Clinical trial NCT02242487
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: 2018-05-01
Enrollment: 325 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a 12-month, dose-level blinded, multicenter study of 2 inhaled dose levels of CVT-301 for the treatment of up to 5 OFF episodes per day in PD patients experiencing motor fluctuations (OFF episodes). All patients will receive active treatment, but patients will be blinded to dose level. This will serve as an extension to the CVT-301-004 (NCT02240030) study for those patients who participated in that study and remain eligible for this study. In addition, patients who previously completed the CVT-301-003 (NCT01777555), CVT-301-009 (NCT02807675) and CVT-301-005 (NCT02352363) (observational arm completers), as well as CVT-301 naïve patients may be enrolled if they meet the CVT-301-004E eligibility criteria.

Detailed description:

Arms: arm 1: Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 12 months duration arm 2: Capsules of levodopa inhalational powder used up to 5 times/day for OFF episodes for 12 months duration
Interventions: intervention 1: CVT-301
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
 
1. 
TITLE PAGE 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A 14-Month, Dose-Level Blinded Study Investigating the Safety 
and Efficacy of CVT-301 (Levodopa Inhalation Powder) in 
Parkinson’s Disease Patients With Motor Response Fluctuations 
OFF Phenomena)  
Protocol Number: 
CVT-301-004E 
US IND Number: 
115750 
EudraCT Number: 
2015-005626-19 
Development Phase: 
Phase 3 
Study Sponsor: 
Civitas Therapeutics, Inc. 
190 Everett Ave 
Chelsea, MA 02150 
USA 
Protocol Version: 
5.2 
Version Date: 
07-Dec-2016 
 
-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. 


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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: 
 
 
Sponsor’s Responsible Medical Director: 
 
 
 
  
  
 
CRO Global Study Manager: 
 
 
CRO Medical Monitor: 
 
 
CRO Safety (Pharmacovigilance) Reporting: 
 
 
 
 
Clinical Laboratory: 
 
 
 
 
 
 
 
 
 
 
Spirometry and ECG Central Laboratory 
 
 


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DLco-Related Services and Analysis 
 
Rater Training, Diary, and Endpoint 
Surveillance 
 
 
   


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2. 
SYNOPSIS 
Title of Study: 
A 14-Month, Dose-Level Blinded Study Investigating the Safety and 
Efficacy of CVT-301 (Levodopa Inhalation Powder) in Parkinson’s 
Disease Patients With Motor Response Fluctuations (OFF 
Phenomena) 
Protocol Number: 
CVT-301-004E 
Investigators/Study Sites: 
This study will be conducted at approximately 70 sites in the United 
States of America (USA), Canada, and Europe. 
Phase of Development: 
3 
Objectives: 
Primary Objective 
• 
To characterize the effects of CVT-301 on pulmonary safety, 
as assessed by spirometry (forced expiratory volume in 1 
second [FEV1], forced vital capacity [FVC], and FEV1/ 
FVC ratio) over a 14-month period. 
Secondary Objectives 
• 
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 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 Schwab and England (S&E) 
Activities of Daily Living (ADL) score. 
• 
Change from baseline visit 9-Item Patient Health 
Questionnaire (PHQ-9). 
• 
Change from baseline visit Impact of Parkinson’s OFF 
Episodes Patient Survey 
• 
Change from baseline visit UPDRS Part 2 score. 
Safety Objectives 
• 
To characterize the effects of CVT-301 on safety over a 14-
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 


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Impulsive-Compulsive Disorders Questionnaire (QUIP), the 
Epworth Sleepiness Scale, the Columbia-Suicide Severity 
Rating Scale (C-SSRS), the Amphetamine Withdrawal 
Questionnaire (AWQ), the Dopamine Dysregulation 
Syndrome - Patient and Caregiver Inventory (DDS-PC), and 
the self-administered MDS-UPDRS Parts 1B and 2 
(Movement Disorder Society -UPDRS) . 
• 
To describe the effects of CVT-301 on DLco. 
• 
To compare the pulmonary safety, as assessed by spirometry 
(FEV1 and FEV1/FVC ratio) between the group of patients 
who were treated with CVT-301 in study CVT-301-004 
versus the patients treated with placebo in CVT-301-004. 
• 
Change from baseline in the UPDRS Part 4 measures of 
motor fluctuations (dyskinesias [Questions 32-35] and 
wearing off [Questions 36-39]). 
• 
Occurrence and severity of examiner-rated dyskinesia 
following treatment of patients experiencing an OFF episode 
in the clinic. 
Study Design: 
This study is a 14-month, dose-level blinded, multicenter study of 
2 inhaled dose levels of CVT-301 for the treatment of up to 5 OFF 
episodes per day in PD patients experiencing motor fluctuations 
(OFF episodes).  The 14 month period includes a 4-week drug 
holiday to administer withdrawal assessments.  All patients will 
receive active treatment, but patients will be blinded to dose level.  
This will serve as an extension to the CVT-301-004 study for those 
patients who participated in that study and remain eligible for this 
study.  In addition, patients who completed study CVT-301-009 per 
protocol may be enrolled if they meet the CVT-301-004E eligibility 
criteria.  Patients who are CVT-301-naïve, including patients who 
were randomized to the observational arm of the CVT-301-005 
study, also may be enrolled if they meet the CVT-301-004E 
eligibility criteria.  Patients must have completed all of the preceding 
CVT-301 study visits per protocol without any safety issues that 
would preclude participation in this study according to the 
investigator.  Patients who withdrew from the CVT-301-004, CVT-
301-009 or CVT-301-005 studies prior to completion, for any 
reason, will not be eligible. 
Patients who are already enrolled in CVT-301-004E under the prior 
version of this protocol, including any former CVT-301-003 study 
patients, will be re-consented to continue in the study under the 
current amendment. No new patients from the CVT-301-003 study 
will be permitted to enter the CVT-301-004E study. New patients 
from CVT-301-004, patients from CVT-301-009, patients from the 
observational arm of CVT-301-005, and other new CVT-301 naïve 
patients who meet eligibility criteria will be enrolled in CVT-301-
004E under the current amendment. 
Patients who received CVT-301 in the double-blinded CVT-301-004 
study will remain on their same blinded dose level:  patients who 


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received DL1 (target nominal dose of 35 mg levodopa [LD] fine 
particle dose [FPD]) in CVT-301-004 will receive DL1 (target 
nominal dose of 35 mg LD FPD) in CVT-301-004E.  Patients who 
received DL2 (target nominal dose of 50 mg LD FPD) in CVT-301-
004 will receive DL2 (target nominal dose of 50 mg LD FPD) in 
CVT-301-004E.  Patients who received placebo in CVT-301-004, 
and all former CVT-301-009 patients, as well as any additional 
CVT-301-naïve patients, will be randomized in 1:1 ratio to DL1 or 
DL2 in the CVT-301-004E study.  Randomization will be 
differentiated by the patient’s Hoehn and Yahr disease severity scale 
rating (<2.5 versus ≥2.5) to balance for disease severity 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%).  For the patients who received placebo 
in CVT-301-004, the differentiation of CVT-301-004 will be used.  
Each treated episode will require 2-capsule inhalations (i.e., 
2 capsules used in the inhaler per treated episode) to deliver the 
intended dose.  Capsules for DL1 and DL2 will appear identical in 
order to maintain blinding. 
The study includes a screening period of up to 35 days (for CVT-
301-naïve patients and patients from the CVT-301-009 study) and a 
treatment period of approximately 13 months.  The screening visits 
are not required for CVT-301-004 patients.  CVT-301-004 patients 
will have a 1- to 14-day period between the last dose of study drug in 
the CVT-301-004 study and the first dose of study drug in this study.  
A longer period may be permitted with approval from the Sponsor.  
Planned visits will occur at 0, and approximately 1, 3, 6, 9, and 14 
months.  
For CVT-301-naïve patients and CVT-301-009 patients, spirometry 
will be assessed at the neurology sites for screening and TV1. The 
baseline DLco will be performed at dedicated pulmonary sites prior 
to TV1, and the pulmonary sites will be exclusively responsible for 
the conduct of spirometry and DLco after TV1 (within 2 weeks prior 
to the 3-, 6-, 9-, and 14-month visits, and 4 to 5 weeks following 
completion of Treatment Visit 6 [TV6]). For patients from CVT-
301-004, spirometry will be assessed at the neurology sites at TV1, 
and the pulmonary sites will be exclusively responsible for the 
conduct of spirometry and DLco after TV1 as described for the 
CVT-301-naïve patients.  
For all patients, the treatment period will be approximately 
13 months (56±2 weeks) in duration.  The maximum anticipated 
duration of this study for patients from the CVT-301-004 study will 
be approximately 67 weeks, including the final spirometry and DLco 
assessment which takes place 4 to 5 weeks following the treatment 
period.  The maximum anticipated duration of this study for CVT-
301-naïve patients and CVT-301-009 patients, including the 
screening period and the final spirometry and DLco assessments, 
will be approximately 72 weeks.  
If a patient develops significant tolerability concerns that in the 


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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- 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.).  If a 
patient has a dose reduction due to tolerability concerns, he/she may 
be titrated back up to his/her randomized dose (i.e., 2 capsules) at the 
next scheduled study visit if the investigator determines that the 
tolerability issue has adequately resolved and the patient could 
potentially benefit from escalating back up to the original 
randomized dose level (i.e., 2 capsules).  This return to randomized 
dose may take place at the in-clinic visit or in between visits (if the 
patient and clinic staff talk by telephone) and may only be done once 
during the study.  Clinic staff will call the patient 1-2 days after the 
dose escalation to see if the patient has any questions or concerns.  If 
a patient who has a tolerability-related dose reduction is re-escalated 
to the randomized dose and experiences another tolerability issue 
related to dose level that requires dose reduction, he/she will be dose 
reduced for a second time and will remain on that dose for the 
remainder of the study; he/she will not be eligible for any additional 
up-titration to the original dose.  
All patients should continue with their usual prescribed standard PD 
medication regimen for the study duration.  This regimen may be 
altered if needed during the course of the 14-month study.  The 
addition or modification of medications or treatments may include 
other forms of oral medications except oral “as needed” (PRN) PD 
medications while taking study medication.  During the study drug 
holiday, patients are allowed to take oral PRN PD medication to 
manage their 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.  The total daily 
LD dose of the modified PD regimen (not including CVT-301) must 
not exceed 1600 mg per day while taking study medication.  
Apomorphine is not permitted during the study. 
Safety data will be reviewed by an independent Data Safety 
Monitoring Board (DSMB) that will include relevant experts as 
defined in the DSMB Charter.  There will be no prospective interim 
evaluation of efficacy endpoint data. 
Screening Period 
CVT-301-naïve patients (including CVT-301-005 observational arm 
patients) and patients from the CVT-301-009 study will undergo a 
screening period (of up to 35 days) prior to randomization.  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).  CVT-301-004 patients will not be required 


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to undergo the screening visits and will undergo TV1 after a 1- to 
14-day period (or longer if approved by the Sponsor) following 
Treatment Visit 4 (TV4) of the CVT-301-004 study. 
SV1 for CVT-301-Naïve Patients and CVT-301-009 Patients  
Within 35 days prior to randomization 
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), concurrent conditions, 
and PD history will be documented.  PD diagnosis will be confirmed 
in the ON state using Steps 1 and 2 of the United Kingdom (UK) 
Brain Bank Criteria and PD severity will be staged using 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 the patient is in an ON state; a full 
physical examination; review of pulmonary function and pulmonary 
history by completion of the Pulmonary 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 Parts 1, 2, 3 
and 4 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 dyskinesias.  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-


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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 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 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 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 
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).   
SV2 for CVT-301-Naïve Patients and CVT-301-009 Patients  
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. 


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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/regimen.  
Any changes in concomitant medication 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 also 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.  
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 
states), UPDRS Parts 1, 2 and 4 (assessed in the ON state), ON/OFF 
concordance testing (assessed in both ON and OFF states), and 
clinical laboratory tests (with documentation of fasting status) 
including serum pregnancy tests, if applicable.   
In addition the following assessments will be recorded, preferably in 
the ON state: the Parkinson’s Disease Impulsive-Compulsive 
Disorders Questionnaire (QUIP); the Epworth Sleepiness Scale; and 
the Columbia-Suicide Severity Rating Scale (C-SSRS). 
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.   
During the 3 consecutive days prior to TV1, patients will complete 
the PD Diary and the Screening ON/OFF Episodes Log.  Before 
arrival at the clinic for TV1, the patients will take all of their usual 
prescribed non-PD medications and PD medications, including LD-
containing PD medications.  
Following completion of SV2 and prior to randomization (for CVT-
301-naïve patients and CVT-301-009 patients), eligibility criteria 
will be reviewed by delegated staff. 
Before TV1, patients will be assigned/randomized to treatment.  
Patients who received DL1 (target nominal dose of 35 mg LD FPD) 
in the CVT-301-004 study will receive DL1 (target nominal dose of 
35 mg LD FPD) in this study, and patients who received DL2 (target 
nominal dose of 50 mg LD FPD) in the CVT-301-004 study will 
receive DL2 (target nominal dose of 50 mg LD FPD) in this study.  
Patients who received placebo in the CVT-301-004 study, CVT-301-
009 patients and CVT-301-naïve patients will be randomized in a 1:1 
ratio to DL1 or DL2.  If a patient meets final eligibility requirements, 
eligibility will be reviewed by delegated staff.  Randomization will 


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be differentiated by the patient’s Hoehn and Yahr disease severity 
rating (<2.5 versus ≥2.5) to balance for disease severity 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%).  For the patients who received placebo 
in CVT-301-004, the differentiation of CVT-301-004 will be used.  
Patients and site staff will be blinded to treatment level. 
The clinic staff will schedule the next visit and schedule patients to 
undergo DLco assessment at the pulmonary function lab.  This 
should be scheduled to occur after SV2 and before TV1, and should 
be performed with the patient in the ON state (as reported by the 
patient to the pulmonary technician). As part of the visit, a slow vital 
capacity maneuver will be performed, followed by DLco, and then 
spirometry. 
Clinic staff will arrange to speak with patients by telephone 
approximately 4-6 days prior to TV1 confirm the DLco assessment 
has been done or is scheduled to occur prior to TV1, to confirm the 
next study visit, and to remind patients of the study procedures 
required prior to the next scheduled study visit (including the DLco 
assessment and 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 
TV1 and that they should contact the site if an intervening illness 
occurs prior to TV1.  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 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. 
Treatment Period  
The assessments and procedures performed at TV1 will differ for 
patients entering from the CVT-301-004 study and for CVT-301-
naïve patients and prior CVT-301-009 patients. 
CVT-301-004E TV1 for patients entering from CVT-301-004 
1 to 14 days after TV4 in the CVT-301-004 Study 
Informed consent will be obtained prior to receiving drug for this 
extension study.  Patients should provide written informed consent 
for this study at TV4 of the CVT-301-004 study.  
Patients will be instructed to take their prescribed oral PD 
medications on their usual schedule. The timing of arrival for TV1 
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 of their usual PD 


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medications. 
The following assessments will be performed:  recording of usual 
PD medications; recording of time of usual PD medication taken 
prior to the visit; recording of concomitant medication; full physical 
examination; 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; the C-SSRS assessment, Epworth Sleepiness 
Scale, and UPDRS Parts 1 and 2 (preferably in the ON state).   
In addition, the following assessments will be recorded: the Patient 
Health Questionnaire-9 (PHQ-9), AWQ, and DDS-PC (all in the ON 
state) and the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in the ON state). 
Patients will be trained again on the proper technique to prepare and 
use the inhaler system (using sham capsules) per the IFU.  The clinic 
staff will distribute 2 outpatient data collection tools: 
(1) PD Diary:  for recording time asleep, time OFF, time ON 
without dyskinesia, time ON with non-troublesome dyskinesia, and 
time ON with troublesome dyskinesia (to be completed for the 
3 consecutive days prior to Treatment Visit 2 [TV2], Treatment 
Visit 3 [TV3], TV4, Treatment Visit 5 [TV5], and TV6). 
(2) 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 13-month treatment period).   
The clinic staff will distribute the study drug kits.   
Under clinic staff supervision, preferably between 2 and 5 hours 
after receiving their previous dose of PD medications (in the OFF 
state), patients will prepare and self-administer study their entire 
dose of inhaled study drug.      
Spirometry evaluations will be performed immediately prior to 
inhalation, and at 15, 30, and 60 minutes post-dose.  At the time of 
each spirometry assessment, staff will record the patient’s motor 
state.  If within the first 60 minutes after inhalation, the patient’s 
spirometry assessment shows either of the following, the patient will 
NOT be sent home with study drug, and the site will follow the 
Spirometry Alert and Review Process:   
a decrease in FEV1 ≥ 20% AND a decrease in FEV1 by 200 mL 
compared with pre-dose results, and/or a reduction in the FEV1/FVC 
ratio to <60%.   
If either criteria are met, the patient will NOT be sent home with 
study drug and the following procedures will be followed:  (1) 
manage any emergent medical conditions, if necessary; (2a) 
complete a Spirometry Alert and Review Worksheet, including 
documentation of medical assessments and recording the 
presence/absence of pulmonary and any other signs or symptoms, 
and transmit the worksheet to prespecified personnel; (2b) 
immediately transmit the spirometry assessments to the Spirometry 
Core Laboratory; and (3) complete all other TV1 safety assessments.  


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The site will ensure that the patient is clinically stable before leaving 
the site.  Spirometry assessments will be over-read by the 
Spirometry Core Laboratory.  If abnormal ranges in spirometry 
values are determined likely to be related to problems in 
spirometry/breathing technique and/or related to disordered 
neuromuscular strength or coordination as is frequently observed 
with PD patients, the patient will be permitted to repeat the visit.  
The medical monitor and Sponsor will determine whether or not the 
patient may continue study participation (when possible, this 
determination will be completed within 48 hours).  If the patient is 
cleared to continue study participation, TV1 will be repeated in its 
entirety.  If upon repeated testing abnormal spirometry results are 
seen again, the same procedures will be followed; the patient may 
still be eligible for participation, after consultation with the medical 
monitor, if it is documented that the abnormal results are not related 
to pulmonary disease. 
Vital signs (standard and orthostatic 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).   
Patients will remain in the clinic until completion of the safety 
evaluations. 
The next visit will be scheduled.  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.  Additionally, clinic staff will arrange to 
speak with patients by telephone 1 week before TV2 to monitor for 
AEs, to discuss concerns or challenges with the inhaler systems or 
Inhaled Dosing Log, to confirm the next visit, to ask the patients 
how many empty study drug kits will be returned at the next visit, 
and to remind patients to complete the PD Diary and Inhaled Dosing 
Log. 
TV1 for CVT-301-Naïve Patients and CVT-301-009 Patients  
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 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 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 of their usual PD medications. 
The clinic staff will collect the Screening ON/OFF Episodes Log and 
PD Diary and review the information, sign and date each, and will 


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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 the standard 
PD medication dose/regimen.  The following assessments will be 
performed:  review of concomitant medication; a brief physical 
examination, standard and orthostatic vital sign assessments (BP, 
HR, and RR), and ECG.  
In addition, the following assessments will be recorded: PDQ-39, the 
Patient Health Questionnaire-9 (PHQ-9), AWQ, DDS-PC, all 
assessed in the ON state; UPDRS Part 1 and Part 2 (preferably in 
ON state); S&E ADL scale (preferably in ON state); UPDRS Part 4 
(Questions 32-35 and 36-39); QUIP; Epworth Sleepiness Scale; C-
SSRS; and the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in the ON state). 
Patients will also undergo spirometry (preferably in ON state), and 
clinical laboratory tests (with documentation of fasting status) 
including serum pregnancy test, if applicable.   
Patients will be trained again on the proper technique to prepare and 
use the inhaler system (using sham capsules) per the IFU.  The clinic 
staff will distribute 2 outpatient data collection tools: 
(1) PD Diary:  for recording time asleep, time OFF, time ON 
without dyskinesia, time ON with non-troublesome dyskinesia, and 
time ON with troublesome dyskinesia (to be completed for the 
3 consecutive days prior to TV2, TV3, TV4, TV5, and TV6). 
(2) 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 13-month treatment period).   
The clinic staff will provide study drug kits.   
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 previous dose of PD medications (in the OFF state), 
patients will prepare and self-administer study their entire dose of 
inhaled study drug.   
Spirometry evaluations will be performed immediately prior to 
inhalation, and at 15, 30, and 60 minutes post-dose.  At the time of 
each spirometry assessment, staff will record the patient’s motor 
state.  If within the first 60 minutes after inhalation, the patient’s 
spirometry assessment shows either of the following, the patient will 
NOT be sent home with study drug, and the site will follow the 
Spirometry Alert and Review Process:   
a decrease in FEV1 ≥ 20% AND a decrease in FEV1 by 200 mL 
compared with pre-dose results, and/or a reduction in the FEV1/FVC 
ratio to <60%.   
If either criteria are met, the patient will NOT be sent home with 
study drug and the following procedures will be followed:  (1) 
manage any emergent medical conditions, if necessary; (2a) 


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complete a Spirometry Alert and Review Worksheet, including 
documentation of medical assessments and recording the 
presence/absence of pulmonary and any other signs or symptoms, 
and transmit the worksheet to prespecified personnel; (2b) 
immediately transmit the spirometry assessments to the Spirometry 
Core Laboratory; and (3) complete all other TV1 safety assessments.  
The site will ensure that the patient is clinically stable before leaving 
the site.  Spirometry assessments will be over-read by the 
Spirometry Core Laboratory.  If abnormal ranges in spirometry 
values are determined likely to be related to problems in 
spirometry/breathing technique and/or related to disordered 
neuromuscular strength or coordination as is frequently observed 
with PD patients, the patient will be permitted to repeat the visit.  
The medical monitor and Sponsor will determine whether or not the 
patient may continue study participation (when possible, this 
determination will be completed within 48 hours).  If the patient is 
cleared to continue study participation, TV1 will be repeated in its 
entirety.  If upon repeated testing abnormal spirometry results are 
seen again, the same procedures will be followed; the patient may 
still be eligible for participation, after consultation with the medical 
monitor, if it is documented that the abnormal results are not related 
to pulmonary disease. 
Vital signs (standard and orthostatic 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).   
The next visit will be scheduled.  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.  Additionally, clinic staff will arrange to 
speak with patients by telephone 1 week before TV2 to address any 
concerns or challenges with the inhaler systems, PD Diary, or 
Inhaled Dosing Log, 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, and also to remind patients of the study 
procedures required prior to the next scheduled study visit (including 
completion of the PD Diary and Inhaled Dosing Log).   
At-Home Dosing for all Patients 
At TV1, TV2, TV3, TV4, and TV5, patients will receive study drug 
kits and the IFU to take home with them, except during the study 
drug holiday.  Patients will also receive study drug kits and the IFU 
to take home with them at TV4.1, TV5.1, or at an Unscheduled 
Visit. Patients will be instructed to continue with their usual 
prescribed standard PD medication regimen for the study duration.  


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This regimen may be altered if needed during the course of the 14-
month study.  The addition or modification of medications or 
treatments may include other forms of oral medications except oral 
PRN PD medications while taking study medication. During the 
study drug holiday, patients are allowed to take oral PRN PD 
medication to manage their 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.  The total daily LD dose of the modified PD 
regimen (not including CVT-301) must not exceed 1600 mg per day 
while taking study medication.  Apomorphine is not permitted 
during the study. 
Any modifications to the standard PD dose and/or regimen will be 
recorded in the electronic case report form (eCRF). 
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.  Patients may not take oral PRN 
medications to manage OFF states during the study.  
*Note: If Study CVT-301-009 supports the safety and tolerability 
of CVT-301 administration in the early morning, investigators 
will be informed that participants in the current study CVT-301-
004E can start to take study drug for early morning OFF periods. 
Until that time study drug may not be used to treat morning 
akinesia.   
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 oral 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 13-month treatment period.  
As described previously, patients will be contacted by the clinic staff 
1 to 3 days after TV1 and 1 week prior to each visit for TV2, TV3, 
TV4, TV5, and TV6. 


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Patients will bring the PD Diary, Inhaled Dosing Log, empty 
capsules, inhalers, and unused supplies to the clinic visit.  
TV2 for all Patients 
1 month (4 weeks ±5 days) after TV1 
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV2, and patients will complete 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).  
Clinic staff will collect, review, sign and date all PD Diary and 
Inhaled Dosing Log and will collect empty capsules, inhalers, and 
unused supplies.  Clinic staff will record any changes in the standard 
PD medication dose/regimen and will 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 medication; brief physical examination; standard vital 
signs (BP, HR, and RR) and orthostatic vital signs (BP and HR); and 
ECG. 
In addition the following assessments will be recorded: PDQ-39, 
PHQ-9 and PGI-C (all assessed in an ON state); UPDRS Part 2 
(preferably in the ON state); S&E ADL scale (preferably in the ON 
state); UPDRS Part 4 (Questions 32-35 and 36-39); QUIP; Epworth 
Sleepiness Scale; C-SSRS; and the Impact of Parkinson’s OFF 
Episodes Patient Survey (preferably in the ON state). 
The clinic staff will provide study drug kits and review the inhaler 
training.  The staff will also 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 prepare and then self-
administer (under staff supervision) the entire dose of inhaled study 
drug. The dosing time is preferably between 2 and 5 hours after their 
prior oral PD medication.    
Efficacy responses will be assessed by recording:  (1) the occurrence 
and severity of dyskinesia and (2) whether the patient converted to 
an ON state during the 60-minute post-dose time period and if so, 


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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).   
Clinic staff will also schedule a DLco and spirometry assessment to 
occur at the pulmonary function facility within 2 weeks prior to the 
next visit.  These assessments should be performed in an ON state 
(as reported by the patient to the pulmonary technician).  As part of 
the visit, a slow vital capacity maneuver will be performed, followed 
by DLco, and then spirometry.  
The next study visit will be scheduled.  Clinic staff will arrange to 
speak with patients by phone 1 week prior to TV3 to address any 
potential concerns or challenges with the inhaler systems, PD Diary, 
or Inhaled Dosing Log, to monitor for any AEs, to confirm that the 
DLco and spirometry visit at the pulmonary function lab has taken 
place or has been 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 
Inhaled Dosing Log).   
TV3 for all Patients 
3 months (12±2 weeks) after TV1 
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV3, and patients will complete the Inhaled Dosing Log daily 
throughout the treatment period.  They 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). 
Clinic staff will collect, review, sign, and date the PD Diary and 
Inhaled Dosing Log and will collect empty capsules, inhalers, and 
unused supplies.  They will confirm that the DLco and spirometry 
visit has taken place within 2 weeks prior to the visit (and if not, re-
schedule the study visit).  Clinic staff will record any changes in the 
standard PD medication dose/regimen and will 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 medication; a brief physical examination, standard 


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and orthostatic vital sign assessments (BP, HR, and RR), ECG; 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 
and PHQ-39, both assessed in the ON state, PGI-C scale, UPDRS 
Part 2 and S&E ADL (each preferably assessed in the ON state prior 
to other study evaluations); UPDRS Part 4 (Questions 32-35 and 36-
39); C-SSRS; Epworth Sleepiness Scale; QUIP; and the Impact of 
Parkinson’s OFF Episodes Patient Survey (preferably in the ON 
state). 
The clinic staff will provide study drug kits and review the inhaler 
training (if needed).  The staff will also provide the PD Diary and 
Inhaled Dosing Log and review instructions for completion.  
The patient will remain in the clinic until he/she goes into the OFF 
state.  In the OFF state, the patient will prepare and then self-
administer (under staff supervision) the entire dose of inhaled study 
drug. The dosing time is preferably between 2 and 5 hours after their 
prior oral PD medication.    
Efficacy responses will be assessed by recording:  (1) the occurrence 
and severity of dyskinesia, and (2) 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).   
Clinic staff will also schedule a DLco and spirometry assessment to 
occur at the pulmonary function facility within 2 weeks prior to the 
next visit.  These assessments should be performed in an ON state 
(as reported by the patient to the pulmonary technician).  As part of 
the visit, a slow vital capacity maneuver will be performed, followed 
by DLco, and then spirometry.  
The next study visit will be scheduled.  Clinic staff will arrange to 
speak with patients by phone 1 week prior to TV4 to address any 
potential concerns or challenges with the inhaler systems, PD Diary, 
or Inhaled Dosing Log, to monitor for any AEs, to confirm that the 
DLco and spirometry visit at the pulmonary function lab has taken 
place or has been 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 
Inhaled Dosing Log).   
TV4 for all Patients 
6 months (24±2 weeks) after TV1 
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV4, and patients will complete the Inhaled Dosing Log daily 
throughout the treatment period.  They will bring their usual PD 


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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).  
Clinic staff will collect, review, sign, and date the PD Diary and 
Inhaled Dosing Log and will collect empty capsules, inhalers, and 
unused supplies.  They will confirm that the DLco and spirometry 
visit has taken place within 2 weeks prior to the visit (and if not, re-
schedule the study visit).  Clinic staff will record any changes in the 
standard PD medication dose/regimen and will 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 medication; full physical examination; standard vital 
signs (BP, HR, and RR and orthostatic vital signs (BP and HR); 
ECG; 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 
and PHQ-9, both assessed in the ON state; PGI-C scale, UPDRS 
Part 2 and S&E ADL (each preferably assessed in the ON state prior 
to other study evaluations); UPDRS Part 4 (Questions 32-35 and 36-
39); C-SSRS; Epworth Sleepiness Scale; QUIP; and the Impact of 
Parkinson’s OFF Episodes Patient Survey (preferably in the ON 
state). 
The clinic staff will provide study drug kits and review the inhaler 
training (if needed) for patients not entering the study drug holiday.  
The staff will also provide the PD Diary and Inhaled Dosing Log and 
review instructions for completion. 
The patient will remain in the clinic until he/she goes into the OFF 
state.  In the OFF state, the patient will prepare and then self-
administer (under staff supervision) the entire dose of inhaled study 
drug. The dosing time is preferably between 2 and 5 hours after their 
prior oral PD medication.    
Efficacy responses will be assessed by recording:  (1) the occurrence 
and severity of dyskinesia, and (2) 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 


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he/she leaves the clinic on that day if needed for OFF episodes).   
The next study visit will be scheduled.  Clinic staff will arrange to 
speak with patients by phone 1 week prior to TV5 to address any 
potential concerns or challenges with the inhaler systems, PD Diary, 
or Inhaled Dosing Log, 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 Inhaled Dosing Log).  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 
maneuver will be performed, followed by DLco, and then 
spirometry.   
TV5 for all Patients  
9 months (36±2 weeks) after TV1  
Patients will complete the PD Diary for the 3 consecutive days prior 
to TV5, and patients will complete the Inhaled Dosing Log daily 
throughout the treatment period.  They 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).  
Clinic staff will collect, review, sign, and date the PD Diary and 
Inhaled Dosing Log and will collect empty capsules, inhalers, and 
unused supplies.  They will confirm that the DLco and spirometry 
visit has taken place within 2 weeks prior to the visit (and if not, re-
schedule the study visit).  Clinic staff will record any changes in the 
standard PD medication dose/regimen and will 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 medication; brief physical examination; standard 
vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR); ECG; 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, 
PHQ-9, and PGI-C scale (all assessed in the ON state), UPDRS 
Part 2 and S&E ADL (each preferably assessed in the ON state prior 


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to other study evaluations); UPDRS Part 4 (Questions 32-35 and 36-
39); C-SSRS; Epworth Sleepiness Scale; QUIP; and the Impact of 
Parkinson’s OFF Episodes Patient Survey (preferably in the ON 
state). 
The clinic staff will provide study drug kits and review the inhaler 
training (if needed) for patients not entering the study drug holiday.  
The staff will also provide the PD Diary and Inhaled Dosing Log and 
review instructions for completion. 
The patient will remain in the clinic until he/she goes into the OFF 
state.  In the OFF state, the patient will prepare and then self-
administer (under staff supervision) the entire dose of inhaled study 
drug. The dosing time is preferably between 2 and 5 hours after their 
prior oral PD medication.    
Efficacy responses will be assessed by recording:  (1) the occurrence 
and severity of dyskinesia, and (2) 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).   
Clinic staff will also schedule a DLco and spirometry assessment to 
occur at the pulmonary function facility within 2 weeks prior to the 
next visit.  These assessments should be performed in an ON state 
(as reported by the patient to the pulmonary technician).  As part of 
the visit, a slow vital capacity maneuver will be performed, followed 
by DLco, and then spirometry.  
The next study visit will be scheduled.*  Clinic staff will arrange to 
speak with patients by phone 1 week prior to TV6 to address any 
potential concerns or challenges with the inhaler systems, PD Diary, 
or Inhaled Dosing Log, to monitor for any AEs, to confirm that the 
DLco and spirometry visit at the pulmonary function lab has taken 
place or has been done, 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 Inhaled 
Dosing Log).   
*Patients who have already completed TV5 at the time of 
implementation of protocol Version 5.2 will have the option to 
consent to this amendment at an Unscheduled Visit prior to TV6, 
at which time they will receive an additional 4 weeks of study 
drug so that TV6 can be scheduled for approximately 13 months 
(56±2 weeks) after TV1.  These patients will participate in the 
withdrawal sub-study post-TV6 as described below. 
TV6 for all Patients/ Early Withdrawal Visit 
13 months (56±2 weeks) or 14 months (60 ±2 weeks) after TV1 
Treatment Visit 6 will constitute the end-of-study visit.  Patients will 


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complete the PD Diary for the 3 consecutive days prior to TV6, and 
patients will complete the Inhaled Dosing Log daily up until TV6.  
They 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).  
Clinic staff will collect, review, sign, and date the PD Diary and 
Inhaled Dosing Log and will collect empty capsules, inhalers, and 
unused supplies.  They will confirm that DLco and spirometry visit 
at the pulmonary function lab was performed within 2 weeks prior to 
the visit (and if not, re-schedule the study visit).  Clinic staff will 
record any changes in the standard PD medication dose/regimen has 
not changed and will 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 medication; 
brief physical examination; standard vital signs (BP, HR, and RR) 
and orthostatic vital signs (BP and HR); ECG; 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, PHQ-9, and PGI-C scale (all assessed in the ON state), UPDRS 
Part 2 and S&E ADL (each preferably assessed in the ON state prior 
to other study evaluations); UPDRS Part 4 (Questions 32-35 and 36-
39); C-SSRS; Epworth Sleepiness Scale; QUIP; and the Impact of 
Parkinson’s OFF Episodes Patient Survey (preferably in the ON 
state). 
The patient will remain in the clinic until he/she goes into the OFF 
state.  In the OFF state, the patient will prepare and then self-
administer (under staff supervision) the entire dose of inhaled study 
drug. The dosing time is preferably between 2 and 5 hours after their 
prior oral PD medication.    
Efficacy responses will be assessed by recording:  (1) 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.  Once all of 
the assessments are complete, schedule the patient to undergo a 
DLco and spirometry assessment 4 to 5 weeks after completion of 
TV6.  These assessments should be performed in an ON state (as 
reported by the patient to the pulmonary technician) in the 


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pulmonary function facility.  As part of the procedure, a slow vital 
capacity maneuver will be first, followed by DLco, and then 
spirometry. 
Sub-Study to Assess Potential Withdrawal Symptoms 
After patients are consented to protocol Version 5.2, they will 
participate in a withdrawal symptom sub-study at the end of TV4, 
TV5, or TV6, depending on which of the visits is the next scheduled 
one for the patient. In addition to the assessments detailed in the 
sections above for the treatment visit, the AWQ and DDS-PC will be 
performed upon arrival in the ON state, and the UPDRS Part 1 will 
be performed preferably in the ON state.  
When study activities for the visit are completed, patients will begin 
a 28-day period of assessment of potential drug withdrawal 
symptoms. To this end, patients who are at TV4 or TV5 at the time 
of consent will go on a study drug holiday for this time period. All 
patients in the withdrawal sub-study (patients consented to protocol 
Version 5.2) will be given copies of the AWQ, the DDS-PC, PHQ-9, 
Epworth Sleepiness Scale, C-SSRS (self-report version), and the 
self-administered MDS-UPDRS Parts 1B and 2 (Movement Disorder 
Society -UPDRS) to be completed at home at 1, 3, 6, 8, 11, 14, 17, 
24, and 28 days after the treatment visit. Patients should fill out the 
questionnaires during their first ON state (after the intake of their 
first scheduled dose of standard oral PD medication) on each of 
these days. The site will call patients at 14 (±3) days after the 
treatment visit to remind them to complete the questionnaires, and to 
inquire about potential adverse events and changes in concomitant 
medications.  Patients who enter the withdrawal sub-study after TV6 
will also receive a call at 28 (±3) days. 
Patients who entered the study drug holiday will be scheduled to 
return to the clinic for a drug re-supply visit and resumption of the 
full course of study treatment. Patients who entered the withdrawal 
sub-study after TV6 will be completed with the study after they 
return the questionnaires and undergo the DLco and spirometry 
assessment 4 to 5 weeks after completion of TV6, as described in the 
TV6 section. 
Patients who withdraw prematurely will complete the TV6 
assessments (not including the pre-TV6 DLco and spirometry 
assessment) at the time of withdrawal and will be scheduled to 
undergo a DLco and spirometry assessment 4 to 5 weeks after 
completion of the Early Withdrawal Visit.  Patients who withdraw 
prematurely and prior to participating in the sub-study to assess 
potential withdrawal symptoms will complete the withdrawal 
assessments during the 28 days following completion of the TV6 
assessments. 
Selection of Patients: 
CVT-301-004, CVT-301-005 observational arm, and CVT-301-009 
study patients who have met the eligibility criteria for CVT-301-
004E and who have completed all prior study visits per protocol 
without any safety issues that would preclude participation in this 
study according to the investigator are eligible for participation in 


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this study.  Patients who withdrew from any of the prior studies prior 
to completion, for any reason, will not be eligible.  
Other CVT-301-naïve patients must meet all of the inclusion criteria 
and must not meet any of the exclusion criteria. 
Inclusion Criteria (not assessed for the CVT-301-004 study 
patients): 
• 
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 86 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 United Kingdom (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  
• 
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 
of ≥25 on the MMSE (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 


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state at screening.  (A pulmonologist will review the 
spirometry tracings/morphology of any patients with an 
FEV1 that is ≥ 50% to < 60% of predicted or an FEV1/FVC 
ratio that is >60% to <70% in order to determine eligibility.  
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 cell transplantation) or plan to have 
stereotactic surgery during the study period. Patients who 
have had deep brain stimulation [DBS] will also be excluded 
unless the procedure was performed more than 6 months 
prior to study enrollment. 
• 
Patients with a history of psychotic symptoms requiring 
treatment, or suicidal ideation or attempt within the prior 
12 months.   
• 
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. 
• 
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 16 for a list of contraindications).  
• 
Patients with a current history of symptomatic orthostatic 


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hypotension despite adequate treatment.   
• 
Patients with any condition that in the investigator’s opinion 
would make patients unable to comply with study 
procedures or make them unsuitable for their participation in 
the study.   
• 
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. 
• 
For new CVT-301 naïve patients, 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). 
Planned Sample Size: 
The study is planned is to enroll approximately 390 patients to 
ensure that approximately 290 patients will complete the 12 month 
study. All patients who completed the CVT-301-004 and the CVT-
301-009 study per protocol without any safety issues are eligible. In 
addition, CVT-301-naïve patients, including those who participated 
in the CVT-301-005 observational arm may be enrolled to achieve 
the planned enrollment. 
Investigational Therapy: 
CVT-301 (levodopa inhalation powder [LIP]) 
Two CVT-301 dose levels will be investigated.  Each dose level 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 for patients randomized to 
DL1 (target nominal respirable dose of approximately 35 mg LD 
FPD) will deliver approximately 17.5 mg LD FPD to the lung per 
capsule inhalation.  The capsules provided for patients randomized 
to DL2 (target nominal respirable dose of approximately 50 mg LD 
FPD) will deliver approximately 25 mg LD FPD to the lung per 
capsule inhalation. 
In order to maintain the blind to treatment assignment, all patients 
will be given identical-looking study drug kits and instructed to 
inhale 2 capsules sequentially for each dose (1 capsule for each 
inhalation) for each dose.  Patients may sip water in between capsule 
inhalations, if needed.   
Reference Therapy: 
None. 
Treatment Duration: 
The planned treatment period will be 52 ±2 weeks for all patients.  
Each patient will self-administer up to 5 doses of inhaled study drug 
per day.  The maximum anticipated study duration for patients from 
the CVT-301-004 study will be approximately 59 weeks, including 


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the final DLco assessment which takes place 4 to 5 weeks following 
the treatment period.  The maximum anticipated duration of this 
study for CVT-301-naïve patients and CVT-301-009 patients, 
including the screening period and the final DLco assessment, will 
be approximately 64 weeks. 
Criteria for Evaluation: 
Safety 
Pulmonary safety will be evaluated from assessments of lung 
function, as measured from spirometry (FEV1, FVC, FEV1/FVC 
ratio).  In addition, DLco will be evaluated. 
Safety will be also assessed from physical examinations, AE 
reporting, standard and orthostatic vital signs (BP, RR, and HR), 
clinical laboratory values (hematology and biochemistry), ECGs, the 
QUIP, Epworth Sleepiness Scale, the C-SSRS, the AWQ, the DDS-
PC, and the self-administered MDS-UPDRS Parts 1B and 2. 
Additionally, safety will be assessed with: 
• 
Occurrence and severity of examiner-rated dyskinesia after 
study drug is administered in the clinic.  
• 
UPDRS Part 4 (Questions 32-35 and 36-39) 
Efficacy 
• 
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 
• 
PHQ-9 
• 
Impact of Parkinson’s OFF Episodes Patient Survey 
• 
PGI-C 
• 
S&E ADL 
• 
UPDRS Part 2 
Based on Out-Patient Evaluations: 
• 
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. 
Statistical Methods and 
Planned Analyses: 
For all statistical analyses, the visit at which the CVT-301 treatment 
is initiated will be used as the baseline. This will be TV1 from the 
CVT-301-004 study for actively treated patients, i.e. randomized to 
DL1 or DL2. However, TV1 of the CVT-301-004E study will be 
used as the baseline for all placebo-treated subjects from study CVT-
301-004, for patients from study CVT-301-009, and for patients 


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from the observational arm of study CVT-301-005 and other CVT-
301 naïve patients. All patients who are enrolled in CVT-301-004E 
and receive at least 1 dose of CVT-301 will be included in the safety 
analyses and will be grouped according to the highest dose received.  
All patients who are enrolled in CVT-301-004E and who receive at 
least 1 dose of CVT-301 will be included in the efficacy analyses as 
well but will be grouped according to the randomized treatment. 
Safety Analyses  
The extent of exposure to study treatment will be summarized for 
each dose level.  For the patients who received CVT-301 treatment 
in the CVT-301-004 study, the total exposure will be the sum of 
exposure in the CVT-301-004 study and the CVT-301-004E study. 
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.  All TEAEs which 
start after the baseline, as defined above will be included in the 
analysis.  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 
(DL1/DL2 or patients treated with CVT-301/placebo in CVT-301-
004) will be estimated using a Mixed Model for Repeated 
Measurements (MMRM) similar to the one used for the efficacy 
variables.  The proportions of patients meeting ATS quality criteria 
(and also for those ‘rejected’) will be summarized.  Changes from 
baseline to follow-up in the rating scales for assessing suicidality, 
somnolence, and impulse control disorders will be summarized 
descriptively.  
For the AWQ, DDS-PC, PHQ-9, Epworth Sleepiness Scale, C-
SSRS, and UPDRS Parts 1 and 2, the change from baseline to days 
1, 3, 6, 8, 11, 14, 17, 24, and 28 of the withdrawal symptom 
assessment period will be summarized descriptively. 
Demographics and baseline characteristics will be summarized 
descriptively. 
Efficacy Analyses 
The data for patients who were enrolled in the CVT-301-004 study, 
the CVT-301-009 study and for the CVT-301-naïve patients study 
will be primarily analyzed together, while the patients who were 
enrolled in the CVT-301-003 study will be analyzed separately.  A 
sensitivity analysis will be performed for the patients who enrolled 
in the CVT-301-004 study separately and for the CVT-301-naïve 
patients separately. 
The changes within each dose level and the overall change from 
baseline in continuous efficacy variables will be estimated using an 


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MMRM.  Although the focus of this study is to describe the within-
group changes, the differences between the dose levels will be 
estimated as well, but no inferential analyses regarding the between-
group differences will be done.  The model will include the 
treatment group (CVT-301 DL1 or CVT-301 DL2), visit, the 
stratification variables (Hoehn and Yahr disease severity scale rating 
and screening FEV1 and/or FEV1/FVC) and the interaction between 
the treatment group and visit as fixed factors. The baseline value will 
be used as a covariate, if available.  The categorical data will be 
primarily evaluated descriptively. Each visit will be tested 
separately. 


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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 ...........................................................................................33 
4. 
LIST OF ABBREVIATIONS.....................................................................................37 
5. 
INTRODUCTION ......................................................................................................40 
5.1. 
Background and Rationale ..........................................................................................40 
5.1.1. 
Background on Motor Fluctuations in Parkinson’s Disease Patients .........................40 
5.1.2. 
Background on CVT-301 (Levodopa Inhalation Powder) .........................................40 
5.2. 
Rationale .....................................................................................................................42 
5.2.1. 
Rationale for Selection of Doses ................................................................................44 
6. 
STUDY OBJECTIVES ..............................................................................................47 
7. 
INVESTIGATIONAL PLAN .....................................................................................48 
8. 
STUDY POPULATION .............................................................................................50 
8.1. 
Inclusion Criteria (not assessed for the CVT-301-004 study patients) .......................50 
8.2. 
Exclusion Criteria .......................................................................................................51 
8.3. 
Removal of Patients from Study .................................................................................52 
9. 
TREATMENTS ..........................................................................................................53 
9.1. 
Details of Study Treatments .......................................................................................53 
9.1.1. 
CVT-301 Capsule for Inhalation (Test Product) ........................................................54 
9.1.2. 
Sham Capsule for Inhalation ......................................................................................54 
9.1.3. 
Civitas CVT-301 Inhaler ............................................................................................54 
9.1.4. 
Packaging of Blinded Inhaled Study Treatment .........................................................54 
9.2. 
Randomization, Blinding, and Administration of Study Treatment ...........................55 
9.2.1. 
Randomization and Assignment of Study Treatment .................................................55 
9.2.2. 
Distributing Blinded Inhaled Study Treatment ...........................................................55 
9.2.3. 
Defining “Time 0” (T0) ..............................................................................................56 
9.3. 
Treatment Accountability and Compliance ................................................................56 


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9.4. 
Prior and Concomitant Illnesses and Medications ......................................................56 
9.4.1. 
Prior and Concomitant Illnesses .................................................................................56 
9.4.2. 
Prior and Concomitant Medications ...........................................................................57 
10. 
STUDY PROCEDURES ............................................................................................59 
10.1. 
Assessments by Visit ..................................................................................................59 
10.1.1. 
Screening Period .........................................................................................................59 
10.1.1.1. 
Screening Visit 1 for CVT-301-Naïve Patients and CVT-301-009 Patients 
(within 35 days prior to randomization) .....................................................................60 
10.1.1.2. 
Screening Visit 2 for CVT-301-Naïve Patients and CVT-301-009 Patients 
(at least 4 days after SV1) ...........................................................................................62 
10.1.2. 
Randomization to Study Drug ....................................................................................63 
10.1.3. 
Treatment Period ........................................................................................................63 
10.1.3.1. 
Telephone Calls Before Treatment Visits ...................................................................64 
10.1.3.2. 
Treatment Visit 1 for CVT-301-004 Patients (1-14 days after TV4 in the 
CVT-301-004 study) ...................................................................................................65 
10.1.3.3. 
Treatment Visit 1 for CVT-301-Naïve Patients and CVT-301-009 Patients 
(at least 7 days after SV2) ...........................................................................................67 
10.1.3.4. 
At-Home Dosing .........................................................................................................70 
10.1.3.5. 
Treatment Visit 2 for all Patients (1 month [4 weeks ±5 days] after TV1) ................71 
10.1.3.6. 
Treatment Visit 3 for all Patients (3 months 12±2 weeks after TV1) ........................72 
10.1.3.7. 
Treatment Visit 4 for all Patients (6 months [24±2 weeks] after TV1) ......................74 
10.1.3.8. 
Treatment Visit 5 for all Patients (9 months [36±2 weeks] after TV1) ......................76 
10.1.3.9. 
Treatment Visit 6 for all Patients (13 months [56±2 weeks] or 14 months (60 
±2 weeks) after TV1)/Early Withdrawal Visit ...........................................................78 
10.1.4. 
Sub-Study to Assess Potential Withdrawal Symptoms ..............................................79 
10.1.4.1. 
Treatment Visit 4.1/5.1 (28 days+1 week after TV4 or TV5) ....................................80 
10.1.5. 
Early Withdrawal Visit ...............................................................................................80 
10.1.6. 
Unscheduled Visits .....................................................................................................80 
11. 
DESCRIPTION OF ASSESSMENTS .......................................................................81 
11.1. 
Safety Assessments .....................................................................................................81 
11.1.1. 
Physical Examination .................................................................................................81 
11.1.2. 
Vital Signs ..................................................................................................................82 
11.1.3. 
Electrocardiogram .......................................................................................................83 
11.1.4. 
Laboratory Parameters ................................................................................................83 


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11.1.5. 
Pregnancy Status .........................................................................................................83 
11.1.6. 
Spirometry ..................................................................................................................84 
11.1.7. 
Carbon Monoxide Diffusing Capacity (diffusing capacity of the lungs for 
carbon monoxide-DLco) .............................................................................................84 
11.1.8. 
Adverse Events ...........................................................................................................85 
11.1.9. 
Serious Adverse Events ..............................................................................................86 
11.1.10. 
Suspected Unexpected Serious Adverse Reactions ....................................................87 
11.1.11. 
Other Significant Adverse Events ..............................................................................87 
11.1.12. 
Other Safety Assessments ...........................................................................................88 
11.1.12.1. UPDRS Part 4 and Examiner-Rated Dyskinesia ........................................................88 
11.1.12.2. Columbia-Suicide Severity Rating Scale ....................................................................88 
11.1.12.3. Epworth Sleepiness Scale ...........................................................................................88 
11.1.12.4. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease .............89 
11.1.12.5. Dopamine Dysregulation Syndrome - Patient and Caregiver Inventory 
(DDS-PC) ...................................................................................................................89 
11.1.12.6. Amphetamine Withdrawal Questionnaire (AWQ) .....................................................89 
11.2. 
Efficacy Assessments .................................................................................................89 
11.2.1. 
Assessment of ON and OFF States and Dyskinesia ...................................................90 
11.2.1.1. 
In-Clinic Assessments ................................................................................................90 
11.2.1.2. 
At-Home Assessments ................................................................................................90 
11.2.2. 
UPDRS Part 3 .............................................................................................................91 
11.2.3. 
PDQ-39 .......................................................................................................................91 
11.2.4. 
PHQ-9 .........................................................................................................................91 
11.2.5. 
PGI-C ..........................................................................................................................92 
11.2.6. 
Impact of Parkinson’s OFF Episodes Patient Survey .................................................92 
11.2.7. 
Schwab & England Activities of Daily Living ...........................................................92 
11.2.8. 
UPDRS Part 2 and MDS-UPDRS Part 2 ....................................................................92 
11.3. 
Other Assessments Used for Baseline Disease Characteristics ..................................92 
11.3.1. 
UK Brain Bank Criteria ..............................................................................................92 
11.3.2. 
Modified Hoehn and Yahr PD Severity Scale Assessment ........................................93 
11.3.3. 
UPDRS Part 1 and MDS-UPDRS Part 1B .................................................................93 
11.3.4. 
MMSE.........................................................................................................................93 
11.3.5. 
Pulmonary Function Baseline Questionnaire .............................................................93 


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11.4. 
Optional Videotaping at Select Study Sites ................................................................93 
11.5. 
Appropriateness of Measurements .............................................................................93 
12. 
DATA MANAGEMENT AND STATISTICAL ANALYSIS...................................94 
12.1. 
Determination of Sample Size ....................................................................................94 
12.2. 
Study Populations .......................................................................................................94 
12.3. 
Definition of Baseline .................................................................................................94 
12.4. 
Background and Demographic Characteristics ..........................................................95 
12.5. 
Safety Analysis ...........................................................................................................95 
12.5.1. 
Interim Safety Data Review........................................................................................96 
12.6. 
Efficacy Analysis ........................................................................................................96 
13. 
STUDY MANAGEMENT .........................................................................................97 
13.1. 
Approval and Consent ................................................................................................97 
13.1.1. 
Regulatory Guidelines ................................................................................................97 
13.1.2. 
Institutional Review Board/Independent Ethic Committees ......................................97 
13.1.3. 
Informed Consent .......................................................................................................97 
13.2. 
Financing and Insurance .............................................................................................98 
13.3. 
Discontinuation of the Study by the Sponsor .............................................................98 
13.4. 
Study Documentation .................................................................................................98 
13.5. 
Data Handling .............................................................................................................99 
13.6. 
Study Monitoring and Auditing ..................................................................................99 
13.7. 
Retention of Records ..................................................................................................99 
13.8. 
Use of Study Findings ..............................................................................................100 
13.9. 
Publication ................................................................................................................100 
14. 
REFERENCES .........................................................................................................101 
15. 
APPENDICES – TABLE OF CONTENTS .............................................................103 
 
 
LIST OF TABLES 
Table 1 
Details of Study Drug .................................................................................................54 
Table 2 
Classification of Adverse Events by Intensity ............................................................85 
Table 3 
Classification of Adverse Events by Relationship to Study Medication ....................86 


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4. 
LIST OF ABBREVIATIONS 
ADL 
Activities of Daily Living 
AE 
adverse event 
ATS 
American Thoracic Society 
AUC 
area under the plasma concentration-time curve 
AWQ 
Amphetamine Withdrawal Questionnaire 
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 
DDS-PC 
Dopamine Dysregulation Syndrome - Patient and Caregiver Inventory 
DPPC 
dipalmitoyl phosphatidylcholine 
DBP 
diastolic blood pressure 
DBS 
deep brain stimulation 
DL1 
Dose Level 1 
DL2 
Dose Level 2 
DLco 
carbon monoxide diffusing capacity 
DSMB 
Data Safety Monitoring Board 
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 


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GI 
gastrointestinal  
hCG 
human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
 
 
HR 
heart rate 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LD 
levodopa 
LIP 
levodopa inhalation powder (CVT-301) 
MAO-B 
monoamine oxidase-B 
MDS-UPDRS 
Movement Disorder Society - Unified Parkinson’s Disease Rating Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters mercury 
MMRM 
Mixed Model for Repeated Measurements 
MMSE 
Mini Mental State Examination 
NaCl 
sodium chloride 
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 
PHQ-9 
Patient Health Questionnaire 
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 
SUSAR 
suspected unexpected serious adverse reaction 
SV1 
Screening Visit 1 


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SV2 
Screening Visit 2 
T0 
time of completion of inhalation of the last capsule of inhaled study treatment 
administered 
TEAE 
treatment-emergent adverse event 
TV1 
Treatment Visit 1 
TV2 
Treatment Visit 2 
TV3 
Treatment Visit 3 
TV4 
Treatment Visit 4 
TV5 
Treatment Visit 5 
TV6 
Treatment 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). 
By avoiding the GI tract, pulmonary delivery of LD has the potential to provide rapid, reliable, 
and consistent delivery of LD to the systemic circulation and central nervous system, which is 
expected to translate into reliable and rapid improvement in motor symptoms. 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, 
Chipman 2005, Walvoord 2009, Dewey 2001, Dunbar 2004, Oleson 2010).  This delivery system 


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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 Parkinson’s disease.  CVT-301 will be used as an adjunct to the patient’s existing 
decarboxylase inhibitor (i.e., carbidopa [CD] or benserazide)-inclusive Parkinson’s disease 
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 Parkinson’s 
disease (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.   
 
 
 
 
 
  CVT-301-
004E, the present study, is a 14-month extension study in which all patients will receive active 
treatment, but will remain blinded to dose level.  Two inhaled dose levels of CVT-301 (35 mg 
and 50 mg LD FPD) will be used for treatment of up to 5 OFF episodes per day in PD patients 
over a 13-month period.  Although this is an extension of the CVT-301-004 study, CVT-301-009 
patients and CVT-301-naïve patients, including patients who were randomized to the 
observational arm of study CVT-301-005, may also be enrolled if they meet the CVT-301-004E 
eligibility criteria. Patients must have completed all of the preceding CVT-301 study visits per 
protocol without any safety issues that would preclude participation in this study according to the 
investigator.  Patients who withdrew from the CVT-301-004, CVT-301-005, or CVT-301-009 
study prior to completion, for any reason, will not be eligible.  Patients who received Dose Level 
1 (DL1) (35 mg LD FPD) in CVT-301-004 will receive DL1 (35 mg LD FPD) in CVT-301-
004E.  Patients who received Dose Level 2 (DL2) (50 mg LD FPD) in CVT-301-004 will receive 
DL2 (50 mg LD FPD) in CVT-301-004E.  Patients who received placebo in CVT-301-004, and 
all former CVT-301-009 patients, as well as CVT-301-naïve patients, will be randomized in 1:1 
ratio to DL1 or DL2 in the CVT-301-004E study.  Randomization will be differentiated by the 


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patient’s Hoehn and Yahr disease severity scale rating (<2.5 versus ≥2.5) to balance for disease 
severity across each treatment group and by screening spirometry (forced expiratory volume in 1 
second [FEV1] <60% of predicted or FEV1/forced vital capacity [FVC] ratio <70% versus 
FEV1 ≥60% of predicted and FEV1/FVC ratio ≥70%).  For the patients who received placebo in 
CVT-301-004, the differentiation of CVT-301-004 will be used. 
During the 13-month treatment period, patients 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, 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.  For the 3 consecutive days prior to Screening Visit 2 (SV2), 
Treatment Visit 1 (TV1), Treatment Visit 2 (TV2), Treatment Visit 3 (TV3), and Treatment Visit 
4 (TV4), Treatment Visit 5 (TV5), and Treatment Visit 6 (TV6) in the PD Diary, patients will 
record their time asleep and their waking time in different PD states:  time OFF, time ON 
without dyskinesia, time ON with troublesome dyskinesia, and time ON with non-troublesome 
dyskinesia.  
The treatment period has 6 in-clinic visits (TV1, TV2, TV3, TV4, TV5, and TV6).  In-clinic 
efficacy measures include the occurrence and severity of dyskinesia following treatment in the 
clinic, the 39-Item Parkinson’s Disease Questionnaire (PDQ-39), the Patient Health 
Questionnaire (PHQ-9), the Impact of Parkinson’s OFF Episodes Patient Survey, the Patient 
Global Impression of Change (PGI-C) rating scale, the Schwab and England (S&E) Activities of 
Daily Living (ADL) score; and UPDRS Part 2 score. In-clinic and at-home efficacy and safety 
measures will be compared between treatment groups.  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-ead electrocardiograms (ECGs), 
spirometry, carbon monoxide diffusing capacity (DLco) maneuver, the UPDRS Part 4 
(Questions 32-35 and 36-39) score, the Parkinson’s Disease Impulsive-Compulsive Disorders 
Questionnaire (QUIP), the Epworth Sleepiness Scale, the Columbia-Suicide Severity Rating 
Scale (C-SSRS), the Amphetamine Withdrawal Questionnaire (AWQ), the Dopamine 
Dysregulation Syndrome -  Patient and Caregiver Inventory (DDS-PC), and the self-administered 
MDS-UPDRS Parts 1B and 2 (Movement Disorder Society -UPDRS). 
The design of this study, including evaluation of the temporal objective motor responses in-clinic 
following development of an ‘induced’ OFF episode after the first morning LD dose is in 
keeping with studies of other therapeutics that have been developed for treating PD motor 
fluctuations (Dewey 2001, Grosset 2011). 
 
 
 
 
 


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5.2.1. 
Rationale for Selection of Doses 
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 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.   
The dose levels that are being studied have been observed to be clinically effective, safe, and 
tolerated in healthy adult volunteers as well as in PD patients in previously conducted CVT-301 
clinical studies.  
 
 
 
 
 
 
 
 
 
 
 
   
CVT-301 (Levodopa Inhalation Powder) 
 
 
 
  
   
 
  
  
 
 
 
 
 
 
 
 


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Clinically, CVT-301 is intended for use as an adjunct to a PD patient’s standard oral LD/DDI 
combination-based regimen. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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6. 
STUDY OBJECTIVES 
Primary Objective 
• To characterize the effects of CVT-301 on pulmonary safety, as assessed by 
spirometry (FEV1, FVC, and FEV1/FVC ratio) over a 14-month period. 
Secondary Objectives 
• 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 PDQ-39. 
• Proportion of patients who improved based on the PGI-C rating scale measured pre-
dose. 
• Change from baseline visit S&E ADL score. 
• Change from baseline visit PHQ-9. 
• Change from baseline visit Impact of Parkinson’s OFF Episodes Patient Survey. 
• Change from baseline visit UPDRS Part 2 score. 
Safety Objectives: 
• To characterize the effects of CVT-301 on safety over a 14-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, the QUIP, the Epworth 
Sleepiness Scale, the C-SSRS, the AWQ, the DDS-PC, and the self-administered 
MDS-UPDRS Parts 1B and 2. 
• To characterize the effect of CVT-301 on DLco. 
• To compare the pulmonary safety, as assessed by spirometry (FEV1 and FEV1/FVC 
ratio), between the group of patients who were treated with CVT-301 in study CVT-
301-004 versus the patients treated with placebo in CVT-301-004. 
• Change from baseline in the UPDRS Part 4 measures of motor fluctuations 
(dyskinesias [Questions 32-35] and wearing off [Questions 36-39]). 
• Occurrence and severity of examiner-rated dyskinesia following treatment of patients 
experiencing an OFF episode in the clinic. 


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7. 
INVESTIGATIONAL PLAN 
This study is a 14-month, dose-level blinded, multicenter study of 2 inhaled dose levels of CVT-
301 for the treatment of up to 5 OFF episodes per day in PD patients experiencing motor 
fluctuations (OFF episodes).  The 14 month period includes a 4-week drug holiday to administer 
withdrawal assessments.  All patients will receive active treatment, but patients will be blinded to 
dose level.  This will serve as an extension to the CVT-301-004 study for those patients who 
participated in that study and remain eligible for this study. In addition, patients who completed 
study CVT-301-009 per protocol may be enrolled if they meet the CVT-301-004E eligibility 
criteria. Patients who were randomized to the observational arm of the CVT-301-005 study and 
completed that study, and other CVT-301-naïve patients may also be enrolled if they meet the 
CVT-301-004E eligibility criteria.  Patients must have completed all of the preceding CVT-301 
study visits per protocol without any safety issues that would preclude participation in this study 
according to the investigator.  Patients who withdrew from the CVT-301-004, CVT-301-005, or 
CVT-301-009 study prior to completion, for any reason, will not be eligible.  
Patients who are already enrolled in CVT-301-004E under the prior version of this protocol, 
including any former CVT-301-003 study patients, will be re-consented to continue in the study 
under the current amendment. No new patients from the CVT-301-003 study will be permitted to 
enter the CVT-301-004E study. New patients from CVT-301-004, patients from CVT-301-009, 
CVT-301-005 observational arm, and other new CVT-301 naïve patients who meet eligibility 
criteria will be enrolled in CVT-301-004E under the current amendment. 
Patients who received CVT-301 in the double-blinded CVT-301-004 study will remain on their 
same blinded dose level: patients who received DL1 (target nominal dose of 35 mg LD FPD) in 
CVT-301-004 will receive DL1 (target nominal dose of 35 mg LD FPD) in CVT-301-004E.  
Patients who received DL2 (target nominal dose of 50 mg LD FPD) in CVT-301-004 will 
receive DL2 (target nominal dose of 50 mg LD FPD) in CVT-301-004E.  Patients who received 
placebo in CVT-301-004, and all former CVT-301-009 patients, as well as any CVT-301-naïve 
patients (including patients from the observational arm of CVT-301-005), will be randomized in 
1:1 ratio to DL1 or DL2 in the CVT-301-004E study.  Randomization will be differentiated by 
the patient’s Hoehn and Yahr disease severity scale rating (<2.5 versus ≥2.5) to balance for 
disease severity across each treatment group and by screening spirometry (forced expiratory 
volume in 1 second [FEV1] <60% of predicted or FEV1/FVC ratio <70% versus FEV1 ≥60% of 
predicted and FEV1/FVC ratio ≥70%).  For the patients who received placebo in CVT-301-004, 
the differentiation of CVT-301-004 will be used. 
Each treated episode will require 2-capsule inhalations (i.e., 2 capsules used in the inhaler per 
treated episode) to deliver the intended dose.  Capsules for DL1 and DL2 will appear identical in 
order to maintain blinding. 
The study includes a screening period of up to 35 days (for CVT-301-naïve patients and patients 
from the CVT-301-009 study) and a treatment period of approximately 13 months.  The 
screening visits are not required for CVT-301-004 patients.  CVT-301-004 patients will have a 1- 
to 14-day period between the last dose of study drug in the CVT-301-004 study and the first dose 
of study drug in this study.  A longer period may be permitted with approval from the Sponsor.  
Planned visits will occur at 0, and approximately 1, 3, 6, 9, and 14 months.   


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For CVT-301-naïve patients and patients from study CVT-301-009, spirometry will be assessed 
at the neurology sites for screening and TV1. The baseline DLco will be performed at dedicated 
pulmonary sites prior to TV1, and the pulmonary sites will be exclusively responsible for the 
conduct of spirometry and DLco after TV1 (within 2 weeks prior to the 3-, 6-, 9-, and 14-month 
visits, and 4 to 5 weeks following completion of Treatment Visit 6 [TV6]). For patients from 
CVT-301-004, spirometry will be assessed at the neurology sites at TV1, and the pulmonary sites 
will be exclusively responsible for the conduct of spirometry and DLco after TV1 as described 
for the CVT-301-naïve patients.  
For all patients, the treatment period will be approximately 13 months (56±2 weeks) in duration.  
The maximum anticipated duration of this study for patients from the CVT-301-004 study will 
be approximately 67 weeks, including the final spirometry and DLco assessment which takes 
place 4 to 5 weeks following the treatment period.  The maximum anticipated duration of this 
study for CVT-301-naïve patients and CVT-301-009 patients, including the screening period and 
final spirometry and DLco assessments, will be approximately 72 weeks. 
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 the 
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.).  If a patient has a 
dose reduction due to tolerability concerns, he/she may be titrated back up to his/her randomized 
dose (i.e., 2 capsules) at the next scheduled study visit if the investigator determines that the 
tolerability issue has adequately resolved and the patient could potentially benefit from 
escalating back up to the original randomized dose level (i.e., 2 capsules).  This return to 
randomized dose may take place at the in-clinic visit or in between visits (if the patient and clinic 
staff talk by telephone) and may only be done once during the study.  Clinic staff will call the 
patient 1-2 days after the dose escalation to see if the patient has any questions or concerns.  If a 
patient who has a tolerability-related dose reduction is re-escalated to the randomized dose and 
experiences another tolerability issue related to dose level that requires dose reduction, he/she 
will be dose reduced for a second time and will remain on that dose for the remainder of the 
study; he/she will not be eligible for any additional up-titration to the original dose.  
All patients should continue with their usual prescribed standard PD medication regimen for the 
study duration.  The addition or modification of medications or treatments may include other 
forms of oral medications except oral PRN PD medications while taking study medication.  
During the study drug holiday, patients are allowed to take oral PRN PD medication to manage 
their 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.  The total 
daily LD dose of the modified PD regimen (not including CVT-301) must not exceed 1600 mg 
per day while taking study medication.  Apomorphine is not permitted during the study. 
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 defined in the DSMB Charter).  Safety data, 
including but not limited to AEs, spirometry, vital signs, and ECG data will be reviewed.  The 


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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, 
Institutional Review Boards (IRBs), Independent Ethics Committees (IECs), and regulatory 
agencies, in accordance with legal and regulatory requirements.  There will be no prospective 
interim evaluation of efficacy endpoint data. 
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 11 and in 
Section 10.1. 
8. 
STUDY POPULATION 
CVT-301-004 study patients who have met the eligibility criteria for CVT-301-004 and who 
have completed all CVT-301-004 study visits per protocol without any safety issues that would 
preclude participation in this study according to the investigator are eligible for participation in 
this study.  Patients who withdrew from the CVT-301-004 study prior to completion, for any 
reason, will not be eligible.  
Additionally, patients from the observational arm of the CVT-301-005 study and patients from 
the CVT-301-009 study who have completed all prior study visits per protocol and without any 
safety issues that would preclude participation in this study according to the investigator are 
eligible for participation in this study if they meet all of the inclusion criteria and if they do not 
meet any of the exclusion criteria listed below.  Patients who withdrew from the CVT-301-005 
study or the CVT-301-009 study prior to completion, for any reason, will not be eligible. 
Other CVT-301-naïve patients must meet all of the inclusion criteria and must not meet any of 
the exclusion criteria. 
8.1. 
Inclusion Criteria (not assessed for the CVT-301-004 study patients) 
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 86 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 disease) 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. 


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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.   
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 have normal cognition as confirmed by a score of ≥25 on the MMSE 
performed in the ON state. 
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.  Patients with an FEV1/FVC >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 cell 
transplantation) or plan to have stereotactic surgery during the study period. Patients who 
have had deep brain stimulation [DBS] will also be excluded unless the procedure was 
performed more than 6 months prior to study enrollment. 
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 


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anti-depressant medications 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. 
10. Patients with any contraindication to performing routine spirometry or who are unable to 
perform a spirometry maneuver (see Appendix 15 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. For new CVT-301 naïve patients, 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). 
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 (TV1) (the screening period may be extended for up to 2 weeks to accommodate 
this recovery). 
8.3. 
Removal of Patients from Study 
A patient will be considered to have completed the study (and be considered a 14-month 
completer) when he or she has completed all study visits up to and including TV6.  A patient will 
be considered to be a 6-month completer if he/she completes all study visits up to and including 
TV4.  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 TV6 and post-
TV6 assessments as shown Appendix 10 and Appendix 11.  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, 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 


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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. 
• 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 Treatments 
Basic information about the study drugs is provided in Table 1. 
 
 


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Table 1 
Details of Study Drug 
 
CVT-301 (Test Product) 
Name 
CVT-301 (levodopa inhalation powder) 
Manufacturer 
Civitas Therapeutics, Inc. 
Doses 
DL1:  2 CVT-301 capsules delivering a target nominal respirable dose of 
approximately 35 mg LD FPD 
DL2:  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 
DL1 capsule units:  
Capsule fill weight of LD:  30 mg  
Respirable LD dose/FPD per capsule: 17.5 mg 
(Emitted LD per capsule:  25 mg) 
DL2 capsule units:  
Capsule fill weight of LD:  42 mg 
Respirable LD dose/FPD per capsule: 25.0 mg  
(Emitted LD per capsule:  35 mg) 
Abbreviations:  DL1=Dose Level 1; DL2=Dose Level 2; FPD=fine particle dose; LD=levodopa. 
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 
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 DL1 and CVT-301 DL2 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 Blinded 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 randomized patient will be issued a sufficient supply of study drug 


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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 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.   
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, or send an email to the Quality Clinical Complaints mailbox: 
 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, Blinding, and Administration of Study Treatment  
9.2.1. 
Randomization and Assignment of Study Treatment  
Following completion of SV2 and prior to randomization (for CVT-301-009, CVT-301-005 and 
other CVT-301-naïve patients), eligibility criteria will be reviewed by delegated staff to confirm 
eligibility. Sites must leave a minimum of 5 days between randomization and Treatment Visit 1.   
Before TV1, patients will be assigned/randomized to treatment.  Patients who received DL1 
(target nominal dose of 35 mg LD FPD) in the CVT-301-004 study will receive DL1 (target 
nominal dose of 35 mg LD FPD) in this study, and patients who received DL2 (target nominal 
dose of 50 mg LD FPD) in the CVT-301-004 study will receive DL2 (target nominal dose of 
50 mg LD FPD) in this study.   
Patients who received placebo in the CVT-301-004 study, CVT-301-009 patients, and CVT-301-
naïve patients (including CVT-301-005 observational arm patients) will be randomized in a 1:1 
ratio to DL1 or DL2.  Upon confirmation of eligibility, the site will randomize an eligible patient 
using the Interactive Web Response System (IWRS).  Randomization will be differentiated by 
the patient’s Hoehn and Yahr PD disease severity scale rating (<2.5 versus ≥2.5) to balance for 
disease severity 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%).  For the patients who received placebo in CVT-301-004, the differentiation of CVT-301-
004 will be used.  Patients and site staff will be blinded to treatment level. 
9.2.2. 
Distributing Blinded Inhaled Study Treatment 
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 IFU.  The IFU will be provided to 
each patient and will be part of the permanent study record. 
In order to blind the study treatment, study kits with identical number and appearance of capsules 
will be distributed to patients in the DL1 and DL2 groups.   
The patient, investigator, study site personnel, the Sponsor, and representatives of the contract 
research organization (CRO) involved in monitoring, data management, or other aspects of the 
study, and Core Laboratories will be blinded to the inhaled study treatment. 


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Except in the case of an emergency, the study treatment codes will not be available to the 
investigator, the study site personnel, representatives of the CRO, or the Sponsor until after the 
completion of the study and final data review.  All randomization data will be kept strictly 
confidential and accessible only to authorized persons until the time of unblinding after the end 
of the study; for emergency unblinding, the site will access the IWRS or call the IWRS helpdesk.  
When the data file has been verified and the protocol violations have been determined, the drug 
codes will be made available for data analysis. 
9.2.3. 
Defining “Time 0” (T0) 
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 in the clinic and at home, “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. 
9.3. 
Treatment Accountability and Compliance 
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, 
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  
For CVT-301-naïve patients and patients from the CVT-301-009 study, 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 CVT-301-naïve patients and former CVT-301-009 patients 4-6 days 
prior to TV1 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 TV1.  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. 


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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.  
For CVT-naïve patients and patients from the CVT-301-009 study, medications taken by or 
administered to the patient for 3 months prior to SV1 will be recorded in the eCRF.  These 
patients must be stable on oral LD-containing therapy which 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).  This regimen must have been stable for at least 2 weeks prior to SV1 when not 
including Rytary, and stable for at least 6 weeks prior to SV1 when including Rytary, 
During the study, all patients’ standard PD medication regimens may be altered if needed to 
manage PD symptoms.  The addition or modification of medications or treatments may include 
other forms of oral medications except oral PRN PD medications while taking study medication.  
During the study drug holiday, patients are allowed to take oral PRN PD medication to manage 
their 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.  The total 
daily LD dose of the modified PD regimen (not including CVT-301) must not exceed 1600 mg 
per day while taking study medication.  Apomorphine is not permitted during the study. 
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, or other non-LD-containing PD medications, 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, the dose must be stable for at least 4 weeks prior to SV1. 
Patients who may be using medical marijuana as a treatment for their PD in states where the use 
of marijuana is legal for medical purposes 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.). 
Patients meet all other eligibility criteria (including spirometry). 
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 standard PD medications during the study including on 
the morning of each in-clinic treatment visit.  The timing of the administration of the usual 
morning dose of PD medications may be adjusted by the investigator to accommodate the 


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patient’s and/or clinic’s schedule.  On designated in-clinic dosing days, 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 patient will resume their standard schedule of PD medications. 
At home, patients should maintain their usual schedule of standard oral PD medications, in 
addition to using the inhaled study drug for the treatment of OFF episodes.  Patients should not 
take inhaled study drug within 45 minutes following their prior dose of standard oral PD 
medication.  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 should not take 
oral PRN PD medications to manage their OFF states throughout the treatment period. 
Standard Prescribed Oral PD Medication Use for Prolonged OFF Episodes  
In the clinic, 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 standard oral 
dose of PD medication 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, patients will be permitted to take their next scheduled dose of 
their standard prescribed PD medication; patients may not re-dose with inhaled study drug for 
that 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, and they may not take additional 
inhaled study medication. 
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: 
• Apomorphine.  Patients must not have used apomorphine for at least 4 weeks prior to 
SV1 and must not use apomorphine for the duration of the study. 
• 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. 


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• 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 visits). 
• Oral PRN PD medications during the treatment period.  CVT-301-naïve patients and 
CVT-301-009 patients are permitted to take oral PRN PD medications during the 
screening period and during the study drug holiday.  However, oral PRN PD 
medications are not permitted during the treatment period while taking study 
medication. 
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 visits are provided in Appendix 2 
through Appendix 11.  Unless otherwise specified, all assessments will be performed by the 
investigator or other assigned personnel.  
10.1. 
Assessments by Visit 
Assessments are to be performed as outlined in the following by-visit subsections.  Study 
assessments are also outlined in the Appendix 2 through Appendix 11. 
10.1.1. 
Screening Period 
CVT-301-004 patients will not be required to undergo the screening visits and will undergo TV1 
after a 1- to 14-day period (or longer if approved by the Sponsor) following TV4 of the CVT-
301-004 study. 
CVT-301-naïve patients (including CVT-301-005 observational arm patients) and patients from 
the CVT-301-009 study will undergo a screening period of up to 35 days before randomization.  
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 
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 TV1 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. 


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10.1.1.1. Screening Visit 1 for CVT-301-Naïve Patients and CVT-301-009 Patients (within 
35 days prior to randomization) 
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 14.) 
5. Use the modified Hoehn and Yahr scale to assess PD severity (in an ON state).  (Refer to 
Appendix 15.) 
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). 
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 Parts 1, 2, 3 and 4 in an ON state. 


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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. Take samples for clinical laboratory tests, including a serum pregnancy test for females 
of childbearing potential (see Appendix 13 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) 
18. Introduce the inhaler and perform inhaler training using sham capsules with the CVT-301 
inhaler while in the ON state. 
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 
days prior to SV2.  
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. 


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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 Item 26 in the above list. 
10.1.1.2. Screening Visit 2 for CVT-301-Naïve Patients and CVT-301-009 Patients (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. 
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 TV1. 
7. 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 
Parts 1, 2 and 4 (in an ON state); 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).  
8. Complete the C-SSRS, Epworth Sleepiness Scale, and QUIP (preferably in an ON state). 
9. Monitor for AEs throughout the visit.  


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10. Schedule a DLco assessment to be performed at an outside pulmonary laboratory after 
SV2 and prior to TV1.  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.  
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 TV1 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 TV1 and that they should contact the site if an intervening illness occurs prior to TV1.  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. 
10.1.2. 
Randomization to Study Drug 
Following completion of SV2 and prior to randomization (for CVT-301-naïve patients and CVT-
301-009 patients), eligibility criteria will be reviewed by the external reviewer (subjects 
requiring pulmonary adjudication may not be randomized until completion of pulmonologist 
reviewer). 
Before TV1, patients will be assigned/randomized to treatment.  Patients who received DL1 
(target nominal dose of 35 mg LD FPD) in the CVT-301-004 study will receive DL1 (target 
nominal dose of 35 mg LD FPD) in this study, and patients who received DL2 (target nominal 
dose of 50 mg LD FPD) in the CVT-301-004 study will receive DL2 (target nominal dose of 
50 mg LD FPD) in this study.  Patients who received placebo in the CVT-301-004 study, CVT-
301-009 patients, and CVT-301-naïve patients (including those from CVT-301-005 
observational arm) will be randomized in a 1:1 ratio to DL1 or DL2.  If a patient meets final 
eligibility requirements, eligibility will be reviewed by delegated staff.  Randomization will be 
differentiated by the patient’s Hoehn and Yahr disease severity scale rating (<2.5 versus ≥2.5) to 
balance for disease severity 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%).  For the patients who received placebo in CVT-301-004, the differentiation of 
CVT-301-004 will be used.  Patients and site staff will be blinded to treatment level.  Site staff 
must allow at least 5 days between date of randomization in the IWRS and the date of TV1. 
Refer to Section 9.2 for further randomization details. 
10.1.3. 
Treatment Period 
The assessments and procedures performed at TV1 will differ for patients entering from the 
CVT-301-004 study than for CVT-301-naïve patients (including those from CVT-301-005 
observational arm) and prior CVT-301-009 patients. 
All patients, regardless of treatment assignment, should continue with their usual prescribed 
standard PD medication regimen for the study duration.  This regimen may be altered if needed 


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during the course of the 14-month study.  The addition or modification of medications or 
treatments may include other forms of oral medications except oral PRN PD medications while 
taking study medication.  During the study drug holiday, patients are allowed to take oral PRN 
PD medication to manage their 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.  The total daily LD dose of the modified PD regimen (not including CVT-301) 
must not exceed 1600 mg per day while taking study medication.  Apomorphine is not 
permitted during the study. 
The treatment period includes 6 separate in-clinic 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. 
During this period, patients will self-administer inhaled study treatment (CVT-301 DL1 or CVT-
301 DL2) up to 5 times daily to treat OFF episodes during their waking day.  The first dose of 
blinded study drug will be given in the clinic at TV1 (i.e., 2-capsule inhalations per dose of either 
CVT-301 DL1 or CVT-301 DL2); patients will be given study drug kits at TV1, TV2, TV3, 
TV4, and TV5. 
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 the 
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.).  If a patient has a 
dose reduction due to tolerability concerns, he/she may be titrated back up to his/her randomized 
dose (i.e., 2 capsules) at the next scheduled study visit if the investigator determines that the 
tolerability issue has adequately resolved and the patient could potentially benefit from 
escalating back up to the original randomized dose level (i.e., 2 capsules).  This return to 
randomized dose may take place at the in-clinic visit or in between visits (if the patient and clinic 
staff talk by telephone) and may only be done once during the study.  Clinic staff will call the 
patient 1-2 days after the dose escalation to see if the patient has any questions or concerns.  If a 
patient who has a tolerability-related dose reduction is re-escalated to the randomized dose and 
experiences another tolerability issue related to dose level that requires dose reduction, he/she 
will be dose reduced for a second time and will remain on that dose for the remainder of the 
study; he/she will not be eligible for any additional up-titration to the original dose.  
Refer to Appendix 2 through Appendix 11 for tables of study assessments at each visit during the 
treatment period. 
10.1.3.1. Telephone Calls Before Treatment Visits 
• Pre TV1 call:  
− Call the CVT-301-naïve patients and CVT-301-009 patients within 4-6 days 
before TV1 for the following reasons:  to confirm the DLco assessment has been 


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done or is scheduled to occur before TV1 (can be done any time after SV2); to 
confirm the next study visit; 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 the 
CVT-301-naïve patients and CVT-301-009 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 TV1.  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.  
• Post TV1 call: 
− Call the patients 1 to 3 days after TV1 to address any potential concerns or 
challenges with the inhaler systems or Inhaled Dosing Log.   
• Pre TV2, TV3, and TV4 calls: 
− Call the patients 1 week 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 
that the DLco and spirometry visit at the pulmonary function lab has been done or 
is scheduled to occur (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. 
10.1.3.2. Treatment Visit 1 for CVT-301-004 Patients (1-14 days after TV4 in the CVT-
301-004 study) 
Informed consent will be obtained prior to receiving drug for this extension study.  Patients 
should provide written informed consent for this study at TV4 of the CVT-301-004 study.  
Patients will be instructed to take their prescribed oral PD medications on their usual schedule. 
The timing of arrival for TV1 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 of their usual 
PD medications.   
 


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On Arrival to the Clinic  
The following list is a suggested schedule for this visit: 
• Record the usual PD medication dose/regimen. 
• Record the time that patients took their usual PD medications prior to the visit. 
• Record all concomitant medications. 
• Perform a full physical examination. 
• Patient will complete the PHQ-9 in an ON state. 
• Patient will complete the AWQ and DDS-PC in an ON state. 
• Perform a 12-lead ECG (as described in Section 11.1.3). 
• Record standard and orthostatic BP and HR (see Section 11.1.2).  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. 
• Complete the C-SSRS and Epworth Sleepiness Scale, (preferably in the ON state). 
• Complete the UPDRS Parts 1 and 2 (preferably in the ON state). 
• Patient will complete the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in an ON state) 
• Re-train patients on the proper use of the inhaler with sham capsules, including a 
review of the IFU. 
• Distribute the PD Diary and review instructions for recording time asleep, time OFF, 
time ON without dyskinesia, time ON with non-troublesome dyskinesia, and time ON 
with troublesome dyskinesia (to be completed for the 3 consecutive days prior to 
TV2, TV3, TV4, TV5, and TV6). 
• Distribute the Inhaled Dosing Log and review instructions 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 13-month treatment period). 
• Distribute study drug kits to patients.   
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 blinded study drug from the study drug kits that were provided 
(i.e., 2 capsule inhalations of either CVT-301 DL1 or CVT-301 DL2).  Patients will be permitted 
sips of water between capsule inhalations as needed.  


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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 Appendix 17 for 
additional system information. 
Post-dose (10 – 60 minutes) 
After dosing, patients will undergo serial safety evaluations.  Refer to Appendix 4 for the 
detailed time and events table.  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. 
• Evaluate spirometry at 15, 30, and 60 minutes post-dose.  At the time of each 
spirometry assessment, clinic staff will record the patient’s motor state.  If within the 
first 60 minutes after inhalation, the patient’s spirometry assessment shows either of 
the following, the patient will NOT be sent home with study drug, and the site will 
follow the Spirometry Alert and Review Process:  a decrease in FEV1 ≥ 20% AND a 
decrease in FEV1 by 200 mL compared with pre-dose results, and/or a reduction in 
the FEV1/FVC ratio to <60%.  If either criteria are met, the patient will NOT be sent 
home with study drug and the procedures described in Appendix 18 will be followed. 
• 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).  Clinic staff will arrange to 
speak with patients by telephone 1 to 3 days after TV1 to monitor for AEs and to address any 
potential concerns or challenges with the inhaler systems or Inhaled Dosing Log.  The next visit 
will be scheduled.  Additionally, clinic staff will arrange to speak with patients by telephone 1 
week 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 and spirometry visit at the pulmonary function lab 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 required prior to the next scheduled study visit (including completion of the PD Diary 
and Inhaled Dosing Log).   
10.1.3.3. Treatment Visit 1 for CVT-301-Naïve Patients and CVT-301-009 Patients (at 
least 7 days after SV2) 
Patients will complete the PD Diary and the Screening ON/OFF Episodes Log 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 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 of their usual PD medications. 
 


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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 at the pulmonary lab.  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. 
• Patient will complete the PDQ-39 and PHQ-9 in an ON state. 
• Patient will complete the AWQ and DDS-PC in an ON state. 
• Perform a brief physical examination. 
• Complete the UPDRS Parts 1 and 2 and S&E ADL scales (preferably in the ON 
state). 
• Complete the UPDRS Part 4 (Questions 32-35 and 36-39) (preferably in the ON 
state). 
• 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 C-SSRS, Epworth Sleepiness Scale, and the QUIP (preferably in the ON 
state). 
• Patient will complete the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in an ON state) 
• Re-train patients on the proper use of the inhaler with sham capsules, including a 
review of the IFU. 
• Distribute the PD Diary and review instructions for completion for recording time 
asleep, time OFF, time ON without dyskinesia, time ON with non-troublesome 
dyskinesia, and time ON with troublesome dyskinesia (to be completed for the 
3 consecutive days prior to TV2, TV3, TV4, TV5, and TV6). 
• 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 


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for each inhalation treatment (to be completed daily throughout the 13-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. 
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 blinded study drug from the study drug kits provided (i.e., 
2 capsule inhalations of either CVT-301 DL1 or CVT-301 DL2).  Patients will be permitted sips 
of water between capsule inhalations as needed.  
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 Appendix 17 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. 
• Evaluate spirometry at 15, 30, and 60 minutes post-dose.  At the time of each 
spirometry assessment, clinic staff will record the patient’s motor state.  If within the 
first 60 minutes after inhalation, the patient’s spirometry assessment shows either of 
the following, the patient will NOT be sent home with study drug, and the site will 
follow the Spirometry Alert and Review Process:  a decrease in FEV1 ≥ 20% AND a 
decrease in FEV1 by 200 mL compared with pre-dose results, and/or a reduction in 
the FEV1/FVC ratio to <60%.  If either criteria are met, the patient will NOT be sent 
home with study drug and the procedures described in Appendix 18 will be followed. 
• 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 TV1 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 1 
week 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 and spirometry visit at the pulmonary function lab 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 


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procedures required prior to the next scheduled study visit (including completion of the PD Diary 
and Inhaled Dosing Log). 
10.1.3.4. At-Home Dosing 
At TV1, TV2, TV3, TV4, and TV5, patients will receive study drug kits and the IFU to take 
home with them, except during the study drug holiday.  Patients will also receive study drug kits 
and the IFU to take home with them at TV4.1, TV5.1, or at an Unscheduled Visit. Patients will 
be instructed to continue with their usual prescribed standard PD medication regimen for the 
study duration.  This regimen may be altered if needed during the course of the 14-month study.  
The addition or modification of medications or treatments may include other forms of oral 
medications except oral PRN PD medications while taking study medication.  During the study 
drug holiday, patients are allowed to take oral PRN PD medication to manage their 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.  The total daily LD dose of the 
modified PD regimen (not including CVT-301) must not exceed 1600 mg per day while taking 
study medication.  Apomorphine is not permitted during the study. 
Any modifications to the standard PD dose and/or regimen will be recorded in the eCRF. 
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.  Patients may not take oral PRN medications to 
manage OFF states during the treatment period.   
*Note: If Study CVT-301-009 supports the safety and tolerability of CVT-301 administration 
in the early morning, investigators will be informed that participants in the current study 
CVT-301-004E can start to take study drug for early morning OFF periods. Until that time 
study drug may not be used to treat morning akinesia.   
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 oral 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 13-month 
treatment period, excluding the study drug holiday.  As described previously, patients will be 
contacted by the clinic staff 1 to 3 days after TV1 and 1 week prior to each visit for TV2, TV3, 


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TV4, TV5, and TV6.Patients will bring the PD Diary, Inhaled Dosing Log, and used supplies, 
including empty capsules and inhalers, as well as any unused supplies to the clinic visit. 
10.1.3.5. Treatment Visit 2 for all Patients (1 month [4 weeks ±5 days] after TV1) 
Patients will complete the PD Diary for the 3 consecutive days prior to TV2, and patients will 
complete 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. 
• 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. 
• Patient will complete the PDQ-39, PHQ-9, and PGI-C in an ON state. 
• Complete the UPDRS Part 2 and S&E ADL scales (preferably in the ON state). 
• Complete the UPDRS Part 4 (Questions 32-35 and 36-39) (preferably in the ON 
state). 
• 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 the C-SSRS, Epworth Sleepiness Scale, and the QUIP (preferably in the ON 
state). 
• Patient will complete the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in an ON state) 
• Distribute new study drug kits.  
• Review inhaler training with the patient. 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion. 


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• 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. Under clinic staff 
supervision, patients will prepare and self-administer their entire dose of inhaled 
study drug (CVT-301 DL1 or CVT-301 DL2).  
• Observe the patient for the appearance of dyskinesia and note in the source record if 
the patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of the dyskinesia.   
• 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. 
• 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. 
• 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 also schedule the DLco and spirometry visit 
within 2 weeks prior to TV3.  These assessments 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. Clinic staff will arrange to speak with patients by telephone 1 week 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 and spirometry visit at the pulmonary function lab 
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).   
10.1.3.6. Treatment Visit 3 for all Patients (3 months 12±2 weeks after TV1) 
Patients will complete the PD Diary for the 3 consecutive days prior to TV3, and patients will 
complete the Inhaled Dosing Log daily throughout the treatment period.  They 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.   


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• Collect used empty capsules and inhalers and unused supplies. 
• Confirm that the DLco and spirometry visit at the pulmonary function lab was 
performed within 2 weeks prior to TV3.  If these assessments were not 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. 
• Patient will complete the PDQ-39, PHQ-9, and PGI-C scale in an ON state. 
• Complete the UPDRS Part 2 and S&E ADL scales (preferably in the ON state). 
• Complete the UPDRS Part 4 (Questions 32-35 and 36-39) (preferably in the ON 
state). 
• Perform the C-SSRS, Epworth Sleepiness Scale, and QUIP (preferably in the ON 
state). 
• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Patient will complete the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in an ON state) 
• Perform a 12-lead ECG. 
• 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 (if needed). 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion. 
• 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. Under clinic staff 
supervision, patients will prepare and self-administer their entire dose of inhaled 
study drug (CVT-301 DL1 or CVT-301 DL2).  
• Observe the patient for the appearance of dyskinesia and note in the source record if 
the patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of the dyskinesia.   
• 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. 


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• 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. 
• 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 also schedule the DLco and spirometry visit 
within 2 weeks prior to TV4.  These assessments 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. Clinic staff will arrange to speak with patients by telephone 1 week 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 and spirometry visit at the pulmonary function lab 
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).   
10.1.3.7. Treatment Visit 4 for all Patients (6 months [24±2 weeks] after TV1) 
Patients will complete the PD Diary for the 3 consecutive days prior to TV4, and patients will 
complete the Inhaled Dosing Log daily throughout the treatment period.  They 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 (also refer to Section 10.1.4 for patients entering the 
study drug holiday and withdrawal sub-study): 
• 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 and spirometry visit at the pulmonary function lab was 
performed within 2 weeks prior to TV4.  If these assessments were not 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. 
• Patient will complete the PDQ-39, PHQ-9, and PGI-C scale in an ON state. 


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• Complete the UPDRS Part 2 and S&E ADL scales (preferably in the ON state). 
• Complete the UPDRS Part 4 (Questions 32-35 and 36-39) (preferably in the ON 
state). 
• Perform the C-SSRS, Epworth Sleepiness Scale, and QUIP (preferably in the ON 
state). 
• Perform a full physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Patient will complete the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in an ON state) 
• Perform a 12-lead ECG. 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Distribute new study drug kits for patients not entering the study drug holiday.  
• Review inhaler training with the patient (if needed) for patients not entering the study 
drug holiday. 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion for patients not entering the study drug holiday. 
• 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. Under clinic staff 
supervision, patients will prepare and self-administer their entire dose of inhaled 
study drug (CVT-301 DL1 or CVT-301 DL2).  
• Observe the patient for the appearance of dyskinesia and note in the source record if 
the patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of the dyskinesia.   
• 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. 
• 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 for patients not 
entering the study drug holiday. 
• 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 for patients not entering the 
study drug holiday). 


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The next visit will be scheduled.  Clinic staff will also schedule the DLco and spirometry visit at 
the pulmonary function lab within 2 weeks prior to TV5.  These assessments 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.  Clinic staff will arrange to speak with 
patients by telephone 1 week 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 and 
spirometry visit at the pulmonary function lab 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).   
10.1.3.8. Treatment Visit 5 for all Patients (9 months [36±2 weeks] after TV1) 
Patients will complete the PD Diary for the 3 consecutive days prior to TV5, and patients will 
complete the Inhaled Dosing Log daily throughout the treatment period.  They 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 (also refer to Section 10.1.4 for patients entering the 
study drug holiday and withdrawal sub-study): 
• 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 and spirometry visit at the pulmonary function lab was 
performed within 2 weeks prior to TV5.  If these assessments were not 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. 
• Patient will complete the PDQ-39, PHQ-9, and PGI-C scale in an ON state. 
• Complete the UPDRS Part 2 and S&E ADL scales (preferably in the ON state). 
• Complete the UPDRS Part 4 (Questions 32-35 and 36-39) (preferably in the ON 
state). 
• Perform the C-SSRS, Epworth Sleepiness Scale, and QUIP (preferably in the ON 
state). 


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• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Patient will complete the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in an ON state) 
• Perform a 12-lead ECG. 
• Collect blood for clinical laboratory tests including serum pregnancy test, if 
applicable.  Document fasting status. 
• Distribute new study drug kits for patients not entering the study drug holiday. 
• Review inhaler training with the patient (if needed) for patients not entering the study 
drug holiday. 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion for patients not entering the study drug holiday. 
• 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. Under clinic staff 
supervision, patients will prepare and self-administer their entire dose of inhaled 
study drug (CVT-301 DL1 or CVT-301 DL2).  
• Observe the patient for the appearance of dyskinesia and note in the source record if 
the patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of the dyskinesia.   
• 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. 
• 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 for patients not 
entering the study drug holiday. 
• 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 for patients not entering the 
study drug holiday). 
The next visit will be scheduled.*Clinic staff will also schedule the DLco and spirometry visit 
within 2 weeks prior to TV6.  These assessments 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. Clinic staff will arrange to speak with patients by telephone 1 week 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 and spirometry visit at the pulmonary function lab 


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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).  
*Patients who have already completed TV5 at the time of implementation of protocol 
Version 5.2 will have the option to consent to this amendment at an Unscheduled Visit prior 
to TV6, at which time they will receive an additional 4 weeks of study drug so that TV6 can 
be scheduled for approximately 13 months (56±2 weeks) after TV1. These patients will 
participate in the withdrawal sub-study post-TV6 as described in Section 10.1.4. 
10.1.3.9. Treatment Visit 6 for all Patients (13 months [56±2 weeks] or 14 months (60 ±2 
weeks) after TV1)/Early Withdrawal Visit 
Treatment Visit 6 will constitute the end-of-study visit.  Patients will complete the PD Diary for 
the 3 consecutive days prior to TV6, and patients will complete the Inhaled Dosing Log daily 
throughout the treatment period.  They 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 (also refer to Section 10.1.4 for patients entering the 
withdrawal sub-study): 
• 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 and spirometry visit at the pulmonary function lab was 
performed within 2 weeks prior to TV6.  If these assessments were not 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. 
• Patient will complete the PDQ-39, PHQ-9, and PGI-C scale in an ON state. 
• Complete the UPDRS Part 2 and S&E ADL scales (preferably in the ON state). 
• Complete the UPDRS Part 4 (Questions 32-35 and 36-39) (preferably in the ON 
state). 
• Perform the C-SSRS, Epworth Sleepiness Scale, and QUIP (preferably in the ON 
state). 


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• Perform a brief physical examination. 
• Record standard vital signs (BP, HR, and RR) and orthostatic vital signs (BP and 
HR). 
• Patient will complete the Impact of Parkinson’s OFF Episodes Patient Survey 
(preferably in an ON state) 
• Perform a 12-lead ECG. 
• 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. Under clinic staff 
supervision, patients will prepare and self-administer their entire dose of inhaled 
study drug (CVT-301 DL1 or CVT-301 DL2).  
• Observe the patient for the appearance of dyskinesia and note in the source record if 
the patient experiences dyskinesia at any time within the 60-minute post-dose period.  
Also, if applicable, record the maximum severity of the dyskinesia.   
• 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 and spirometry 
visit at the pulmonary lab 4 to 5 weeks after completion of TV6.  These assessments 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. 
10.1.4. 
Sub-Study to Assess Potential Withdrawal Symptoms 
After patients are consented to protocol Version 5.2, they will participate in a withdrawal 
symptom sub-study at the end of TV4, TV5, or TV6, depending on which of the visits is the next 
scheduled one for the patient.  In addition to the assessments detailed in the previous sections for 
the treatment visit, the AWQ and DDS-PC will be performed upon arrival in the ON state, and 
the UPDRS Part 1 will be performed preferably in the ON state.  
When study activities for the visit are completed, patients will begin a 28-day period of 
assessment of potential drug withdrawal symptoms. To this end, patients who are at TV4 or TV5 
at the time of consent will go on a study drug holiday for this time period. All patients in the 
withdrawal sub-study (patients consented to protocol Version 5.2) will be given copies of the 
AWQ, the DDS-PC, PHQ-9, Epworth Sleepiness Scale, C-SSRS (self-report version), and the 
self-administered MDS-UPDRS Parts 1B and 2 (Movement Disorder Society -UPDRS) to be 
completed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 28 days after the treatment visit. Patients 
should fill out the questionnaires during their first ON state (after the intake of their first 
scheduled dose of standard oral PD medication) on each of these days. The site will call patients 


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at 14 (±3) days after the treatment visit to remind them to complete the questionnaires, and to 
inquire about potential adverse events and changes in concomitant medications.  Patients who 
enter the withdrawal sub-study after TV6 will also receive a call at 28 (±3) days. 
Patients who entered the study drug holiday will be scheduled to return to the clinic for a drug re-
supply visit (see Section 10.1.4.1), and resumption of the full course of study treatment. Patients 
who entered the withdrawal sub-study after TV6 will be completed with the study after they 
return the questionnaires and undergo the DLco and spirometry assessment 4 to 5 weeks after 
completion of TV6, as described in Section 10.1.3.9. 
10.1.4.1. Treatment Visit 4.1/5.1 (28 days+1 week after TV4 or TV5)  
The following procedures will be performed at the drug re-supply visit to be scheduled at the 
conclusion of the patient’s study drug holiday: 
• Collect completed questionnaires 
• Record any changes in the usual PD medication dose/regimen. 
• Record any changes in concomitant medications. 
• Record any adverse events. 
• Distribute new study drug kits. 
• Review inhaler training with the patient (if needed). 
• Distribute the PD Diary and Inhaled Dosing Log and review instructions for 
completion 
10.1.5. 
Early Withdrawal Visit 
Patients who withdraw prematurely will complete the TV6 assessments (see Section 10.1.3.9), 
except for the pre-TV6 DLco and spirometry assessments, at the time of withdrawal.  In addition, 
patients will be scheduled the DLco and spirometry visit 4 to 5 weeks after completion of the 
Early Withdrawal Visit.  The DLco and spirometry assessments 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. Patients who withdraw prematurely and prior to participating in the sub-study to 
assess potential withdrawal symptoms will complete the withdrawal assessments during the 28 
days following completion of the TV6 assessments (see Section 10.1.4). 
10.1.6. 
Unscheduled Visits 
An unscheduled visit may occur when indicated at the discretion of the Investigator.  The 
following are potential circumstances for unplanned visits: 
• For CVT-301-naïve patients, 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 
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• For CVT-301-naïve patients, 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.).   
• Patients who have completed TV5 at the time of implementation of protocol Version 
5.2 will have the option to consent to this amendment at an Unscheduled Visit prior to 
TV6, at which time they will receive an additional 4 weeks of study drug so that TV6 
can be scheduled for approximately 13 months (56±2 weeks) after TV1. 
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, impulse control disorders, and withdrawal 
symptoms 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 10.  Genital, rectal, and 
breast examination may be excluded if not clinically indicated.  The physical examination will 
include height (cm) and weight (kg) only at screening.  Physical examinations will be performed 
by a 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 10.  
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. 
 
 


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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. 
• 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. 


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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 10 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 13.  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 
 
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) for CVT-301-naïve 
patients and CVT-301-009 patients, and at TV1, TV3, TV4, TV5, and TV6, 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 
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. 


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11.1.6. 
Spirometry 
The following is a description of the pulmonary function testing at clinical sites and at dedicated 
pulmonary function facilities: 
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 collected by the 
study sites will reviewed by a central spirometry laboratory 
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.  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/European 
Respiratory Society (ERS) criteria.  The results of the bronchodilator challenge will be reviewed 
by a pulmonologist prior to potential randomization. Any CVT-301-naïve patients or CVT-301-
009 patients requiring pulmonary adjudication at screening will not be randomized until after full 
pulmonologist review. 
Spirometry assessments will be done at the time points indicated in Appendix 2 through 
Appendix 10.  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 
for CVT-301-naïve patients and CVT-301-009 patients at SV1, SV2 (if necessary) and TV1 (all 
patients). All other spirometry assessments will be collected during the DLco and spirometry 
visits that take place at the pulmonary function lab.  Spirometry data collected at pulmonary 
function labs will be reviewed immediately by a pulmonologist on site for safety signals and then 
sent to and reviewed by a central Pulmonary Function Testing reviewer (TechEd Consultants).   
11.1.7. 
Carbon Monoxide Diffusing Capacity (diffusing capacity of the lungs for carbon 
monoxide-DLco) 
Patients will undergo DLco assessments, which will be acquired in accordance with ATS criteria 
(Miller et al., 2005), at a dedicated pulmonary function facility after SV2 (and prior to TV1; 301-
naïve patients and CVT-301-009 patients), within 2 weeks prior to TV3, TV4, TV5, and TV6, 
and at 4 to 5 weeks after TV6, as described in the Appendix 3 through Appendix 10.  These 
assessments should be performed while the patient is in the ON state (as reported by the patient 
to the pulmonary technician).  Pulmonary function facility technicians will perform a slow vital 
capacity maneuver, followed by DLco, and then spirometry.  The pulmonary facilities will use 


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their own equipment to perform all necessary pulmonary function testing relevant to DLco 
acquisition. 
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 (defined as SV1 of the CVT-301-004E 
study for CVT-301-naïve and CVT-301-009 patients and SV1 of the CVT-301-004 study for 
CVT-301-004 patients) and new symptoms, physical signs, syndromes, or diseases should be 
noted on the AE page of the eCRF during the study.  For these AEs captured on the AE eCRF for 
CVT-301- naïve and CVT-301-009 patients, AEs reported prior to the first study treatment at 
TV1 will be considered baseline AEs, and AEs reported from first treatment 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 2 and Table 3, respectively. 
Table 2 
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. 
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 3 
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.  
 
 
 
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 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 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 as 
indicated in the time and events tables in Appendix 2 through Appendix 10.  The baseline 
assessment for CVT-301-naïve and CVT-301-009 patients will be completed at TV1.  The 
baseline assessment for CVT-301-004 patients will have been completed at TV1 of CVT-301-
004 study.  
Additionally, during the post-dosing follow-up period at TV2, TV3, TV4, TV5, and TV6, the 
examiner will observe the patient for the appearance of dyskinesia during the 60-minute post-
dose period and the maximum severity (mild, moderate, or severe) of any dyskinesia in the 60-
minute post-dose period will be noted in the eCRF.  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-Suicide 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.  For 
CVT-301-naïve and CVT-301-009 patients, an initial baseline version will be given at SV2, and 
for all patients, a “since last visit” version will be given at all treatment visits to detect any 
emergence of suicidal ideation or behavior.  CVT-301-004 patients will have completed the 
baseline version during TV1 of the CVT-301-004 study.  The clinic staff should address any 
emerging neuropsychiatric needs in the event that the C-SSRS indicates active suicidal ideation. 
Additional assessments of the C-SSRS will be completed as indicated in the time and events 
tables in Appendix 4 through Appendix 10. The self-report version of the C-SSRS will be 
completed at home during the withdrawal assessment period. 
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 for CVT-301-naïve patients and CVT-301-009 patients will be completed at TV1 of 
this study.  The baseline assessment for CVT-301-004 patients will have been performed at TV1 
of the CVT-301-004 study (except for assessment of withdrawal symptoms).  As described in 
Appendix 3 through Appendix 10, additional assessments will be completed at TV2, TV3, TV4, 
TV5, and TV6 (or Early Withdrawal, if applicable), and post-TV6. 


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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 for CVT-301-naïve 
patients and CVT-301-009 patients will be completed at TV1 of this study.  The baseline 
assessment for CVT-301-004 patients will have been performed at TV1 of the CVT-301-004 
study.  As described in Appendix 4 through Appendix 10, additional assessments will be 
completed at TV2, TV3, TV4, TV5, and TV6 (or Early Withdrawal, if applicable). 
11.1.12.5. Dopamine Dysregulation Syndrome - Patient and Caregiver Inventory (DDS-
PC) 
The DDS-PC inventory is used to help identify patients who experience impulsive-compulsive 
behaviors associated with dopamine dysregulation syndrome.  Patients will complete the 
questionnaire upon arrival at the clinic in an ON state at TV1 and at the visit at which the 
withdrawal assessment period begins (TV4, TV5, TV6 or Early Withdrawal). Additional 
assessments will be completed in an ON state at home during the withdrawal assessment period 
at the time points indicated in Appendix 8 through Appendix 10. 
11.1.12.6. Amphetamine Withdrawal Questionnaire (AWQ) 
The AWQ will be completed by patients to assess potential withdrawal symptoms.  Patients will 
complete the scale upon arrival at the clinic in an ON state at TV1 and at the visit at which the 
withdrawal assessment period begins (TV4, TV5, TV6 or Early Withdrawal). Additional 
assessments will be completed in an ON state at home during the withdrawal assessment period 
at the time points indicated in Appendix 8 through Appendix 10. 
11.2. 
Efficacy Assessments 
Efficacy will be evaluated from both in-clinic and at-home assessments, as outlined by the 
following criteria: 
In-Clinic Criteria: 
• 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  
• PDQ-39 
• PHQ-9 
• Impact of Parkinson’s OFF Episodes Patient Survey 
• PGI-C 
• S&E ADL 
• UPDRS Part 2 
 


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At-Home Criteria: 
• 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.  
11.2.1. 
Assessment of ON and OFF States and Dyskinesia 
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.   
11.2.1.1. In-Clinic Assessments 
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 TV1 (for CVT-301-naïve and CVT-301-009 
patients), and TV2, TV3, TV4, TV5, and TV6, patients 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). 
New diaries will be distributed at each study visit, except for TV6, 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) 
The CVT-301-naïve patients and CVT-301-009 patients will record the discrete number of OFF 
episodes experienced by the patient during their waking day in the Screening ON/OFF Episodes 


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Log for the 3 consecutive days prior to SV2 and TV1.  These logs will be distributed at SV1 and 
SV2, and patients will bring the completed logs to the clinic at SV2 and TV1.  Information in the 
logs will be reviewed and recorded by clinic staff. 
11.2.1.2.3. Inhaled Dosing Log (for the Treatment Period) 
Every day during the treatment period, patients 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 TV1, TV2, TV3, TV4, and TV5, and patients will bring the 
completed logs to the clinic at TV2, TV3, TV4, TV5, and TV6.  Information in the logs will be 
reviewed and recorded by clinic staff. 
11.2.2. 
UPDRS Part 3 
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 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%.   
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 
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 in the ON state as indicated in the time and events tables in 
Appendix 5 through Appendix 10.  The baseline assessment for CVT-301-naïve and CVT-301-
009 patients will be completed at TV1.  The baseline assessment for CVT-301-004 patients will 
have been completed at TV1 of CVT-301-004 study. 
11.2.4. 
PHQ-9 
The PHQ-9 is the nine item self-report depression scale of the Patient Health Questionnaire 
which incorporates the nine diagnostic criteria for major depressive disorder in the DSM-IV 
(Diagnostic and Statistical Manual Fourth Edition). Patients are asked to rate the frequency of 
symptoms on a scale of 0 (“not at all”) to 3 (“nearly every day”). The PHQ-9 is used to 
characterize affective and motivational states (apathy) in these patients. 
The PHQ-9 will be completed in the ON state as indicated in the time and events tables in 
Appendix 4 through Appendix 10, including during the withdrawal assessment period at home.   


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11.2.5. 
PGI-C 
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 will be completed in the ON state as indicated in the time and events tables in 
Appendix 6 through Appendix 10. The extent of change will be determined in relation to when 
the patient first received active study medication.  
11.2.6. 
Impact of Parkinson’s OFF Episodes Patient Survey 
The Impact of Parkinson’s Off Episodes Patient Survey is a survey for patients with PD to report 
on their symptom management with medications.  Patients will complete the survey at all 
treatment visits or the Early Termination visit, if applicable. 
11.2.7. 
Schwab & England Activities of Daily Living 
The S&E ADL scale will be completed by a qualified rater upon arrival as indicated in the time 
and events tables in Appendix 5 through Appendix 10, preferably while the patient is in the ON 
state.  The baseline assessment for CVT-301-naïve and CVT-301-009 patients will be completed 
at TV1.  The baseline assessment for CVT-301-004 patients will have been completed at TV1 of 
CVT-301-004 study. 
11.2.8. 
UPDRS Part 2 and MDS-UPDRS Part 2 
The UPDRS Part 2 is an evaluation of the ADL; this will be assessed by a qualified rater as 
indicated in the time and events tables in Appendix 2 through Appendix 10, preferably while the 
patient is in the ON state.  The baseline assessment for CVT-301-naïve and CVT-301-009 
patients will be completed at TV1.  The baseline assessment for CVT-301-004 patients will have 
been completed at TV1 of CVT-301-004 study (except for assessment of withdrawal symptoms).   
The self-administered MDS-UPDRS Part 2 will be completed at home during the withdrawal 
assessment period (see Appendix 8 through Appendix 10).  
11.3. 
Other Assessments Used for Baseline Disease Characteristics 
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. 
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 14 and discussed in Hughes (1992). 


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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 15).  
11.3.3. 
UPDRS Part 1 and MDS-UPDRS Part 1B 
The UPDRS Part 1 assesses the non-motor impact of Parkinson’s disease (PD) on patients’ 
experiences of daily living, and will be performed at SV1 as part of the baseline characterization 
of the patient (not used to determine eligibility).  Additionally, it will be performed at TV1 and at 
the visit at which the withdrawal assessment period begins (TV4, TV5, TV6 or Early 
Withdrawal), The self-administered MDS-UPDRS Part 1B will be completed at home during the 
withdrawal assessment period (see Appendix 8 through Appendix 10). 
11.3.4. 
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. 
11.3.5. 
Pulmonary Function Baseline Questionnaire 
The patient’s pulmonary history will be recorded by completing the Pulmonary Function 
Baseline Questionnaire at SV1 of this study for CVT-301-naïve and CVT-301-009 patients and 
at SV1 of the CVT-301-004 study for CVT-301-004 patients.  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. 
Optional Videotaping at Select Study Sites 
At select study sites, and in compliance with all applicable country-specific, state, and local laws 
and regulations, patients may be invited to participate in a videotaping of the inhaled medication 
dosing procedure and some specified study procedures.  These videos will be used by the 
Sponsor for purposes of reviewing and improving the dosing procedure.  Additionally, the videos 
may be used for educational and demonstration purposes for Sponsor staff, regulatory 
authorities, patients, nurses, and physicians.  Any potential identifying features will be blurred in 
any final video reproduction that is prepared.  If a selected study site does not possess the 
capabilities to perform the videography, a third-party company will manage the videotaping.  
Patients who agree to be videotaped and/or photographed will sign a separate consent form. 
11.5. 
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 


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training in UPDRS Part 2, UPDRS Part 3, UPDRS Part 4, S&E ADL scales and C-SSRS 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 PHQ-9 is a 9-item depression scale of the Patient 
Health Questionnaire. 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 
summary tables will be provided.  Summary statistics will be presented by dose group. 
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.  The SAP 
may be updated during the conduct of the study and will be finalized before the data base lock. 
However, the analyses defined after the blind of study CVT-301-004 has been broken will be 
considered as exploratory. 
12.1. 
Determination of Sample Size 
The study is planned is to enroll approximately 390 patients to ensure that approximately 290 
patients will complete the 12 month study. All patients who completed the CVT-301-004 and the 
CVT-301-009 study per protocol without any safety issues are eligible. In addition, CVT-301-
naïve patients, including those who participated in the CVT-301-005 observational arm may be 
enrolled to achieve the planned enrollment. The sample size will also include former CVT-301-
003 subjects who enrolled under previous versions of this protocol, but were no longer eligible 
under V4.0. 
12.2. 
Study Populations 
All patients who are enrolled in CVT-301-004E and receive at least 1 dose of CVT-301 will be 
included in the safety analyses and will be grouped according to the highest dose received.  All 
patients who are enrolled in CVT-301-004E and who receive at least 1 dose of CVT-301 will be 
included in the efficacy analyses as well but will be grouped according to the randomized 
treatment. 
12.3. 
Definition of Baseline 
For all statistical analyses, except for assessments of withdrawal symptoms, the visit at which the 
CVT-301 treatment is initiated will be used as the baseline. This will be TV1 from the CVT-301-


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004 study for actively treated patients, i.e. randomized to DL1 or DL2. However, TV1 of the 
CVT-301-004E study will be used as the baseline for all placebo-treated subjects from study 
CVT-301-004, for patients from study CVT-301-009, and for patients from the observational 
arm of study CVT-301-005 and other CVT-301 naïve patients. 
12.4. 
Background and Demographic Characteristics 
Demographics and baseline characteristics will be summarized descriptively for the safety/ITT 
population.  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) 
• 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 each dose level.  For the 
patients who received CVT-301 treatment in the CVT-301-004 study, the total exposure will be 
the sum of exposure in the CVT-301-004 study and the CVT-301-004E study. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary.  The TEAEs (i.e., events which start or worsen during the study treatment) will be 
tabulated by treatment group, system organ class, and preferred term.  Both patient and event 
counts will be calculated.  In addition, the TEAEs will be evaluated by seriousness, severity, and 
causality to the study treatment.  The AEs leading to a premature discontinuation or dose 
adjustment will also be summarized.  The AEs will be summarized by dose level (CVT-301 DL1 
or CVT-301 DL2).  Descriptive statistics will be used to describe the overall incidence of TEAE 
normalized for duration of exposure (number of TEAEs divided by the total exposure to CVT-
301 measured as patient years).  Furthermore, the time of onset of the TEAEs will be 
summarized.   


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For vital signs, ECG parameters, spirometry, the changes from pre-dose to post-dose assessments 
of the corresponding day will be calculated and compared between the treatment groups using 
descriptive statistics.  For spirometry and safety laboratory variables, the differences in pre-dose 
values between study days will be described.  Furthermore, the changes in the spirometry values 
and difference between the groups (DL1/DL2 or patients treated with CVT-301/placebo in CVT-
301-004) will be estimated using a Mixed Model for Repeated Measurements (MMRM) similar 
to the one used for the efficacy variables.  The proportions of patients meeting ATS quality 
criteria (and also for those ‘rejected’) will be summarized.  Changes from baseline to follow-up 
in the rating scales for assessing suicidality, somnolence, and impulse control disorders will be 
summarized descriptively.  
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 
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. 
• For the AWQ, DDS-PC, PHQ-9, Epworth Sleepiness Scale, C-SSRS, and UPDRS 
Parts 1 and 2, the change from baseline to days 1, 3, 6, 8, 11, 14, 17, 24, and 28 of the 
withdrawal symptom assessment period will be summarized descriptively. 
12.5.1. 
Interim Safety Data Review 
Safety data will be reviewed by an independent 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, 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. 
There will be no prospective interim evaluation of efficacy endpoint data. 
12.6. 
Efficacy Analysis 
The derivation of the efficacy variables will be defined in detail in the SAP. 


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All patients who are enrolled in CVT-301-004E and who receive at least 1 dose of CVT-301 will 
be included in the efficacy analyses as well but will be grouped according to the randomized 
treatment.  
The data for patients who were enrolled in the CVT-301-004 study, the CVT-301-009 study and 
for the CVT-301-naïve patients study will be primarily analyzed together, while the patients who 
were enrolled in the CVT-301-003 study will be analyzed separately.  A sensitivity analysis will be 
performed for the patients who enrolled in the CVT-301-004 study separately and for the CVT-
301-naïve patients separately. 
The changes within each dose level and the overall change from baseline in continuous efficacy 
variables will be estimated using an MMRM.  Although the focus of this study is to describe the 
within-group changes, the differences between the dose levels will be estimated as well, but no 
inferential analyses regarding the between-group differences will be done.  The model will 
include the treatment group (CVT-301 DL1 or CVT-301 DL2), visit, the stratification variables 
(Hoehn and Yahr disease severity scale rating and screening FEV1 and/or FEV1/FVC) and the 
interaction between the treatment group and visit as fixed factors.    The baseline value will be 
used as a covariate, if available.  The categorical data will be primarily evaluated descriptively. 
Each visit will be tested separately. 
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 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 


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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. 
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 


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• 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 
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 


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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. 
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. 
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. 
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. 
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. 
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. 
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. 
Grosset KA, Morgan F, Grosset D. Inhaled apomorphine (VR040) for “off” periods in 
Parkinson’s disease. Movement Disorders 2011; 26(2):S129-130. 
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. 
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. 
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. 
Kassirer JP, Angell M. On authorship and acknowledgments. N Engl J Med 1991; 325(21): 
1510-1512. 
LeWitt PA. Levodopa for the Treatment of Parkinson’s Disease. N Engl J Med 2008; 
359:2468-2476. 
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 
26:319-338. 
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. 


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Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of PD – 
2009. Neurology 2009; 72(Suppl 4):S1-136. 
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. 
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. 
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. 
Pfeiffer RF. Antiparkinsonian agents: drug interactions of clinical significance. Drug Safety 
1996; 14 (5):343-354. 
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. 
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. 
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. 
 


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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) for CVT-301-Naïve 
Patients (including CVT-301-005 observational arm patients) and CVT-
301-009 Patients (within 35 days prior to randomization) 
Appendix 3 
Time and Events Table-Screening Visit 2 (SV2) for CVT-301-Naïve 
Patients (including CVT-301-005 observational arm patients) and CVT-
301-009 Patients (at least 4 days after SV1) 
Appendix 4 
Time and Events Table-Treatment Visit 1 (TV1) for CVT-301-004 
Patients (1-14 days after TV4 in the CVT-301-004 study) 
Appendix 5 
Time and Events Table-Treatment Visit 1 (TV1) for CVT-301-Naïve 
Patients (including CVT-301-005 observational arm patients) and CVT-
301-009 Patients (at least 7 days after SV2) 
Appendix 6 
Time and Events Table-Treatment Visit 2 (TV2) for all Patients (1 Month 
[4 Weeks ±5 days] after TV1)  
Appendix 7 
Time and Events Table-Treatment Visit 3 (TV3) for all Patients (3 Months 
[12±2 Weeks] after TV1) 
Appendix 8 
Time and Events Table-Treatment Visit 4 (TV4) for all Patients (6 Months 
[24±2 Weeks] after TV1)  
Appendix 9 
Time and Events Table-Treatment Visit 5 (TV5) for all Patients (9 Months 
[36±2 Weeks] after TV1) 
Appendix 10 
Time and Events Table-Treatment Visit 6 (TV6) for all Patients (13 
Months [56±2 Weeks or 14 Months [60 ±2 Weeks] after TV1)/ Early 
Withdrawal Visit 
Appendix 11 
Time and Events Table-Treatment Visit (TV) 4.1 and TV5.1 for all 
Patients (28 days+1 week] after TV4 or TV5)  
Appendix 12 
In-Clinic Assessment of ON/OFF States and Dyskinesia 
Appendix 13 
Laboratory Parameters 
Appendix 14 
UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria 
Appendix 15 
Modified Hoehn and Yahr PD Severity Scale Assessment 
Appendix 16 
Contraindications to Performing Routine Spirometry 
Appendix 17 
CVT-301 System Additional Information 
Appendix 18 
Spirometry Alert and Review Process Diagram 
 


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Appendix 1:  Overall Visit Schedule Schematic 
 
 
Abbreviations: DL1 = Dose Level 1; DL2 = Dose Level 2; DLco = carbon monoxide diffusing capacity; M = month; SV = screening visit; TV = treatment visit; 
W = weeks. 
*TV4.1 for patients who enter the study drug holiday after TV4; TV5.1 for patients who enter the study drug holiday after TV5. 
 
 
 


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Appendix 2:  Time and Events Table-Screening Visit 1 (SV1) for CVT-301-Naïve Patients (including CVT-301-005 
observational arm patients) and CVT-301-009 Patients (within 35 days prior to randomization) 
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 medication 
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 Parts 1, 2 and 4 
 
X 
 
 
 
UPDRS Part 3 
 
X 
X 
 
 
Patient training on self-report of ON/OFF states  
 
X 
X 
 
 
ON/OFF Concordance testing3 
 
X 
X 
 
 
Clinical laboratory tests (including serum pregnancy test, if applicable) 
X4 
 
 
 
 
Inhaler training using sham capsules 
 
X 
X 
 
 


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Procedures1 
At arrival 
(assess in ON 
or OFF state) 
Assess in  
ON state2 
Assess 
in OFF 
state 
End 
of 
SV1 
Post-SV1 
Telephone 
Contact 
Distribute PD Diary and Screening ON/OFF Episodes Log and review 
instructions for completion5 
 
 
 
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. 
3If 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.   
4Document whether patient is fasting (≥4 hours after last snack or meal). 
5The 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) for CVT-301-Naïve Patients (including CVT-301-005 
observational arm patients) and CVT-301-009 Patients (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 PD medication dose/regimen 
X 
 
 
 
 
Record any changes in concomitant medication 
X 
 
 
 
 
Inhaler training using sham capsules and IFU3 
 
X 
X 
 
 
Patient training on assessment of ON/OFF state 
 
X 
X 
 
 
C-CSSR 
 
X 
 
 
 
Epworth Sleepiness Scale 
 
X 
 
 
 
QUIP  
 
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 TV1)  
 
 
 
X 
 
Post-SV2 telephone contact: call patient 4 to 6 days prior to TV1 
 
 
 
 
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 
 
 
 
 


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Spirometry 
 
X 
X 
 
 
UPDRS Parts 1, 2, and 4 
 
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 10.1.1.2 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 TV1. 
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) for CVT-301-004 Patients  
(1-14 days after TV4 in the CVT-301-004 study) 
Procedures1 
Arrival 
Pre-dose 
Time 0 
(Dosing)2 
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 
Record usual PD medications 
X 
 
 
 
 
 
 
 
 
 
Record time of patient’s prior 
usual PD medication dose 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
 
 
 
 
 
 
 
 
 
Physical examination (full) 
X 
 
 
 
 
 
 
 
 
 
ECG 
X3 
 
 
 
 
 
 
 
 
Standard and orthostatic BP 
and HR 
X3 
 
 
 
X 
 
X 
 
 
Respiratory rate 
X3 
 
X 
 
X 
X 
X 
 
 
Spirometry 
X4 
X 
 
 
X 
 
X 
X 
 
 
Clinical laboratory tests 
(including serum pregnancy 
test, if applicable) 
X5 
 
 
 
 
 
 
 
 
C-SSRS 
X4 
 
 
 
 
 
 
 
 
 
Epworth Sleepiness Scale 
X4 
 
 
 
 
 
 
 
 
 
UPDRS Parts 1 and 2  
X4 
 
 
 
 
 
 
 
 
 
PHQ-9 (in ON state) 
X 
 
 
 
 
 
 
 
 
 
AWQ and DDS-PC (in ON 
state) 
X 
 
 
 
 
 
 
 
 
 
Impact of Parkinson’s OFF 
Episodes Patient Survey4 
X 
 
 
 
 
 
 
 
 
 
Review inhaler training 
X 
 
 
 
 
 
 
 
 
 


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Procedures1 
Arrival 
Pre-dose 
Time 0 
(Dosing)2 
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 
Distribute PD Diary and 
Inhaled Dosing Log and 
review instructions for 
completion6 
X 
 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
 
Self-administration of study 
drug (in OFF state) 
 
 
X2 
 
 
 
 
 
 
 
Monitor for AEs 
 
X 
Schedule next visit 
 
 
 
 
 
 
 
 
X 
 
Post-TV1 telephone contact: 
call patient 1-3 days after 
TV1 
 
 
 
 
 
 
 
 
 
X 
Post-TV1 telephone contact: 
call patient 1 week prior to 
TV2 
 
 
 
 
 
 
 
 
 
X 
1Informed consent must be signed prior to performing any study procedures.  Informed consent should have been signed at TV4 of the CVT-301-004 study. 
2First dose of study medication preferably occurs between 2 and 5 hours after patient has taken normal morning dose of PD medication and after all pre-dose 
assessments are complete. 
3Procedures can be done at any point after arrival and 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-Treatment Visit 1 (TV1) for CVT-301-Naïve Patients (including CVT-301-005 
observational arm patients) and CVT-301-009 Patients (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 
 
 
 
 
 
 
 
 
 
Record time of patient’s prior usual PD 
medication dose 
X 
 
 
 
 
 
 
 
 
 
Record any changes in usual PD 
medication dose/regimen 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
 
 
 
 
 
 
 
 
 
PDQ-39 (in ON state) 
X 
 
 
 
 
 
 
 
 
 
PHQ-9 (in ON state) 
X 
 
 
 
 
 
 
 
 
 
AWQ and DDS-PC (in ON state) 
X 
 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
 
UPDRS Parts 1 and 2 (preferably in ON 
state) 
X 
 
 
 
 
 
 
 
 
 
S&E ADL (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
 
UPDRS Part 4 (Questions 32-35 and 36-
39) (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
 
Electrocardiogram 
X3 
 
 
 
 
 
 
 
 
Standard and orthostatic BP and HR 
X3 
 
 
 
X 
 
X 
 
 
Respiratory rate 
X3 
 
X 
 
X 
X 
X 
 
 
Spirometry  
X4 
X 
 
 
X 
 
X 
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 
Clinical laboratory tests (including serum 
pregnancy test, if applicable) 
X3,5 
 
 
 
 
 
 
 
 
C-SSRS 
X3,4 
 
 
 
 
 
 
 
 
 
Epworth Sleepiness Scale 
X3,4 
 
 
 
 
 
 
 
 
 
QUIP 
X3,4 
 
 
 
 
 
 
 
 
 
Impact of Parkinson’s OFF Episodes 
Patient Survey 
X3,4 
 
 
 
 
 
 
 
 
 
Review inhaler training 
X 
 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing 
Log and review instructions for 
completion6 
X 
 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
 
Self-administration of study drug (in 
OFF state) 
 
 
X1 
 
 
 
 
 
 
 
Monitor for AEs 
 
X 
Schedule next visit 
 
 
 
 
 
 
 
 
X 
 
Post-TV1 telephone contact: call patient 
1-3 days after TV1 
 
 
 
 
 
 
 
 
 
X 
Post-TV1 telephone contact: call patient 
1 week before TV2 
 
 
 
 
 
 
 
 
 
X 
1First dose of study medication preferably occurs 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. 
3Procedures can be done at any point after arrival and 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 6:  Time and Events Table-Treatment Visit 2 (TV2) for all Patients (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 
medication 
X 
 
 
 
 
 
 
 
 
PDQ-39 (in ON state) 
X 
 
 
 
 
 
 
 
 
PHQ-9 (in ON state) 
X 
 
 
 
 
 
 
 
 
PGI-C (in ON state) 
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) (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and 
RR and orthostatic BP and HR) 
X3 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
C-SSRS (preferably in ON state) 
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 
TV2 
Post-TV2 
Telephone 
Contact 
Epworth Sleepiness Scale 
(preferably in ON state) 
X 
 
 
 
 
 
 
 
 
QUIP (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Impact of Parkinson’s OFF 
Episodes Patient Survey (preferably 
in ON state) 
X 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
Review inhaler training 
X 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled 
Dosing Log; review instructions for 
completion4 
X 
 
 
 
 
 
 
 
 
Self-administration of study drug 
(in OFF state) 
 
 
X1 
 
 
 
 
 
 
Monitor for dyskinesia and 
ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
Schedule DLco and spirometry 
assessments2 and next visit 
 
 
 
 
 
 
 
X 
 
Post-TV2 telephone contact: call 
patient 1 week before TV3 
 
 
 
 
 
 
 
 
X 
1Dosing of study medication preferably occurs between 2 and 5 hours after patient has taken normal morning dose of PD medication and after all pre-dose 
assessments are complete. 
2DLco and spirometry are to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. 
3Assessment can be done at any point after arrival and before dosing. 
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. 
 
 


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Appendix 7:  Time and Events Table-Treatment Visit 3 (TV3) for all Patients (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 
 
 
 
 
 
 
 
 
Pre-TV3 DLco and spirometry assessments2 
(within 2 weeks prior to TV3/confirm complete 
and if not complete, re-schedule study visit 
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 medication 
X 
 
 
 
 
 
 
 
 
PDQ-39 (in ON state) 
X 
 
 
 
 
 
 
 
 
PHQ-9 (in ON state) 
X 
 
 
 
 
 
 
 
 
PGI-C (in ON state) 
X 
 
 
 
 
 
 
 
 
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) 
(preferably in ON state) 
X 
 
 
 
 
 
 
 
 
C-SSRS (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Epworth Sleepiness Scale (preferably in ON 
state) 
X 
 
 
 
 
 
 
 
 
QUIP (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Impact of Parkinson’s OFF Episodes Patient 
Survey (preferably in ON state) 
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 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and RR and 
orthostatic BP and HR) 
X4 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (including serum 
pregnancy test, if applicable) 
X5 
 
 
 
 
 
 
 
 
Distribute study drug kits  
X 
 
 
 
 
 
 
 
 
Review inhaler training (if needed) 
X 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing Log; 
review instructions for completion6 
X 
 
 
 
 
 
 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 
 
 
 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
Schedule DLco and spirometry assessments2 and 
next visit 
 
 
 
 
 
 
 
X 
 
Post-TV3 telephone contact: call patient 1 week 
before TV4 
 
 
 
 
 
 
 
 
X 
1Dosing of study medication preferably occurs between 2 and 5 hours after patient has taken normal morning dose of PD medication and after all pre-dose 
assessments are complete. 
2DLco and spirometry are to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. 
3Preferably in the ON state, but these must be performed before any other study evaluation. 
4Assessment can be done at any point after arrival and 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 TV4; the Inhaled Dosing Log is to be completed daily through TV6. 
 
 
 


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Appendix 8:  Time and Events Table-Treatment Visit 4 (TV4) for all Patients (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 
 
 
 
 
 
 
 
 
Pre-TV4 DLco and spirometry assessments2 
(within 2 weeks prior to TV4)/confirm complete 
and if not complete, re-schedule study visit 
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 medication 
X 
 
 
 
 
 
 
 
 
AWQ and DDS-PC (in ON state) 
X3 
 
 
 
 
 
 
 
 
PDQ-39 (in ON state) 
X 
 
 
 
 
 
 
 
 
PHQ-9 (in ON state) 
X3 
 
 
 
 
 
 
 
 
PGI-C (in ON state) 
X 
 
 
 
 
 
 
 
 
UPDRS Part 1 (preferably in ON state) 
X3 
 
 
 
 
 
 
 
 
UPDRS Part 2 (preferably in ON state) 
X3,4 
 
 
 
 
 
 
 
 
S&E ADL (preferably in ON state) 
X4 
 
 
 
 
 
 
 
 
UPDRS Part 4 (Questions 32-35 and 36-39) 
(preferably in ON state) 
X 
 
 
 
 
 
 
 
 
C-SSRS (preferably in ON state) 
X3 
 
 
 
 
 
 
 
 
Epworth Sleepiness Scale (preferably in ON 
state) 
X3 
 
 
 
 
 
 
 
 
QUIP (preferably in ON state) 
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 
TV4 
Post-TV4 
Telephone 
Contact 
Impact of Parkinson’s OFF Episodes Patient 
Survey (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Physical examination (full) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and RR and 
orthostatic BP and HR) 
X5 
 
 
 
 
 
 
 
Electrocardiogram 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (including serum 
pregnancy test, if applicable) 
X6 
 
 
 
 
 
 
 
 
Distribute study drug kits for patients not entering 
the study drug holiday 
X 
 
 
 
 
 
 
 
 
Review inhaler training (if needed) for patients 
not entering the study drug holiday 
X 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing Log; 
review instructions for completion7 
X 
 
 
 
 
 
 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 
 
 
 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
Schedule DLco and spirometry assessments 2 and 
next visit 
 
 
 
 
 
 
 
X 
 
Post-TV4 telephone contact: call patient 1 week 
before TV5 
 
 
 
 
 
 
 
 
X 
For patients entering study drug holiday, schedule 
TV4.18 
 
 
 
 
 
 
 
X 
 
For patients entering study drug holiday, post-
TV4 telephone contact9 
 
 
 
 
 
 
 
 
X 
1Dosing of study medication preferably occurs between 2 and 5 hours after patient has taken normal morning dose of PD medication and after all pre-dose 
assessments are complete. 
2DLco and spirometry are to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. 


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3For patients who enter the study drug holiday at this visit. Also dispense copies to be completed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 28 days after TV4. 
Complete in ON state after intake of first scheduled dose of standard oral PD medication. The self-report version of the C-SSRS and self-administered MDS-
UPDRS Parts 1B and 2 will be dispensed for completion at home. 
4Preferably in the ON state, but these must be performed before any other study evaluation. 
5Assessment can be done at any point after arrival and before dosing. 
6Document whether patient is fasting (≥4 hours after last snack or meal). 
7The PD Diary is to be completed for the 3 consecutive days prior to TV5; the Inhaled Dosing Log is to be completed daily through TV6, except during the study 
drug holiday. 
8If applicable, study drug re-supply visit to be scheduled 28 days (+1 week) after TV4.  
9If applicable, site staff will call the patient at 14 (±3) days after TV4 to remind them to complete the withdrawal questionnaires, and to inquire about potential 
adverse events and changes in concomitant medications. 
 
 
 


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Appendix 9:  Time and Events Table-Treatment Visit 5 (TV5) for all Patients (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 
 
 
 
 
 
 
 
 
Pre-TV5 DLco and spirometry assessments2 
(within 2 weeks prior to TV5)/confirm complete 
and if not complete, re-schedule study visit 
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 medication 
X 
 
 
 
 
 
 
 
 
AWQ and DDS-PC (in ON state) 
X3 
 
 
 
 
 
 
 
 
PDQ-39 (in ON state) 
X 
 
 
 
 
 
 
 
 
PHQ-9 (in ON state) 
X3 
 
 
 
 
 
 
 
 
PGI-C (in ON state) 
X 
 
 
 
 
 
 
 
 
UPDRS Part 1 (preferably in ON state) 
X3 
 
 
 
 
 
 
 
 
UPDRS Part 2 (preferably in ON state) 
X3,4 
 
 
 
 
 
 
 
 
S&E ADL(preferably in ON state) 
X 
 
 
 
 
 
 
 
 
UPDRS Part 4 (Questions 32-35 and 36-39) 
(preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and RR and 
orthostatic BP and HR) 
X4 
 
 
 
 
 
 
 
Electrocardiogram 
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 
TV5 
Post-TV5 
Telephone 
Contact 
Clinical laboratory tests (serum pregnancy test, if 
applicable) 
X5 
 
 
 
 
 
 
 
 
C-SSRS (preferably in ON state) 
X3 
 
 
 
 
 
 
 
 
Epworth Sleepiness Scale (preferably in ON 
state) 
X3 
 
 
 
 
 
 
 
 
QUIP (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Impact of Parkinson’s OFF Episodes Patient 
Survey (preferably in ON state) 
X 
 
 
 
 
 
 
 
 
Distribute study drug kits for patients not entering 
the study drug holiday 
X 
 
 
 
 
 
 
 
 
Review inhaler training (if needed) for patients 
not entering the study drug holiday 
X 
 
 
 
 
 
 
 
 
Distribute PD Diary and Inhaled Dosing Log; 
review instructions for completion6 
X 
 
 
 
 
 
 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 
 
 
 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
 
Monitor for AEs 
X 
Schedule DLco and spirometry assessments2 and 
next visit 
 
 
 
 
 
 
 
X 
 
Post-TV5 telephone contact: call patient 1 week 
before TV6 
 
 
 
 
 
 
 
 
X 
For patients entering study drug holiday, schedule 
TV5.17 
 
 
 
 
 
 
 
X 
 
For patients entering study drug holiday, post-
TV5 telephone contact8 
 
 
 
 
 
 
 
 
X 
Schedule an Unscheduled Visit, if applicable9 
 
 
 
 
 
 
 
 
X 
1Dosing of study medication preferably occurs between 2 and 5 hours after patient has taken normal morning dose of PD medication and after all pre-dose 
assessments are complete. 


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2DLco and spirometry are to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. 
3For patients who begin the study drug holiday at the end of this visit. Also dispense copies to be completed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 28 days after 
TV5. Complete in ON state after intake of first scheduled dose of standard oral PD medication. The self-report version of the C-SSRS and self-administered 
MDS-UPDRS Parts 1B and 2 will be dispensed for completion at home. 
4Assessment can be done at any point after arrival and 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 TV6; the Inhaled Dosing Log is to be completed daily through TV6, except during the study 
drug holiday 
7If applicable, study drug re-supply visit to be scheduled 28 days (+1 week) after TV5. 
8If applicable, site staff will call the patient at 14 (±3) days after TV5 to remind them to complete the withdrawal questionnaires, and to inquire about potential 
adverse events and changes in concomitant medications. 
9Patients who have already completed TV5 at the time of implementation of protocol Version 5.2 will have the option to consent to this amendment at an 
Unscheduled Visit prior to TV6, at which time they will receive an additional 4 weeks of study drug. 
 
 


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Appendix 10:  Time and Events Table-Treatment Visit (TV6) for all Patients (13 Months [56±2 Weeks or 14 Months [60 ±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 
Post-TV6 
DLco/spirometry 
Assessment 
Collect, review, sign and date PD Diary and 
Inhaled Dosing Log 
X 
 
 
 
 
 
 
 
Collect empty capsules, inhalers, and unused 
supplies 
X 
 
 
 
 
 
 
 
Pre-TV6 DLco and spirometry assessments2 
(within 2 weeks prior to TV6)/confirm complete 
(and if not re-schedule study visit)3 
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 medication 
X 
 
 
 
 
 
 
 
AWQ and DDS-PC (in ON state) 
X4 
 
 
 
 
 
 
 
PDQ-39 (in ON state) 
X 
 
 
 
 
 
 
 
PHQ-9 (in ON state) 
X4 
 
 
 
 
 
 
 
PGI-C (in ON state) 
X 
 
 
 
 
 
 
 
UPDRS Part 1 (preferably in ON state) 
X4 
 
 
 
 
 
 
 
UPDRS Part 2 (preferably in ON state) 
X4,5 
 
 
 
 
 
 
 
S&E ADL (preferably in ON state) 
X5 
 
 
 
 
 
 
 
UPDRS Part 4 (Questions 32-35 and 36-39) 
(preferably in ON state) 
X 
 
 
 
 
 
 
 
Physical examination (brief) 
X 
 
 
 
 
 
 
 
Vital signs (standard BP, HR, and RR and 
orthostatic BP and HR) 
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 
Post-TV6 
DLco/spirometry 
Assessment 
Electrocardiogram 
X 
 
 
 
 
 
 
 
C-SSRS (preferably in ON state) 
X4 
 
 
 
 
 
 
 
Epworth Sleepiness Scale (preferably in ON 
state) 
X4 
 
 
 
 
 
 
 
QUIP (preferably in ON state) 
X 
 
 
 
 
 
 
 
Impact of Parkinson’s OFF Episodes Patient 
Survey (preferably in ON state) 
X 
 
 
 
 
 
 
 
Clinical laboratory tests (including serum 
pregnancy test, if applicable) 
X7 
 
 
 
 
 
 
 
Self-administration of study drug (in OFF state) 
 
 
X1 
 
 
 
 
 
Monitor for dyskinesia and ON/OFF states 
 
 
 
X 
 
Monitor for AEs 
X 
 
Post-TV6 DLco and spirometry assessments2 (at 
4-5 weeks after TV6/Early Termination Visit)3 
 
 
 
 
 
 
 
X 
For patients entering the withdrawal sub-study, 
post-TV6 Telephone contact8 
 
1Dosing of study medication preferably occurs between 2 and 5 hours after patient has taken normal morning dose of PD medication and after all pre-dose 
assessments are complete. 
2DLco and spirometry are to be performed in a dedicated pulmonary facility and includes slow vital capacity maneuver, DLco, and spirometry. 
3Patients who withdraw early will undergo all of the TV6 assessments (except the pre-TV6 DLco and spirometry assessment) at the time of withdrawal.  They 
will be scheduled to undergo the post-TV6 DLco and spirometry assessments 4-5 weeks following completion of the Early Withdrawal Visit. 
4 For patients who begin the study drug holiday at the end of this visit. Also dispense copies to be completed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 28 days 
after TV6/ET. Complete in ON state after intake of first scheduled dose of standard oral PD medication. The self-report version of the C-SSRS and self-
administered MDS-UPDRS Parts 1B and 2 will be dispensed for the post TV6 time points. 
5Preferably in the ON state, but these must be performed before any other study evaluation. 
6Assessment can be done at any point after arrival and before dosing.  
7Document whether patient is fasting (≥4 hours after last snack or meal). 
8If applicable, site staff will call the patient at 14 (±3) days and 28 (±3) days after TV6/Early Withdrawal to remind them to complete and return the withdrawal 
questionnaires, and to inquire about potential adverse events and changes in concomitant medications.


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Appendix 11:  Time and Events Table-Treatment Visit (TV) 4.1 and TV5.1 for all Patients 
(28 days+1 week] after TV4 or TV5)*  
Procedures 
 
Collect completed questionnaires 
X 
Record any changes in usual PD medication dose/regimen 
X 
Record any changes in other concomitant medications 
X 
Record any adverse events 
X 
Distribute study drug kits  
X 
Review inhaler training (if needed) 
X 
Distribute PD Diary and Inhaled Dosing Log; review instructions for completion 
(if not done at prior visit) 
X 
*To occur 28 days (+1 week) after TV4 or TV5 (depending on when the patient begins the study drug holiday)  
 
 


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Version 5.2 
Appendix 12:  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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Version 5.2 
Appendix 13:  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) for CVT-301-naïve patients and CVT-301-009 
patients, and at TV1, TV3, TV4, TV5, and TV6, if applicable; magnesium; C-Reactive Protein 
 
 
 
 


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Version 5.2 
Appendix 14:  UK Parkinson’s Disease Society Brain Bank  
Clinical Diagnostic Criteria* 
Step 1. Diagnosis of Parkinsonian syndrome 
• Bradykinesia 
• At least one of the following 
− Muscular rigidity 
− 4-6 Hz rest tremor 
− 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 Step 1: 
• Unilateral onset 
• Rest tremor present 
• Progressive disorder 
• Persistent asymmetry affecting side of onset most 


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Version 5.2 
• 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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Version 5.2 
Appendix 15:  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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Version 5.2 
Appendix 16:  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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Version 5.2 
Appendix 17:  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: 
− Check that a capsule is inserted 
− Make sure mouthpiece is firmly attached 
− Inhale deeper or longer 
 
 
 
 
 
 
 


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07-Dec-2016 
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Version 5.2 
Appendix 18:  Spirometry Alert and Review Process Diagram 
 
 
 
 
 
 
 
 
 
Spirometry Alert and Review Process:  a decrease in FEV1 ≥ 20% AND a decrease in FEV1 by 200 mL 
compared with pre-dose results, and/or a reduction in the FEV1/FVC ratio to <60%  
 
(1) Manage emergent medical condition(s) 
(2a) Complete Spirometry Alert 
Review Worksheet and transmit to 
prespecified personnel 
(3) Complete all other TV1 safety assessments if patient is stable and able to continue 
(2b) Transmit spirometry data to 
Spirometry Core Lab 
 

SAP_001.pdf: 
16.1.9 
Documentation of Statistical Methods 
16.1.9.1 Statistical Analysis Plans 
Statistical Analysis Plan version 2.0 dated 29 June 2017 
16.1.9.2 Method for Analysis of Abuse Related Adverse Events 
Abuse Assessment Section Terms 
CVT-301 (Levodopa Inhalation Powder) 
Clinical Study Report: CVT-301-004E
Civitas Therapeutics, Inc 
                       Date of Final Report: 03 Dec 2018
________________________________________________
________________________________________________
________________________________________________
Page 1 of 81


Study No. CVT-301-004E 
Summary of SAP Changes from Interim Analysis SAP Version 1.0 (11Jan2017) to Interim Analysis 
SAP Version 2.0 (29Jun2017) 
Interim Analysis SAP Version 1.0 (11Jan2017) 
Interim Analysis SAP Version 2.0 (29Jun2017) 
Cover page: 
Protocol Number and Title: A 12-Month, Dose-Level Blinded 
Study Investigating the Safety and Efficacy of CVT-301 
(Levodopa Inhalation Powder) in Parkinson’s Disease Patients 
With Motor Response Fluctuations (OFF Phenomena) 
 
Protocol Version and Date:  Version 5.0/5.1, 14-Nov-
2016/30-Nov-2016 
 
SAP version and date:  Interim Analysis SAP Version 1.0, 11-
Jan-2017 
Cover page: 
Protocol Number and Title:  A 12-Month (or 14-Month for 
Patients Enrolled into sub-Study), Dose-Level Blinded Study 
Investigating the Safety and Efficacy of CVT-301 (Levodopa 
Inhalation Powder) in Parkinson’s Disease Patients With Motor 
Response Fluctuations (OFF Phenomena) (SPANPD™) 
 
Protocol Version and Date:   Version 5.0/5.1, 14-Nov-
2016/30-Nov-2016; Version 5.2 for sub-Study, 07-Dec-
2017 
 
SAP version and date:  SAP Version 2.0, 29-Jun-2017 
 
3.3 Safety Objectives 
• To  characterize  the  effects  of  CVT-301  on  safety  and 
tolerability  over  a  12-month  period,  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),  spirometry  (forced  expiratory 
volume  
in  1  second  
[FEV1]  and  FEV1/forced  vital  capacity 
[FVC] ratio), the Parkinson’s Disease Impulsive Compulsive 
Disorders  Questionnaire  (QUIP),  the  Epworth  Sleepiness 
Scale,  and  the  Columbia-Suicide  Severity  Rating  Scale  (C-
3.3 Safety Objectives 
• To  characterize  the effects  of  CVT-301  on  safety  and 
tolerability  over  a  12-month  period,  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),  spirometry  (forced  expiratory 
volume  
in  1  second  
[FEV1]  and  FEV1/forced  vital  capacity 
[FVC] ratio), the Parkinson’s Disease Impulsive Compulsive 
Disorders  Questionnaire  (QUIP),  the  Epworth  Sleepiness 
Scale, the Columbia-Suicide Severity Rating Scale (C-SSRS), 
Page 2 of 81


SSRS). 
 
the  Amphetamine  Withdrawal  Questionnaire  (AWQ),    the 
Dopamine  Dysregulation  Syndrome - Patient  and  Caregiver 
Inventory  (DDS-PC),  and  the  self-administered  MDS-UPDRS 
Parts 1B and 2 (Movement Disorder Society -UPDRS). 
 
4.3 Safety Endpoints 
 
4.3 Safety Endpoints 
•   Amphetamine  Withdrawal  Questionnaire  (AWQ)  will  be 
assessed at the clinic in an ON state at TV1 and TV6 or Early 
Termination (ET) or TV4, TV5 or TV6, depending on which of 
the  visits is  the  next  scheduled  visit after the  patients 
enrolled  
into  sub-study.  For  patients  who  didn’t  enrolled 
into the sub-study, the AWQ will also be completed at home 
at 1, 3, 6, 8, 11, 14, 17, 24, and 28 days after TV6/ET. For 
patients who enrolled into the sub-study, the AWQ will be 
assessed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 28 days 
after TV4, TV5 or TV6, depending on which of the visits is 
the next scheduled visit for those patients. The total score 
will be calculated as the sum of the individual items 1 to 10.  
Missing  
individual  
items  will  not  be  
imputed  and  the  sum 
score will be missing in case of 1 or more missing items.  
• Dopamine  Dysregulation  Syndrome - Patient  and  Caregiver 
Inventory  
(DDS-PC) will  be  assessed  at  the  clinic  
in  an  ON 
state  at  TV1  and  TV6  or  Termination  (ET)  or TV4,  TV5  or 
TV6, depending on which of the visits is the next scheduled 
visit after the patients enrolled into sub-study. For patients 
who didn’t  enrolled into the sub-study, the DDS-PC will also 
be completed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 28 
days after TV6/ET.  For patients who enrolled into the sub-
study, the DDS-PC will be assessed at home at 1, 3, 6, 8, 11, 
14, 17, 24, and 28 days after TV4, TV5 or TV6, depending on 
which  of  the  visits  is  the  next scheduled  visit  for  those 
patients. The  total  score  will  be  calculated  as  the  sum  of 
the individual items 1 to 45. The below score will be used 
Page 3 of 81


for each individual item: 0 = Not at all, 1 = Very little, 2 = A 
little, 3 = Quite a lot, 4 = Very much.
 Missing individual items 
will not be imputed and the sum score will be missing in case 
of 1 or more missing items.  
 
• Movement  Disorder  Society - Unified  Parkinson’s Disease 
Rating  Scale  (MDS-UPDRS)  Parts  1B  and  2  will  be  assessed 
during  drug withdrawal  period. For  patients  who  didn’t 
enrolled  into  the  sub-study,  the  MDS-UPDRS  will  be 
completed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 28 days 
after TV6/ET.  For patients who enrolled in the sub-study, 
the MDS-UPDRS will be assessed at home at 1, 3, 6, 8, 11, 
14, 17, 24, and 28 days after TV4, TV5 or TV6, depending on 
which  of  the  visits  is  the  next  scheduled  visit  for  those 
patients.  The Part 1B score will be calculated as the sum of 
the individual items 1.7 to 1.13 and the Part 2 score as sum 
of 2.1 to 2.13.  Missing individual items will not be imputed 
and  the  sum  score  will  be  missing  in  case  of  1  or  more 
missing items.  
 
8.1 Efficacy Endpoints and Analyses 
 
8.1 Efficacy Endpoints and Analyses 
• Change from baseline (TV1) and Last Day of Treatment 
(LDOT) to days 1, 3, 6, 8, 11, 14, 17, 24, and 28 after 
TV6  in  the PHQ-9 will  be  summarized  descriptively. 
LDOT  
is  defined  as  assessment  taken  on  TV6  or  ET  
for 
patients who didn’t enrolled into the sub-study and TV4, 
TV5 or TV6 for patients who enrolled into sub-study. 
 
9.9 COLUMBIA-SUICIDALITY SEVERITY RATING SCALE 
9.9 COLUMBIA-SUICIDALITY SEVERITY RATING SCALE 
A shift table from baseline to each visit, days 1, 3, 6, 8, 11, 
14, 17, 24, and 
Page 4 of 81


A shift from baseline table will be constructed to assess any 
changes in the subjects’ suicidal ideation and behavior during 
the treatment period. 
 
28 after LDOT will be constructed to assess any changes in the 
subjects’ suicidal ideation and behavior during the treatment 
period. 
A shift table from LDOT to days 1, 3, 6, 8, 11, 14, 17, 24, and 
28 after TV6 will be constructed to assess any changes in the 
subjects’ suicidal ideation and behavior during the treatment 
period. 
9.10 EPSWORTH SLEEPINESS SCALE 
All Epworth Sleepiness Scale data will be listed.  The total score 
and change from baseline to each visit will be summarized by 
treatment group and overall (for handing of data from the ET 
visit, see Section 6.4). 
 
9.10 EPSWORTH SLEEPINESS SCALE 
All Epworth Sleepiness Scale data will be listed.  The total 
score and change from baseline to each visit will be 
summarized by treatment group and overall (for handing of 
data from the ET visit, see Section 6.4). The total score and 
change from baseline (TV1) and  Last  Day of Treatment  to 
days 1, 3, 6, 8, 11, 14, 17, 24, and 28 after Last  Day of 
Treatment will also be summarized. LDOT is defined as 
assessment taken on TV6 or ET for patients who didn’t 
enrolled into the sub-study and TV4, TV5 or TV6 for patients 
who enrolled into sub-study. 
 
 
9.14 AMPHETAMINE WITHDRAWAL QUESTIONAIRE (AWQ) 
The actual values and changes from baseline (TV1) and LDOT to 
days 1, 3, 6, 8, 11, 14, 17, 24, and 28 after LDOT in AWQ total 
score  will  be  summarized  descriptively  for  patients  in  safety 
population. LDOT is defined as assessment taken on TV6 or ET 
for patients who didn’t enrolled into the sub-study and TV4, TV5 
or TV6 for patients who enrolled into sub-study. 
 
9.15 DOPAMINE DYSREGULATION SYNDROME – PATIENT AND 
CAREGIVER INVENTORY (DDS-PC) 
The actual values and changes from baseline (TV1) and Last Day 
of Treatment to days 1, 3, 6, 8, 11, 14, 17, 24, and 28 after Last 
Day  of  Treatment in DDS-PC total  score  will  be  summarized 
descriptively for patients in safety population. LDOT is defined 
Page 5 of 81


 
as  assessment  taken  on  TV6  or  ET  for  patients  who  didn’t 
enrolled  
into  the  sub-study  and TV4,  TV5  or  TV6 for  patients 
who enrolled into sub-study. 
 
9.16 MOVEMENT DISORDER SOCIETY – UNIFIED PARKINSON’S 
DISEASE RATING SCALE (MDS-UPDRS) 
The  MDS-UPDRS  Part  1  and  Part  2 value  will  be  summarized 
descriptively on days 1, 3, 6, 8, 11, 14, 17, 24, and 28 after Last 
Day  of  Treatment by  treatment for  patients  in  the  safety 
population.  
Page 6 of 81


Statistical Analysis Plan 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 1 of 72 
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-301-004E 
A 12-Month (or 14-Month for Patients Enrolled 
into sub-Study), Dose-Level Blinded Study 
Investigating the Safety and Efficacy of CVT-
301 (Levodopa Inhalation Powder) in 
Parkinson’s Disease Patients With Motor 
Response Fluctuations (OFF Phenomena) 
(SPANPD™) 
 
Protocol Version and Date: Version 5.0/5.1, 14-Nov-2016/30-Nov-2016; 
Version 5.2 for sub-Study, 07-Dec-2017 
INC Research Project Code: 1003804 
Author(s): 
  
  
  
   
SAP Version: 
  SAP Version 2.0 
SAP Version Date:  
29-Jun-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. 
Page 7 of 81
 
 


1003804 
• :nc 
Research" 
Civitas Therapeutics, Inc. 
CVT • 
301-004E 
-
......... ---
SAP Version 2.0 
Statistical Analysis Plan 
Version: 
SAP Version 2.0 
Version Date: 
29-Jun-2017 
I confirm that I have reviewed this document and agree with the content. 
APPROVALS 
INC Research 
This document is proprietary and confidential to 
INC Research LLC. 
03.007A.
OO 
INC Research O LLC 
Page 2 of 
Page 8 of 81
72 


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 3 of 72 
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. Safety Objectives................................................................................................................ 
10 
3.4. Patient Selection 
................................................................................................................ 
11 
3.5. Determination of Sample Size 
........................................................................................... 
13 
3.6. Treatment Assignment & Blinding..................................................................................... 
14 
3.7. Administration of Study Medication 
.................................................................................. 
14 
3.8. Study Procedures and Flowchart 
...................................................................................... 
15 
4. ENDPOINTS 
.................................................................................................... 
17 
4.1. Primary Endpoint 
................................................................................................................ 
17 
4.2. Secondary Endpoints 
.......................................................................................................... 
17 
4.3. Safety Endpoints 
................................................................................................................. 
20 
5. ANALYSIS SETS 
.............................................................................................. 
22 
5.1. All Available Population (AAP) .......................................................................................... 
22 
5.2. Safety Population ............................................................................................................... 
22 
Page 9 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 4 of 72 
5.3. Intent-to-Treat Population (ITT) 
....................................................................................... 
22 
5.4. Protocol Deviations ............................................................................................................ 
22 
6. GENERAL ASPECTS FOR STATISTICAL ANALYSIS ......................................... 
24 
6.1. General Methods 
................................................................................................................. 
24 
6.2. Key Definitions.................................................................................................................... 
25 
6.3. Missing Data......................................................................................................................... 
27 
6.4. Visit Windows 
...................................................................................................................... 
28 
6.5. Pooling of Sites ................................................................................................................... 
29 
6.6. Subgroups 
............................................................................................................................ 
29 
7. DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION 
.... 
30 
7.1. Patient Disposition and Withdrawals 
................................................................................ 
30 
7.2. Demographic and Other Baseline Characteristics ........................................................... 
30 
7.3. Medical History 
................................................................................................................... 
32 
7.4. Medication 
........................................................................................................................... 
32 
8. EFFICACY 
....................................................................................................... 
34 
8.1. Efficacy Endpoints and Analyses 
....................................................................................... 
34 
9. SAFETY 
.......................................................................................................... 
38 
9.1. Spirometry .......................................................................................................................... 
38 
9.2. Extent of Exposure 
............................................................................................................. 
42 
9.3. Treatment Compliance ...................................................................................................... 
43 
9.4. Adverse Events ................................................................................................................... 
43 
9.5. Laboratory Evaluations 
...................................................................................................... 
45 
Page 10 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 5 of 72 
9.6. Vital Signs 
............................................................................................................................ 
46 
9.7. Electrocardiogram 
.............................................................................................................. 
47 
9.8. Physical Examination ......................................................................................................... 
48 
9.9. Columbia-Suicidality Severity Rating Scale ...................................................................... 
48 
9.10. Epworth Sleepiness Scale 
................................................................................................... 
49 
9.11. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
................... 
49 
9.12. UPDRS Part 4 
....................................................................................................................... 
50 
9.13. Examiner-rated Dyskinesia 
................................................................................................ 
50 
9.14. Amphetamine Withdrawal Questionnaire (AWQ)............................................................. 
50 
9.15. Dopamine Dysregulation Syndrome - Patient and Caregiver Inventory (DDS-PC) 
......... 
50 
9.16. Movement Disorder Society - Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) 51 
9.17. UPDRS Part 1 
....................................................................................................................... 
51 
10. INTERIM ANALYSES 
.................................................................................... 
52 
11. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
.................................. 
53 
12. PROGRAMMING CONSIDERATIONS 
............................................................. 
54 
13. QUALITY CONTROL.................................................................................... 
57 
14. INDEX OF TABLES 
...................................................................................... 
58 
15. INDEX OF LISTINGS 
.................................................................................... 
70 
16. INDEX OF FIGURES 
..................................................................................... 
72 
 
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-
E
004 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 6 of 72 
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  
AWQ 
Amphetamine Withdrawal Questionnaire 
BMI 
Body Mass Index 
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 
DDS-PC 
Dopamine Dysregulation Syndrome - Patient and Caregiver 
Inventory 
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 
Page 12 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-
E
004 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 7 of 72 
Abbreviation 
Description 
Hb 
Hemoglobin  
HR 
Heart Rate 
HCG 
human chorionic gonadotropin 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat  
IWRS 
Interactive Web Response System 
LD 
Levodopa 
LDOT 
Last Day of Treatment 
LS 
least square 
MAR 
Missing At Random 
MCMC 
Markov Chain Monte Carlo 
MDS-UPDRS 
Movement Disorder Society - Unified Parkinson’s Disease 
Rating Scale 
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  
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Abbreviation 
Description 
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 
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 the  data  base  
lock. However,  the  analyses  defined  after  the  blind  of 
study CVT-301-004 has been broken 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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SAP Version  2.0 
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03.007A.00     
  INC Research © LLC 
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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 
The following secondary objectives will be assessed for the patients who were 
previously enrolled in the CVT-301-004 study and for the CVT-301-naïve patients 
(including CVT-301-005 observational arm patients):  
• 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). 
• Change from baseline in 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 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 at baseline. 
• Change from baseline visit in Schwab and England (S&E) Activities of Daily Living 
(ADL) score. 
• Change from baseline visit in 9-Item Patient Health Questionnaire (PHQ-9). 
• Change from baseline visit in Impact of Parkinson’s OFF Episodes Patient Survey 
• Change from baseline visit in UPDRS Part 2 score. 
 
3.3. SAFETY OBJECTIVES 
• To  characterize  the  effects  of  CVT-301  on  safety  and  tolerability over  a  12-month 
period, 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),  spirometry 
(forced  expiratory  volume  
in  1  second [FEV1] and  FEV1/forced  vital  capacity  
[FVC] 
ratio), the Parkinson’s Disease Impulsive Compulsive Disorders Questionnaire (QUIP), 
the Epworth  Sleepiness  Scale,  
the  Columbia-Suicide  Severity  Rating  Scale  
(C-SSRS), 
the  Amphetamine  Withdrawal  Questionnaire  (AWQ),    the  Dopamine  Dysregulation 
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Syndrome - Patient  and  Caregiver  Inventory  (DDS-PC),  and  the  self-administered 
MDS-UPDRS Parts 1B and 2 (Movement Disorder Society -UPDRS). 
• To describe the effect of CVT-301 on DLCO. 
• To compare the pulmonary safety, as assessed by spirometry (FEV1, FVC and 
FEV1/FVC ratio) between the group of patients who were treated with CVT-301 in 
study CVT 301-004 versus the CVT-301 patients treated with placebo in CVT 301-004. 
• Change  from  baseline  visit in UPDRS  Part  4  measures  of  motor  fluctuations 
(dyskinesias [Questions 32-35] and wearing off [Questions 36-39]). 
• Occurrence  and  severity  of  examiner-rated  dyskinesia following  treatment  of 
patients experiencing an OFF episode in the clinic. 
3.4. PATIENT SELECTION 
The following patients are eligible for study CVT-301-004E: 
1. Patients who completed study CVT-301-004, treated with either CVT-301 35 mg LD 
FPD, CVT-301 50 mg LD FPD or placebo 
2. Patients who completed study CVT-301-003, treated with either CVT-301 35 mg LD 
FPD followed by CVT-301 50 mg LD FPD or placebo (enrolled prior to Amendment 4) 
3. Patients who completed study CVT-301-009, treated with either single dose of CVT-
301 50 mg LD FPD or placebo 
4. Patients who were randomized to the observational arm of study CVT-301-005 and 
completed that study 
5. CVT 301 naïve patients who did not participate to previous CVT-301 studies. 
Patients who withdrew from the CVT-301-004, CVT-301-003, CVT-301-009 or CVT-301-
005 studies prior to completion, for any reason, are not eligible.  
3.4.1. Inclusion Criteria 
CVT-301-004  study  patients  who  have  met  the  eligibility  criteria  for CVT-301-004 and 
who have completed all CVT-301-004 study visits per protocol without any safety issues 
that would preclude participation in this study according to the investigator are eligible 
for participation in this study.  Patients who withdrew from the CVT-301-004 study prior 
to completion, for any reason, are not eligible. 
The inclusion criteria listed below are not assessed for the CVT-301-004 study patients. 
In  order  to  be  eligible  to  enter  the  study,  patients  must  meet  all  of  the  following 
criteria:  
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•   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 86 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 United Kingdom (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  
• Patients should be stable on other PD medications for at least 4 weeks prior to SV1.   
• 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 patients with an FEV1 that is ≥ 50% to < 60% of predicted 
or an FEV1/FVC ratio that is >60% to <70% in order to determine eligibility.  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:  
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• 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 cell 
transplantation) or plan to have stereotactic surgery during the study period. 
Patients who have had deep brain stimulation [DBS] will also be excluded unless the 
procedure was performed more than 6 months prior to study enrollment. 
• Patients with a history of psychotic symptoms requiring treatment, or suicidal 
ideation or attempt within the prior 12 months.   
• 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 
unable to comply with study procedures or make them unsuitable for their 
participation in the study.   
• 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. 
• For  new  CVT-301  naïve  patients,  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). 
3.5. DETERMINATION OF SAMPLE SIZE 
The  study  
is  planned to  enroll 390 patients  to  ensure  that  approximately 290 patients 
will complete the 12 month study.  The sample size of this study is designed in order to 
Appendix 15
protocol Section 9.4.2
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capture sufficient amount of safety data required for regulatory submissions and is not 
based on formal statistical calculations. 
3.6. TREATMENT ASSIGNMENT & BLINDING 
This study is a randomized, dose-level blinded, multicenter study of inhaled CVT-301 for 
the  treatment  of  up  to  5  OFF  episodes  per  day  in  PD  patients  experiencing  motor 
fluctuations (OFF episodes). Following completion of SV2 and prior to randomization (for 
CVT-301-003, CVT-301-009, CVT-301-005  and  other  CVT-301-naïve  patients),  eligibility 
criteria  will  be  reviewed  by  delegated  staff.   Sites  must  leave  a  minimum  of  5  days 
between randomization and Treatment Visit 1.  
 
Before TV1, patients will be assigned/randomized to treatment group [Dose Level (DL) 
1, or 2].  Patients who received DL1 (target nominal dose of 35 mg LD FPD) in the CVT-
301-004 study will receive DL1 (target nominal dose of 35 mg LD FPD) in this study, and 
patients  who  received  DL2  
(target  nominal  dose  of  50  mg  LD  FPD)  
in  the  CVT-301-004 
study will receive DL2 (target nominal dose of 50 mg LD FPD) in this study. Patients who 
received  placebo  in  the CVT-301-004  study, CVT-301-003  patients, CVT-301-009 
patients, and  CVT-301-naïve  patients  (including CVT-301-005  observational  arm 
patients) will be randomized in a 1:1 ratio to DL1 or DL2.  
 
Upon  confirmation  of  eligibility,  the  site  will  randomize  an  eligible  patient  using  the 
Interactive Web Response System (IWRS).  Randomization will be differentiated by the 
patient’s Hoehn and Yahr PD disease severity scale rating (<2.5 versus ≥2.5) to balance 
for  disease  severity  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%).  For the patients who received placebo in CVT 301 004, the differentiation 
of CVT 301 004 will be used.  Patients and site staff will be blinded to treatment group. 
 
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. 
In order to blind the treatment group, study kits with identical number and appearance 
of capsules will be distributed to patients in the CVT-301 groups. 
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  blinded  to  the  inhaled 
treatment group. 
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Except in the case of an emergency, the treatment group codes will not be available to 
the  
investigator,  the  study  site  personnel,  representatives  of  the  CRO,  or  the  Sponsor 
until  after  the completion  of  
the  study  and  
final  data  
review.  
  All  
randomization  data 
will  be  kept  strictly  confidential  and  accessible  only  to  authorized  persons  until  the 
time  of  unblinding  after  the  end  of  the  study;  
for  emergency  unblinding,  the  site  will 
access  the IWRS  or  call  
the  
IWRS  helpdesk.  
  When  the  data  
file  has  been  verified  and 
the protocol violations have been determined, the drug codes will be made available for 
data analysis. 
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  re-inhaled,  T0  is  at  the  end  of  the  re-inhalation 
administration. 
During  the  treatment  period,  patients  will  self-administer  inhaled study  treatment 
(CVT-301  DL1  or  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.  
The  maximum  anticipated  duration  of  this  study  for  patients  from  the CVT-301-004 
study  will  be  approximately  59 weeks,  including  the  final  spirometry  and DLCO 
assessment  which  takes  place  4 to  5 weeks  following  the  treatment  period.    The 
maximum anticipated duration of this study for CVT-301-naïve patients and CVT-301-009 
patients, including the screening period and the final spirometry and DLCO assessments, 
will be approximately 64 weeks. 
CVT-301-naïve patients (including CVT-301-005 observational arm patients) will undergo 
a screening period (of up to 35 days) prior to randomization.  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).   CVT-301-004  patients  will  not  be  required  to  undergo  the 
screening visits and will undergo TV1 after a 1- to 14-day period (or longer if approved 
by the Sponsor) following Treatment Visit 4 (TV4) of the CVT-301-004 study. 
Before patients return to the clinic for TV1, they will be randomized to treatment group 
(see section  3.6  
for  details).  
 The  treatment  period  
includes  6  separate  
in-clinic  visits 
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over approximately 52 weeks.  The first dose of study drug will be given in the clinic at 
TV1.  The subsequent visits during the treatment period take place as follows: 
• TV2: Week 4; 28±5 days after TV1. 
• TV3: Week 12; 84±14 days after TV1. 
• TV4: Week 24; 168±14 days after TV1. 
• TV5: Week 36; 252±14 days after TV1. 
• TV6: Week 52; 364±14 days after TV1. 
Patients who terminate the study early will complete TV6 and return for the Follow-up 
DLCO visit 4-5 weeks after TV6. 
Refer to Protocol 
to  for tables of study assessments at each visit. 
10
Appendices 2 
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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 (TV1) for each variable will be calculated at each subsequent visit.  
Percent Predicted = 100 * (Observed) / Predicted, where predicted values are 
calculated using the formulae by 
 
): 
Caucasian males ≥20 years of age:  
• FVC predicted = -0.1933 + 0.00064*age - 0.000269*age2 + 0.00018642*height2 
• FEV1 predicted = 0.5536-0.01303*age -0.000172*age2 + 0.00014098*height2 
Caucasian females ≥18 years of age:  
• FVC predicted = -0.3560 + 0.01870*age -0.000382*age2 + 0.014815*height2 
• FEV1 predicted = 0.4333 - 0.00361*age -0.000194*age2 + 0.00011496*height2 
, Please see Hankinson et al (1999) for formulae for other races and age categories 
4.2. SECONDARY ENDPOINTS 
The following endpoints related to the secondary objectives will be calculated. 
• 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  not  achieving  resolution  of  an 
OFF to an ON state. 
Sample of the General U.S. Population, 1999
Hankinson et al (Spirometric Reference Values from a
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• 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, in 
total daily ON time with non-troublesome dyskinesia, and in 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 
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 TV1 (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 
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03.007A.00     
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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. 
 
• Change  from  TV1  (pre-dose)  in  9-Item  PHQ-9  sum  score.    The  sum  score  will  be 
calculated  as  the  sum  of  the  9  
individual  questions.  
  
In  case  of  1  or  more  missing 
questions, the sum score will be set as missing. 
• Change  from  baseline  in  Impact  of  Parkinson’s  OFF  Episodes  Patient  Survey.  The 
Impact  of  Parkinson’s  OFF  episodes  patient  survey  score  will  be  calculated  as  the 
sum of the individual items of the Impact of Parkinson’s OFF Episodes Patient Survey 
questionnaire.  Missing individual items will not be imputed and the sum score will 
be missing in case of 1 or more missing items. 
• 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). 
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• Change from TV1 (baseline) in Schwab and England (S&E) Activities of Daily Living 
(ADL). No further derivation will be done for the S&E scores. 
• Change from TV1 (pre-dose) 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.  
4.3. SAFETY ENDPOINTS  
The following endpoints related to the secondary objectives will be calculated. 
 
• Standard safety endpoints; for definitions see Section 9 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) 
 
• 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. 
• Change  from  TV1  (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. 
• Carbon  Monoxide  Diffusion  Capacity  (DLCO)  assessed  over  a  12  month  period. 
Variables  will  include  the  absolute DLCO values  and DLCO expressed  as  %  of 
predicted value. 
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• Amphetamine  Withdrawal  Questionnaire  (AWQ) will  be  assessed  at  the  clinic  
in  an 
ON state at TV1 and TV6 or Early Termination (ET) or TV4, TV5 or TV6, depending on 
which  of  the  visits is  the  next  scheduled  visit after the  patients enrolled  
into  sub-
study. For  patients  who  didn’t  enrolled  
into  the sub-study,  the  AWQ  will  also  be 
completed  at  home  at  1,  3,  6,  8,  11,  14,  17,  24,  and  28  days  after  TV6/ET. For 
patients who enrolled into the sub-study, the AWQ will be assessed at home at 1, 3, 
6, 8, 11, 14, 17, 24, and 28 days after TV4, TV5 or TV6, depending on which of the 
visits  is  the  next  scheduled  visit  for  those patients. The  total  score  will  be 
calculated as the sum of the individual items 1 to 10.  Missing individual items will 
not be imputed and the sum score will be missing in case of 1 or more missing items.  
• Dopamine  Dysregulation  Syndrome - Patient  and  Caregiver  
Inventory  (DDS-PC) will 
be assessed at the clinic in an ON state at TV1 and TV6 or Termination (ET) or TV4, 
TV5  or  TV6,  depending  on  which  of  the  visits  
is  the  next  scheduled  visit  after  the 
patients  enrolled  into  sub-study.  For  patients  who  didn’t    enrolled  into  the  sub-
study, the DDS-PC will also be completed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 
28 days after TV6/ET.  For patients who enrolled into the sub-study, the DDS-PC will 
be assessed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 28 days after TV4, TV5 or TV6, 
depending on which of the visits is the next scheduled visit for those patients. The 
total score will be calculated as the sum of the individual items 1 to 45. The below 
score will be used for each individual item: 0 = Not at all, 1 = Very little, 2 = A little, 
3 = Quite a lot, 4 = Very much. Missing individual items will not be imputed and the 
sum score will be missing in case of 1 or more missing items.  
• Movement  Disorder  Society - Unified  Parkinson’s Disease  Rating  Scale  
(MDS-UPDRS) 
Parts  1B  and  2 will  be  assessed  during  drug withdrawal  period. For  patients  who 
didn’t enrolled into the sub-study, the MDS-UPDRS will be completed at home at 1, 
3, 6, 8, 11, 14, 17, 24, and 28 days after TV6/ET.  For patients who enrolled in the 
sub-study, the MDS-UPDRS will be assessed at home at 1, 3, 6, 8, 11, 14, 17, 24, and 
28  days  after  TV4,  TV5  or  TV6,  depending  on  which  of  the  visits  is  the  next 
scheduled visit for those patients.  The Part 1B score will be calculated as the sum 
of  the  individual  items  1.7  to  1.13  and  the  Part  2  score  as  sum  of 2.1  to  2.13.  
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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CVT-301-004E 
SAP Version  2.0 
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03.007A.00     
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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 patients in AAP who are enrolled in CVT-301-004E 
and received at least 1 dose of inhaled CVT-301.  Patients will be analysed according to 
the  highest  dose  
level  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. However, due to 
the  different  study  designs,  the  patients  enrolled  from CVT-301-003  and CVT-301-009 
will not be included in efficacy summaries (i.e. the patients enrolled from CVT-301-003 
and CVT-301-009 will be excluded from ITT population). The rationale for excluding the 
CVT-301-003 patients from the efficacy summaries is the gap between the end of CVT-
301-003  and  start  of  CVT-301-004E.  The  rationale  for  excluding  the CVT-301-009 
patients from the efficacy summaries is the study design (single-dose study) which is not 
comparable to the design of the rest of the studies. Patients will be analyzed according 
to  randomized  treatment  group.  The  ITT  Population  will  be  used  for  all  analyses  of 
efficacy  endpoints and  summaries  of  patient  demographic  and  baseline disease 
characteristics.  
  
In case of variables which are not captured throughout the whole study but only added 
after  an  protocol  amendment (e.g.  PHQ-9),  the  ITT  population for  the  variable  in 
question includes  only  the  subset  of  the  
ITT  population  
in  which  at  
least  the  baseline 
and one post-baseline assessment of the variable in question were done. 
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. 
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CVT-301-004E 
SAP Version  2.0 
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The deviations will be classified during a blind review process with the Sponsor and 
other study personnel (as appropriate) before database lock. The deviations will be 
classified as minor or major during a blind review process.  All decisions regarding 
major/minor 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 number of subjects with protocol deviations will be summarized by treatment group 
and overall. All protocol deviations will be listed. 
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
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03.007A.00     
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Page 24 of 72 
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  
the  study 
(and  treatment) from  which  the  patient  was  enrolled,  Patient  
ID (and  by  visit  and  by 
time point, if applicable) within treatment group, unless specified otherwise.  
All applicable data will be summarized by treatment group (CVT-301 DL1, CVT-301 DL2, 
CVT-301  overall) in  tables,  unless  specified  otherwise.  Furthermore, selected 
summaries  will  be  broken  down  into  three  groups  as  follows:  patients  who  received 
CVT-301 in CVT-301-004 study, patients who received placebo in CVT-301-004 study and 
CVT-301 naïve patients (including CVT-301-005 observational arm patients) (referred to 
as  “treatment/study  group”  in  the  SAP).    The efficacy  data  from patients  who  were 
enrolled in the CVT-301-003 or CVT-301-009 study will be analyzed separately, as data 
listings.  
In  addition, a  patient  disposition  table  will  be  provided  for CVT-301-003 and 
CVT-301-009 patients.   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. 
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 spirometry and  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 each 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 and  information  on  whether  the  deviation  was  done 
before or after the blind of study CVT-301-004E was broken. 
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6.2. KEY DEFINITIONS 
Age 
Age, as an integer, will be calculated using the date of birth and baseline date.   
          Age = int ((baseline date - 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) =  
Baseline Date (M/Y) - Date of diagnosis (M/Y) 
Duration of levodopa treatment (months) =  
Baseline Date (M/Y) - Start date of levodopa treatment (M/Y) 
Time since onset of wearing off episodes (months) =  
Baseline Date (M/Y) - Date of onset of wearing off episodes (M/Y) 
For the definition of baseline data, see below. 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 =  
(Post-dose value – Pre-dose value)*100/Pre-dose value 
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Baseline 
Baseline  
is  defined  as  the  
last  non-missing  assessment  before  the  first  dose  of 
CVT-301 in study CVT-301-004 for the patients who received CVT-301 in CVT-301-
004  and  as  the  
last  non-missing  assessment  before  the  
first  dose  of  CVT-301  
in 
CVT-301-004E for the rest of the patients. 
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  
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)  
• Women predicted DLCO = 2.2382 - (0.1111 x age) + (0.4068 x height)  
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. 
 
• 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) 
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Page 27 of 72 
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 the predicted value is the value calculated based on formulae by Hankinson et al 
(1999) . The details are listed in table below. 
DLCOpredicted, percent predicted of 
FEV1 and FVC  
In case a variable used to calculate the predicted value 
(age, height, Hb) is missing, the following imputation 
rules will be used in order to calculate the predicted 
value: 
Screening  (prior to randomization) 
Age, height or Hb from TV1 or the value closest to the 
date of DLCO/FEV1/FVC assessment if the value at TV1 is 
missing 
TV3, within 2 weeks  prior to 3 
Age, height or Hb from TV3 or the value closest to the 
date of DLCO/FEV1/FVC assessment if the value at TV3 is 
missing 
TV4, within 2 weeks  prior to 6 
Age, height or Hb from TV4 or the value closest to the 
date of DLCO/FEV1/FVC assessment if the value at TV4 is 
missing 
TV5, within 2 weeks  prior to 9 
Age, height or Hb from TV5 or the value closest to the 
date of DLCO/FEV1/FVC assessment if the value at TV5 is 
missing 
TV6, within 2 weeks  prior to 12 
Age, height or Hb from TV6 or the value closest to the 
date of DLCO/FEV1/FVC assessment if the value at TV6 is 
missing 
4 to 5 weeks after TV6 
The latest non-missing Hb closest to the date of 
DLCO/FEV1/FVC assessment taken. 
 
6.3. MISSING DATA 
Several  different  methods  to  handle  the  missing  data  in  efficacy  assessments  will  be 
used. 
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• For  the  primary  analysis  of  spirometry  and  selected  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 9.1. 
 
• 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 8.1.  
 
• 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 9.4. 
The Safety and ITT population will be used for the analysis of the primary and secondary 
endpoints.    This  population  
includes  all  patients  enrolled  to  study  CVT-301-004E who 
received  at  least  1  dose  of  inhaled  CVT-301,  regardless  of  whether  they  have  post-
baseline  data  or  not  for  the  variable  
in  question.  
 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.  
Safety data (other than the primary endpoint) will not be subjected to any imputation 
and will be summarized on an observed case basis. 
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 ET visit (PDQ-39, PHQ-9, PGI-C, UPDRS Part 2, UPDRS 
Part  4,  S&E  ADL  score  and  safety  assessments).  The  following  rules  will  be  used  to 
analyze the data collected at the ET visit: 
 
• For the PDQ-39, PHQ-9, PGI-C, UPDRS Part 2, UPDRS Part 4 and S&E ADL score, the 
data from the ET visit will be re-assigned to TV6 in case there is no TV6 assessment. 
 
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E
004 
SAP Version  2.0 
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• 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. 
 
• 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 safety/efficacy endpoints (at  least the change  from 
baseline  in  total  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  TV1 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 TV1 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 
TV1 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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Statistical Analysis Plan 
 
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03.007A.00     
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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 for APP.  In addition, the data will be 
broken down by treatment/study group (patients who received inhaled CVT-301 in CVT-
301-004 study, patients who received placebo in CVT-301-004 study and CVT 301 naïve 
patients (including CVT-301-005 observational  arm patients). The  patient  disposition 
table  will  also  be  provided  for CVT-301-003 and CVT-301-009 roll-over  patients. The 
percentages will be calculated based on the number of patients enrolled to study CVT-
301-004E, unless otherwise specified).  
 
• 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 enrolled into  the CVT-301-004E 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, % calculated from the Safety population) 
• 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 and ITT population by treatment group and overall.  In addition, the data will be 
broken down by treatment/study group.  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 TV1 will be used 
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03.007A.00     
  INC Research © LLC 
Page 31 of 72 
as  baseline.  If the data  are  only  available  on  1  or  2  days  prior  to  TV1,  the 
available data will be used as baseline. If there is no data prior to TV1, the data 
collected on 3 days prior to SV2 will be used as baseline.  
• 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  TV1  will  be  used  as  baseline.  
If  the  data  are 
only  available  on  1  or  2  days  prior  to  TV1,  the  available  data  will  be  used  as 
baseline. If there is no data prior to TV1, 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 TV1) 
• Proportion of  patients  with  
total daily OFF time <4.5 hours or ≥4.5 hours (from 
PD diary before TV1) 
• 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  TV1, Non-dyskinetic  before  TV1).  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). 
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CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
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03.007A.00     
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• 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 TV1 versus  non-dyskinetic; Patient  with  the  baseline daily 
levodopa dose 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 TV1 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). 
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  will  be  sorted  by  overall 
descending frequency of SOC and then, within  a SOC, by overall descending frequency 
of  PT. The  medical  history  will  be  summarized  based  on  the  baseline  definition,  see 
Section 6.2. 
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  will  be 
considered prior medications. Medications with  start date or  stop date  on or after the 
first date of inhaled CVT-301 dosing will be considered concomitant medications. 
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 
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CVT-301-004E 
SAP Version  2.0 
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03.007A.00     
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Page 33 of 72 
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:  
• 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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CVT-301-004E 
SAP Version  2.0 
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03.007A.00     
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Page 34 of 72 
8. 
EFFICACY 
The efficacy evaluation defined below includes data from the patients who were 
previously enrolled in the CVT-301-004 study and for the CVT 301 naïve patients 
(including patients from CVT-301-005 observational arm). The data from patients who 
were enrolled to study CVT-301-003 or CVT-301-009 will not be included in the efficacy 
summaries and will be listed only.  
In general, for the purpose of the efficacy analyses, the visits will be pooled as follows: 
 
Study CVT-301-004 
Study CVT-301-004E 
Treatment/study 
group 
Baseline 
visit 
Week 4 
visit 
Week 8 
visit 
Week 
12 visit 
Baseline 
visit 
Month 
1 visit 
Month 
3-9 
visits 
Month 
12 visit 
CVT-301-004, 
CVT-301 group 
Baseline Month 
1 
not 
used 
Month 
3 
not used 
not 
used 
Months 
6-12 
not 
used 
CVT-301-004, 
placebo group 
not used 
not 
used 
not 
used 
not 
used 
Baseline Month 
1 
Months 
3-9 
Month 
12 
CVT-301 naïve 
patients 
NA 
NA 
NA 
NA 
Baseline Month 
1 
Months 
3-9 
Month 
12 
CVT-301-005, 
Observational, 
Arm  
NA 
NA 
NA 
NA 
Baseline Month 
1 
Months 
3-9 
Month 
12 
 
8.1. EFFICACY ENDPOINTS AND ANALYSES 
The  ITT  population  will  be  used  for  the  efficacy  analysis.  Patients  will  be  analyzed 
according  to  randomized treatment  group.  
 The  changes  within  each treatment  group 
and the overall change from baseline in continuous efficacy variables will be estimated 
using  an  MMRM.  Although  the  focus  of  this  study  is  to  describe  the  within-group 
changes, the differences between the treatment groups will be estimated as well, but 
no  inferential  analyses  regarding  the  between-group  differences  will  be  done.   The 
model  will  include  visit, stratification  variables  (Hoehn  and  Yahr  stage  and  screening 
FEV1  and/or  FEV1/FVC), treatment  group, treatment/study  group,  and  
the  
interaction 
between  
the treatment  group and  visit  as  
fixed  
factors as  
fixed  
factors.  
  The  baseline 
value will be used as a covariate.  An unstructured covariance structure will be applied 
for  the  MMRM.  
  
In  case  
the  model  will  not  converge  with  the  unstructured  covariance 
structure, the heterogeneous compound symmetry (CSH) or the heterogeneous Toeplitz 
structure  (TOEPH). If  the  unstructured  covariance  structure  will  be  used,  the 
denominator degrees of freedom will be computed using the Kenward-Roger method. In 
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1003804 
  
 
                      
 
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CVT-301-
E
004 
SAP Version  2.0 
Statistical Analysis Plan 
 
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03.007A.00     
  INC Research © LLC 
Page 35 of 72 
case  of  other  covariance  structures,  the  BETWITHIN  option  will  be  used  for  the 
denominator degrees of freedom.   
For  all  patients,  categorical  data  will  be  evaluated  descriptively.    Each  visit  will  be 
evaluated  separately  for  the  categorical  endpoints.  The  efficacy  endpoints  and 
associated  analyses  are  as  follows.  For  the  detailed  definition  of  the  endpoints,  see 
Section 4.3. 
• 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. The data will be summarized with descriptive statistics 
within each treatment group and overall. The GLIMMIX procedure for binomial data 
with  logic  link  will  be  used  to  estimate  the treatment  group difference.    Factors 
similar  
to  
the  ones  used  described  above  will  be  
included  
in  
the  model  
(sensitivity 
method).  An  unstructured  covariance  structure  will  be  used.  The  missing  data  will 
not be imputed as non-responders in this sensitivity analysis. Below sample code will 
be used for analysis. 
 
proc glimmix data=t2212; 
class pdsevbl fev1bl trtpn avisitn stdygrp usubjid; 
model avalc(event=
'Y
')= updoffsc pdsevbl fev1bl stdygrp trtpn avisitn trtpn*avisitn/s  dist=binary link=logit cl 
oddsratio (diff=first) solution; 
random avisitn/subject=usubjid residual type=un ; 
lsmeans  avisitn*trtpn/ cl ilink; 
ods output tests3=PVAL lsmeans=lsmeans(keep=trtpn avisitn mu) estimates=estimates(keep=statement label 
expestimate explower expupper); 
/* tv4 */ 
estimate "tv4 trt 2 vs 1" trtpn -1 1   trtpn*avisitn  0 0 0 -1 0   0 0 0 1 0  /cl or e; 
run; 
 
• 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.   The  baseline daily OFF time will  be used as a covariate in  
the  MMRM. 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 will 
be analyzed similarly using the MMRM. For the total daily OFF time only, MI analysis 
will  be  performed  as  a  sensitivity  analysis and  subgroup  analysis  on  subgroups in 
section 6.6 will also be prepared. 
 
• 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 
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CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
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03.007A.00     
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Page 36 of 72 
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.  The data will be 
summarized with descriptive statistics within each treatment group and overall.  
• Changes  from baseline in  endpoints  based  on  S&E  ADL  score,  UPDRS  Part  2  score, 
PHQ-9 total score, and PDQ-39 sub-scores and index score.  An ANCOVA model with 
the treatment  group, treatment/study group  and  stratification  variables  as  fixed 
factors and the baseline value as a covariate will be used to estimate the treatment 
group differences.  In addition, the data will be presented with descriptive statistics 
classified  by treatment  group and  visit.    The  observed  cases  will  be  used  in  the 
analysis and summaries. 
• Change from baseline (TV1) and Last Day of Treatment (LDOT) to days 1, 3, 6, 8, 11, 
14, 17, 24, and 28 after TV6 in the PHQ-9 will be summarized descriptively. LDOT is 
defined as assessment taken on TV6 or ET for patients who didn’t enrolled into the 
sub-study and TV4, TV5 or TV6 for patients who enrolled into sub-study. 
 
Sensitivity analyses of the efficacy data 
 
The  following  sensitivity  analysis  will  be  performed  for  the  daily  OFF  time  efficacy 
endpoint. 
 
• 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 
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 group 
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 
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1003804 
  
 
                      
 
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CVT-301-
E
004 
SAP Version  2.0 
Statistical Analysis Plan 
 
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03.007A.00     
  INC Research © LLC 
Page 37 of 72 
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, treatment group, treatment/study group 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  value, treatment  group, 
treatment/study  group  and  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. 
 
Exploratory analyses of the efficacy data 
 
• Changes from baseline in endpoints based on S&E ADL score, UPDRS Part 2 score, 
PHQ-9 total score, Impact of Parkinson’s OFF Episodes Patient Survey score along 
with numeric individual score (i.e. Impact of OFF Time on Disability - ON State 
Disability and Impact of OFF Time on Disability - ON State Disability), and PDQ-39 
sub-scores and index score.  An ANCOVA model with the treatment group, 
treatment/study group and stratification variables as fixed factors and the baseline 
value as a covariate will be used to estimate the treatment group differences.  In 
addition, the data will be presented with descriptive statistics classified by 
treatment group and visit.  The observed cases will be used in the analysis and 
summaries. 
• For Impact  of  Parkinson’s  OFF  Episodes  Patient  Survey,  the  frequency and 
percentage  of  patients  for  each response  will  be  summarized by  treatment  group 
and overall for each of the item within each section.   
 
 
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03.007A.00     
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9. 
SAFETY 
The population used for safety analyses will be the Safety Population.  The analyses are 
outlined  below. The  safety  evaluation  defined  below  includes  data  from  all  patients 
included in the Safety population. 
For the statistical analysis of the spirometry data, the visits will be pooled as described 
in Section 8.  Otherwise, all safety data will be presented in the summaries, 
9.1. SPIROMETRY 
For  CVT-301-naïve  patients  and CVT-301-009  patients,  spirometry  will  be  assessed  at 
the  neurology  sites  for  screening  and  TV1  and  the  pulmonary  sites  will  be  exclusively 
responsible for the conduct of spirometry after TV1 (within 2 weeks prior to the 3-, 6-, 
9-,  and  12-month  visits,  and  4  to  5  weeks  following  completion  of  Treatment  Visit  6 
[TV6]).  For  patients  from CVT-301-004,  spirometry  will  be  assessed  at  the  neurology 
sites at TV1, and the pulmonary sites will be exclusively responsible for the conduct of 
spirometry  after  TV1  as  described  for  the  CVT-301-naïve  patients.   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 will be  summarized  descriptively by 
treatment  group and  overall. In  addition,  the  data  will  be summarized by 
treatment/study group.   
 
• Change from baseline to other visits for each parameter.  
• 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.  
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  INC Research © LLC 
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• 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  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.  
 
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 DL1 or CVT-301  DL2), treatment/study  group  
(patients  who  received  
inhaled  CVT-
301 in CVT-301-004 study, patients who received placebo in CVT-301-004 study and CVT 
301 naïve patients), 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  for  the  changes  from  baseline  within  each treatment  group and 
overall, and between the treatment group at each visit; along with the 95% confidence 
interval  (CI)  will  be  provided  
in  a  table. Treatment  group 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 stdygrp avisit usubjid; 
model chg=base pdsevbl fev1bl stdygrp avisit trta trta*avisit / ddfm=kr; 
repeated avisit / subject=usubjid(trta) type=un; 
lsmeans trta*avisit / cl pdiff; 
ods output Diffs=DIFF_MI LSMeans=LSM_MI tests3=tests ;  
run; 
 
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 40 of 72 
The safety  population  will  be  used  for  the descriptive  analysis. The CVT-301-003  and 
CVT-301-009 rollover subjects will be excluded for MMRM analysis. 
In  addition,  the  changes  
in  the  spirometry  values  within  treatment  arm  
in  CT-301-004 
(CVT-301 vs Placebo) and differences between the CVT-301-004 treatments (CVT-301 vs 
Placebo)  will  be  estimated  with  MMRM.  The  model  will  include  the treatment  group 
(CVT-301 DL1 or CVT-301 DL2), CVT-301-004 treatment, 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 CVT-301-004  treatment  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  for  the  changes 
from baseline within CVT-301-004 treatment, and between the CVT-301-004 treatment 
arm  at  each  visit;  along  with  the  95%  confidence  interval  (CI)  will  be  provided  in  a 
table. CVT-301-004 treatment arm 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 stdygrp avisit usubjid; 
model  chg=base  pdsevbl  fev1bl stdygrp avisit  trta stdygrp*avisit  / 
ddfm=kr; 
repeated avisit / subject=usubjid(stdygrp) type=un; 
lsmeans stdygrp*avisit / cl pdiff; 
ods output Diffs=DIFF_MI LSMeans=LSM_MI tests3=tests ;  
run; 
 
The CVT-301-004 rollover patients in safety population will be used for the analysis. 
 
Sensitivity analyses of the spirometry data 
 
The  following  sensitivity  analysis  will  be  performed  for FEV1, FEV1/FVC and  DLCO 
assessments. 
 
• 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 
Page 46 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 41 of 72 
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 group 
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, treatment/study group, baseline spirometry 
value, the  stratification  factors and  the  
interaction  between  the treatment  group 
and  visit 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, treatment/study group,  baseline 
spirometry  value, stratification  factors, the  interaction  between  the treatment 
group and  visit 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 group 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  last arrival assessment  before  the  first  dose  of  
inhaled  CVT-301. If  the 
Arrival value is missing, the last available value in ON state before the first dose 
Page 47 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-
E
004 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 42 of 72 
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. 
• Actual values  and  change  from  pre-dose  to  post-dose  time  points  for  each 
parameter at TV1; percent change for FEV1 and FVC will also be summarized. If 
a pre-dose value at TV1 is missing, the last available value in OFF state before 
the  first  dose  of  will  be  used. The  summary  for  FEV1  will  also  be  provided  by 
smoker status. 
• Number  and percentage of  patients  with  percent  of  changes  (<-50%, -50% -<-
40%, -40% -<-30%,  -30% -<-20%, -20% -<-10%, -10% -<10%,10% -<20% , 20% -<30% , 
30% -<40% ,  40% -<50%,  >=50%) at  each post-dose time  point at  TV1  from  pre-
dose for FEV1, FVC and FEV1/FVC. The summary for FEV1 will also be  provided 
by smoker status. 
9.2. EXTENT OF EXPOSURE 
The following information will be summarized by treatment group and overall: 
• The number of patients with dose change 
• Duration of exposure to CVT-301 inhalations (days) 
• Total  exposure  to  CVT-301  inhalation,  expressed  as  person  years  (sum  of 
exposure to CVT-301 inhalations over all patients, classified by treatment group) 
• 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: 
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 43 of 72 
• 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. 
In addition, all the data will be broken down by treatment/study group. 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. 
9.3. 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.  
9.4. 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 CVT-301 after  
the  
relevant  baseline  
(see  Section  6.2 
for  the  definition  of  baseline).   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.  
Page 49 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 44 of 72 
• 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 CVT-301 overall.  
TEAEs  with  onset  after  the  treatment  period  are  attributed  to the treatment  group 
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  to  CVT-301  will  be  presented  (number  of  TEAEs 
divided by the total exposure to CVT-301, 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 
Page 50 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 45 of 72 
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. 
In addition, selected AE tables will be broken down by treatment/study group. 
9.5. LABORATORY EVALUATIONS 
Laboratory samples for hematology and clinical chemistry will be analyzed by a central 
laboratory (located in the United States of America) 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 handing 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  
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%  
Page 51 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 46 of 72 
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 last non-missing assessment before the first dose of CVT-301 in study 
CVT-301-004 for the patients who received CVT-301 in CVT-301-004 and as the last non-missing 
assessment  before  the  first  dose  of  CVT-301  in  CVT-301-004E  for  the  rest  of  the  patients. 
 
' * 
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.  
9.6. 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 pre-dose values for each parameter. Baseline 
is defined as the last non-missing assessment before the first dose of CVT-301 in 
study CVT-301-004 for the patients who received CVT-301 in CVT-301-004 and as 
the last non-missing assessment before the first dose of CVT-301 in CVT-301-004E 
for the rest of the patients. 
' 
Page 52 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 47 of 72 
• Actual values and change from pre-dose to post-dose time points at TV1 by time 
point for each parameter 
• 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 TV1.  
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. 
9.7. 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 pre-dose values for each parameter. Baseline 
is defined as the last non-missing assessment before the first dose of CVT-301 in 
study CVT-301-004 for the patients who received CVT-301 in CVT-301-004 and as 
the last non-missing assessment before the first dose of CVT-301 in CVT-301-004E 
for the rest of the patients. 
'. 
Page 53 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 48 of 72 
• 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  
 
9.8. 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 
9.9. 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 
Page 54 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-
E
004 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 49 of 72 
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 table from baseline to each visit, days 1, 3, 6, 8, 11, 14, 17, 24, and 
28 after LDOT will be constructed to assess any changes in the subjects’ suicidal 
ideation and behavior during the treatment period. 
A shift table from LDOT  to days 1, 3, 6, 8, 11, 14, 17, 24, and 28 after TV6 will be 
constructed to assess any changes in the subjects’ suicidal ideation and behavior during 
the treatment period. 
9.10. 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 to each visit will be summarized by treatment group and overall (for handing of 
data from the ET visit, see Section 6.4). The total score and change from baseline (TV1) 
and  Last  Day of Treatment  to days 1, 3, 6, 8, 11, 14, 17, 24, and 28 after Last  Day of 
Treatment will also be summarized. LDOT is defined as assessment taken on TV6 or ET 
for patients who didn’t enrolled into the sub-study and TV4, TV5 or TV6 for patients 
who enrolled into sub-study. 
9.11. 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.  
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1003804 
  
 
                      
 
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CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 50 of 72 
The  
frequency  and  percentage  of  patients  with  positive  
response  
for  each  of  the  
item 
within  each  section  will  be  summarized by  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  
 
Hobbyism 
 item #1A  
Punding  
 item #1B  
Walkabout  
 item #1C  
C. Compulsive Medication Use  
items #1 and #4  
 
9.12. UPDRS PART 4 
Changes  from  TV1  (pre-dose)  to each  visit (pre-dose)  
in  UPDRS  Part  4  sum  scores and 
each  sub-scores  (Dyskinesias  and  Fluctuations)will  be  summarized  and analyzed using 
similar MMRM methods as for the spirometry data.  
9.13. 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. 
9.14. AMPHETAMINE WITHDRAWAL QUESTIONNAIRE (AWQ) 
The actual values and changes from baseline (TV1) and LDOT to days 1, 3, 6, 8, 11, 14, 
17,  24,  and  28  after LDOT in  AWQ  total  score  will  be  summarized  descriptively for 
patients  in  safety  population. LDOT is  defined  as  assessment  taken  on  TV6  or  ET  for 
patients  who  didn’t  enrolled  
into  
the  sub-study  and TV4,  TV5  or  TV6 for  patients  who 
enrolled into sub-study. 
9.15. DOPAMINE DYSREGULATION SYNDROME - PATIENT AND CAREGIVER 
INVENTORY (DDS-PC) 
The actual values and changes from baseline (TV1) and Last  Day of Treatment to days 
1, 3, 6, 8, 11, 14, 17, 24, and 28 after Last  Day of Treatment in DDS-PC total score will 
be  summarized  descriptively for  patients  in  safety  population. LDOT is  defined  as 
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 51 of 72 
assessment taken on TV6 or ET for patients who didn’t enrolled into the sub-study and 
TV4, TV5 or TV6 for patients who enrolled into sub-study. 
9.16. MOVEMENT DISORDER SOCIETY - UNIFIED PARKINSON’S DISEASE RATING 
SCALE (MDS-UPDRS) 
The MDS-UPDRS Part 1 and Part 2 value will be summarized descriptively on days 1, 3, 
6, 8, 11, 14, 17, 24, and 28 after Last Day of Treatment by treatment for patients in the 
safety population. 
9.17. UPDRS PART 1 
The  actual  values  and  changes  from baseline to  each  visit  (pre-dose)  
in  UPDRS  Part 1 
total score will be summarized using observed data.  The total score will be calculated 
as the sum of the individual items 1 to 4.  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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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 52 of 72 
10. 
INTERIM ANALYSES 
Two  interim analyses are  planned.  The  first  interim  analyses  were  based  on  interim 
analysis  SAP version  1.0  and  data cut  on  Feb  10
th,  2017.  
  The  second  
interim  will  be 
based on this SAP and planned data cut June 30, 2017. 
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 53 of 72 
11. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
The protocol stated that the data for patients who were enrolled in the CVT-301-004 
study, the CVT-301-009 study and for the CVT-301-naïve patients study will be primarily 
analyzed together, while the patients who were enrolled in the CVT-301-003 study will 
be analyzed separately. In the SAP, the patients enrolled from CVT-301-003 and CVT-
301-009 will not be included in efficacy summaries (i.e. the patients enrolled from CVT-
301-003 and CVT-301-009 will be excluded from ITT population) due to the different 
study designs. Instead the efficacy data from patients who were enrolled in the CVT-
301-003 or CVT-301-009 study will be analyzed separately, as data listings. The 
rationale for excluding the CVT-301-003 patients from the efficacy summaries is the gap 
between the end of CVT-301-003 and start of CVT-301-004E.  
 
 
 
 
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 54 of 72 
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 
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Civitas Therapeutics, Inc. 
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SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 55 of 72 
• All output should have the following header at the top left of each page: 
Civitas Therapeutics, Inc.   
Protocol No. CVT-301-004E                 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 treatment group in the tables will be DL1 first, followed by DL2 and an 
overall 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 
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 56 of 72 
• Unless  otherwise  specified,  the  estimated  mean  and  median  for  a  set  of  values 
should  be  printed  out  to  1  more  significant  digit  than  the  original  values,  and 
standard  deviations  should  be  printed  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 
Min, Max 
XXX,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, unless specified otherwise. 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. 
• 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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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 57 of 72 
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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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 58 of 72 
14. 
INDEX OF TABLES 
Table 14.1.1.1 
Number of Subjects Enrolled and Study Termination by Treatment Group 
(All Available Population) 
 
Table 14.1.1.2 
Number of Subjects Enrolled and Study Termination by Treatment/Study  
(All Available Population - Excluding Patients enrolled from CVT-301-
003/CVT-301-009) 
 
Table 14.1.1.3 
Number of Subjects Enrolled and Study Termination by Treatment Group 
(CVT-301-003 and CVT-301-009 Patients) 
Table 14.1.1.4 
Number of Subjects in Each Population by Study Center 
 (All Available Population) 
 
Table 14.1.1.5 
Number of Subjects in Each Population by Treatment/Study and Study 
Center (All Available Population - Excluding Patients enrolled from CVT-
301-003/CVT-301-009)   
Table 14.1.2.1 
Summary of Protocol Deviation by Treatment Group Randomized Set  
Table 14.1.3.1.1 
Demographic and Baseline Characteristics by Treatment Group (Safety 
Population) 
 
Table 14.1.3.1.2   
Demographic and Baseline Characteristics by Treatment Group (ITT 
Population) 
Table 14.1.3.1.3 
Demographic and Baseline Characteristics by Treatment Group and 
Baseline PD Severity (ITT Population)  
Table 14.1.3.1.4 
Demographic and Baseline Characteristics by Treatment Group and 
Baseline Dyskinesia  (ITT Population)  
Table 14.1.3.1.5 
Demographic and Baseline Characteristics by Treatment Group and 
Baseline Daily Levodopa Dose (ITT Population)  
Table 14.1.3.1.6 
Demographic and Baseline Characteristics by Treatment Group and PD 
Diary Mean Daily OFF Time during Screening (ITT Population)  
Table 14.1.3.1.7 
Demographic and Baseline Characteristics by Treatment Group and 
Screening Spirometry  (ITT Population)  
Table 14.1.3.1.8 
Demographic and Baseline Characteristics by Treatment Group and Age 
Group (ITT Population)  
Table 14.1.3.1.9 
Demographic and Baseline Characteristics by Treatment Group and Gender 
(ITT Population) 
 
Table 14.1.3.1.10 
Demographic and Baseline Characteristics by Treatment/Study (ITT 
Population) 
Table 14.1.3.2.1 
Parkinson’s Disease History by Treatment Group (Safety Population) 
 
Table 14.1.3.2.2 
Parkinson’s Disease History by Treatment Group (ITT Population) 
 
Table 14.1.3.2.3 
Parkinson’s Disease History by Treatment Group and Baseline PD Severity 
(ITT Population) 
 
Table 14.1.3.2.4 
Parkinson’s Disease History by Treatment Group and Baseline Dyskinesia  
(ITT Population) 
 
Table 14.1.3.2.5 
Parkinson’s Disease History by Treatment Group and Baseline Daily 
Levodopa Dose (ITT Population) 
 
Table 14.1.3.2.6 
Parkinson’s Disease History by Treatment Group and PD Diary Mean Daily 
OFF Time during Screening (ITT Population) 
 
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1003804 
  
 
                      
 
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CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 59 of 72 
Table 14.1.3.2.7 
Parkinson’s Disease History by Treatment Group and Screening Spirometry  
(ITT Population) 
 
Table 14.1.3.2.8 
Parkinson’s Disease History by Treatment Group and Age Group (ITT 
Population) 
Table 14.1.3.2.9 
Parkinson’s Disease History by Treatment Group and Gender (ITT 
Population) 
 
Table 14.1.3.2.10 
Parkinson’s Disease History by Treatment/Study (ITT Population) 
Table 14.1.3.2.11 
Modified Hoehn and Yahr Staging in “ON” State by Treatment Group 
(Safety Population) 
 
Table 14.1.3.2.12 
Modified Hoehn and Yahr Staging in “ON” State Treatment Group and (ITT 
Population) 
 
Table 14.1.3.2.13 
Modified Hoehn and Yahr Staging in “ON” State by Treatment/Study(ITT 
Population) 
Table 14.1.3.2.14   Distribution of Average Daily OFF Time by Treatment Group (Safety 
Population) 
Table 14.1.3.2.15 
Distribution of cumulative Average Daily OFF Time by Treatment Group 
(Safety Population) 
 
Table 14.1.3.3 
Medical History by Treatment Group (Safety Population) 
 
Table 14.1.4.1 
Prior Medications by Treatment Group (Safety Population) 
 
Table 14.1.4.2 
Concomitant Medications by Treatment Group (Safety Population) 
 
Table 14.1.4.3 
Parkinson’s disease Treatment Medications at Baseline by Treatment Group 
(Safety Population) 
 
Table 14.2.1.1 
Efficacy Analysis: Subjects Achieving Resolution of an OFF to an ON State 
within 60 Minutes by Treatment Group and Visit Worst Case Imputation [a] 
(ITT Population) 
 
Table 14.2.1.2 
Efficacy Analysis: Subjects Achieving Resolution of an OFF to an ON State 
within 60 Minutes by Treatment Group and Visit Logistic Regression by 
GLIMMIX (ITT Population)  
Table 14.2.2.1.1   
Efficacy Analysis (MMRM): Change from Baseline in Total Daily OFF Time by 
Treatment Group and Visit (ITT Population) 
 
Table 14.2.2.1.2    Sensitivity Analysis: Change from Baseline in Total Daily OFF Time by 
Treatment Group and Visit MI analysis with Missing At Random Assumption  
(ITT Population) 
Table 14.2.2.1.3 
Efficacy Subgroup Analysis: Change from Baseline in Total Daily OFF Time 
by Treatment Group, Visit and Baseline PD Severity  (ITT Population)  
Table 14.2.2.1.4 
Efficacy Subgroup Analysis: Change from Baseline in Total Daily OFF Time 
by Treatment Group, Visit and Baseline Dyskinesia (ITT Population) 
Table 14.2.2.1.5 
Efficacy Subgroup Analysis: Change from Baseline in Total Daily OFF Time 
by Treatment Group, Visit and Baseline Daily Levodopa Dose (ITT 
Population) 
 
Table 14.2.2.1.6 
Efficacy Subgroup Analysis: Change from Baseline in Total Daily OFF Time 
by Treatment Group, Visit and PD Diary Mean Daily OFF Time during 
Screening (ITT Population) 
 
Table 14.2.2.1.7 
Efficacy Subgroup Analysis: Change from Baseline in Total Daily OFF Time 
by Visit, Treatment Group and Screening Spirometry  (ITT Population) 
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1003804 
  
 
                      
 
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SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 60 of 72 
Table 14.2.2.1.8 
Efficacy Subgroup Analysis: Change from Baseline in Total Daily OFF Time 
by Treatment Group, Visit and Age Group (ITT Population) 
 
Table 14.2.2.1.9 
Efficacy Subgroup Analysis: Change from Baseline in Total Daily OFF Time 
by Treatment Group, Visit and Gender (ITT Population)  
Table 14.2.2.2.1 
Efficacy Analysis: Mean of Total Daily ON Time without Dyskinesia by 
Treatment Group and Visit (ITT Population) 
Table 14.2.2.3.1 
Efficacy Analysis: Mean of Total Daily ON Time with non-Troublesome 
Dyskinesia by Treatment Group and Visit (ITT Population) 
Table 14.2.2.4.1 
Efficacy Analysis: Mean of Total Daily ON Time with Troublesome 
Dyskinesia by Treatment Group and Visit (ITT Population) 
Table 14.2.3.1 
Efficacy Analysis: Subjects Global Impression of Change (PGI-C) by 
Treatment Group and Visit  Worst Case Imputation [a] (ITT Population)  
Table 14.2.4.1 
Efficacy Analysis:  UPDRS Part 2 Score by Treatment Group and Visit (ITT 
Population) 
  
Table 14.2.4.2 
Efficacy Analysis:  Schwab and England (S&E) Activities of Daily Living 
(ADL) Score by Treatment Group and Visit (ITT Population) 
  
Table 14.2.4.3 
Efficacy Analysis:  39 Item Parkinson
's disease Questionnaire (PDQ-39) Sub-
scores and Summary Index Score by Treatment Group, Visit (ITT 
Population) 
  
Table 14.2.4.4 
Efficacy Analysis: 9-Item PHQ-9 Sum Score by Treatment Group and Visit 
(ITT Population) 
Table 14.2.4.4.1 
Change from Baseline (TV1) and Last Day of Treatment (LDOT) to Days 1, 
3, 6, 8, 11, 14, 17, 24, and 28 after LDOT in PHQ-9 Total Score by 
Treatment Group (ITT Population) 
Table 14.2.4.5.1 
Efficacy Analysis: Impact of Parkinson’s OFF Episodes Patient Survey Score 
by Treatment Group and Visit (ITT Population) 
Table 14.2.4.5.2 
Exploratory Efficacy Analysis: Frequency of Impact of Parkinson’s OFF 
Episodes Patient Survey by Treatment Group and Visit 
(ITT Population) 
Table 14.3.1.1.1   
Extent of Exposure: Overall Exposure by Treatment Group (Safety 
Population) 
  
Table 14.3.1.1.2   
Extent of Exposure: Overall Exposure by Treatment/Study (ITT Population)   
Table 14.3.1.2.1   
In-Clinic Study Drug Administration by Treatment Group (Safety 
Population) 
  
Table 14.3.1.2.2   
In-Clinic Study Drug Administration by Treatment/Study (ITT Population) 
Table 14.3.1.3.1 
Distribution of Time of Study Drug Administration by Treatment Group 
(Safety Population) 
  
Table 14.3.1.3.2 
Distribution of Time of Study Drug Administration by Treatment/Study (ITT  
Population) 
  
Table 14.3.2.1.1   
Treatment-emergent adverse events -Overall Summary  by Treatment 
Group (Safety Population) 
  
Table 14.3.2.1.2   
Treatment-emergent adverse events -Overall Summary  by 
Treatment/Study (ITT Population) 
  
Table 14.3.2.2.1 
Treatment-emergent adverse events by System Organ Class, Preferred 
Term and Treatment Group (Safety Population)  
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03.007A.00     
  INC Research © LLC 
Page 61 of 72 
Table 14.3.2.2.2 
Treatment-emergent adverse events by System Organ Class, Preferred 
Term and Treatment/Study  (ITT Population)  
Table 14.3.2.2.3   
Treatment-emergent adverse events by Preferred Term  by Treatment 
Group  (Safety Population)   
Table 14.3.2.2.4   
Treatment-emergent adverse events by Preferred Term  by 
Treatment/Study  (ITT Population)   
Table 14.3.2.2.5   
Number of Treatment-Emergent Adverse Events per Subject-year by 
System Organ Class, Preferred Term and Treatment Group  (Safety 
Population) 
Table 14.3.2.2.6   
Number of Treatment-Emergent Adverse Events per Subject-year by 
System Organ Class, Preferred Term and Treatment/Study  (ITT 
Population) 
Table 14.3.2.3 
Drug-Related Treatment-emergent adverse events by System Organ Class, 
Preferred Term, Severity and Treatment Group(Safety Population) 
  
Table 14.3.2.4 
Drug –Related Treatment-emergent adverse events by System Organ Class, 
Preferred Term, Relationship and Treatment Group (Safety Population)   
Table 14.3.2.5.1   
Drug-related Treatment-emergent adverse events by System Organ Class, 
Preferred Term and Treatment Group (Safety Population) 
  
Table 14.3.2.5.2   
Drug-related Treatment-emergent adverse events by System Organ Class, 
Preferred Term and Treatment/Study (ITT Population)   
Table 14.3.2.6.1 
Serious Treatment-emergent adverse events by System Organ Class, 
Preferred Term and Treatment Group (Safety Population) 
  
Table 14.3.2.6.2 
Serious Treatment-emergent adverse events by System Organ Class, 
Preferred Term and Treatment/Study (ITT Population)   
Table 14.3.2.7 
Listing of Serious Adverse Events (All Available Population) 
  
Table 14.3.2.8 
Listing of Adverse Events Leading to Death(All Available Population) 
  
Table 14.3.2.9.1 
Severe Treatment-emergent adverse events by System Organ Class, 
Preferred Term  and Treatment Group(Safety Population) 
  
Table 14.3.2.9.2 
Severe Treatment-emergent adverse events by System Organ Class, 
Preferred Term  By Treatment/Study (ITT Population)   
Table 14.3.2.10 
Listing of Severe Treatment-Emergent Adverse Events (Safety Population)   
Table 14.3.2.11.1 
Treatment-emergent adverse events Leading to Study Drug Interruption by 
System Organ Class, Preferred Term and Treatment Group (Safety 
Population) 
  
Table 14.3.2.11.2 
Treatment-emergent adverse events Leading to Study Drug Interruption by 
System Organ Class, Preferred Term and Treatment/Study (ITT Population)   
Table 14.3.2.12   
Listing of Adverse Events Leading to Study Drug Interruption(Safety 
Population) 
  
Table 14.3.2.13.1 
Treatment-emergent adverse events Leading to Study Drug Discontinuation 
by System Organ Class, Preferred Term  and Treatment Group (Safety 
Population) 
Table 14.3.2.13.2 
Treatment-emergent adverse events Leading to Study Drug Discontinuation 
by System Organ Class, Preferred Term  and Treatment/Study (ITT 
Population) 
 
Table 14.3.2.14 
Listing of Adverse Events Leading to Study Drug Discontinuation (Safety 
Population) 
  
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SAP Version  2.0 
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Page 62 of 72 
Table 14.3.2.15.1 
Treatment-emergent adverse events Leading to Dose Reduction by System 
Organ Class, Preferred Term and Treatment Group (Safety Population)   
Table 14.3.2.15.2 
Treatment-emergent adverse events Leading to Dose Reduction by System 
Organ Class, Preferred Term and Treatment/Study (ITT Population) 
  
Table 14.3.2.16 
Listing of Adverse Events Leading to Dose Reduction(Safety  Population)  
Table 14.3.2.17.1 
Most Common Treatment-Emergent Adverse Events (Preferred Term 
Occurred in >10% of Over Patients) by System Organ Class, Preferred Term 
and Treatment Group (Safety Population) 
Table 14.3.2.17.2 
Most Common Treatment-Emergent Adverse Events (Preferred Term 
Occurred in >10% of Over Patients) by System Organ Class, Preferred Term 
and Treatment/Study (ITT Population) 
Table 14.3.2.18 
Listing of Most Common Treatment-Emergent Adverse Events (Safety 
Population) 
Table 14.3.2.19.1 
Time to first Onset of most Common Treatment-Emergent Adverse Events 
by Treatment Group (Safety Population) 
Table 14.3.2.19.2 
Time to first Onset of most Common Treatment-Emergent Adverse Events 
by Treatment/Study (ITT 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 by Treatment Group 
and Visit (Safety Population)   
Table 14.3.4.1.1.2 Summary of Clinical Laboratory Results: Hematology Abnormal Values by 
Treatment Group and Visit (Safety Population)   
Table 14.3.4.1.1.3 Summary of Clinical Laboratory Results: Hematology Abnormal Values –
Shift from Baseline by Treatment Group and Visit (Safety Population)   
Table 14.3.4.1.1.4 Summary of Clinical Laboratory Results: Hematology PCS Values –Shift from 
Baseline by Treatment Group and Visit (Safety Population) 
  
Table 14.3.4.1.1.5 Summary of Clinical Laboratory Results: Hematology PCSC Values –Shift 
from Baseline by Treatment Group and Visit (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 by Treatment Group 
and Visit (Safety Population)   
Table 14.3.4.1.2.2 Summary of Clinical Laboratory Results: Chemistry Abnormal Values by 
Treatment Group and Visit (Safety Population)   
Table 14.3.4.1.2.3 Summary of Clinical Laboratory Results: Chemistry Abnormal Values –Shift 
from Baseline by Treatment Group and Visit (Safety Population) 
  
Table 14.3.4.1.2.4   Summary of Clinical Laboratory Results: Chemistry PCS Values –Shift from 
Baseline by Treatment Group and Visit (Safety Population) 
  
Table 14.3.4.1.2.5 Summary of Clinical Laboratory Results: Chemistry PCSC Values –Shift from 
Baseline by Treatment Group and Visit (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 by 
Treatment Group and Visit  (Safety Population)  
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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 Treatment Group 
and 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 (Safety Population)   
Table 14.3.4.2.6 
Summary of Vital Signs: Orthostatic Hypotension by Treatment Group and 
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  (Safety  Population)  
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 by Treatment Group 
and Visit (Safety Population)   
Table 14.3.4.3.2 
Summary of 12-Lead ECG: PCS and PCSC Values  by Treatment Group and 
Visit (Safety Population) 
  
Table 14.3.4.3.3 
12-Lead Electrocardiogram (ECG): PCS and PCSC Values (All Available 
Population) 
  
Table 14.3.4.4 
Physical Examination by Treatment Group and Visit  (Safety Population) 
  
Table 
14.3.4.5.1.1.1 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1 and FVC by Treatment Group and Visit  
(Safety Population) 
  
Table 
14.3.4.5.1.1.2 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1 and FVC by Treatment/Study and Visit 
(Safety Population)  
Table 
14.3.4.5.1.1.3 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1 by Treatment Group, Visit and Smoker 
Status 
(Safety Population) 
Table 
14.3.4.5.1.1.4 
Summary of Spirometry (Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1 by Treatment/Study, Visit and Smoker 
Status  
(Safety Population) 
Table 
14.3.4.5.1.2.1 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1 and FVC by Treatment Group and Visit  
Using Subset of Assessments Meeting the ATS Quality Criteria (Safety 
Population) 
  
Table 
14.3.4.5.1.2.2 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1 and FVC by Treatment/Study and Visit 
Using Subset of Assessments Meeting the ATS Quality Criteria (Safety 
Population) 
  
Table 
14.3.4.5.1.3.1 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1 and FVC by Treatment Group and Visit 
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5% 
(Safety Population) 
  
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Table 
14.3.4.5.1.3.2 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1 and FVC by Treatment/Study and Visit 
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5% 
(Safety Population) 
  
Table 
14.3.4.5.1.4.1 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1 by Treatment Group and Visit  (Safety Population) 
Table 
14.3.4.5.1.4.2 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1 by CVT-301-004 Treatment and Visit CVT-301-004 
Rollover Patients (Safety Population) 
Table 
14.3.4.5.1.5.1 
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 
14.3.4.5.1.5.2 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1 by CVT-301-004 Treatment and Visit Using Subset of 
Assessments Meeting the ATS Quality Criteria for CVT-301-004 Rollover 
Patients (Safety Population) 
Table 
14.3.4.5.1.6.1 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1 by Treatment Group and Visit Excluding Patients 
with Co-efficient of Variation (CV) of FEV1 >7.5% (Safety Population) 
Table 
14.3.4.5.1.6.2 
 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1 by CVT-301-004 Treatment and Visit CVT-301-004 
Rollover Patients and 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 
Treatment Group and Visit MI analysis with Missing At Random Assumption  
(Safety Population) 
Table 
14.3.4.5.1.8.1 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for Calculated DLco Parameters by Treatment Group 
and Visit  (Safety Population) 
Table 
14.3.4.5.1.9.1 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for Calculated DLco Parameters by Treatment Group 
and Visit  Using Subset of Assessments Meeting the ATS Quality Criteria for 
CVT-301-004 Rollover Patients (Safety Population) 
  
Table 
14.3.4.5.1.10.1 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for Calculated DLco Parameters by Treatment Group 
and Visit  Excluding Patients with Co-efficient of Variation (CV) of FEV1 
>7.5% (Safety Population) 
Table 
14.3.4.5.1.8.2 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for Calculated DLco Parameters by Treatment/Study 
and Visit  (Safety Population)  
Table 
14.3.4.5.1.9.2 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for Calculated DLco Parameters by Treatment/Study 
and Visit Using Subset of Assessments Meeting the ATS Quality Criteria for 
CVT-301-004 Rollover Patients (Safety Population) 
 
Table 
14.3.4.5.1.10.2 
Summary of Spirometry(Pulmonary Function Facility): Actual Values and 
Change from Baseline for Calculated DLco Parameters by Treatment/Study 
and Visit  Excluding Patients with Co-efficient of Variation (CV) of FEV1 
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Page 65 of 72 
>7.5%  (Safety Population) 
  
Table 
14.3.4.5.1.11.1 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for DLCO by Treatment Group and Visit  (Safety Population) 
Table 
14.3.4.5.1.11.2 
 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for DLCO by CVT-301-004 Treatment and Visit  CVT-301-004 
Rollover Patients (Safety Population) 
Table 
14.3.4.5.1.12.1 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for DLCO by Treatment Group and Visit Using Subset of 
Assessments Meeting the ATS Quality Criteria (Safety Population) 
Table 
14.3.4.5.1.12.2 
 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for DLCO by CVT-301-004 Treatment and Visit Using Subset 
of Assessments Meeting the ATS Quality Criteria for CVT-301-004 Rollover 
Patients  (Safety Population) 
Table 
14.3.4.5.1.13.1 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for DLCO by Treatment Group and Visit Excluding Patients 
with Co-efficient of Variation (CV) of FEV1 >7.5% (Safety Population) 
Table 
14.3.4.5.1.13.2 
 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for DLCO by CVT-301-004 Treatment and Visit CVT-301-004 
Rollover Patients and 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 
Treatment Group and Visit MI analysis with Missing At Random Assumption  
(Safety Population) 
Table 
14.3.4.5.1.15.1 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change 
from Baseline for FEV1 and FVC  by Treatment Group and Visit 
(Safety Population) 
Table 
14.3.4.5.1.15.2 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change 
from Baseline for FEV1 and FVC  by Treatment/Study and Visit (Safety 
Population) 
Table 
14.3.4.5.1.15.3 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change 
from Baseline for FEV1  by Treatment Group, Visit and Smoker Status 
(Safety Population) 
Table 
14.3.4.5.1.15.4 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change 
from Baseline for FEV1 by Treatment/Study, Visit and Smoker Status 
(Safety Population) 
Table 
14.3.4.5.1.16.1 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change 
from Baseline for DLCO by Treatment Group and Visit (Safety Population) 
Table 
14.3.4.5.1.16.2 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change 
from Baseline for DLCO by Treatment/Study and Visit (Safety Population) 
Table 
14.3.4.5.2.1.1 
Summary of Spirometry:(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1/FVC by Treatment Group and Visit  (Safety 
Population)   
Table 
14.3.4.5.2.2.1 
Summary of Spirometry:(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1/FVC by Treatment Group and Visit  Using 
Subset of Assessments Meeting the ATS Quality Criteria (Safety Population)
 
  
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03.007A.00     
  INC Research © LLC 
Page 66 of 72 
Table 
14.3.4.5.2.3.1 
Summary of Spirometry:(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1/FVC by Treatment Group and Visit  
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5% 
(Safety Population) 
  
Table 
14.3.4.5.2.1.2 
Summary of Spirometry:(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1/FVC by Treatment/Study and Visit (Safety 
Population) 
Table 
14.3.4.5.2.2.2 
Summary of Spirometry:(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1/FVC by Treatment/Study and Visit Using 
Subset of Assessments Meeting the ATS Quality Criteria (Safety Population) 
Table 
14.3.4.5.2.3.2 
Summary of Spirometry:(Pulmonary Function Facility): Actual Values and 
Change from Baseline for FEV1/FVC by Treatment/Study and Visit 
Excluding Patients with Co-efficient of Variation (CV) of FEV1 >7.5% 
(Safety Population  
Table 
14.3.4.5.2.4.1 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1/FVC by Treatment Group and Visit  (Safety 
Population) 
Table 
14.3.4.5.2.4.2 
 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1/FVC by CVT-301-004 Treatment and Visit CVT-301-
 Rollover Patients  (Safety Population) 
004
Table 
14.3.4.5.2.5.1 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1/FVC by Treatment Group and Visit  Using Subset of 
Assessments Meeting the ATS Quality Criteria (Safety Population) 
Table 
14.3.4.5.2.5.2 
 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1/FVC by CVT-301-004 Treatment and Visit Using 
Subset of Assessments Meeting the ATS Quality Criteria for CVT-301-004 
Rollover Patients (Safety Population) 
Table 
14.3.4.5.2.6.1 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1/FVC by Treatment Group and Visit Excluding 
Patients with Co-efficient of Variation (CV) of FEV1 >7.5% (Safety 
Population) 
Table 
14.3.4.5.2.6.2 
 
MMRM Analysis of Spirometry Data (Pulmonary Function Facility): Change 
from Baseline for FEV1/FVC by CVT-301-004 Treatment and Visit CVT-301-
004 Rollover Patients and 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 
Treatment Group and Visit MI analysis with Missing At Random Assumption  
(Safety Population) 
Table 
14.3.4.5.2.8.1 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change 
from Baseline for FEV1/FVC by Treatment Group and Visit (Safety 
Population) 
Table 
14.3.4.5.2.8.2 
Summary of Spirometry(Pulmonary Function Facility):Categories of Change 
from Baseline for FEV1/FVC by Treatment/Study and Visit (Safety 
Population) 
Table 
14.3.4.5.3.1.1 
Summary of Spirometry (Pulmonary Function Facility): Summary of 
FEV1/FVC < 60% and <70% by Treatment Group and Visit  (Safety 
Population)  
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Table 
14.3.4.5.3.2.1 
Summary of Spirometry (Pulmonary Function Facility): Summary of 
FEV1/FVC < 60% and <70% by Treatment Group and Visit Using Subset of 
Assessments Meeting the ATS Quality Criteria (Safety Population)  
Table 
14.3.4.5.3.3.1 
Summary of Spirometry (Pulmonary Function Facility): Summary of 
FEV1/FVC < 60% and <70% by Treatment Group and Visit Excluding Patients 
with Co-efficient of Variation (CV) of FEV1 >7.5% (Safety Population)  
Table 
14.3.4.5.3.1.2 
Summary of Spirometry (Pulmonary Function Facility): Summary of 
FEV1/FVC < 60% and <70% by Treatment/Study and Visit (Safety 
Population)  
Table 
14.3.4.5.3.2.2 
Summary of Spirometry (Pulmonary Function Facility): Summary of 
FEV1/FVC < 60% and <70% by Treatment/Study and Visit Using Subset of 
Assessments Meeting the ATS Quality Criteria (Safety Population)  
Table 
14.3.4.5.3.3.2 
Summary of Spirometry (Pulmonary Function Facility): Summary of 
FEV1/FVC < 60% and <70% by Treatment/Study and 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 
by Treatment Group and Visit  (Safety Population) 
Table 14.3.4.5.5 
 Summary of Spirometry(Pulmonary Function Facility): Measurements 
Meeting ATS Quality Criteria (Safety Population)  
Table 14.3.4.5.6.1 Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1 and FVC by Treatment Group and Visit  (Safety 
Population) 
  
Table 14.3.4.5.6.2 Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1 and FVC by Treatment/Study and Visit  (Safety 
Population) 
  
Table 14.3.4.5.6.3 Summary of Spirometry (Neurology Office): Actual Values and Change from 
Baseline for FEV1 by Treatment Group, Visit and Smoker Status(Safety 
Population) 
Table 14.3.4.5.6.4 Summary of Spirometry (Neurology Office): Actual Values and Change from 
Baseline for FEV1 by Treatment/Study, Visit and Smoker Status (Safety 
Population) 
Table 14.3.4.5.7.1 Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1/FVC by Treatment Group and Visit  (Safety Population)  
Table 14.3.4.5.7.2 Summary of Spirometry(Neurology Office): Actual Values and Change from 
Baseline for FEV1/FVC by Treatment/Study and Visit  (Safety Population)  
Table 14.3.4.5.8.1 Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% 
and <70% by Treatment Group and Visit (Safety Population)  
Table 14.3.4.5.8.2 Summary of Spirometry (Neurology Office): Summary of FEV1/FVC < 60% 
and <70% by Treatment/Study and Visit (Safety Population)  
Table 14.3.4.5.9 
Spirometry(Neurology Office): 70% or Smaller FEV1/FVC Values and >=200 
Reduction from Pre-dose (Safety Population) (Safety Population) 
Table 14.3.4.5.10 
Summary of Spirometry(Neurology Office): Measurements Meeting ATS 
Quality Criteria  (Safety Population)  
Table 14.3.4.5.11.1 Summary of Spirometry(Neurology Office):Categories of Change from 
Baseline for FEV1 and FVC by Treatment Group and Visit 
(Safety Population) 
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Table 14.3.4.5.11.2 Summary of Spirometry(Neurology Office):Categories of Change from 
Baseline for FEV1 and FVC by Treatment/Study and Visit 
(Safety Population) 
Table 14.3.4.5.11.3 Summary of Spirometry(Neurology Office):Categories of Change from 
Baseline for FEV1 by Treatment Group, Visit and Smoker Status (Safety 
Population) 
Table 14.3.4.5.11.4 Summary of Spirometry(Neurology Office):Categories of Change from 
Baseline for FEV1 by Treatment/Study, Visit and Smoker Status(Safety 
Population) 
Table 14.3.4.5.12.1 Summary of Spirometry(Neurology Office):Categories of Change from 
Baseline for FEV1/FVC by Treatment Group and Visit 
(Safety Population) 
Table 14.3.4.5.12.2 Summary of Spirometry(Neurology Office):Categories of Change from 
Baseline for FEV1/FVC by Treatment/Study and Visit 
(Safety Population) 
Table 14.3.4.5.13.1 Summary of Spirometry (Neurology Office): Actual Values and Change from 
Pre-dose for FEV1 and FVC at TV1 (Safety Population) 
Table 14.3.4.5.13.2 Summary of Spirometry (Neurology Office): Actual Values and Change from 
Pre-dose for FEV1/FVC at TV1 (Safety Population) 
Table 14.3.4.5.13.3 Summary of Spirometry (Neurology Office): Actual Values and Change from 
Pre-dose for FEV1 at TV1 by Smoker Status  (Safety Population) 
Table 14.3.4.5.14.1 Summary of Spirometry (Neurology Office): Categories of Percent Change 
from Pre-dose for FEV1, FVC at TV1 (Safety Population) 
Table 14.3.4.5.14.2 Summary of Spirometry (Neurology Office): Categories of Percent Change 
from Pre-dose for FEV1/FVC at TV1 (Safety Population) 
Table 14.3.4.5.14.3 Summary of Spirometry (Neurology Office): Categories of Percent Change 
from Pre-dose for FEV1 at TV1 by Smoker Status (Safety Population) 
Table 14.3.4.6.1 
Summary of Columbia-Suicide Severity Rating Scale (C-SSRS) by Treatment 
Group and Visit (Safety Population) 
  
Table 14.3.4.6.2 
Shift from Baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) by 
Treatment Group and Visit (Safety Population)  
Table 14.3.4.6.3 
Summary of Self-Reported Columbia-Suicide Severity Rating Scale (C-SSRS) 
by Treatment Group and Visit (Safety Population) 
Table 14.3.4.7 
Summary of Epworth Sleepiness Scale Total Score: Actual Values and 
Change from Baseline by Treatment Group and Visit (Safety Population)  
Table 14.3.4.7.1    Summary of Epworth Sleepiness Scale Total Score: Change from Baseline 
(TV1) and Last Day of Treatment (LDOT) to Days 1, 3, 6, 8, 11, 14, 17, 24, 
and 28 after LDOT by Treatment Group  (Safety Population) 
Table 14.3.4.8 
Summary of Questionnaire for Impulsive-Compulsive Disorders in 
Parkinson’s (QUIP) by Treatment Group and Visit (Safety Population)  
Table 14.3.4.9.1 
MMRM Analysis of UPDRS Part 4: Change from Baseline in the UPDRS Part 4 
Score by Treatment Group and Visit (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 by Treatment Group and Visit (Safety Population)  
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  INC Research © LLC 
Page 69 of 72 
Table 14.3.4.9.3 
 MMRM Analysis of UPDRS Part 4 Fluctuations Score: Change from Baseline 
in the UPDRS Part 4 Score by Treatment Group and Visit  (Safety 
Population)  
Table 14.3.4.9.4 
Summary of UPDRS Part 4: Actual Values and Change from Baseline by 
Treatment Group and Visit  (Safety Population)   
Table 14.3.4.9.5 
Summary of UPDRS Part 4 Dyskinesias Score: Actual Values and Change 
from Baseline by Treatment Group and Visit  (Safety Population) 
  
Table 14.3.4.9.6 
Summary of UPDRS Part 4 Fluctuations Score: Actual Values and Change 
from Baseline by Treatment Group and Visit  (Safety Population) 
  
Table 14.3.4.10 
Dyskinesia: Occurrence and Severity (In-clinic) by Treatment Group and 
Visit  (Safety Population)   
Table 14.3.4.11    
 
Amphetamine Withdrawal Questionnaire (AWQ) total Score: Change from 
Baseline (TV1) and Last Day of Treatment (LDOT) to Days 1, 3, 6, 8, 11, 14, 
17, 24, and 28 after LDOT by Treatment Group  (Safety Population) 
Table 14.3.4.12    
 
Dopamine Dysregulation Syndrome - Patient and Caregiver Inventory (DDS-
PC): Change from Baseline (TV1) and Last Day of Treatment (LDOT) to Days 
1, 3, 6, 8, 11, 14, 17, 24, and 28 after LDOT by Treatment Group (Safety 
Population) 
Table 14.3.4.13.1    
 
Movement Disorder Society - Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Part 2: Summary of Actual Value on Days 1, 3, 6, 8, 11, 14, 
17, 24, and 28 after LDOT by Treatment Group   (Safety Population) 
Table 14.3.4.13.2    
 
Movement Disorder Society - Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) Part 1: Summary of Actual Value on Days 1, 3, 6, 8, 11, 14, 
17, 24, and 28 after LDOT by Treatment Group   (Safety Population) 
Table 14.3.4.14 
 
Summary of UPDRS Part 1 Total Score: Actual Values and Change from 
Baseline by Treatment Group and Visit  (Safety Population) 
 
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1003804 
  
 
                      
 
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CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 70 of 72 
15. 
INDEX OF LISTINGS 
Listing 16.2.1 
 Patient Disposition (All Available Population)   
Listing 16.2.2.1 
 Protocol Deviations (All Available Population)   
Listing 16.2.3.1 
Inclusion Criteria not Met at Screening (All Available Population) 
  
Listing 16.2.3.2 
Exclusion Criteria Met at Screening (All Available Population)   
Listing 16.2.3.3 
 Analysis Populations (All Available Population)   
Listing 16.2.4.1 
 Demographics (All Available Population)  
Listing 16.2.4.2 
 Medical History (All Available Population) 
Listing 16.2.4.3 
 Parkinson’s Disease History (All Available Population)   
Listing 16.2.4.4 
 Smoking History (All Available Population) 
  
Listing 16.2.4.5 
 ON and OFF Concordance Testing at Screening (All Available Population)   
Listing 16.2.4.6 
 Modified Hoehn and Yahr Staging in “ON” State at Screening (All Available 
Population) 
  
Listing 16.2.4.7 
 Mini Mental State Examination (MMSE) at Screening (All Available 
Population) 
  
Listing 16.2.4.8 
 Parkinson’s Disease Diary Data at Screening: Derived Time (All Available 
Population) 
  
Listing 16.2.4.9 
 Screening ON/OFF Log (All Available Population) 
  
Listing 16.2.4.10 
 Randomization   (All Available Population) 
Listing 16.2.4.11.1 
 Prior and Concomitant Medications (All Available Population)   
Listing 16.2.4.11.2 
 Parkinson’s disease Treatment Medications at Baseline  (All Available 
Population)  
Listing 16.2.4.12 
 Baseline Pulmonary Assessment Part 2 - Pulmonary History (All Available 
Population) 
  
Listing 16.2.4.13 
 Baseline Pulmonary Assessment Part 3 - Assessments of Symptoms (All 
Available Population)   
Listing 16.2.5.1.1 
 Study Drug Administration: in Clinic and at Home (All Available 
Population) 
  
Listing 16.2.5.1.2 
 Study Drug Administration: Derived Variables (in Clinic)  (All Available 
Population) 
Listing 16.2.5.1.3 
 Study Drug Administration: Derived Variables (Overall) (All Available 
Population) 
  
Listing 16.2.5.1.4 
 Study Drug Administration: Derived Variables (Overall by Visit)  (All 
Available Population)  
Listing 16.2.5.1.5 
 Listing of Study Drug Dose Change (All Available Population)   
Listing 16.2.5.2 
 Study Drug Kit Dispensation (All Available Population)   
Listing 16.2.5.3 
 Daily Levodopa Dose (All Available Population)   
Listing 16.2.6.1.1 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 3 at Screening    
Listing 16.2.6.2.1 
 Clinic Assessment (All Available Population)   
Listing 16.2.6.2.2 
 Parkinson’s Disease Diary Data (All Available Population)  
Listing 16.2.6.2.3.1 
Parkinson’s Disease Diary Data – Derived Variable by Dairy Date (All 
Available Population)   
Listing 16.2.6.2.3.2 
Parkinson’s Disease Diary Data – Derived Variable by Visit (All Available 
Population) 
  
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1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 71 of 72 
Listing 16.2.6.2.4 
Patient’s Global Impression of Change (PGI-C) (All Available Population) 
  
Listing 16.2.6.3.1 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 2 (All Available 
Population)  
Listing 16.2.6.3.2 
Listing of S&E Activities of Daily Living (All Available Population) 
  
Listing 16.2.6.3.3 
39 Item Parkinson
's Disease Questionnaire (PDQ-39) (All Available 
Population) 
  
Listing 16.2.6.3.4 
9-Item Patient Health Questionnaire (PHQ-9) Sum Score (All Available 
Population) 
Listing 16.2.6.3.5 
Impact of Parkinson’s OFF Episodes (All Available Population)   
Listing 16.2.7.1 
Adverse Events (All Available Population)  
Listing 16.2.8.1.1 
Clinical Laboratory Results – Hematology (All Available Population) 
  
Listing 16.2.8.1.2 
Clinical Laboratory Results – Chemistry (All Available Population) 
  
Listing 16.2.8.1.3 
Serum Pregnancy Test – Positive Only (All Available Population)   
Listing 16.2.8.2.1 
Vital Signs (All Available Population)   
Listing 16.2.8.2.2 
12-Lead Electrocardiogram (ECG) (All Available Population) 
  
Listing 16.2.8.2.3 
Physical Examination (All Available Population)    
Listing 16.2.8.2.4.1 
Spirometry( Neurology Office) (All Available Population)  
Listing 16.2.8.2.4.2 
Spirometry( Neurology Office) Measurements Not Meeting ATS Quality 
Criteria 
 (All Available Population) 
Listing 16.2.8.2.4.3 
Spirometry(Pulmonary Function Facility): Spirometry and DLCO 
Parameters (All Available Population) 
Listing 16.2.8.2.4.4 
 Spirometry(Pulmonary Function Facility): Spirometry/DLCO Measurements 
Not Meeting ATS Quality Criteria (All Available Population) 
Listing 16.2.8.2.5.1 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
  (All Available Population) 
Listing 16.2.8.2.5.2 
Columbia-Suicide Severity Rating Scale (C-SSRS) – Subject Answered ‘Yes’ 
to any Questions   
Listing 16.2.8.2.5.3 
Self-Reported Columbia-Suicide Severity Rating Scale (C-SSRS) (All 
Available Population) 
Listing 16.2.8.2.6 
Epworth Sleepiness Scale (All Available Population) 
  
Listing 16.2.8.2.7 
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s (QUIP)  
(All Available Population)  
Listing 16.2.8.2.8.1 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4 (All Available 
Population) 
  
Listing 16.2.8.2.8.2 
 Unified Parkinson’s Disease Rating Scale (UPDRS) Part 4: Derived 
Variables (All Available Population) 
  
Listing 16.2.8.2.9 
 Telephone Contact: Challenges with Inhaler or Capsules Data (All 
Available Population)   
Listing 16.2.8.2.10 
Amphetamine Withdrawal Questionnaire (AWQ)  (All Available Population) 
Listing 16.2.8.2.11 
Dopamine Dysregulation Syndrome - Patient and Caregiver Inventory (DDS-
PC)  (All Available Population) 
Listing 16.2.8.2.12 
Movement Disorder Society - Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) (All Available Population) 
Listing 16.2.8.2.13 
Unified Parkinson’s Disease Rating Scale (UPDRS) Part 1  (All Available 
Population) 
 
Page 77 of 81


1003804 
  
 
                      
 
Civitas Therapeutics, Inc. 
CVT-301-004E 
SAP Version  2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.00     
  INC Research © LLC 
Page 72 of 72 
16. 
INDEX OF FIGURES 
NA 
Page 78 of 81


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 
Page 79 of 81


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 
 
 
Page 80 of 81


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. 
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. 
 
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. 
 
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