will be used in the MI procedure.  The imputation is 
based on the missing at random (MAR) assumption, i.e. the missing data are assumed 
to follow the same model as the other patients in their respective treatment arm 
that have complete data. 
 
After this, the remaining missing data can be imputed using a method for monotone 
missingness, also based on the MAR assumption.  Thus, for each of the created 
datasets with a monotone missing data pattern, the MI procedure in SAS will used to 
impute missing values based on a sequential procedure reflecting the monotone 
missing data pattern.  Patients with the first missing value occurring at visit at 
Month 1 will have their missing Month 1 value replaced by an imputed value from a 
regression model with baseline value and the stratification factors as explanatory 
variables.  In the next step, patients with their Month 3 value missing will have their 
missing Month 3 value replaced by an imputed value from a regression mode with 
baseline spirometry value, stratification factors and the Month 1 value as 
explanatory variables.  Similar procedure will be used to replace the missing values 
at Month 6, 9 and 12. 
 
The imputed datasets generated with the approach described above do contain only 
non-missing values and are used as input in the model for the exploratory efficacy 
endpoint.  MMRM models similar as described above will thus be run on each of the 
generated imputed datasets.  Finally, the MIANALYZE procedure in SAS will be 
applied to combine the results from these several datasets to derive an overall 
estimate of the within-group changes. 
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10. 
INTERIM ANALYSES 
Safety data will be reviewed by a Data Safety Monitoring Committee (DSMC) that will 
include relevant medical experts (including a neurologist and pulmonologist), an 
independent statistician, and additional representatives (as will be defined in the DSMC 
Charter).  Safety data, including but not limited to AEs, spirometry, vital signs, and ECG 
data will be reviewed.  The safety review will be documented in a DSMC Charter prior 
to the start of the study.  In the event that potential safety issues are identified, the 
committee may recommend modification of the study design or study termination, 
which will be communicated promptly with investigators, IRBs, IECs, and regulatory 
agencies, in accordance with legal and regulatory requirements.   
Data summary, which will not affect study conduct, may be prepared to support 
regulatory submission. 
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11. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
There are no changes from the analyses planned in the protocol. 
 
 
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12. PROGRAMMING CONSIDERATIONS 
All tables, listings, figures (TLFs), and statistical analyses will be generated using SAS® 
for Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA) or higher. Computer-
generated table, listing and figure output produced by INC Research will adhere to the 
following specifications.   
12.1. GENERAL CONSIDERATIONS 
• 
One SAS program can create several outputs.  
• 
One output file can contain several outputs.  
• 
Output files will be delivered in Word format. 
• 
Numbering of TFLs will follow ICH E3 guidance 
12.2. TABLE, LISTING, AND FIGURE FORMAT 
12.2.1. 
General 
• 
All TLFs will be produced in landscape format, unless otherwise specified. 
• 
All TLFs will be produced using the Courier New font, size 8  
• 
The data displays for all TLFs will have a 1.5-inch binding margin on top of a 
landscape oriented page and a minimum 1-inch margin on the other 3 sides. 
• 
Headers and footers for figures will be in Courier New font, size 8. 
• 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
• 
TLFs will be in black and white (no color), unless otherwise specified. For spirometry 
graphs, separate colors will be used for ON (red circles) and OFF (blue triangles) 
State data. 
• 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified.  
• 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. 
• 
Mixed case will be used for all titles, column headers, and programmer-supplied 
formats, as appropriate. 
12.2.2. 
Headers 
• 
All output should have the following header at the top left of each page: 
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Protocol No. CVT-301-005                 Confidential 
          
• 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
• 
The date and time (date and time output was generated) should appear along with 
program name and location as the last footer on each page. 
12.2.3. 
Display Titles 
• 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
The title is centered. The title and table designation are single spaced. A solid line 
spanning the margins will separate the display titles from the column headers. There 
will be 1 blank line between the last title and the solid line. 
12.2.4. 
Column Headers 
• 
Column headings should be displayed immediately below the solid line described 
above.  
• 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of patients in the analysis set. 
• 
The order of treatments in the tables will be Placebo first, followed by CVT-301 and 
a total column (if applicable in tables). 
12.2.5. 
Body of the Data Display 
12.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
 
12.2.5.2. Table Conventions 
• 
Units will be included where available 
• 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
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standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
X.XX 
Median 
XXX.X 
Minimum 
XXX, 
Maximum 
XXX 
• 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value is returned as >0.999 then present as >0.999. 
• 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count, e.g., 7 (12.8%), 13 (5.4%). For a value that rounds 
down to 0.0, display it as “<0.1”. Unless otherwise noted, for all percentages, the 
number of patients in the analysis set for the treatment group who have an 
observation will be the denominator. Percentages after zero counts should not be 
displayed and percentages equating to 100% should be presented as 100%, without 
any decimal places.  
 
12.2.5.3. Listing Conventions 
• 
Listings will be sorted for presentation in order of patient number, visit/collection 
day, and visit/collection time. 
• 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on patient listings as dashes (--JUL2000).  
• 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26).  
 
12.2.6. 
Footnotes 
• 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
• 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
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• 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date and time the program 
was run.  
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13. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 
03.010.00 and 03.013.00 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009.00 describes the quality control procedures that are 
performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs 
produce the proper clinical trial output by checking for their logic, efficiency and 
commenting and by review of the produced output. 
 
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14. 
INDEX OF TABLES 
Table 14.1.1.1 
Number of Subjects Enrolled and Study Termination  (All Available Population)  
Table 14.1.1.2 
Number of Subjects in Each Population by Study Center All Subjects 
 
Table 14.1.2.1 
Summary of Protocol Deviation  Randomized Set 
 
Table 
14.1.3.1.1 
Demographic and Baseline Characteristics  (Safety Population)  
Table 
14.1.3.1.2   
Demographic and Baseline Characteristics  (ITT Population) 
 
Table 
14.1.3.1.3 
Demographic and Baseline Characteristics by Baseline PD Severity (ITT 
Population) 
 
Table 
14.1.3.1.4 
Demographic and Baseline Characteristics by Baseline Dyskinesia  (ITT 
Population) 
 
Table 
14.1.3.1.5 
Demographic and Baseline Characteristics by Baseline Daily Levodopa Dose (ITT 
Population) 
 
Table 
14.1.3.1.6 
Demographic and Baseline Characteristics by PD Diary Mean Daily OFF Time 
during Screening (ITT Population) 
 
Table 
14.1.3.1.7 
Demographic and Baseline Characteristics by Screening Spirometry  (ITT 
Population) 
 
Table 
14.1.3.1.8 
Demographic and Baseline Characteristics by Age Group (ITT Population) 
 
Table 
14.1.3.1.9 
Demographic and Baseline Characteristics by Gender (ITT Population) 
 
Table 
14.1.3.2.1 
Parkinson’s Disease History (Safety Population)  
Table 
14.1.3.2.2 
Parkinson’s Disease History (ITT Population) 
 
Table 
14.1.3.2.3 
Parkinson’s Disease History by Baseline PD Severity (ITT Population) 
 
Table 
14.1.3.2.4 
Parkinson’s Disease History by Baseline Dyskinesia  (ITT Population) 
 
Table 
14.1.3.2.5 
Parkinson’s Disease History by Baseline Daily Levodopa Dose (ITT Population) 
 
Table 
14.1.3.2.6 
Parkinson’s Disease History by PD Diary Mean Daily OFF Time during Screening 
(ITT Population) 
 
Table 
14.1.3.2.7 
Parkinson’s Disease History by Screening Spirometry  (ITT Population) 
 
Table 
14.1.3.2.8 
Parkinson’s Disease History by Age Group (ITT Population) 
 
Table 
14.1.3.2.9 
Parkinson’s Disease History by Gender (ITT Population)  
Table 
14.1.3.2.10 
Modified Hoehn and Yahr Staging in “ON” State (Safety Population) 
 
Table 
14.1.3.2.11 
Modified Hoehn and Yahr Staging in “ON” State (ITT Population) 
Table 
Distribution of Average Daily OFF Time (Safety Population) 
 
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14.1.3.2.12   
Table 
14.1.3.2.13 
Distribution of cumulative Average Daily OFF Time (Safety Population)  
Table 14.1.3.3 
Medical History  (Safety Population) 
 
Table 14.1.4.1 
Prior Medications  (Safety Population)  
Table 14.1.4.2 
Concomitant Medications  (Safety Population)  
Table 14.1.4.3 
Parkinson’s disease Treatment Medications at Baseline (ITT Population)  
Table 14.2.1.1 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 
10 Minutes Post-dose by Visit (ITT Population)  
Table 14.2.1.2 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 
20 Minutes Post-dose by Visit (ITT Population)  
Table 
14.2.1.3.1 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 
30 Minutes Post-dose by Visit (ITT Population)  
Table 
14.2.1.3.2 
Sensitivity Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 30 
Minutes Post-dose by Visit (ITT Population) 
 
Table 
14.2.1.3.3 
Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 
3 Score at 30 Minutes Post-dose by Visit by Baseline PD Severity  (ITT Population)
 
 
Table 
14.2.1.3.4 
Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 
3 Score at 30 Minutes Post-dose by Visit by Baseline Dyskinesia (ITT Population)  
Table 
14.2.1.3.5   
Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 
3 Score at 30 Minutes Post-dose by Visit by Baseline Daily Levodopa Dose  (ITT 
Population)  
Table 
14.2.1.3.6  
Exploratory Efficacy Subgroup Analysis: Change from Pre-dose in the UPDRS Part 
3 Score at 30 Minutes Post-dose by Visit by PD Diary Mean Daily OFF Time during 
Screening  (ITT Population) 
 
Table 
14.2.1.3.7 
Exploratory Efficacy Exploratory Efficacy Subgroup Analysis: Change from Pre-
dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Screening 
Spirometry  (ITT Population) 
 
Table 
14.2.1.3.8 
Exploratory Efficacy Exploratory Efficacy Subgroup Analysis: Mean Change from 
Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Age Group 
(ITT Population) 
 
Table 
14.2.1.3.9   
Exploratory Efficacy Exploratory Efficacy Subgroup Analysis: Mean Change from 
Pre-dose in the UPDRS Part 3 Score at 30 Minutes Post-dose by Visit by Gender  
(ITT Population) 
 
Table 14.2.1.4 
Exploratory Efficacy Analysis: Change from Pre-dose in the UPDRS Part 3 Score at 
60 Minutes Post-dose by Visit (ITT Population)  
Table 14.2.1.5 
 Exploratory Efficacy Analysis:  Change from Pre-dose in the Average UPDRS Part 
3 Score at 10 to 60 Minutes Post-dose by Visit (ITT Population)  
Table 14.2.2.1 
 Exploratory Efficacy Analysis: Change from Pre-dose in UPDRS Part 3 Score to 10, 
20, 30, 60 minutes Post-dose by Visit (ITT Population)  
Table 14.2.2.2 
 Exploratory Efficacy Analysis: Change from Pre-Dose to 10, 20, 30, 60 minutes 
Post-dose in UPDRS Part 3 Score by Visit and Timepoint  (ITT Population) 
  
Table 14.2.2.3 
 Exploratory Efficacy Analysis: Change from Pre-Dose to 10, 20, 30, 60 minutes 
Post-dose in UPDRS Part 3 Score by Timepoint and Visit  (ITT Population) 
  
Table 14.2.3.1 
Exploratory Efficacy Analysis Subjects with a >=3 Reduction from Pre-dose to 
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Post-dose in the UPDRS Part 3 Score by Visit (ITT Population)  
Table 14.2.3.2 
Exploratory Efficacy Analysis Subjects with a >=3 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit With Percentages Based on N  (ITT 
Population) 
  
Table 14.2.3.3 
Exploratory Efficacy Analysis Subjects with a >=6 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit (ITT Population)  
Table 14.2.3.4 
Exploratory Efficacy Analysis Subjects with a >=6 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit With Percentages Based on N  (ITT 
Population)   
Table 14.2.3.5   Exploratory Efficacy Analysis Subjects with a >=11 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit (ITT Population)  
Table 14.2.3.6 
Exploratory Efficacy Analysis Subjects with a >=11 Reduction from Pre-dose to 
Post-dose in the UPDRS Part 3 Score by Visit With Percentages Based on N  (ITT 
Population) 
  
Table 14.2.4.1 
 Exploratory Efficacy Analysis: Subjects Achieving Resolution of an OFF to an ON 
State within 60 Minutes by Visit Worst Case Imputation [a] (ITT Population) 
 
Table 
14.2.5.1.1    
Exploratory Efficacy Analysis: Mean of Total Daily OFF Time by Visit (ITT 
Population) 
 
Table 
14.2.5.1.2    
Sensitivity Analysis: Mean of Total Daily OFF Time by Visit MI analysis with Missing 
At Random Assumption  (ITT Population 
Table 
14.2.5.1.3 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Baseline PD Severity  (ITT Population)  
Table 
14.2.5.1.4 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Baseline Dyskinesia (ITT Population) 
 
Table 
14.2.5.1.5 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Baseline Daily Levodopa Dose (ITT Population)  
Table 
14.2.5.1.6 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
PD Diary Mean Daily OFF Time during Screening (ITT Population) 
 
Table 
14.2.5.1.7 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Screening Spirometry  (ITT Population)  
Table 
14.2.5.1.8 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Age Group (ITT Population) 
 
Table 
14.2.5.1.9 
Exploratory Efficacy Subgroup Analysis: Mean of Total Daily OFF Time by Visit by 
Gender (ITT Population) 
 
Table 14.2.5.2 
Exploratory Efficacy Analysis: Mean of Total Daily ON Time without Dyskinesia by 
Visit (ITT Population) 
Table 14.2.5.3 
Exploratory Efficacy Analysis: Mean of Total Daily ON Time with non-Troublesome 
Dyskinesia by Visit (ITT Population) 
Table 14.2.5.4 
Exploratory Efficacy Analysis: Mean of Total Daily ON Time with Troublesome 
Dyskinesia by Visit (ITT Population) 
Table 14.2.6.1 
Exploratory Efficacy Analysis: Subjects Global Impression of Change (PGI-C) by 
Visit  Worst Case Imputation [a] (ITT Population) 
 
Table 14.2.7.1 
Exploratory Efficacy Analysis:  UPDRS Part 2 Score at TV4/OV4 (ITT Population)   
Table 14.2.7.2   Exploratory Efficacy Analysis:  UPDRS Part 2 Score at TV6/OV6  (ITT Population)   
Table 14.2.8.1 
Exploratory Efficacy Analysis:  Schwab and England (S&E) Activities of Daily 
Living (ADL) Score at TV4/OV4 (ITT Population)   
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Table 14.2.8.2 
Exploratory Efficacy Analysis: Schwab and England (S&E) Activities of Daily Living 
(ADL) Score at TV6/OV6 (ITT Population) 
  
Table 14.2.9.1 
Exploratory Efficacy Analysis:  39 Item Parkinson's disease Questionnaire (PDQ-
39) Sub-scores and Summary Index Score at TV4/OV4 (ITT Population)   
Table 14.2.9.2 
Exploratory Efficacy Analysis: 39 Item Parkinson's disease Questionnaire (PDQ-39) 
Sub-scores and Summary Index Score at TV6/OV6 (ITT Population) 
  
Table 14.3.1.1   Extent of Exposure: Overall  (Safety Population)  
Table 14.3.1.2   In-Clinic Study Drug Administration  (Safety Population)   
Table 14.3.1.3 
Distribution of Time of Study Drug Administration (Safety Population) 
  
Table 14.3.2.1   Treatment-emergent adverse events -Overall Summary  (Safety Population) 
  
Table 
14.3.2.2.1 
Treatment-emergent adverse events by System Organ Class and Preferred Term  
(Safety Population)  
Table 
14.3.2.2.2   
Treatment-emergent adverse events by Preferred Term  (Safety Population)   
Table 
14.3.2.2.3 
Number of Treatment-Emergent Adverse Events per Subject-year by System 
Organ Class and Preferred Term  (Safety Population) 
Table 14.3.2.3 
Drug-Related Treatment-emergent adverse events by System Organ Class, 
Preferred Term and Severity  (Safety Population) 
  
Table 14.3.2.4 
Drug –Related Treatment-emergent adverse events by System Organ Class, 
Preferred Term and Relationship  (Safety Population) 
  
Table 14.3.2.5   Drug-related Treatment-emergent adverse events by System Organ Class and 
Preferred Term  (Safety Population) 
  
Table 14.3.2.6 
Serious Treatment-emergent adverse events by System Organ Class and Preferred 
Term  (Safety Population) 
  
Table 14.3.2.7 
Listing of Serious Adverse Events 
  
Table 14.3.2.8 
Listing of Adverse Events Leading to Death 
  
Table 14.3.2.9 
Severe Treatment-emergent adverse events by System Organ Class and Preferred 
Term  (Safety Population) 
  
Table 
14.3.2.10 
Listing of Severe Treatment-Emergent Adverse Events   
Table 
14.3.2.11 
Treatment-emergent adverse events Leading to Study Drug Interruption by 
System Organ Class and Preferred Term  (Safety Population) 
  
Table 
14.3.2.12   
Listing of Adverse Events Leading to Study Drug Interruption 
  
Table 
14.3.2.13 
Treatment-emergent adverse events Leading to Study Drug Discontinuation by 
System Organ Class and Preferred Term  (Safety Population) 
 
Table 
14.3.2.14 
Listing of Adverse Events Leading to Study Drug Discontinuation   
Table 
14.3.2.15 
Treatment-emergent adverse events Leading to Dose Reduction by System Organ 
Class and Preferred Term  (Safety Population)   
Table 
14.3.2.16 
Listing of Adverse Events Leading to Dose Reduction 
  
Table 
14.3.2.17 
Most Common Treatment-Emergent Adverse Events (Preferred Term Occurred in 
>10% of Over Patients) by System Organ Class and Preferred Term (Safety 
Population) 
Table 
Listing of Most Common Treatment-Emergent Adverse Events 
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14.3.2.18 
Table 
14.3.2.19 
Time to first Onset of most Common Treatment-Emergent Adverse Events 
(Preferred Term Occurred in >10% of Over Patients) (Safety Population) 
Table 14.3.4.1 
Clinical Laboratory Results: PCS and PCSC Criteria 
  
Table 
14.3.4.1.1.1 
Summary of Clinical Laboratory Results: Hematology (Safety Population) 
  
Table 
14.3.4.1.1.2 
Summary of Clinical Laboratory Results: Hematology Abnormal Values (Safety 
Population) 
  
Table 
14.3.4.1.1.3 
Summary of Clinical Laboratory Results: Hematology Abnormal Values –Shift from 
Baseline (Safety Population) 
  
Table 
14.3.4.1.1.4 
Summary of Clinical Laboratory Results: Hematology PCS Values –Shift from 
Baseline (Safety Population) 
  
Table 
14.3.4.1.1.5 
Summary of Clinical Laboratory Results: Hematology PCSC Values –Shift from 
Baseline (Safety Population) 
  
Table 
14.3.4.1.1.6 
Clinical Laboratory Results – Hematology PCS and PCSC Values (Safety Population)
 
  
Table 
14.3.4.1.2.1 
Summary of Clinical Laboratory Results: Chemistry (Safety Population)   
Table 
14.3.4.1.2.2 
Summary of Clinical Laboratory Results: Chemistry Abnormal Values (Safety 
Population) 
  
Table 
14.3.4.1.2.3 
Summary of Clinical Laboratory Results: Chemistry Abnormal Values –Shift from 
Baseline (Safety Population) 
  
Table 
14.3.4.1.2.4   
Summary of Clinical Laboratory Results: Chemistry PCS Values –Shift from 
Baseline (Safety Population) 
  
Table 
14.3.4.1.2.5 
Summary of Clinical Laboratory Results: Chemistry PCSC Values –Shift from 
Baseline (Safety Population) 
  
Table 
14.3.4.1.2.6 
Clinical Laboratory Results – Chemistry PCS and PCSC Values  (Safety Population)
 
  
Table 14.3.4.2 
Vital Signs: PCS and PCSC Criteria 
  
Table 
14.3.4.2.1 
Summary of Vital Signs: Actual Values and Change from Baseline across Visits  
(Safety Population)  
Table 
14.3.4.2.2 
Summary of Vital Signs: Actual Values and Change from Pre-dose at TV1 (Safety 
Population) 
  
Table 
14.3.4.2.3 
Summary of Standard Vital Signs: PCS and PCSC Values by Visit (Safety 
Population) 
  
Table 
14.3.4.2.4 
Summary of Standard Vital Signs: PCS and PCSC Values by Scheduled Timepoint at 
TV1 (Safety Population)   
Table 
14.3.4.2.5   
Standard Vital Signs: PCS and PCSC Values 
  
Table 
14.3.4.2.6 
Summary of Vital Signs: Orthostatic Hypotension by Visit  (Safety Population) 
  
Table 
14.3.4.2.7 
Summary of Vital Signs: Orthostatic Hypotension by Scheduled Timepoint at TV1  
(Safety Population)  
Table 
14.3.4.2.8   
Orthostatic Vital Signs   
Table 14.3.4.3 
12-Lead ECG:PCS and PCSC Criteria 
  
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Table 
14.3.4.3.1 
Summary of 12-Lead ECG: Actual Values and Change across Visits  (Safety 
Population) 
  
Table 
14.3.4.3.2 
Summary of 12-Lead ECG: PCS and PCSC Values  (Safety Population) 
  
Table 
14.3.4.3.3 
12-Lead Electrocardiogram (ECG): PCS and PCSC Values   
Table 14.3.4.4 
Physical Examination  (Safety Population) 
  
Table 
14.3.4.5.1.1 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and Change 
from Baseline for FEV1 and FVC by Visit  (Safety Population) 
  
Table 
14.3.4.5.1.2 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and Change 
from Baseline for FEV1 and FVC by Visit  Using Subset of Assessments Meeting the 
ATS Quality Criteria (Safety Population)   
Table 
14.3.4.5.1.3 
Summary of Spirometry(Pulmonary Function Facility: Actual Values and Change 
from Baseline for FEV1 and FVC by Visit Excluding Patients with Co-efficient of 
Variation (CV) of FEV1 >7.5% (Safety Population) 
  
Table 
14.3.4.5.1.4 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change from 
Baseline for FEV1 by Visit  (Safety Population) 
Table 
14.3.4.5.1.5 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change from 
Baseline for FEV1 by Visit Using Subset of Assessments Meeting the ATS Quality 
Criteria (Safety Population) 
Table 
14.3.4.5.1.6 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change from 
Baseline for FEV1 by Visit Excluding Patients with Co-efficient of Variation (CV) 
of FEV1 >7.5% (Safety Population) 
Table 
14.3.4.5.1.7 
Sensitivity Analysis Using MMRM: Change from Baseline for FEV1 by Visit MI 
analysis with Missing At Random Assumption  (Safety Population) 
Table 
14.3.4.5.1.8 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change 
from Baseline for Calculated DLco Parameters by Visit (Safety Population) 
Table 
14.3.4.5.1.9 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change 
from Baseline for Calculated DLco Parameters by Visit Using Subset of 
Assessments Meeting the ATS Quality Criteria (Safety Population) 
Table 
14.3.4.5.1.10 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change 
from Baseline for Calculated DLco Parameters by Visit Excluding Patients with 
Co-efficient of Variation (CV) of FEV1 >7.5% (Safety Population) 
Table 
14.3.4.5.1.11 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change from 
Baseline for DLCO by Visit  (Safety Population) 
Table 
14.3.4.5.1.12 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change from 
Baseline for DLCO by Visit Using Subset of Assessments Meeting the ATS Quality 
Criteria (Safety Population) 
Table 
14.3.4.5.1.13 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change from 
Baseline for DLCO by Visit Excluding Patients with Co-efficient of Variation (CV) 
of FEV1 >7.5% (Safety Population) 
Table 
14.3.4.5.1.14 
Sensitivity Analysis Using MMRM: Change from Baseline for DLCO by Visit MI 
analysis with Missing At Random Assumption  (Safety Population) 
Table 
14.3.4.5.1.15 
Summary of Spirometry (Pulmonary Function Facility): Categories of Change from 
Baseline for FEV1 and FVC by  Visit (Safety Population) 
Table 
Summary of Spirometry (Pulmonary Function Facility): Categories of Change from 
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14.3.4.5.1.16 
Baseline for DLCO by  Visit (Safety Population) 
Table 
14.3.4.5.1.17 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and Change 
from Baseline for FEV1 by Visit and by Smoker Status (Safety Population) 
Table 
14.3.4.5.1.18 
Summary of Spirometry (Pulmonary Function Facility): Categories of Percent 
Change from Baseline for FEV1 by Visit and Smoker Status (Safety Population) 
Table 
14.3.4.5.2.1 
Summary of Spirometry:( Pulmonary Function Facility):): Actual Values and 
Change from Baseline for FEV1/FVC by Visit  (Safety Population) 
  
Table 
14.3.4.5.2.2 
Summary of Spirometry:( Pulmonary Function Facility):): Actual Values and 
Change from Baseline for FEV1/FVC by Visit  Using Subset of Assessments Meeting 
the ATS Quality Criteria (Safety Population) 
  
Table 
14.3.4.5.2.3 
Summary of Spirometry:( Pulmonary Function Facility):): Actual Values and 
Change from Baseline for FEV1/FVC by Visit  Excluding Patients with Co-efficient 
of Variation (CV) of FEV1 >7.5% (Safety Population) 
  
Table 
14.3.4.5.2.4 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility):): Change from 
Baseline for FEV1/FVC by Visit  (Safety Population) 
Table 
14.3.4.5.2.5 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility):): Change from 
Baseline for FEV1/FVC by Visit  Using Subset of Assessments Meeting the ATS 
Quality Criteria (Safety Population) 
Table 
14.3.4.5.2.6 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility):): Change from 
Baseline for FEV1/FVC by Visit Excluding Patients with Co-efficient of Variation 
(CV) of FEV1 >7.5% (Safety Population) 
Table 
14.3.4.5.2.7 
Sensitivity Analysis Using MMRM: Change from Baseline for FEV1/FVC by Visit MI 
analysis with Missing At Random Assumption  (ITT Population) 
Table 
14.3.4.5.2.8 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change from 
Baseline for FEV1/FVC by  Visit (Safety Population) 
Table 
14.3.4.5.3.1 
Summary of Spirometry (Pulmonary Function Facility): Summary of FEV1/FVC < 
60% and <70% by Visit  (Safety Population)  
Table 
14.3.4.5.3.2 
Summary of Spirometry (Pulmonary Function Facility): Summary of FEV1/FVC < 
60% and <70% by Visit Using Subset of Assessments Meeting the ATS Quality 
Criteria (Safety Population)  
Table 
14.3.4.5.3.3 
Summary of Spirometry (Pulmonary Function Facility): Summary of FEV1/FVC < 
60% and <70% by Visit Excluding Patients with Co-efficient of Variation (CV) of 
FEV1 >7.5% (Safety Population)  
Table 
14.3.4.5.4 
Spirometry(Pulmonary Function Facility): 70% or Smaller FEV1/FVC Values and 
>=200 Reduction from Pre-dose  
Table 
14.3.4.5.5 
Summary of Spirometry(Pulmonary Function Facility): Measurements Meeting ATS 
Quality Criteria (Safety Population)  
Table 
14.3.4.5.6 
Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1 and FVC by Visit  (Safety Population)   
Table 
14.3.4.5.7 
Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1/FVC by Visit  (Safety Population) 
  
Table 
14.3.4.5.8 
Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% and 
<70%by Visit (Safety Population)  
Table 
14.3.4.5.9 
Spirometry(Neurology Office):70% or Smaller FEV1/FVC Values by Visit  
Table 
Summary of Spirometry(Neurology Office): Measurements Meeting ATS Quality 
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14.3.4.5.10 
Criteria  (Safety Population)  
Table 
14.3.4.5.11 
Summary of Spirometry (Pulmonary Function Facility): Categories of Change from 
Baseline for FEV1 and FVC by  Visit (Safety Population 
Table 
14.3.4.5.12 
Summary of Spirometry (Pulmonary Function Facility): Categories of Change from 
Baseline for FEV1/FVC by  Visit (Safety Population) 
Table 
14.3.4.5.13 
 
Summary of Spirometry (Neurology Office): Actual Values and Change from 
Baseline for FEV1 by Visit and by Smoker Status (Safety Population) 
Table 
14.3.4.5.14 
 
Summary of Spirometry (Neurology Office): Categories of Percent Change from 
Baseline for FEV1 by Visit and Smoker Status (Safety Population) 
Table 
14.3.4.6.1 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) (Safety Population)
 
  
Table 
14.3.4.6.2 
Shift from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) (Safety 
Population)  
Table 14.3.4.7 
Summary of Epworth Sleepiness Scale Total Score: Actual Values and Change 
from Baseline by Visit (Safety Population)  
Table 14.3.4.8 
Summary of Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
(QUIP) by Visit (Safety Population)  
Table 
14.3.4.9.1 
MMRM Analysis of UPDRS Part 4: Change from Baseline in the UPDRS Part 4 Score 
at TV4 (Safety Population)  
Table 
14.3.4.9.2 
 MMRM Analysis of UPDRS Part 4 Dyskinesias Score: Change from Baseline in the 
UPDRS Part 4 Score at TV4  (Safety Population)   
Table 
14.3.4.9.3 
 MMRM Analysis of UPDRS Part 4 Fluctuations Score: Change from Baseline in the 
UPDRS Part 4 Score at TV4  (Safety Population)   
Table 
14.3.4.9.4 
Summary of UPDRS Part 4: Actual Values and Change from Baseline by Visit  
(Safety Population) 
  
Table 
14.3.4.9.5 
Summary of UPDRS Part 4 Dyskinesias Score: Actual Values and Change from 
Baseline by Visit  (Safety Population) 
  
Table 
14.3.4.9.6 
Summary of UPDRS Part 4 Fluctuations Score: Actual Values and Change from 
Baseline by Visit  (Safety Population) 
  
Table 
14.3.4.10 
Dyskinesia: Occurrence and Severity (In-clinic) by Visit  (ITT Population)   
 
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15. 
INDEX OF LISTINGS 
Listing 16.2.1 
 Patient Disposition 
  
Listing 16.2.2.1 
 Protocol Deviations 
  
Listing 16.2.3.1 
Inclusion Criteria not Met at Screening   
Listing 16.2.3.2 
Exclusion Criteria Met at Screening 
  
Listing 16.2.3.3 
 Analysis Populations 
  
Listing 16.2.4.1 
 Demographics   
Listing 16.2.4.2 
 Medical History  
Listing 16.2.4.3 
 Parkinson’s Disease History 
  
Listing 16.2.4.4 
 Smoking History 
  
Listing 16.2.4.5 
 ON and OFF Concordance Testing at Screening   
Listing 16.2.4.6 
 Modified Hoehn and Yahr Staging in “ON” State at Screening 
  
Listing 16.2.4.7 
 Mini Mental State Examination (MMSE) at Screening 
  
Listing 16.2.4.8 
 Parkinson’s Disease Diary Data at Screening: Derived Time 
  
Listing 16.2.4.9 
 Screening ON/OFF Log   
Listing 16.2.4.10 
 Randomization   
Listing 16.2.4.11.1 
 Prior and Concomitant Medications 
  
Listing 16.2.4.11.2 
 Parkinson’s disease Treatment Medications at Baseline   
Listing 16.2.4.12 
 Baseline Pulmonary Assessment Part 2 - Pulmonary History 
  
Listing 16.2.4.13 
 Baseline Pulmonary Assessment Part 3 - Assessments of Symptoms 
  
Listing 16.2.5.1.1 
 Study Drug Administration: in Clinic and at Home 
  
Listing 16.2.5.1.2 
 Study Drug Administration: Derived Variables (in Clinic)  
Listing 16.2.5.1.3 
 Study Drug Administration: Derived Variables (Overall)   
Listing 16.2.5.1.4 
 Study Drug Administration: Derived Variables (Overall by Visit)   
Listing 16.2.5.1.5 
 Listing of Study Drug Dose Change 
  
Listing 16.2.5.2 
 Study Drug Kit Dispensation 
  
Listing 16.2.5.3 
 Daily Levodopa Dose 
  
Listing 16.2.6.1.1 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 
  
Listing 16.2.6.1.2 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3: Derived 
Variables 
  
Listing 16.2.6.2.1 
 Clinic Assessment 
  
Listing 16.2.6.2.2 
 Parkinson’s Disease Diary Data   
Listing 16.2.6.2.3.1 
Parkinson’s Disease Diary Data – Derived Variable by Dairy Date   
Listing 16.2.6.2.3.2 
Parkinson’s Disease Diary Data – Derived Variable by Visit 
  
Listing 16.2.6.2.4 
Patient’s Global Impression of Change (PGI-C)   
Listing 16.2.6.2.5   
Impact of Parkinson’s OFF Episodes 
  
Listing 16.2.6.3.1 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 2   
Listing 16.2.6.3.2 
Listing of S&E Activities of Daily Living   
Listing 16.2.6.3.3 
39 Item Parkinson's Disease Questionnaire (PDQ-39) 
  
Listing 16.2.7.1 
Adverse Events   
Listing 16.2.8.1.1 
Clinical Laboratory Results - Hematology 
  
Listing 16.2.8.1.2 
Clinical Laboratory Results – Chemistry   
Listing 16.2.8.1.3 
Serum Pregnancy Test – Positive Only 
  
Listing 16.2.8.2.1 
Vital Signs 
  
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Listing 16.2.8.2.2 
12-Lead Electrocardiogram (ECG) 
  
Listing 16.2.8.2.3 
Physical Examination 
  
Listing 16.2.8.2.4.1 
Spirometry( Neurology Office)   
Listing 16.2.8.2.4.2 
Spirometry( Neurology Office) Measurements Not Meeting ATS Quality 
Criteria   
Listing 16.2.8.2.4.3 
Spirometry(Pulmonary Function Facility): DLCO Parameters 
  
Listing 16.2.8.2.4.4 
 Spirometry(Pulmonary Function Facility): Spirometry/DLCO Measurements 
Not Meeting ATS Quality Criteria 
  
Listing 16.2.8.2.5.1 
Columbia-Suicide Severity Rating Scale (C-SSRS)   
Listing 16.2.8.2.5.2 
Columbia-Suicide Severity Rating Scale (C-SSRS)  - Subject Answered ‘Yes’ 
to any Questions    
Listing 16.2.8.2.6 
Epworth Sleepiness Scale 
  
Listing 16.2.8.2.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP)   
Listing 16.2.8.2.8.1 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4 
  
Listing 16.2.8.2.8.2 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4: Derived 
Variables 
  
Listing 16.2.8.2.9 
 Telephone Contact: Challenges with Inhaler or Capsules Data   
 
 
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16. 
INDEX OF FIGURES 
Not Applicable. 
 
 
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Abuse Assessment Methodology and Adverse Event Terms 
A pre-NDA meeting was held with the Agency on 28 September 2016 (see FDA pre-NDA 
Meeting Minutes) to gain agreement on the adequacy of the nonclinical and clinical program and 
content and format and assessment of abuse potential for the 505(b)(2) NDA for CVT-301. In the 
CVT-301 Pre-NDA Meeting Package submitted to IND 115750 in Sequence 086 on 25 August 
2016, Acorda provided a Draft Abuse Potential Assessment report and indicated that abuse 
related adverse event terms were assessed based on the terms published by Love and Sun (2013) 
for the completed clinical studies and for the clinical study reports and Integrated Summary of 
Safety for the ongoing clinical studies.  In the CVT-301 pre-NDA Meeting minutes regarding 
question 4a, “Does the Division agree with the plan for assessment and reporting of abuse 
potential?” The Division indicated in the FDA Response to Question 4a, point 5, that the 
following AE terms were of particular interest: 
 
“5.  
Because abuse of levodopa is mainly known in the population of patients with PD, 
your Abuse Potential Assessment Report, in which you plan to include the analysis of 
published literature, should include the following items:   
•  
Populations: analysis should to be performed separately for PD patients and 
healthy  
subjects   
•  
For the PD study population, the following adverse events are of particular 
interest:  
abuse, misuse, withdrawal, dependence, dopamine dysregulation 
syndrome,  
hedonistic homeostatic dysregulation, euphoria, high, overdose, misuse, 
diversion,  
hoarding of medication, neuroleptic malignant syndrome, hyperpyrexia 
and  
confusion, rebound 
 
6.  Search and analysis of adverse events from your clinical data and the post-marketing 
data for levodopa formulations in publically available data bases should include and use 
the same search terms listed above in point 5.” 
 
In 2016 the International Society for Central Nervous System Clinical Trials and Methodology 
(ISCTM) recommended a list of 41 adverse event terms for assessment of abuse potential 
(Setnik 2016).  Subsequent to the Pre-NDA meeting the FDA also issued a new Final Guidance, 
FDA Guidance for Industry: Assessment of Abuse Potential of Drugs (January 2017) that 
included 19 adverse event terms for assessment of abuse potential. Therefore, based on the FDA 
recommendations and more recent publications, Acorda has modified its methodology for 
assessment of abuse potential based on the list of 213 adverse event terms published by Love and 
Sun (2013). Instead, Acorda is using a shorter more focused composite list of 73 adverse event 
terms including the 15 terms recommended by FDA in the CVT-301 FDA pre-NDA Meeting 
Minutes (October 2016), the 19 terms from the new FDA Guidance for Industry: Assessment of 
Abuse Potential of Drugs (January 2017) and the 41 terms recommended by ISCTM (Setnik 
2016). Note, two terms (euphoria and drug withdrawal) are repeated in two of the lists. All of 
these terms except hedonistic hemostatic dysregulation have been converted into MedDRA, 
Version 19.0 Preferred Terms (PT).  Because there was no MedDRA conversion term for the 
verbatim term hedonistic hemostatic dysregulation it was included in the composite list of 73 
MedDRA terms. The MedDRA PT may provide abuse-related information about a drug, and 
 
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were used for assessment of abuse related adverse events in the CVT-301 clinical studies and 
Integrated Summary of Safety. The verbatim adverse event terms and MedDRA PT are provided 
in Table 1. 
Table 1: 
Drug Adverse Event Terms for Abuse Potential Assessment of CVT-301 
Safety Data  
15 Adverse Event Terms From CVT-301 Pre-NDA Meeting Minutes, page 5, FDA 
Response to Question 4b, Item 5  (October 2016) 
 
Abuse, misuse, withdrawal, dependence, dopamine dysregulation syndrome, hedonistic 
homeostatic dysregulation, euphoria, high, overdose, diversion, hoarding of medication, 
neuroleptic malignant syndrome, hyperpyrexia, confusion, rebound 
 
 
19 Adverse Event Terms From FDA Guidance for Industry: Assessment of Abuse Potential 
of Drugs (January 2017) 
 
Euphoric mood, elevated mood, feeling abnormal, feeling drunk, feeling of relaxation, dizziness, 
thinking abnormal, hallucination, inappropriate affect, somnolence, mood disorders and 
disturbances, psychosis, aggression, confusion, disorientation, drug tolerance, habituation, drug 
withdrawal syndrome, substance related disorders 
 
41 Adverse Event Terms From Setnik, B. A Consensus List Proposal For Adverse Events 
Related To Abuse And Dependence Potential (Setnik 2016)  
 
Abnormal behavior, abnormal thinking, agitation, cognition disorder, concentration impaired, 
concentration loss, confusion and disorientation, confusional state, delirium, delusional disorder 
unspecified type, detachment, disturbance in attention, elation inappropriate, elevated mood, 
emotional disorder, euphoria/euphoric mood, exhilaration inappropriate, feeling abnormal, 
feeling drunk, feeling happy inappropriately, flight of ideas, hallucination(visual and auditory), 
inappropriate affect, inappropriate, elation, inappropriate, laughter, inappropriate mood, 
elevation, irritability, memory impairment, mental disorder 
 
 
 
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MedDRA Preferred Terms based on the composite list of 73 Adverse Event Terms 
Abnormal behavior, acute psychosis, aggression, agitation, cognitive disorder, confusional state, 
delirium, delirium tremens, delusional disorder unspecified type, delusional perception, 
dependence, disorientation, dissociation, disturbance in attention, dizziness, dopamine 
dysregulation syndrome, drug abuse, drug abuser, drug dependence, drug diversion, drug 
tolerance, drug withdrawal convulsions, drug withdrawal syndrome, elevated mood, emotional 
disorder, euphoric mood, feeling abnormal, feeling drunk, feeling of relaxation, flight of ideas, 
hallucination, hallucination auditory, hallucination gustatory, hallucination mixed, hallucination 
olfactory, hallucination synanesthetic, hallucination tactile, hallucination visual, hedonistic 
homeostatic dysregulationa, hyperpyrexia, inappropriate affect, intentional overdose, intentional 
product misuse, irritability, medication overuse headache, memory impairment, mental disorder, 
mental impairment, mood altered, mood swings, neuroleptic malignant syndrome, overdose, 
paranoia, parkinsonism hyperpyrexia syndrome, psychosis, psychotic disorder, reactive 
psychosis, rebound psychosis, rebound tachycardia, sedation, sensory disturbance, somnolence, 
stupor, substance abuse, substance abuse psychotic disorder, substance abuser, substance 
dependence, substance-induced mood disorder, substance-induced psychotic disorder, thinking 
abnormal, thought withdrawal, withdrawal hypertension, withdrawal syndrome 
 
a 
There is no MedDRA PT for “hedonistic hemostatic dysregulation” listed in the pre-NDA 
Meeting Minutes, page 5, FDA Response to Question 4b, Item 5 (October 2016) and it was included in 
the list of MedDRA PT for completeness. 
 
References 
 
Acorda Therapeutics, Inc., CVT-301 Type B Pre-NDA FDA Meeting Minutes dated 27 October 
2016. 
FDA Guidance for Industry: Assessment of Abuse Potential of Drugs January 2017. 
 
 
Love LA, Sun S. Proposed query to capture abuse-related adverse events. Paper presented at the 
annual meeting of the College on Problems of Drug Dependence. San Diego, CA: June 15- 20, 
2013. 
Setnik, B. A consensus list proposal for adverse events related to abuse and dependence potential, 
February 16, 2016, International society for CNS clinical trials and methodology (ISCTM) 12th 
Annual Scientific Meeting, The Fairmont, Washington, DC, February 16, 2016. 
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