A Randomized, Open-Label, Single Oral Dose, Three-Way Cross-Over Trial to Evaluate the Relative Bioavailability of CVN424 Suspension &Tablet Formulations Including an Assessment of the Effect of Food on the Tablet Formulation in Healthy Adult Volunteers
Phase: PHASE1
Conditions: Parkinson's Disease
Sponsor: Cerevance Beta, Inc.

 
16. 
Appendices 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
Note to File 21 October 2022 
Note to File 20 October 2022 
Note To File 30 September 2022 
Final Protocol 30 August 2022 
CVN424-102; CA38736; 16.1.1 Protocol and Protocol Amendments
Page 1 of 70

C V N 4 2 4- 1 0 2; C A 3 8 7 3 6; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
Pa ge 2 of 7 0
P P D
P P D
P P D
er e v a 
N O T E T O FI L E 
T o: C er e v a n c e 4 2 4- 1 0 2 St u d y Tri al M a st er Fil e 
Fr o m: -
C o n s ult a nt t o C er e v a n c e 
D at e: 2 1 O ct 2 0 2 2 
St u d y : C V N 4 2 4- 1 0 2 
R e: Pr o t o c ol Clarifi c ati o n s 
T h e f oll o wi n g ar e cl a rifi c ati o n s f or t h e C V N 4 2 4 - 10 2 pr ot o c ol v er si o n 1. 0 d at e d 3 0 A u g 2 0 2 2 . 
•  
9.1. 5 Vit a l Si g n Pr o c e d ur e 
Si g n e d, 
C o n sult a nt 
C er e va n c e 
o 
Cl arif yi n g t h at r e s pir ati o n r at e i s n ot n e e d e d i n tri plt c at e 
o 
Cl arif yi n g t hat t h e tri pli c at e m e a s ur e m e nt s at t h e "i niti al p o st- d o s e " ti m e poi nt ar e t o b e 
c oll e ct e d fr o m 1- 3 h o u r s p o st a d mi ni str ati o n of t h e st u d y dr u g 
• 
S u b s e q u e nt p o st- d o s e m e a s u r e m e nt s (i. e., 2 4 -, 4 8 -, 7 2 •, a n d 9 6 - h o ur s) ar e n o t 
n e e d e d i n tripli c at e 

 
N O T E  T O  FIL E  
 
 
T o: C er ev a nc e 4 2 4 -1 0 2 St u dy Tri al M ast er Fil e  
Fr o m:  
, C o ns ult a nt t o C er ev a nc e  
D at e: 2 0 Oct 2 0 2 2  
St u dy: C V N 4 2 4 -1 0 2  
 
R e:  Pr ot oc ol Cl arific ati o ns  
 
 
T h e f oll o wi n g ar e  cl arific ati o ns f or t h e C V N 4 2 4 -1 0 2 pr ot oc ol v ersi o n 1 . 0 d at e d 3 0 A u g 2 0 2 2.  
 
T h e l a n g u a g e i n s ecti o n 9. 7. 3 R e p orti n g of A b n or m al L F T , is t o b e u p d at e d as f oll o ws b el o w. T h e 
r ati o n al e f or t h e c h a n g e is t o b ett er ali g n wit h s ecti o n 7. 4 Crit eri a f or Disc o nti n u at i o n or Wit h dr a w al 
of a P artici p a nt .  
 
Existi n g l a n g u a g e:  
If a p artici p a nt is n ot e d t o h a v e AL T or A S T el e v at e d > 3 × UL N o n 2 c o ns ec uti v e occ asi o ns, t h e 
a b n or m ality s h o ul d b e r ec or d e d as a n A E at t h e discr eti o n of t h e PI. I n a d diti o n, a n L F T i ncr e as es 
e C R F m ust b e c o m pl et e d by pr o vi di n g a d diti o n al i nf or m ati o n o n r el e v a nt r ec e nt hist or y, ris k 
f act ors, cli nic al si g ns a n d sy m pt o ms, a n d r es ults of a ny a d diti o n al di a g n ostic t ests p erf or m e d. 
 
If a p artici p a nt is n ot e d t o h a v e AL T or A S T > 3 × UL N a n d t ot al bilir u bi n > 2 × UL N f or w hic h a n 
alt er n ati v e eti ol o g y h as n ot b e e n i d e ntifi e d, t h e e v e nt s h o ul d b e r ec or d e d as a n S A E a n d r e p ort e d 
as p er S ecti o n 9. 7. 2.  T h e I nv esti g at or m ust c o nt act t h e M e dic al M o nit or t o disc uss t h e r el e v a nt 
p artici p a nt d et ails a n d p ossi bl e alt er n ati v e eti ol o gi es, s uc h as ac ut e vir al h e p atitis A or B or ot h er 
ac ut e li v er dis e as e or m e dic al hist ory/c o nc urr e nt m e dic al c o n diti o ns. F oll o w -u p l a b or at or y t ests will 
b e at t h e discr eti o n of t h e I nv esti g at or . 
 
T o b e r e pl ac e d wit h:  
If a p artici p a nt is n ot e d t o h a v e AL T or A S T el e v at e d > 2 × UL N at a ny p oi nt, t h e a b n or m ality s h o ul d 
b e r ec or d e d as a n A E.  
 
If a p artici p a nt is n ot e d t o h a v e  
 
Al a ni n e a mi n otr a nsf er as e ( AL T) or as p art at e a mi n otr a nsf er as e ( A S T) > 8 × u p p er li mit of 
n or m al ( UL N), or  
 
AL T or A S T > 5 × UL N a n d p ersists f or m or e t h a n 2 w e eks, or  
 
AL T or A S T > 3 × UL N i n c o nj u ncti o n wit h el e v at e d t ot al bilir u bi n > 2 × UL N or I N R > 1. 5, or  
 
AL T or A S T > 3 × UL N wit h a p p e ar a nc e of f ati g u e, n a us e a, v o miti n g, ri g ht u p p er q u a dr a nt 
D o c u Si g n E n v el o p e I D: E 3 D 7 9 2 A 1- 2 3 B D- 4 A B 9- 9 2 C 4- 6 8 D 3 9 6 E 8 C 3 1 B
C V N 4 2 4- 1 0 2; C A 3 8 7 3 6; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
Pa ge 3 of 7 0
P P D

 
p ai n or t e n d er n ess, f e v er, r as h a n d/ or e osi n o p hili a ( > 5 %)  
 
t h e e v e nt s h o ul d b e r ec or d e d as a n S A E ( n ot e t h e r e as o n f or S eri o us n ess: m e dic all y i m p ort a nt 
e v e nt) a n d r e p ort e d as p er S ecti o n 9. 7. 2.  T h e I nv esti g at or m ust r ef er t o s ecti o n 7. 4 Crit eri a f or 
Disc o nti n u ati o n or Wit h dr a w al of a P artici p a nt  f or g ui d a nc e as t o t h e a p pr o pri at e n ext st e ps. 
 
 
 
Si g n e d,  
 
 
 
, M D  
C hi ef  M e dic al  Offic er  
C er ev a n c e 
 
D o c u Si g n E n v el o p e I D: E 3 D 7 9 2 A 1- 2 3 B D- 4 A B 9- 9 2 C 4- 6 8 D 3 9 6 E 8 C 3 1 B
1 0 / 2 6 / 2 0 2 2
C V N 4 2 4- 1 0 2; C A 3 8 7 3 6; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
Pa ge 4 of 7 0
P P D
P P D

 
N O T E  T O  FIL E  
 
T o: C er ev a nc e 4 2 4 -1 0 2 St u dy Tri al M ast er Fil e  
Fr o m:  
, C o ns ult a nt t o C er ev a nc e  
D at e: 3 0 S e p 2 0 2 2  
St u dy: C V N 4 2 4 -1 0 2  
 
R e:  Pr ot oc ol Cl arific ati o ns  
 
T h e f oll o wi n g ar e cl arific ati o ns f or t h e C V N 4 2 4 -1 0 2 pr ot oc ol v ersi o n 1 . 0 d at e d 3 0 A u g 2 0 2 2.  
 
 
R a n d o miz ati o n: cl arifyi n g t h at C el eri o n will s erv e as d esi g n e e f or t h e r a n d o miz ati o n g e n er ati o n  
 
P hysic al Ass ess m e nt at f oll o w -u p visit: cl arifyi n g t h at t his is t o b e a s y m pt o m driv e n p hysic al 
ex a mi n ati o n  
 
Vit al si g ns: cl arif yi n g t h at t e m p er at ur e is n ot n e e d e d i n tri plic at e  
 
A p p e n dix A : Sc h e d ul e of St u dy Pr oc e d ur es 
o  F oll o w -U p:  
 
O v er all St u dy D a y # t o b e u p d at e t o 4 2  
o  R a n d o miz ati o n : 
 
T o b e m ov e d fr o m first C h ec k -i n t o first D osi n g d a y 
o  Pr e g n a nc y T est:  
 
A d d ass ess m e nt t o D ay 5 of P eri o d 3  
o  C -S S R S:  
 
R e m ov e ass ess m e nt fr o m D a y 1 of P eri o d s 2 a n d 3 as w ell as fr o m F oll o w -U p visit  
o  P hysic al Ex a mi n ati o n:  
 
A d d ass ess m e nt t o D ay 2 of e ac h P eri o d f or 2 4 -h o urs p ost -d os e  
o  Vit al Si g ns (f o ot n ot e 3): 
 
U p d at e  t o i ncl u d e R es pir ati o ns 
 
R es pir ati o ns s h o ul d als o b e a d d e d t o t h e St u dy S u m m ar y ( p a g e 1 1)  
o  Uri n al ysis (f o ot n ot e 5)  
 
U p d at e t o i ncl u d e st at e m e nt t h at  Pr e d os e l a bs d o n ot n e e d t o b e r evi e w e d pri or t o 
d osi n g  
o  Cli nic al l a b or at ory t ests  (f o ot n ot e 7): 
 
P arti al list s h o ul d b e r e m o v e d as T a bl e 4 i n s ecti o n 9. 1. 1 1 i n dic at es t h e f ull list of t ests  
o  E C G  (f o ot n ot e 1 1):  
 
St u dy d a ys t o b e u p d at e d t o 0, 1 4, a n d 2 8  
 
3 h o urs p ost -d os e wi n d o w t o b e u p d at e d t o +/ - 3 0 mi n ut es  
 
 
Si g n e d,  
 
 
 
 M D  
C hi ef  M e dic al  Offic er  
C er ev a n c e 
 
D o c u Si g n E n v el o p e I D: 1 7 C 7 A 5 1 8- E 9 6 A- 4 7 B 9- B 5 7 4- 6 9 6 2 6 2 8 2 A 1 3 4
C V N 4 2 4- 1 0 2; C A 3 8 7 3 6; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
Pa ge 5 of 7 0
P P D
P P D
P P D

CVN424 
Study No. CVN424-102 
Page 1 of 64 
Clinical Protocol Version 1.0 
30 Aug 2022 
PROTOCOL 
A Randomized, Open-Label, Single Oral Dose, Three-Way Cross-Over Trial to Evaluate 
the Relative Bioavailability of CVN424 Suspension and Tablet Formulations Including an 
Assessment of the Effect of Food on the Tablet Formulation in Healthy Adult Volunteers 
Short Title: Relative Bioavailability and Food Effect Study of CVN424 
Sponsor: 
Cerevance Beta, Inc. 
One Marina Park Drive, Suite 1410 
Boston, MA 02210 
Study Number: 
CVN424-102 
IND Number: 
138119 
EudraCT Number:  
Not Applicable 
Compound: 
CVN424 
Version: 
Date: 
Protocol 1.0 
30 August 2022 
CONFIDENTIAL PROPERTY OF CEREVANCE 
This document is a CONFIDENTIAL communication of Cerevance Beta, Inc. (“Cerevance”). Acceptance of this 
document constitutes the agreement by the recipient that no information contained herein will be published or 
disclosed without written authorization from Cerevance except to the extent necessary to obtain informed consent 
from those persons to whom the drug may be administered. Furthermore, the information is only meant for review 
and compliance by the recipient, his or her staff, and applicable institutional review committee and regulatory 
agencies to enable conduct of the study. 
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CVN424-102; CA38736; 16.1.1 Protocol and Protocol Amendments
Page 6 of 70

C V N 4 2 4  
St u d y N o. C V N 4 2 4 -1 0 2  
P a ge 2  of 6 4  
Cli nic al Pr ot oc ol Versi o n 1. 0  
3 0  A u g  2 0 2 2  
1. 0  
A D MI NI S T R A TI V E I N F O R M A TI O N 
1. 1  
C o nt acts  
C o nt act T y pe / R ole  
C o nt act  
Seri o us a d verse e ve nts a n d pre g na nc y re p orti n g  
Celeri o n  
Me dical M o nit or  
(carries o verall res p o nsi bilit y f or t he c o n d uct of t he 
st u d y)  
Pr o P har ma Re prese ntati ve  
Res p o nsi ble Me dical Officer  
(me dical a d vice o n pr ot oc ol  a n d  c o m p o u n d ) 
 M. D. 
E ma il: 
D o c u Si g n E n v el o p e I D: 7 4 E 0 8 A 9 2- D 5 4 4- 4 5 C F- B 8 6 8- 7 5 1 D F 4 A 7 4 1 5 A
C V N 4 2 4- 1 0 2; C A 3 8 7 3 6; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
Pa ge 7 of 7 0
P P D
P P D
P P D

C V N 4 2 4  
 
St u d y N o. C V N 4 2 4 -1 0 2  
P a ge 3  of 6 4  
Cli nic al Pr ot oc ol Versi o n 1. 0  
3 0  A u g  2 0 2 2  
 
1. 2  
A p pr o v al 
R E P R E S E N T A TI V E S O F C E R E V A N C E  
T his st u d y will be c o n d ucte d wit h t he hi g hest res p ect f or t he i n di vi d ual partici pa nts i n 
acc or d a nce wit h t he re q uire me nts of t his cli nical st u d y pr ot oc ol a n d als o i n acc or d a nce wit h t he 
f oll o wi n g: 
•  T he et hical pri nci ples t h at ha ve t heir ori gi n i n t he Declarati o n  of Helsi n ki. 
•  I nter nati o nal C o u ncil o n Har m o nisati o n (I C H) E 6 [ R 2] G o o d Cli nical Practice ( G C P): 
I nte grate d A d de n d u m t o E 6[ R 1]. 
•  All a p plica ble la ws a n d r e g ulati o ns, i ncl u di n g, wit h o ut li mitati o n, data pri vac y la ws, cli nical 
trial discl os ure la ws, a n d re g ulati o ns. 
 
 
SI G N A T U R E S  
A p pr o ve d b y: 
 
 
 
Si g nat ure _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _        Date _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 M. D. 
Res p o nsi ble Me dical Officer  
Cere va n ce, I n c.  
 
D o c u Si g n E n v el o p e I D: 7 4 E 0 8 A 9 2- D 5 4 4- 4 5 C F- B 8 6 8- 7 5 1 D F 4 A 7 4 1 5 A
C V N 4 2 4- 1 0 2; C A 3 8 7 3 6; 1 6. 1. 1 Pr ot oc ol a n d Pr ot oc ol A me n d me nts
Pa ge 8 of 7 0
P P D
P P D
P P D

CVN424 
 
Study No. CVN424-102 
Page 4 of 64 
Clinical Protocol Version 1.0 
30 Aug 2022 
 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, and 
any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study participants in accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki 
• International Council on Harmonisation, E6 [R2]; GCP Integrated Addendum to E6 [R1] 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations 
• Regulatory requirements for reporting serious adverse events (SAEs) defined in Section 9.7 
of this protocol 
• Terms outlined in the Clinical Study Site Agreement 
• Appendix B – Responsibilities of the Investigator 
 
 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State/Province) 
Location of Facility (Country) 
 
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CVN424 
 
Study No. CVN424-102 
Page 5 of 64 
Clinical Protocol Version 1.0 
30 Aug 2022 
 
TABLE OF CONTENTS 
 
1.0 
ADMINISTRATIVE INFORMATION ..............................................................................2 
1.1 
Contacts..........................................................................................................................2 
1.2 
Approval ........................................................................................................................3 
2.0 
STUDY SUMMARY...........................................................................................................9 
3.0 
STUDY REFERENCE INFORMATION .........................................................................13 
3.1 
List of Abbreviations ...................................................................................................13 
4.0 
INTRODUCTION .............................................................................................................15 
4.1 
Background ..................................................................................................................15 
4.2 
Rationale for the Proposed Study ................................................................................19 
5.0 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................20 
5.1 
Objectives ....................................................................................................................20 
6.0 
STUDY DESIGN AND DESCRIPTION ..........................................................................21 
6.1 
Study Design ................................................................................................................21 
6.2 
Justification for Study Design, Dose, and Endpoints ..................................................22 
6.3 
Premature Termination or Suspension of Study or Investigational Site ......................22 
6.3.1 Criteria for Premature Termination or Suspension of the Study ...........................22 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites ..........22 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s)...................................................................22 
7.0 
PARTICIPANT POPULATION .......................................................................................23 
7.1 
Inclusion Criteria .........................................................................................................23 
7.2 
Exclusion Criteria ........................................................................................................23 
7.3 
Diet, Fluid, and Activity Control .................................................................................26 
7.3.1 On Dosing Days: ....................................................................................................26 
7.4 
Criteria for Discontinuation or Withdrawal of a Participant .......................................27 
7.5 
Procedures for Discontinuation or Withdrawal of a Participant ..................................28 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................29 
8.1 
Study Medication and Materials ..................................................................................29 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling ......................................29 
8.1.2 Drug Storage ..........................................................................................................29 
8.1.3 Dose and Regimen .................................................................................................30 
8.1.4 Overdose ................................................................................................................30 
8.2 
Investigational Drug Assignment and Dispensing Procedures ....................................31 
8.3 
Randomization Code Creation and Storage .................................................................31 
8.4 
Accountability and Destruction of Sponsor-Supplied Drugs.......................................31 
9.0 
STUDY PLAN ...................................................................................................................33 
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CVN424 
 
Study No. CVN424-102 
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Clinical Protocol Version 1.0 
30 Aug 2022 
 
9.1 
Study Procedures .........................................................................................................33 
9.1.1 Informed Consent Procedure .................................................................................33 
9.1.2 Demographics, Medical History, and Medication History Procedure ...................33 
9.1.3 Physical Examination Procedure ...........................................................................33 
9.1.4 Weight, Height, and BMI.......................................................................................33 
9.1.5 Vital Sign Procedure ..............................................................................................34 
9.1.6 Documentation of Concomitant Medications ........................................................34 
9.1.7 Documentation of Concurrent Medical Conditions ...............................................34 
9.1.8 ECG Procedure ......................................................................................................34 
9.1.9 PK Sample Collection ............................................................................................35 
9.1.10 PK Parameters ........................................................................................................35 
9.1.11 Procedures for Clinical Laboratory Samples .........................................................36 
9.1.12 Contraception and Pregnancy Avoidance Procedure .............................................37 
9.1.13 Pregnancy ...............................................................................................................38 
9.1.14 Documentation of Screen Failure ..........................................................................39 
9.1.15 Documentation of Randomization .........................................................................40 
9.2 
Monitoring Participant Treatment Compliance ...........................................................40 
9.3 
Schedule of Observations and Procedures ...................................................................40 
9.3.1 Screening................................................................................................................40 
9.3.2 Inpatient Check-In .................................................................................................40 
9.3.3 Dosing ....................................................................................................................40 
9.3.4 Washout and Discharge .........................................................................................40 
9.3.5 Final Visit (discharge day from clinic) ..................................................................40 
9.3.6 Early Termination ..................................................................................................41 
9.3.7 Follow-up Visit ......................................................................................................41 
9.4 
Biological Sample Retention and Destruction .............................................................41 
9.5 
Blood Volume ..............................................................................................................41 
9.6 
Definitions....................................................................................................................42 
9.6.1 AE ..........................................................................................................................42 
9.6.2 Additional Points to Consider for PTEs and AEs ..................................................42 
9.6.3 SAEs ......................................................................................................................44 
9.6.4 Severity of AEs ......................................................................................................44 
9.6.5 Causality of AEs ....................................................................................................44 
9.6.6 Relationship to Study Procedures ..........................................................................45 
9.6.7 Start Date ...............................................................................................................45 
9.6.8 Stop Date ................................................................................................................45 
9.6.9 Frequency ...............................................................................................................45 
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CVN424 
 
Study No. CVN424-102 
Page 7 of 64 
Clinical Protocol Version 1.0 
30 Aug 2022 
 
9.6.10 Action Concerning Study Medication ...................................................................45 
9.6.11 Outcome .................................................................................................................45 
9.7 
Procedures ....................................................................................................................46 
9.7.1 Collection and Reporting of AEs ...........................................................................46 
9.7.2 Collection and Reporting of SAEs .........................................................................47 
9.7.3 Reporting of Abnormal LFT ..................................................................................47 
9.8 
Follow-up of SAEs ......................................................................................................47 
9.8.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities ...................48 
10.0 
DATA HANDLING AND RECORDKEEPING ..............................................................49 
10.1 
CRFs (Electronic) ........................................................................................................49 
10.2 
Record Retention .........................................................................................................49 
11.0 
STATISTICAL METHODS ..............................................................................................51 
11.1 
Statistical and Analytical Plans ....................................................................................51 
11.1.1 Analysis Sets ..........................................................................................................51 
11.1.2 Analysis of Demographics and Other Baseline Characteristics ............................51 
11.1.3 PK Analysis ...........................................................................................................51 
11.1.4 Safety Analysis ......................................................................................................52 
11.2 
Interim Analysis and Criteria for Early Termination ...................................................52 
11.3 
Determination of Sample Size .....................................................................................53 
12.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................54 
12.1 
Study-Site Monitoring Visits .......................................................................................54 
12.2 
Protocol Deviations ......................................................................................................54 
12.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................................55 
13.0 
ETHICAL ASPECTS OF THE STUDY ...........................................................................56 
13.1 
IRB Approval ...............................................................................................................56 
13.2 
Participant Information, Informed Consent, and Participant Authorization ................56 
13.3 
Participant Confidentiality ...........................................................................................58 
13.4 
Publication, Disclosure, and Clinical Trial Registration Policy ..................................58 
13.4.1 Publication and Disclosure ....................................................................................58 
13.4.2 Clinical Trial Registration......................................................................................59 
13.4.3 Clinical Trial Results Disclosure ...........................................................................59 
13.5 
Insurance and Compensation for Injury .......................................................................59 
14.0 
REFERENCES ..................................................................................................................60 
 
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CVN424 
 
Study No. CVN424-102 
Page 8 of 64 
Clinical Protocol Version 1.0 
30 Aug 2022 
 
LIST OF IN-TEXT TABLES 
Table 1  
Study Schema.........................................................................................................21 
Table 2  
Prohibited Medication and Dietary Products .........................................................25 
Table 3  
Three-Way Cross-Over Sequences ........................................................................30 
Table 4 
Clinical Laboratory Tests .......................................................................................36 
Table 5  
Windows for PK Blood Sample Collection ...........................................................54 
 
LIST OF APPENDICES 
Appendix A: Schedule of Study Procedures ...............................................................................61 
Appendix B: Responsibilities of the Investigator ........................................................................63 
Appendix C: Investigator Consent to Use of Personal Information ............................................64 
 
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CVN424 
 
Study No. CVN424-102 
Page 9 of 64 
Clinical Protocol Version 1.0 
30 Aug 2022 
 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Cerevance Beta, Inc. 
Compound: 
CVN424 
Title of Protocol: A Randomized, Open-Label, Single Oral 
Dose, Three-Way Cross-Over Trial to Evaluate the Relative 
Bioavailability of CVN424 Suspension and Tablet Formulations 
Including an Assessment of the Effect of Food on the Tablet 
Formulation in Healthy Adult Volunteers 
IND No.: 138119 
EudraCT No.: Not applicable 
Study Number: CVN424-102 
Phase: 1 
Study Design: 
This is a Randomized, Open-Label, Single Oral Dose, Three-Way Cross-Over Trial to Evaluate the Relative 
Bioavailability of CVN424 Suspension and Tablet Formulations in Healthy Volunteers Under Fasted and Fed 
Conditions. The overall study design is outlined below: 
 
 
 
 
 
 
Sequence 
Dosing #1 
(Period 1 Day 
1) 
 
Dosing #2  
(Period 2 Day 1) 
 
Dosing #3  
(Period 3 Day 1) 
1 (n=5) 
Suspension 
(fasted) 
W a s h o u t 
Tablet (fasted) 
W a s h o u t 
Tablet (fed) 
 
 
 
2 (n=6) 
Tablet (fasted) 
Tablet (fed) 
Suspension (fasted) 
 
 
 
3 (n=5) 
Tablet (fed) 
Suspension (fasted) 
Tablet (fasted) 
 
 
 
4 (n=5) 
Suspension 
(fasted) 
Tablet (fed) 
Tablet (fasted) 
 
 
 
 
5 (n=5) 
Tablet (fasted) 
Suspension (fasted) 
Tablet (fed) 
 
 
 
6 (n=6) 
Tablet (fed) 
Tablet (fasted) 
Suspension (fasted) 
 
 
 
 
 
 
32 healthy male or female participants will be enrolled in 1 of 6 sequences (designated as 1 through 6, respectively) in 
an ascending fashion. Sequences 1, 3, 4, and 5 will have 5 participants each, and Sequences 2 and 6 will have 6 
participants each.  
 
Each sequence will proceed through the three cross-overs (suspension-fasted, tablet-fed, and tablet-fasted) according to 
the schematic above, with dosing to occur on Days 1 of Periods 1, 2, and 3. Participants in the fasted portion of each 
sequence will be dosed under overnight fasted conditions and will remain fasted for 4 hours post-dose. Water 
consumption is permitted as desired except for 1 hour before and after administration of the Study Drug. 
 
To assess the effect of food on CVN424 bioavailability in tablet formulation, the single dose will be administered after 
ingestion of a standardized high-fat, high-calorie meal according to FDA Guidance for Industry (Food-effect 
bioavailability and fed bioequivalence studies, Jun 2022).  
 
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Participants for all sequences will be admitted to the study unit 1 day prior to dosing and remain in the unit for safety 
and pharmacokinetics (PK) assessments through 96 hours post-dose. The total confinement period will be 5 nights for 
each period unless extended at the discretion of the Investigator, e.g., for monitoring and/or management of adverse 
events (AEs).  
 
Once 96-hour post-dose PK has been collected, participants will be discharged from the unit for the remainder of the 
washout period and return the day prior to their next scheduled dosing period. 
Primary Objective: 
To determine the relative bioavailability of 150 milligrams (mg) of CVN424 administered in a single dose of 
suspension formulation compared to 150 mg tablet. 
Secondary Objectives: 
To establish the effects of food on the rate and extent of absorption of CVN424 150 mg tablet when administered in fed 
conditions compared to administration under fasting conditions. 
To assess the tablet's safety under fast and fed conditions and suspension under fasted conditions. 
Exploratory Objectives: 
To explore serum/plasma (e.g., potential characterization of drug metabolites) that may contribute to variability in 
CVN424. 
To assess urine concentrations and volumes to enable calculation of urine PK parameters where possible. 
Participant Population:  
Healthy male and female participants 18 to 55 years old (inclusive) 
Number of Participants: 
Estimated total: 32 participants  
(4 sequences of 5 and 2 sequences of 6) 
Number of Sites: 
1 (United States) 
Dose Level(s): 
Participants to receive a single-dose level of 150 mg CVN424 in 
either tablet or suspension formulation 
Route of Administration: 
Oral 
 
Duration of Treatment: 
Single oral dose on Day 1 of Periods 1, 2, & 3 (Study Days 0, 14, 
& 28) 
Period of Evaluation: 
• 
Screening Period: up to 28 days 
• 
5 days of inpatient confinement from Check-In 
until after the 96-hour post-dose blood draw on 
Day 5 
• 
9 additional days of washout (Days 6-13) 
• 
To be repeated for the subsequent two Periods 
• 
Total Duration: Approximately 10 weeks 
Main Criteria for Inclusion: 
Healthy male and female participants, 18 to 55 years of age, inclusive, and have a body mass index (BMI) between 
18.0 and 35 kg/m2 inclusive at Screening. 
A complete list of inclusion criteria is provided in Section 7.1. 
Main Criteria for Exclusion: 
Participants are vegan, vegetarian, lactose intolerant, or follow a Kosher diet. Participants have a known 
hypersensitivity to any component of the formulation of CVN424. Participants have evidence of clinically significant 
[CS] neurologic, cardiovascular, pulmonary, hepatic, hematopoietic disease, renal, metabolic, gastrointestinal, urologic, 
immunologic, endocrine disease, serious allergy, allergic skin rash, psychiatric disorder, or other abnormality that may 
impact the ability of the participant to participate or potentially confound the study results. Any finding in the 
participant’s medical history, physical examination, or safety laboratory tests gives reasonable suspicion of a condition 
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that might interfere with the conduct or interpretation of the study.  
A complete list of exclusion criteria is provided in Section 7.2.  
In addition, participants may not use any excluded medications, supplements, or food products. Concomitant 
medications and dietary products to be excluded are listed in Table 2. 
 
Main Criteria for Evaluation and Analyses: 
- Safety assessments:  
Safety parameters will be collected from the signing of the informed consent form (ICF) until final charge and include 
AEs, clinical laboratory results, vital signs, physical examinations, and electrocardiogram (ECG).  
• 
Vital signs will include body temperature measurement, blood pressure, and heart rate (beats per minute 
[bpm]).  
• 
Orthostatic vital signs (blood pressure and heart rate) will be recorded 
• 
Standard 12-lead ECG will be recorded. Clinical laboratory data collected will include hematology, chemistry, 
and urinalysis. 
• 
Physical exams  
A complete list of safety assessments is provided in Section 9.1, and the full Schedule of Study Procedures is provided 
in Appendix A. 
 
- PK: 
Plasma PK parameters will be used to determine the relative bioavailability of CVN424 suspension to tablet. 
Plasma and urine samples will be collected for the determination of concentrations of CVN424 throughout the study as 
prescribed in the Schedule of Assessments (Appendix A).  
PK parameters of CVN424 will be derived using noncompartmental analysis methods from the concentration-time data 
for all evaluable participants. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. The following PK parameters will be determined from concentrations of 
CVN424 in plasma: maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), time taken for drug to 
appear in systemic circulation following administration (Tlag), area under plasma concentration-time curve (AUC) from 
time 0 to the last quantifiable concentration (AUC0-t), and truncated AUC from time 0 to 96 hours (AUC0- 96h), AUCinf, 
terminal elimination half-life (t1/2), apparent clearance after extravascular administration (CL/F), apparent volume of 
distribution after extravascular administration (Vz/F) where possible 
 
- Endpoints:  
The primary endpoints of this study will be the following: the relative bioavailability of the CVN424 solution and 
CVN424 tablet formulation in the fasted state based on Cmax, Tmax, AUCinf, and AUC0- 96h. 
Additionally, the ratio of the PK parameters between CVN424 solution and tablet in the fasted state will be calculated 
and summarized descriptively. An analysis of variance (ANOVA) on log-transformed PK parameters (AUC0-t, AUC0- 
96, Cmax) will be performed. Ratios of geometric means and 90% confidence intervals will be calculated. Tmax will be 
compared between the CVN424 solution and the CVN424 tablet. 
The secondary endpoints will be the following: The ratio of the PK parameters between CVN424 tablets in the fed and 
fasted state will be calculated and summarized descriptively. In addition, an ANOVA on log-transformed PK 
parameters (AUC0-t, AUC0- 96h, Cmax) will be performed. Ratios of geometric means and 90% confidence intervals 
will be calculated. Tmax will be compared between CVN424 tablets in the fed and fasted state. 
The additional endpoints may include the following plasma PK parameters of CVN424: AUC∞ and t1/2z 
Exploratory endpoints may include characterization of metabolic enzyme and transporter polymorphisms and/or 
qualitative metabolite identification in plasma and/or urine. Exploratory endpoints may also include renal PK 
parameters; cumulative amount of unchanged drug excreted into the urine (Ae), fraction of unchanged drug excreted in 
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the urine (fe), and renal clearance (CLR). 
Safety assessments will be measured by treatment-emergent adverse events (TEAEs), and tolerability will be measured 
by discontinuation (D/C) due to AE. 
Statistical Considerations: 
The proportion of participants administered CVN424 in tablet formulation who achieved at least an 80 percent relative 
bioavailability compared to CVN424 administered in suspension formulation as calculated by comparing the plasma 
drug concentration-time curves (AUC - area under the curve). 
 
Safety: 
AEs will be presented in listings, and TEAEs will be summarized. Individual results of laboratory tests (hematology, 
chemistry, and urinalysis) will be recorded at baseline and post-dose, and changes from baseline will be summarized 
using shift tables. Individual vital signs will be recorded and observed values and changes from baseline will be 
summarized. Individual results of quantitative ECG parameters from the 12-lead safety ECGs will be listed and 
observed values and changes from baseline will be summarized. All summaries will be performed by each sequence 
(suspension and table fasted and tablet fed separately), and CVN424 suspension versus tablet overall, and separately 
each of the 6 CVN424 sequences overall. Physical exam findings will be presented in data listings. 
 
PK Analysis: 
Noncompartmental pharmacokinetic (PK) calculations include Cmax, Tmax, and AUC0-96h active ingredients. 
Sample Size Justification:  
It is planned to enroll 32 male or female participants for participation. Based on previous PK studies with CVN424, it 
was determined 28 participants would be needed to show bioequivalence, assuming an intra-participant CV of 16% and 
an expected ratio of 1:10. 32 participants will be enrolled to ensure at least 28 evaluable participants. 
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3.0 
STUDY REFERENCE INFORMATION 
3.1 
List of Abbreviations 
λz 
terminal elimination rate constant 
AE 
adverse event 
Ae 
cumulative amount of unchanged drug excreted into the urine 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC∞ 
area under the plasma concentration-time curve from time 0 to infinity 
AUCt 
area under the plasma concentration-time curve from time 0 to the last 
quantifiable concentration  
BDI 
Beck Depression Inventory 
BMI 
bpm 
CGI 
body mass index 
beats per minute 
Clinical Global Impression Scale 
 
CL/F 
apparent clearance after extravascular administration 
CLR 
renal clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CNS 
COMT 
CRP 
CRU 
central nervous system 
catechol-O-methyl transferase 
c-reactive protein 
clinical research unit 
CS 
clinically significant 
CSF 
DBS 
D/C 
cerebrospinal fluid 
deep brain stimulation 
discontinuation 
ECG 
electrocardiogram 
eCRF 
eGFR 
electronic case report form 
estimated glomerular filtration rate  
FDA 
Food and Drug Administration 
fe 
fraction of unchanged drug excreted in the urine 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
γ-glutamyl transferase 
HBsAg 
hepatitis B surface antigen 
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hCG 
human chorionic gonadotropin 
HCV 
HDPE 
hepatitis C virus 
high-density polyethylene 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
INR 
international normalized ratio 
IRB 
institutional review board 
K2EDTA 
dipotassium ethylenediamine tetraacetic acid 
LFT 
liver function test 
MAO-B 
monoamine oxidase B 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSN 
medium spiny neuron 
NCS 
not clinically significant 
PGI 
PK 
Patient Global Impression 
pharmacokinetic 
PT 
preferred term 
QTcB 
QT interval with Bazett’s correction method 
QTcF 
QT interval with Fridericia’s correction method 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
SUSARs 
suspected unexpected serious adverse reactions 
t1/2z 
terminal elimination half-life 
TEAE 
tlag 
treatment-emergent adverse event 
time taken for drug to appear in systemic circulation following 
administration 
tmax 
time to reach Cmax 
ULN 
UPDRS 
upper limit of normal 
Unified Parkinson’s Disease Rating Scale 
Vz/F 
apparent volume of distribution after extravascular administration 
Vz/Fss 
apparent volume of distribution after extravascular administration at 
steady state 
WHO 
WOCBP 
World Health Organization 
woman of childbearing potential  
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4.0 
INTRODUCTION 
4.1 
Background 
Parkinson’s disease (PD) is a progressive neurodegenerative disorder of the central nervous system 
(CNS) caused by the gradual loss of the dopaminergic neurons of the substantia nigra pars 
compacta that project to the striatum (Wichmann, 2011). PD afflicts >1 million individuals in the 
United States of America and >10 million worldwide (APDAparkinson.org, accessed 26 Jan 
2018), causing cardinal symptoms of tremor, bradykinesia, rigidity, and postural instability. Motor 
fluctuations refer to a decline in the usual benefit from levodopa and develop gradually after 
several years of successful treatment.  Most patients will eventually experience motor fluctuations 
as their disease progresses.  There are several types of motor fluctuations, including wearing off, 
morning off, partial on, delayed on, dose failure, and unpredictable off.  As PD progresses and 
there is a continuous loss of dopamine neurons, the peaks and troughs of the levodopa levels 
become more problematic and result in motor fluctuations.  Changes in the gastrointestinal tract 
due to PD can slow the absorption of levodopa and, thus, the rate at which it reaches the brain, and 
this also contributes to motor fluctuations.  Current treatments for motor fluctuations include 
levodopa dose changes and medications that delay the breakdown of dopamine, including 
catechol-O-methyl transferase (COMT) inhibitors and monoamine oxidase B (MAO-B) inhibitors. 
Dopamine agonists may also be prescribed.  Apomorphine rescue, levodopa gel delivered to the 
small intestine, and deep brain stimulation may also be employed (APDAparkinson.org, April 
2017). The financial burden of PD is significant.  
GPR6 is an orphan G-protein coupled receptor that is selectively expressed in the brain and is a 
nondopaminergic target for the treatment of PD. In the brain, GPR6 is predominantly localized to 
striatopallidal medium spiny neurons (MSNs) that also express dopamine D2 receptors (Lein et al. 
2007; also, Cerevance data on file). GPR6 is a constitutively active Gs-coupled receptor that 
functionally opposes the Gi-coupled D2 receptor in indirect MSNs. Pharmacological intervention 
to inhibit the GPR6 pathway using an inverse agonist is predicted to exert antiparkinsonian effects 
by reducing overactivity of striatopallidal output neurons in the indirect pathway without 
activating the dopamine D1-receptor-expressing MSNs of the direct (striatonigral) pathway. 
CVN424 is a potent and selective inverse agonist of GPR6. Two studies have been completed with 
CVN424 in human participants. 
A first-in-human safety study of CVN424 in 64 healthy volunteers has been completed 
(NCT03657030); the study findings are summarized in the Investigator’s Brochure. In brief, 
CVN424 was safe and well tolerated when administered to healthy participants as a single oral 
dose of between 1 milligram (mg) and 225 mg or when administered as 7 daily oral doses of 
between 25 mg and 150 mg. Study drug-related adverse events (AEs) were reported by 2 of 40 
participants (5.0%) overall in the single-dose cohorts (feeling hot; headache). Study drug-related 
AEs were reported by 2 of 24 participants (8.3%) overall in the multiple-dose cohorts (dysphagia; 
chills). With one exception, all AEs were mild in severity; dysphagia of moderate severity led to 
treatment discontinuation in one participant after their third daily dose (75 mg). There were no 
severe or serious AEs, and all AEs resolved by the end of the study. Administration of the first 
dose of CVN424 was associated with an elevation in group mean and median body temperature. 
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These changes were detectable at 1 hour (h) post-dose (the earliest scheduled post-dose 
assessment), increased further by 6 h post-dose, and spontaneously returned to baseline by 24 h 
post-dose. The increases tended to be larger at higher doses but did not appear strictly dose 
proportional. A trend of increased heart rate while standing was also observed with a similar time 
course and relationship to dosage. These trends were not considered clinically significant, and no 
individual vital sign measurement was reported as an AE. In the multiple-dose cohorts, elevations 
in body temperature and heart rate were observed only after the first dose of CVN424, not 
following subsequent doses. No other trends in vital sign measurements were noted. No treatment-
related trends were observed in the clinical laboratory results or 12-lead electrocardiogram (ECG) 
measurements. In the healthy volunteer study, CVN424 in suspension was rapidly absorbed after 
oral administration in the fasted state; peak plasma concentration was usually attained between 1 
and 3 h post-dose (median 1.5 h). When CVN424 was administered after a meal, the peak plasma 
concentration was delayed and decreased while total exposure was minimally increased compared 
to the same dose level administered under fasted conditions. With repeated once-daily dosing, 
trough plasma concentrations usually reached a steady-state level by Day 4, with a terminal 
elimination half-life of approximately 33 h. Accordingly, CVN424 pharmacokinetics (PK) is 
appropriate for once-daily oral dosing, with or without food.  
In the Phase 2 study, exposure to CVN424 increased with dose level from 50 to 150 mg.  The 
increase in exposure with dose was slightly less than dose-proportional.  After CVN424 50 mg 
dosing, there was a trend for higher exposure in females compared with males.  There were no 
apparent differences between females and males after CVN424 150 mg dosing, and PK parameters 
were comparable.  After CVN424 50 mg dosing, maximum observed plasma concentration (Cmax) 
and area under the plasma concentration-time curve from time 0 to 6 h (AUC6) were slightly higher 
in the < median weight group compared with the ≥ median weight group.  Exposure parameters 
were generally comparable between weight groups after CVN424 150 mg dosing.   
In a Phase 2 study of CVN424 in patients diagnosed with Parkinson’s disease with motor 
fluctuations (NCT04191577), 136 patients were in the primary efficacy analysis safety analysis 
set. After Screening, to establish baseline safety and efficacy assessments, patients were 
randomized in a 1:1:1 ratio into 1 of 3 study groups to receive once-daily low-dose (50 mg) 
CVN424, high-dose (150 mg) CVN424, or matching placebo on Day 0/Visit 1. Patients not 
randomized to placebo-initiated treatment with 50mg CVN424 on Day 1 (Visit 2).  Thereafter, the 
low-dose group continued to receive 50mg per day, while the high-dose cohort increased their 
dosage to 150 mg CVN424 per day beginning on Day 8± 2 days (Visit 3) and continued this dose 
thereafter.  The study drug was self-administered each morning on an outpatient basis as an oral 
suspension.  Efficacy and safety evaluations were made throughout the study on Visit 1 through 
Visit 7, inclusive according to the Schedule of Study Procedures (Appendix A).  Follow-up safety 
and efficacy assessments occurred on Day 35/Visit 7, approximately 7 days after the final study 
drug dose was taken on Day 27 ± 1. The primary efficacy endpoint for the study was OFF time.  
Treatment with CVN424 was associated with a statistically significant and clinically meaningful 
improvement (relative to placebo) in OFF time with the 150 mg dose.  This reduction in OFF time 
was accompanied by numerical improvements in ON time without troublesome dyskinesia 
compared with placebo. Treatment with CVN424 150 mg reduced the average daily hours of OFF 
time relative to placebo at Day 27 in the Primary Efficacy Analysis Set.  Thus, this study met its 
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primary efficacy endpoint with the CVN424 150 mg dose and combined CVN424 dose groups.  
On Day 27, the LS mean (± SE) for average daily hours of OFF time for the CVN424 150 mg vs 
placebo comparison was -1.30 (± 0.56) h; P = 0.0418 (Dunnett) and P = 0.0225 (MMRM).  
However, the CVN424 50 mg vs placebo comparison was not statistically significant at Day 27 (P 
= 0.3302 [Dunnett]; P = 0.1985 [MMRM]).  At Day 27, the LS mean (± SE) for the combined 
CVN424 vs placebo comparison was -1.02 (± 0.50) h; P = 0.0410 (MMRM).  Analysis of the 
Secondary Efficacy Analysis Set and a sensitivity analysis yielded results similar to the Primary 
Efficacy Analysis Set.  Treatment with CVN424 50 mg and CVN424 150 mg was associated with 
a non-statistically significant numerical increase in ON time without troublesome dyskinesia on 
Day 15 and Day 27 vs. placebo. ON time with troublesome dyskinesia was generally constant 
throughout the course of the trial; changes from baseline to Day 27 were less than 12 minutes.  In 
the CVN424 150 mg group, ON time with dyskinesia was generally constant throughout the study; 
the change from baseline was less than 6 minutes on Day 27.  Treatment with CVN424 50 mg and 
CVN424 150 mg was associated with an increase in ON time on Day 15 and Day 27; however, 
the differences between the CVN groups and placebo were not statistically significant.   
Treatment with CVN424 did not demonstrate significant benefit on Unified Parkinson’s Disease 
Rating Scale (UPDRS) Part I, Part III, Part IV Section A, and Part IV Section B scores.  Treatment 
with CVN424 150 mg was associated with a clinically meaningful numerical improvement on the 
UPDRS Part II scores (motor experiences of daily living) vs. placebo, but the difference compared 
to placebo did not reach statistical significance due to the small size of the study.  Treatment with 
CVN424 did not demonstrate significant benefit on the Clinical Global Impression Scale (CGI) or 
the Patient Global Impression (PGI) scores.  On Day 15 and Day 27, numerically higher 
percentages of CVN424-treated patients were considered CGI responders compared with the 
placebo group, but this difference did not reach statistical significance.  On Day 15 and Day 27, 
numerically higher percentages of CVN424-treated patients were considered PGI responders 
compared with the placebo group, but this difference did not reach statistical significance.  
Treatment with CVN424 150 mg led to numeric improvement in the Epworth Sleepiness scores 
from baseline, with numerical improvement compared to placebo on Day 15, Day 27, and Day 35 
(statistically significant difference on Day 15 only). 
At Day 15, there were statistically significant differences for the CVN424 150 mg vs placebo 
comparison (LS mean [± SE] = -1.35 [± 0.68]; P = 0.0493) and for the CVN424 50 mg vs CVN424 
150 mg comparison (LS mean = 1.72 [± 0.67]; P = 0.0119).  CVN424 50 mg vs. placebo favored 
the CVN424 50 mg group for reducing OFF time in the following subgroup population: age ≥ 
median.  CVN424 150 mg vs. placebo favored the CVN424 150 mg group for reducing OFF time 
in the following subgroup populations: age ≥ median; females; weight < median; no dopamine 
agonist; no monoamine oxidase or catechol-o-methyl transferase inhibitor; no amantadine; 
baseline UPDRS Part II Total Score < median and ≥ median; baseline UPDRS Part III Total Score 
≥ median; baseline ON time ≥ median; response rate defined as patients with ≥30% decrease in 
OFF time was significantly increased in the CVN424 150 mg group compared to placebo.  On Day 
27, 33.3%, 36.8%, and 56.8% of patients in the placebo, CVN424 50 mg, and CVN424 150 mg 
groups, respectively, achieved the definition of responder.  The P value for the CVN424 150 mg 
vs. placebo comparison was statistically significant (P = 0.0310).  Analysis of the Secondary 
Efficacy Analysis Set and a sensitivity analysis yielded results similar to the Primary Efficacy 
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Analysis Set.  There were no significant differences for any treatment comparison in any analysis 
set for the percentage of patients meeting ascending OFF time reduction thresholds (≥0.5 hour, ≥1 
hour, ≥1.5 hours, ≥2 hours, ≥2.5 hours).  
The primary endpoint of the study was safety.  During the study (overall), there was a higher 
incidence of treatment-emergent adverse events (TEAE) and treatment-related TEAEs among 
patients treated with CVN424 (both dose groups) compared to placebo. Overall, there was a higher 
incidence of TEAEs in the CVN424 150 mg than in the CVN424 50 mg group; however, 
treatment-related TEAEs had a similar incidence in the 50 mg and 150 mg CVN424 dose groups. 
There were no treatment-related serious adverse events (SAE) in this study, and there was 1 SAE 
unrelated to the study treatment. The SAE unrelated to study treatment was an event of cardiac 
arrest in 1 (2.1%) patient in the CVN424 150 mg group, leading to study drug discontinuation and 
death. Overall, the most common TEAEs (preferred terms) were headache and nausea. A total of 
6 patients developed headaches (1 [2.3%] patient, 1 [2.2%] patient, and 4[8.5%] patients in the 
placebo, CVN424 50 mg, and CVN424 150 mg groups, respectively).  A total of 6 patients 
developed nausea (1 [2.3%] patient, 2 [4.4%] patients, and 3 [6.4%] patients in the placebo, 
CVN424 50 mg, and CVN424 150 mg groups, respectively). Overall, treatment-related TEAEs 
were more common in the CVN424 groups than in the placebo group (9.1%, 17.8%, and 19.1% of 
patients in the placebo, CVN424 50 mg, and CVN424 150 mg groups, respectively). Nausea was 
the most common treatment-related TEAE, with a total of 4 (2.9%) patients experiencing 5 
treatment-related events (0 [0%] patients, 2 [4.4%] patients, and 2 [4.3%] patients in the placebo, 
CVN424 50mg, and CVN424 150 mg groups, respectively).  Hallucinations, somnolence, 
confusion, orthostatic hypotension, and dyskinesia were each observed in fewer than 2 CVN424-
treated patients. Overall, approximately 67% of treatment-related TEAEs were mild in severity; 
the remainder were moderate in severity. There were no severe treatment-related TEAEs. There 
was a higher incidence of moderate treatment-related TEAEs in the CVN424 150mg group (8.5%) 
than in the CVN424 50 mg (2.2%) and placebo groups (4.5%). Overall, 6 (4.4%) patients 
discontinued study drug due to a TEAE: 2 (4.5%), 1 (2.2%), and 3 (6.4%) patients in the placebo, 
CVN424 50 mg, and CVN424 150 mg groups, respectively.   
Of these, 4 patients who received CVN424, 2 patients (1 each in the CVN424 50 mg and 150 mg 
groups) discontinued the study drug due to nausea. During the study, no medically significant 
treatment-related TEAEs (as defined in the protocol) occurred. There were no notable changes in 
laboratory parameters, physical examinations, electrocardiograms (ECGs), and Beck Depression 
Inventory (BDI) scores during the study.  However, patients receiving CVN424 did experience 
transient increases in blood pressure and pulse rate on Day 1 and Day 8. Treatment with CVN424 
did not impact impulsivity as assessed by the Questionnaire for Impulsive-Compulsive Disorders 
(QUIP) with the exception of sex on Day 15.  No statistically significant correlations were 
identified between 3-hour post-dose CVN424 concentration and ECG or vital signs parameters on 
Days 1 and 8 for the 50 mg or 150 mg dose levels.  
Cerevance conducted additional post-hoc analyses on the PD diary data, conforming to the Food 
and Drug Administration (FDA) standardized analysis for the PD diary. The PD diary was 
normalized to a 16-hour waking day, required 44/48 entries per day, required having both days of 
diaries, and only included participants with at least one post-baseline data. This post-hoc analysis 
was first conducted for the full analysis set and confirmed the result of the primary analysis, with 
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greater numeric improvement compared to placebo on the reduction in OFF time (CVN424 150 
had a 1.45-hour benefit compared to placebo; nominal p=0.01) and improvement in ON time 
without troublesome dyskinesia (CVN424 had a 0.96-hour benefit compared to placebo; 
p=0.098).ON time with troublesome dyskinesia was comparable to the primary analysis. A second 
post-hoc analysis was conducted using FDA standards for the PD diary analysis, excluding patients 
with a Baseline OFF time of 2-3 hours. Previous studies in PD patients with motor fluctuations 
with drugs proven effective have demonstrated that patients with 2-3 hours of OFF time do not 
show improvement. A minimum OFF time of 3 hours or more is standard for clinical trials in PD 
patients with motor fluctuations and will be the cutoff for the adequate and well-controlled trial of 
CVN424 in PD patients with motor fluctuations. This analysis showed a more robust effect of 
CVN424 on reduction in OFF time (1.78-hour improvement vs. placebo for the 150 mg dose; 
nominal p=0.005) and improvement in ON time without troublesome dyskinesia (1.30-hour 
improvement vs. placebo for the 150 mg dose; nominal p=0.042). ON time with troublesome 
dyskinesia was similar to the primary analysis.  
CVN424 is expected to be a pharmacological treatment for PD participants, as monotherapy or 
adjunctive to dopaminergic therapy, to elicit sustained improvement of motor activity with a 
reduced risk of troublesome dyskinesia compared with dopaminergic therapies. As a novel, first-
in-class, non-dopaminergic drug for the symptomatic treatment of PD, CVN424 may become a 
significant addition to neurologists’ clinical armamentarium 
4.2 
Rationale for the Proposed Study 
Non-invasive treatments typically reduce OFF time by approximately one hour with similar 
improvement in ON time without troublesome dyskinesias. The majority of approved treatments 
directly stimulate the dopamine receptor or increase levodopa bioavailability. As a result, these 
treatments have high rates of dopaminergic treatment-emergent adverse events and perpetuate the 
underlying cause of motor complications. Non-invasive treatments have limited efficacy, and 
patients continue to have OFF time that poorly impacts quality of life. Approved interventional 
procedures include deep brain stimulation (DBS) and intrajejunal levodopa. Both are highly 
effective but require an invasive procedure and risk serious and significant short-term and long-
term AEs and device complications. Thus, additional non-invasive treatments are needed that can 
provide greater efficacy benefits with low rates of dopaminergic AEs. 
The efficacy of CVN424 in animal models of PD and a prior phase 2a with PD patients supports 
its further investigation into the comparison of the in vivo performance of solution to tablet 
formulation.  
A safety and pharmacokinetic (PK) study previously performed in 64 healthy volunteers supports 
the selected dose levels of CVN424 in this study. Section 6.2 outlines the justification for the 
planned dosages.  
 
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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
Objectives 
Endpoints 
Primary 
Primary 
• 
To determine the relative bioavailability of 
150 mg of CVN424 administered in a single 
dose of suspension formulation compared to 
150 mg tablet. 
• 
The relative bioavailability of the CVN424 solution and 
CVN424 tablet formulation in the fasted state based on 
maximum observed plasma concentration (Cmax), time to 
reach Cmax (Tmax), and area under the plasma concentration-
time curve from time 0 to 96 hours (AUC 0-96h). 
 
• 
The ratio of the PK parameters between CVN424 solution 
and tablet in the fasted state will be calculated and 
summarized descriptively. In addition, an analysis of 
variance (ANOVA) on log-transformed PK parameters 
(AUC0-t, AUC0-96h, Cmax) will be performed. Ratios of 
geometric means and 90% confidence intervals will be 
calculated. Tmax will be compared between CVN424 solution 
and CVN424 tablet. 
Secondary 
Secondary 
• 
To establish the effects of food on the rate and 
extent of absorption of CVN424 150mg tablet 
when administered in fed conditions compared 
to administration under fasting conditions. 
 
• 
To assess the safety of the tablet under fast and 
fed conditions and suspension under fast 
conditions. 
• 
The ratio of the PK parameters between CVN424 tablets in 
the fed and fasted state will be calculated and summarized 
descriptively. In addition, an analysis of variance (ANOVA) 
on log-transformed PK parameters (AUC0-t, AUC0-96h, Cmax) 
will be performed. Ratios of geometric means and 90% 
confidence intervals will be calculated. Tmax will be 
compared between CVN424 tablets in the fed and fasted 
state. Tmax and Tlag will be compared between CVN424 
tablets in the fed and fasted state. 
 
• 
Assessment of safety as measured by TEAEs and tolerability 
as measured by discontinuations (D/Cs) due to AE. 
Exploratory 
Exploratory 
• 
Explore 
serum/plasma 
(e.g., 
potential 
characterization of drug metabolites) that may 
contribute to variability in CVN424. 
 
• 
Assessment of urine concentrations and 
volumes to enable calculation of urine PK 
parameters where possible. 
• 
Potentially characterize metabolic enzyme and transporter 
polymorphisms. 
 
• 
Urine concentrations and volumes of CVN424 tablet 
formulation at pre-dose and 0-12, 12-24, 24-48, 48-96 hours 
post-dose. Urine PK parameters (cumulative amount of 
unchanged drug excreted into the urine [Ae], fraction of 
unchanged drug excreted in the urine [fe], and renal 
clearance [CLR]) to be determined where possible. 
 
 
 
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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a randomized, open-label, single-oral dose, three-way cross-over study under fasted and fed conditions, study 
in healthy participants. 
Table 1  
Study Schema 
 
 
 
 
 
 
Sequence 
Dosing #1  
(Period 1 Day 1) 
 
Dosing #2 
(Period 2 Day 1) 
 
Dosing #3 
(Period 3 Day 1) 
1 (n=5) 
Suspension (fasted) 
W a s h o u t 
Tablet (fasted) 
W a s h o u t 
Tablet (fed) 
 
 
 
2 (n=6) 
Tablet (fasted) 
Tablet (fed) 
Suspension (fasted) 
 
 
 
3 (n=5) 
Tablet (fed) 
Suspension (fasted) 
Tablet (fasted) 
 
 
 
4 (n=5) 
Suspension (fasted) 
Tablet (fed) 
Tablet (fasted) 
 
 
 
 
5 (n=5) 
Tablet (fasted) 
Suspension (fasted) 
Tablet (fed) 
 
 
 
6 (n=6) 
Tablet (fed) 
Tablet (fasted) 
Suspension (fasted) 
 
 
 
 
 
 
6.1.1 Single Oral Dose, Three-Way Cross-Over 
32 healthy male or female participants will be enrolled in 1 of 6 single-dose, three-way cross-over 
sequences (designated as 1 through 6, respectively) in an ascending fashion. Sequences 1, 3, 4, 
and 5 will have 5 participants each, and Sequences 2 and 6 will have 6 participants each.  
Each sequence will proceed through three cross-overs (suspension-fasted, tablet-fed, tablet-fasted) 
according to the schematic above, with dosing to occur on Day 1 of each of the three Periods. 
Participants in the fasted portion of each sequence will be dosed under overnight fasted conditions 
and will remain fasted for 4 hours post-dose. Water consumption is permitted as desired except for 
1 hour before and after administration of Study Drug. 
To assess the effect of food on CVN424 bioavailability in tablet formulation, the single-dose 
administration will be administered after ingestion of a standardized high-fat, high-calorie meal 
according to FDA Guidance for Industry (Food-effect bioavailability and fed bioequivalence 
studies, Jun 2022).  
Participants for all sequences will be admitted to the study unit 1 day prior to dosing and remain 
in the unit for safety and PK assessments through 96 hours post-dose. The total confinement for 
each period will be 5 nights per sequence (15 days total) unless extended at the discretion of the 
Investigator, e.g., for monitoring and/or management of AEs.  
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Once 96-hour post-dose PK has been collected, participants will be discharged from the clinical 
research unit (CRU) for the remainder of the washout period and return the day prior to their next 
dose. 
An outline of the study visit schedule is included in Appendix A. 
6.2 
Justification for Study Design, Dose, and Endpoints 
This is a randomized, open-label, single-oral dose, three-way crossover study under fasted and fed 
conditions in healthy participants. The selected dose level (150 mg) is expected to provide a high 
level of GPR6 occupancy in brain tissue even at its steady-state nadir plasma concentration. 
Based on the Phase 2 data (see Section 4.1) and a previous healthy volunteer study, the planned 
dose of CVN424 is within the dose range previously shown to be safe and well-tolerated. 
AEs, physical exams, vital signs and weight, ECG findings, and clinical laboratory results are used 
as safety assessments to determine the relative bioavailability of the CVN424 suspension and tablet 
formulations. The plasma PK parameters will further elucidate the pharmacology of CVN424 in 
the intended participant population. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless new information or other evaluation regarding the 
safety of the study medication indicates an adverse change in the risk profile for the compound, 
such that the Sponsor or Institutional Review Board (IRB) considers the risk is no longer 
acceptable for participants participating in the study. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the site (including the Investigator) is 
found in significant violation of Good Clinical Practice (GCP), protocol, or contractual agreement 
and is unable to ensure adequate study performance or otherwise permitted by the contractual 
agreement. 
If the Sponsor, IRB, or regulatory authority elects to terminate or suspend the trial or the 
participation of an investigational site, a trial-specific procedure for early termination or 
suspension will be provided by the Sponsor; applicable investigational sites will follow the 
procedure during termination or trial suspension. 
6.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
If the Sponsor, IRB, or regulatory authority elects to terminate or suspend the study or the 
participation of an investigational site, a study-specific procedure for early termination or 
suspension will be provided by the Sponsor; applicable investigational sites will follow the 
procedure during the course of termination or study suspension. 
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7.0 
PARTICIPANT POPULATION 
Screening for eligible participants will be performed within 28 days prior to randomization.  
7.1 
Inclusion Criteria 
Participant eligibility is determined according to the following criteria prior to entry into the study: 
1. In the Investigator's opinion, the participant can understand and sign the Informed 
Consent Form (ICF) and comply with all protocol requirements.  
2. The participant is male or female adult who is 18 to 55 years of age, inclusive at the time 
of Screening. 
3. Participant weighs at least 45 kilograms (kg) (99 pounds [lbs]) and has a BMI between 
18.0 and 35.0 kg/m2, inclusive at Screening.  
4. The participant is medically healthy with no clinically significant (CS) or relevant 
abnormalities in medical history, physical exam, vital signs, ECG, and laboratory 
evaluations (hematology, chemistry, and urinalysis) as assessed by the Investigator. 
5. Female participants of childbearing potential and male participants with female partners 
of childbearing potential must agree to either remain abstinent or use two methods of 
adequate and reliable contraception (see Section 9.1.12) throughout the study and at least 
12 weeks after the last dose of study drug has been taken. 
7.2 
Exclusion Criteria 
Any participant who meets any of the following criteria will not qualify for entry into the study: 
1. Vegetarian, Vegan, Lactose intolerant, or follows a Kosher diet. 
2. Evidence of clinically significant neurologic or other disorder or impairment that, in the 
opinion of the Investigator, is reasonably expected to impact the ability of the participant 
to participate or confound the study results. 
3. A current or recent (within 6 months) gastrointestinal disease that would be expected to 
influence the absorption of drugs (i.e., a history of malabsorption, any surgical 
intervention known to impact absorption [e.g., bariatric surgery or bowel resection]). 
Note, history of cholecystectomy is permitted if there is no evidence of malabsorption per 
the Investigator. 
4. A history of cancer or other malignancy, with the exception of low-grade cervical 
intraepithelial neoplasia, low-grade (low-risk) prostate cancer, or 5-year cancer-free 
survivors of basal or squamous cell carcinoma or higher-grade cervical intraepithelial 
neoplasia or prostate cancer. 
5. A positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) 
antibody, or a human immunodeficiency virus (HIV) infection at Screening. 
6. Any clinically significant abnormalities in labs: biochemistry (including liver function 
test [LFT], estimated glomerular filtration rate [eGFR], and glucose), standard 
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hematology with white blood cell (WBC) differential, c-reactive protein (CRP), 
coagulation tests, lipase, amylase, albumin, and calcium. 
7. A supine blood pressure outside the ranges of 80 to 160 mm Hg for systolic and 50 to 100 
mm Hg for diastolic, confirmed with up to two repeat tests at the Screening Visit; or 
symptomatic orthostatic hypotension, in the opinion of the Investigator. 
8. A resting heart rate outside the range of 40 to 100 beats per minute (bpm) confirmed with 
up to two repeat tests at the Screening Visit. Note that 40-50 and 90-100 bpm may be 
permitted only at the discretion of the Investigator. 
9. Positive urine result for illegal drugs at Screening and Check-In, or history of illicit drug 
use or alcohol abuse within 1 year prior to the Screening Visit. 
10. Received any investigational compound (defined as a drug that has not been FDA-
approved) within 30 days prior to the first dose of study medication or within 5 half-lives 
of the investigational compound, whichever is greater. 
11. Within 14 or 28 days prior to randomization, ingested any of the following excluded 
medication, supplements, or food products: St. John’s wort, ginseng, kava, Ginkgo 
biloba, Chinese herbs, and melatonin, or known strong inhibitors/inducers of cytochrome 
P-4503A4/5, including rifampin, clarithromycin, ketoconazole, itraconazole. For full list 
of prohibited medications and dietary products, (See Table 2). 
12. Regularly uses nicotine-containing products (including but not limited to cigarettes, 
electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch, or nicotine gum). 
The casual users (≤ 10 cigarettes/week) may participate; however, they must agree to 
refrain from 30 days before Day 0 (Inpatient Check-in) for the duration of the study or a 
positive urine cotinine test at Inpatient Check-in. 
13. Known history of coronary artery disease and hospitalization for myocardial infraction, 
ischemic heart disease, or congestive heart failure within the 2 years prior to the 
screening visit.   
14. Any clinically significant medical, psychiatric, or laboratory abnormality that, in the 
judgment of the Investigator, is likely to interfere with study participation 
15. A history of major depression or risk of suicide according to the Investigator’s clinical 
judgment or has made a suicide attempt. 
16. Is a study site employee or an immediate family member of a study site employee. 
 
 
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Table 2  
Prohibited Medication and Dietary Products 
Use of the agents in Table 2 (prescription or nonprescription) is prohibited from the time points 
specified until completion of all study activities. 
The following table defines the prohibited medications and dietary products:  
Prohibited Medication and Dietary Product 
Within 30 days before Randomization: 
• 
Nicotine-containing products 
Within 28 days before Randomization: 
• 
St. John’s wort, ginseng, kava, ginkgo biloba, Chinese herbs, and melatonin 
• 
Known strong inducers of cytochrome P-4503A4/5 or p-gp, including rifampin  
• 
Immunization vaccines: Inclusive of but not limited to H1N1 and flu vaccinations. 
Participants who have received the COVID-19 Vaccine between -10 and -28 days may 
participate, provided they did not experience any side effects of any description. COVID-19 
vaccine doses may be administered 7 days post-study medication dosing.  
Within 14 days before Randomization: 
• 
Known strong inhibitors of cytochrome P-4503A4/5, including clarithromycin, ketoconazole, 
itraconazole 
• 
All prescription and non-prescription medications, herbal remedies, or vitamin supplements. 
Medication listed as part of acceptable birth control (Section 9.1.12), hormone replacement 
therapy, and thyroid hormone replacement therapy medication will be allowed without dose 
changes during the study.  
Potential exceptions: 
• 
Occasional use of acetaminophen (~1 g/day) and 400mg ibuprofen TDS when required or 
other medication as approved by the Sponsor’s Medical Monitor on a case-by-case basis is 
allowed except on Day 1 
• 
Certain prescription medications may be allowed on a case-by-case basis at the discretion of 
the Investigator and Sponsor 
 
 
 
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7.3 
Diet, Fluid, and Activity Control 
Participants will refrain from the consumption of food and beverages containing the following: 
• Xanthines/caffeine: 24 hours prior to each dosing and until last PK sample in each period 
(small amounts of caffeine derived from normal foodstuffs, e.g., 250 mL/8 oz/ 1 cup 
decaffeinated coffee or other decaffeinated beverage per day, except for espresso; 45 
g/1.5 oz chocolate bar, per day, would not be considered a deviation to this restriction). 
• Alcohol: 48 hours prior to each dosing and until last PK sample in each period. 
• Grapefruit/Seville orange: 14 days prior to first dosing and until the last pk sample in 
Period 3. 
Participants will be confined to the clinic on three separate sequences for approximately 5 days 
which will allow dosing sufficient time to collect additional post-dose PK samples and monitor for 
safety and tolerability (Check-in through Day 5 for each of the three Periods). During confinement, 
with the exception of the dosing day (See Section 7.3.1), participants will be provided 3 standard 
meals and a snack per day, each containing approximately 30% fat (relative to the total calories). 
Each meal and/or snacks served at the CRU will be standardized, similar in caloric content and 
composition, and taken at approximately the same time in each period. When confined, standard 
meals and snacks will be provided at appropriate times, except when they are required to fast. 
When confined in the CRU, participants will be required to fast from all food and drink except 
water between meals and snacks. 
The study menu should be recorded and submitted to the study file, with a copy provided to the 
Sponsor following treatment. Other fluids may be given as part of meals and snacks but will be 
restricted at all other times throughout the confinement period.  
If a blood draw or any study procedure coincides with a meal, the blood draw will take precedence, 
followed by the study procedure and then the meal. 
Participants will remain in bed at a semi-supine position for 4 hours following the dose 
administration, except as necessitated by an AE or study procedures (e.g., obtaining a 12-lead 
ECG). Participants must refrain from strenuous exercise for 72 hours before Inpatient Check-in 
and until check-out. 
7.3.1 On Dosing Days: 
For the Suspension (fasted) and Tablet (fasted) portions: Breakfast will not be provided on 
dosing days. Participants must fast for a minimum of 4 hours after dose administration unless 
otherwise indicated. CVN424 will be administered with approximately 240 mL of water after a 
fast of at least 10 hours. Participants will continue to fast for an additional 4 hours after dosing 
and eat lunch following the 4-hour PK blood collection. Participants may consume water ad 
libitum except for 1 hour before and 1 hour after drug administration. 
 
For the Tablet (fed) portion (food effect): CVN424 will be administered after ingesting a 
standardized high-fat, high-calorie meal according to FDA Guidance for Industry (Food-effect 
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bioavailability and fed bioequivalence studies, June 2022). Participants will finish their breakfast 
in its entirety within 30 minutes and will receive an investigational product 30 minutes (±5 
minutes) after beginning the meal. The meal start and stop times, and percentage of the meal 
consumed will be recorded in the source, and the appropriate electronic case report form (eCRF) 
for all meals served on dosing days. 
7.4 
Criteria for Discontinuation or Withdrawal of a Participant 
Participants are free to withdraw from the study at any time upon request. The Investigator may 
remove a participant from the study if, in the Investigator’s opinion, it is not in the best interest of 
the participant to continue the study. Participants may be discontinued due to the following (not 
inclusive): 
1. The participant has experienced an AE that requires early termination because continued 
participation imposes an unacceptable risk to the participant’s health, or the participant is 
unwilling to continue because of the AE. 
2. Liver Function Test (LFT) Abnormalities 
Study medication should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests until a participant’s laboratory profile has returned to 
normal/baseline status) if the following circumstances occur at any time during study 
medication treatment: 
– Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper 
limit of normal (ULN), or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN or INR 
>1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
3. Significant protocol deviation. The discovery post-randomization that the participant 
failed to meet protocol entry criteria or did not adhere to protocol requirements and 
continued participation poses an unacceptable risk to the participant’s health. 
4. Lost to follow-up. The participant did not return to the clinic and attempts to contact the 
participant were unsuccessful. Attempts to reach the participant must be documented. 
5. Voluntary withdrawal. The participant (or participant’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be 
recorded in the eCRF. 
Note: Attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (e.g., withdrawal 
due to an AE; withdrawal due to relocation). 
6. The Sponsor, IRB, or regulatory agency terminates the study. 
7. Other. 
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The primary reason for discontinuation or withdrawal of the participant from the study or study 
medication should be recorded in the eCRF using the following categories. For screen failure 
participants, refer to Section 9.1.14. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.5 
Procedures for Discontinuation or Withdrawal of a Participant 
The Investigator must discontinue a participant’s study participation at any time during the study 
when the participant meets the study discontinuation criteria described in Section 7.4. In addition, 
a participant may discontinue their participation without giving a reason at any time during the 
study. Should a participant’s involvement be terminated, the primary criterion for termination must 
be recorded by the Investigator. In addition, efforts should be made to perform all procedures 
scheduled for the Early Termination Visit. Discontinued or withdrawn participants may be 
replaced at the Sponsor’s discretion. Participants who withdraw from the study prior to dosing may 
be replaced. 
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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
8.1 
Study Medication and Materials 
This section contains information regarding all medication and materials provided directly by the 
Sponsor and/or sourced by other means required by the study protocol, including important 
sections describing the management of clinical trial material. 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
Study drug refers to CVN424 in both suspension and tablet formulations. 
In this protocol, the term study medication refers to all or any of the drugs defined below. 
8.1.1.1 Investigational Drug 
CVN424 Suspension: 
The oral suspension drug product will be compounded by an accredited compounding pharmacy, 
e.g., Infuserve America Inc. 
CVN424 oral suspension is prepared by suspending CVN424 drug substance in 2% Methocel, E15 
Premium LV Hydroxypropyl Methylcellulose (HPMC)/0.5% Tween 80 vehicle. CVN424 oral 
suspension is supplied to the clinical site in bottles with contents clearly labeled, along with the 
appropriate study information and caution statements. 
CVN424 Tablet: 
Patheon Milton Park UK will manufacture the bulk drug product (150 mg tablets) and bottle it, 
and Patheon Allentown, US, will perform labeling and distribution of the study drug. 
The components of the CVN424 tablet include the CVN424 API, Colloidal Silicon Dioxide, 
Croscarmellose Sodium, Hydroxypropylcellulose, Magnesium Stearate, Mannitol, and 
Microcrystalline Cellulose.   
The tablets will be packaged in a high-density polyethylene (HDPE) bottle with an induction seal 
and a child-resistant cap; each bottle will contain 30 tablets. 
Ancillary Materials: 
Ancillary materials will be provided by either the clinical site and/or the Sponsor based on 
availability. Unused ancillary materials provided by the Sponsor will be accounted for and 
disposed of as directed by the Sponsor or their designee. 
8.1.2 Drug Storage 
All study drug stored at the investigative site must be kept in an appropriate, limited-access, secure 
place until it is used or returned to the Sponsor or designee for destruction. All study drug must be 
stored under the conditions specified on the label and remain in the original container until 
dispensed. A daily temperature log of the drug storage area must be maintained every working 
day; short excursions are allowed but must be evaluated by the Sponsor. 
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8.1.3 Dose and Regimen 
Prior to dosing initiation, the Investigator or Investigator’s designee will instruct the participant 
on dosing procedures. 
All dosing will occur while participants are in the clinic under the supervision of the Investigator 
or designee and in fed or fasting conditions as outlined in Section 7.3. 
The exact time of dose will be recorded in the source documents and on the appropriate eCRF. 
The planned sequences to be studied are provided in Table 3.  
Table 3  
Three-Way Cross-Over Sequences 
 
 
 
 
 
 
Sequence 
Dosing #1  
(Period 1 Day 1) 
(Study Day 0) 
 
Dosing #2  
(Period 2 Day 1) 
(Study Day 14) 
 
Dosing #3  
(Period 3 Day 1) 
(Study Day 28) 
1 (n=5) 
Suspension (fasted) 
W a s h o u t 
Tablet (fasted) 
W a s h o u t 
Tablet (fed) 
 
 
 
2 (n=6) 
Tablet (fasted) 
Tablet (fed) 
Suspension (fasted) 
 
 
 
3 (n=5) 
Tablet (fed) 
Suspension (fasted) 
Tablet (fasted) 
 
 
 
4 (n=5) 
Suspension (fasted) 
Tablet (fed) 
Tablet (fasted) 
 
 
 
 
5 (n=5) 
Tablet (fasted) 
Suspension (fasted) 
Tablet (fed) 
 
 
 
6 (n=6) 
Tablet (fed) 
Tablet (fasted) 
Suspension (fasted) 
 
 
 
 
 
 
8.1.4 Overdose 
An overdose is defined as a known, deliberate, or accidental administration of an investigational 
drug, to or by a study participant, at a dose above that assigned to that individual participant 
according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on AE eCRF(s) according to Section 9.7.1. 
Serious adverse events (SAEs) associated with an overdose should be reported according to the 
procedure outlined in Section 9.7.2. 
In the event of an overdose, supportive measures should be employed as needed, e.g., 
administration of supportive therapy as dictated by the participant’s clinical status, removal of 
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unabsorbed material from the gastrointestinal tract, or the initiation of additional clinical 
monitoring.  
8.2 
Investigational Drug Assignment and Dispensing Procedures 
Participants will be assigned to receive a unique randomization number. Study drug will be 
dispensed to participants as either tablets or suspensions. The tablets must be stored at controlled 
room temperature, and the suspensions must be stored refrigerated. See Pharmacy Manual for 
specifics.  
8.3 
Randomization Code Creation and Storage  
The Sponsor or their designee will generate the randomization schedule and provide a copy to the 
site pharmacist and bioanalytical laboratory prior to the start of the study. All randomization 
information will be stored in a secured area. 
8.4 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the Sponsor or 
designee or before being destroyed. 
The Investigator or designee must ensure that the study medication is used in accordance with the 
approved protocol and is dispensed only to participants enrolled in the study. To document the 
appropriate use of study medication, the Investigator must maintain records of all study medication 
delivery to the site, site inventory used by each participant, and return to the Sponsor or designee. 
 Upon receipt of study medication, the Investigator or designee must verify the contents of the 
shipments against the packing list, ensure the quantity is correct, and the medication is received 
within the labeled storage conditions. If quantity and conditions are acceptable, the Investigator or 
designee should acknowledge the receipt of the shipment by signing the bottom half of the packing 
list and send via email and per instructions provided on the form. If discrepancies exist between 
the packing list and the actual product received, the Sponsor must be contacted to resolve the issue. 
The packing list should be filed in the Investigator’s essential document file. The Investigator must 
maintain 100% accountability for all study medication received and dispensed during their entire 
participation in the study. Proper drug accountability includes, but is not limited to: 
• Continuously monitoring expiration dates 
• Frequently verifying that actual inventory matches documented inventory 
• Verifying that the log is completed for the drug lot used to prepare each dose 
• Verifying that all containers used are documented accurately on the log 
• Verifying that required fields are completed accurately and legibly 
If any dispensing errors or discrepancies are discovered, the Sponsor must be notified immediately. 
The Investigator or designee must record the current inventory of all study medication on a 
Sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of the Investigator, site identifier and number, 
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description of study medication, expiry date, and amount dispensed, including the initials of the 
person dispensing and receiving the study medication. The log should include all required 
information as a separate entry for each participant to whom study medication is dispensed. 
Prior to site closure or at appropriate intervals, a representative from the Sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the Sponsor or its designee for destruction or destroyed at the site, as 
applicable. The Investigator will retain the original documentation regarding clinical study 
material accountability, return, and/or destruction, and copies will be sent to the Sponsor or 
designee. 
The Investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the Sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the Sponsor or its designee for destruction. 
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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each procedure, 
participants are to be assessed by the same Investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A.  
9.1.1 Informed Consent Procedure 
The requirements of the ICF are described in Section 13.2. 
A properly signed ICF must be obtained prior to the participant entering the study and before any 
protocol-related procedures are performed. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, ethnicity, race as described 
by the participant, smoking status, and caffeine consumption at Screening. 
Medical history to be obtained will include determining whether the participant has any significant 
conditions or diseases that stopped at or prior to signing the ICF. Ongoing conditions are 
considered concurrent medical conditions (see Section 9.6.2). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 28 days before signing ICF. 
9.1.3 Physical Examination Procedure 
A physical examination performed by the Investigator or designee consists of the following body 
systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; (4) respiratory system; (5) 
gastrointestinal system; (6) dermatologic system; (7) extremities; (8) musculoskeletal system; (9) 
nervous system; (10) lymph nodes; and (11) other. 
Any abnormal change from the baseline physical examination must be assessed as not clinically 
significant (NCS) or clinically significant (CS) by the Investigator and recorded in the source 
document and eCRF. Any CS change or new diagnosis as a result of a CS change, as determined 
by the Investigator, will be recorded as an AE in source documentation and on the AE eCRF 
described in Section 9.7.1. 
9.1.4 Weight, Height, and BMI 
A participant should have weight and height measured while wearing indoor clothing and with 
shoes off. The BMI is calculated using metric units with the formula provided below: 
Height is recorded centimeters without decimal places and for weight it is kilograms (kg) with 1 
decimal place. BMI should be derived as: 
Metric:  
BMI = weight (kg)/[height (m)]2 
Results for BMI will be expressed with 1 decimal place. 
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Example: 
Height=176 centimeter (cm) (or 1.76 m), weight=79.2 kg; BMI=79.2/1.762=25.57 kg/m2 
captured as 25.5 kg/m2.  
9.1.5 Vital Sign Procedure 
Orthostatic vital signs will be measured after the participant has been at rest in a supine position 
for at least 3 minutes. Vital signs include blood pressure (BP), pulse rate, respiration rate, and body 
temperature. Triplicate measurements will be taken at pre-dose, initial post-dose, and final study 
assessment to ensure accuracy unless values are unexpected and additional measurements are 
clinically indicated for confirmation. Additionally, abnormal or unexpected measurements are to 
be rechecked manually. 
Vital signs should be measured at the same time (+/- 1 hour) of the day across visits if possible. 
When vital signs are scheduled at the same time as blood draws, the blood draw will take priority, 
and vital signs will be obtained within approximately 15 minutes before or after the scheduled 
blood draw. 
9.1.6 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the participant over the counter. Concomitant medication 
is not provided by the Sponsor. At each study visit, participants will be asked whether they have 
taken any medication other than the study medication (used from the signing of ICF through the 
end of the study), and all medication, including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. Documentation will 
include generic medication name, dose, unit, frequency, route of administration, start and end 
dates, and reason for use. Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at the signing of ICF. This includes CS laboratory, ECG, or physical examination abnormalities 
noted at Screening examination. The condition (i.e., diagnosis) should be described. 
9.1.7 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at the signing of ICF. This includes CS laboratory, ECG, or physical examination abnormalities 
noted at Screening examination. The condition (i.e., diagnosis) should be described. 
9.1.8 ECG Procedure 
Triplicate ECGs will be taken at least 1-minute apart at each scheduled time. The average of the 
ECG measurements will be used for determining eligibility. Additional unscheduled ECGs may 
be recorded where clinically necessary for participant safety. 
When an ECG is scheduled at the same time as blood draws or vital signs, then the blood draws 
and vital signs will take priority, and the ECG will be obtained within 30 minutes before or after 
the scheduled blood draw/vital sign assessment. If an ECG coincides with a meal, ECG will take 
precedence, followed by the meal. 
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All stationary 12-lead ECG machines will be supplied by the site. Participants should be in a supine 
position following an approximate 5-minute rest period for ECG recordings. Should technical 
difficulties occur during the recording of the ECG, a reasonable attempt should be made to repeat 
the ECG shortly after the failed attempt.  
ECGs will be interpreted by qualified personnel. The Investigator or sub-Investigator will 
categorize the ECG findings using 1 of the following categories: within normal limits, abnormal 
but not CS, or abnormal and CS. All 12-lead ECGs will be stored for manual measurement of 
intervals, if necessary. Twelve-lead ECGs will be recorded using an ECG machine that 
automatically calculates the heart rate and measures PR interval, RR interval, QRS interval, QT 
interval, and QTcF and QTcB (Fridericia’s and Bazett’s correction method) intervals. 
9.1.9 PK Sample Collection 
9.1.9.1 Collection of Blood for PK Sampling 
Blood samples for analysis of CVN424 plasma concentrations will be collected into chilled 
Vacutainers containing K2EDTA.  
Instructions for sample processing and shipment are provided in a separate lab manual. 
In all sequences, serial blood samples to determine CVN424 concentrations in plasma will be 
collected according to the Schedule of Study Procedures (Appendix A). 
The PK samples will be collected at the nominal time point; all other assessments will be collected, 
before or after, within the allowable windows. The actual time of sample collection will be 
recorded on the source document and eCRF.  
Sampling time points may be adjusted or added based on the preliminary emerging PK data 
collected from prior sequence(s).  
9.1.9.2 Collection of Urine for PK Sampling 
In Tablet (fasted) sequences only, urine samples for analysis of CVN424 (or its metabolites) 
concentration in urine will be collected: pre-dose (within 12 hours prior to dosing), 0-12, 12-24, 
24-48, and 48-96-hours post-dose. Volume of urine collected is to be recorded. Instructions for 
sample processing and shipment are provided in a separate lab manual. 
9.1.9.3 Bioanalytical Methods 
Plasma and urine concentrations of CVN424 will be measured by high-performance liquid 
chromatography with tandem mass spectrometry using validated (for plasma) and qualified (for 
urine) assays. 
Plasma and urine samples will be archived for potential analysis of metabolites and/or target-
related biomarkers, if appropriate. 
9.1.10 PK Parameters  
PK parameters of CVN424 will be derived using non-compartmental analysis methods from the 
concentration-time data for all evaluable participants. Actual sampling times, rather than scheduled 
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sampling times, will be used in all computations involving sampling times. The following PK 
parameters will be determined from concentrations of CVN424 in plasma. 
 
Symbol/Term 
Definition 
Plasma 
AUCt 
Area under the plasma concentration-time curve from the time of dosing to the time of the 
last measurable concentration 
AUC0-96h 
Area under the plasma concentration-time curve from time 0 to 96 hours  
Cmax 
Maximum observed plasma concentration. 
Tmax 
Time to reach Cmax. 
 
Additional PK parameters may be calculated as appropriate. 
9.1.11 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures.  
Table 4 lists the tests that will be obtained for each laboratory specimen. 
Table 4 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
RBC 
WBC with differential  
     (% and absolute) 
Hemoglobin 
Hematocrit 
Platelets 
PT/INR 
ALT 
Albumin 
Alkaline phosphatase 
Amylase 
AST 
Total bilirubin 
Direct bilirubin 
Total protein 
Coagulation 
Creatinine 
CRP 
BUN/Urea 
Creatine kinase 
GGT 
eGFR 
Lipase 
Potassium 
Sodium 
Glucose 
Chloride 
Bicarbonate 
Calcium 
pH 
Specific gravity 
Protein 
Glucose 
Blood  
Nitrite 
Microscopic Analysis 
(only if positive dipstick results):  
RBC/high power field 
WBC/high power field 
Epithelial cells, casts etc. 
Diagnostic Screening: 
Serum 
Urine/ Blood 
Serum hCG 
FSH 
Drug screen including amphetamines (AMP), 
barbiturates (BAR), benzodiazepines (BZO), 
cannabinoids, cocaine (COC), opiates (OPI), 
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The in-house laboratory will perform all clinical laboratory tests. The results of laboratory tests 
will be returned to the Investigator, who is responsible for reviewing and filing these results. All 
laboratory safety data will be transferred electronically to the Sponsor or designee in the format 
requested by the Sponsor. The Investigator will maintain a copy of the laboratory accreditation 
and the reference ranges for the laboratory used. 
Laboratory reports must be signed and dated by the Investigator or sub-Investigator, indicating 
that the report has been reviewed and any abnormalities have been assessed for clinical 
significance. Participants will be referred to their primary care physician for follow-up of any 
clinically significant findings or where the Investigator or medically trained sub-Investigator 
deems appropriate. 
All CS laboratory abnormalities must be recorded as an AE in the participant’s source documents 
and on the appropriate eCRF. A CS laboratory abnormality that has been verified by retesting will 
be followed until the abnormality returns to an acceptable level or a satisfactory explanation has 
been obtained. 
If participants experience ALT or AST >3 ×ULN, follow-up laboratory tests at a minimum, serum 
alkaline phosphatase, ALT, AST, total bilirubin, γ-glutamyl transferase (GGT), and international 
normalized ratio (INR) should be performed within a maximum of 7 days and preferably within 
48 to 72 hours after the abnormality was found. 
(Please refer to Section 7.4 for discontinuation criteria and Section 9.7.3 for the appropriate 
guidance on Reporting of Abnormal LFT in relation to ALT or AST >3 ×ULN in conjunction with 
total bilirubin >2 ×ULN). 
If the ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions, the Investigator 
must contact the Medical Monitor for consideration of additional testing, close monitoring, 
possible discontinuation of study medication, and discussion of the relevant participant details, 
and possible alternative etiologies. The abnormality should be recorded as an AE (please refer to 
Section 9.7.3 for reporting requirements). 
9.1.12 Contraception and Pregnancy Avoidance Procedure 
From the date of signing of ICF, throughout the duration of the study, and for 12 weeks after the 
last dose of study medication, females of childbearing potential* must use two acceptable methods 
of contraception and must agree not to donate eggs; Nonsterilized** male participants who are 
sexually active with a female partner of childbearing potential* must use two acceptable method(s) 
of contraception throughout the duration of the study, and for 12 weeks after the last dose of study 
Hepatitis panel, including HBsAg and anti-HCV 
Human Immunodeficiency Virus (HIV) antibody 
alcohol, methamphetamines, methadone 
(MET), methylenedioxymethamphetamine 
(MDMA), phencyclidine (PCP), 
tetrahydrocannabinol (THC) 
Cotinine 
Urine Pregnancy Test  
Alcohol (may be performed via breath test or 
urine) 
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medication. In addition, males must be advised not to donate sperm for 12 weeks after the last dose 
of study medication. 
*Females of childbearing potential are defined as any female who has experienced menarche and 
has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not 
postmenopausal.  
Menopause is defined as at least 1 years since the last regular menses with a follicle-stimulating 
hormone (FSH)>40 IU/L or at least 5 years since the last regular menses, confirmed before any 
study medication is implemented. Male participants with potentially postmenopausal partners who 
are under the age of 55 years must use condoms unless their partner’s postmenopausal status has 
been confirmed by FSH level.  
**Sterilized males should be at least 120 days post-vasectomy and confirm that they have obtained 
documentation of the absence of sperm in the ejaculate. 
Participants in a same-sex relationship must use a barrier form of birth control (for example, 
condom or diaphragm) to protect against the transfer of the study drug in any bodily fluids for 12 
weeks after the last dose of study medication. 
Acceptable and highly effective methods of contraception are: 
• Abstinence is defined as refraining from heterosexual intercourse during the entire period 
of risk associated with the study treatments. The investigator will assess the reliability of 
abstinence concerning the duration of the clinical trial and the preferred and usual 
lifestyle of the participant.  
• Intrauterine device (IUD) 
• Surgical sterilization or postmenopausal 
• Condom, diaphragm, or cervical cap with spermicide  
• Hormonal contraception, including oral, injectable, transdermal, or implantable methods  
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner (if the partner is the sole sexual partner of the woman of 
childbearing potential [WOCBP] participant and the vasectomized partner has received 
medical assessment of the surgical success) 
Participants will be provided with information on acceptable methods of contraception as part of 
the participant’s informed consent process and will be asked to sign an ICF stating that they 
understand the requirements for avoidance of pregnancy, egg donation, and sperm donation during 
the study. 
9.1.13 Pregnancy 
Women who are pregnant or breastfeeding will not be included in this study.  
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If any participant is found to be pregnant during the study, she should be withdrawn, and any 
Sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male participant during the study or for 90 days after the last dose, should also be 
recorded following authorization from the participant’s partner.  
If the pregnancy occurs during administration of active study medication, e.g., after Period 1 or 
within 90 days of the last dose of active study medication, the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0. 
If the female participant and/or female partner of a male participant agrees to the primary care 
physician being informed, the Investigator should notify the primary care physician that the 
participant/female partner of the participant was participating in a clinical study at the time she 
became pregnant and provide details of treatment the participant received (blinded or unblinded, 
as applicable). 
All reported pregnancies will be followed up to final outcome using the pregnancy form and you 
may be asked to report the outcome. An evaluation after the birth of the child will also be 
conducted. 
9.1.14 Documentation of Screen Failure 
Investigators must account for all participants who sign ICF. If the participant is not eligible at this 
visit, the Investigator should complete the eCRF screen failure form. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
• AE 
• Did not meet inclusion criteria or did meet exclusion criteria 
• Significant protocol deviation 
• Lost to follow-up 
• Voluntary withdrawal 
• Study termination 
• Other 
Participant numbers assigned to participants who fail Screening should not be reused.  
If a participant fails Screening, but is later successfully rescreened, the data for the participant will 
be entered as if these were two separate participants. Therefore, the data should be entered as 
follows: 
1. The screen failure data should be entered as a screen failure participant. 
2. Rescreened participants should be assigned a new participant number and treated as a 
stand-alone participant. 
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9.1.15 Documentation of Randomization 
Only participants who meet all of the inclusion criteria and none of the exclusion criteria are 
eligible for randomization into the treatment phase. 
If the participant is not eligible for randomization, the Investigator should record the primary 
reason for failure on the applicable eCRF. 
9.2 
Monitoring Participant Treatment Compliance 
Study medication will first be administered while participants are under observation in the clinical 
research unit. Following administration of the study medication, appropriate mouth and/or hand 
checks will be performed to ensure that the dose is swallowed and noted in the source document. 
The date and time of each dose will be recorded in the source documents and on the eCRFs. An 
inventory of the study medication supplies dispensed will be performed by the site pharmacist or 
authorized study designee and recorded onto the Drug Accountability Log in the participant’s 
source document records or equivalent. The exact dose time of consecutive participants may be 
staggered to facilitate logistics at the site. 
9.3 
Schedule of Observations and Procedures 
The study-related procedures schedule for all evaluations is shown in Appendix A. 
9.3.1 Screening 
Participants will be screened within 28 days prior to randomization. Participants will be screened 
in accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.14 for procedures for documenting screening failures. Participants who are screening 
failures may be screened a second time if their reason for failing Screening is thought to be 
resolved. Rescreened participants will receive a new Screening number. 
9.3.2 Inpatient Check-In 
Following Screening and Baseline assessments, eligible participants will be randomized to one of 
the 6 sequences at the time of the first administration of study drug (Period 1 Day 1). Additionally, 
all participants will be admitted to the study clinic the day prior to subsequent dosing days, See 
Schedule of Study Procedures (Appendix A). 
9.3.3 Dosing 
Participants will be dosed according to the schema (See Table 1) on Day 1 of Periods 1, 2, and 3. 
9.3.4 Washout and Discharge 
Participants will be discharged after 5 consecutive days for a 14-day washout period (following 
96-hour post-dose blood draw). 
9.3.5 Final Visit (discharge day from clinic) 
Participants will be confined to the study clinic for the first 96 hours of each washout period to 
permit supervised dosing of study drug and repeat study assessments.   
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The Investigator must complete the End of Study eCRF page for all participants. 
9.3.6 Early Termination 
If a participant withdraws from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal, including the date of last study 
drug treatment and the reason for withdrawal. If the participant is withdrawn due to an AE, the 
Investigator will follow the participant until the AE has resolved or stabilized. In all cases, the 
reason for and date of withdrawal must be recorded in the eCRF and in the participant's medical 
records.  Efforts will be made to perform all early termination procedures for safety purposes prior 
to discharge.  The early termination visit should be performed 2 weeks after the last dose if agreed 
to by the participant.   
The Investigator must complete the End of Study eCRF page for all participants receiving study 
medication. 
9.3.7 Follow-up Visit 
The Follow-up Visit will occur by telephone 14 days (±2) after the final dose of study drug unless 
abnormal CS findings are observed upon discharge. In these cases, participants must be brought 
back to the clinic for re-evaluation per the Investigator’s discretion. 
9.4 
Biological Sample Retention and Destruction 
Blood and urine samples for PK analysis will be collected as described in Section 9.1.9. Once PK 
analysis is complete, backup plasma and urine samples will be preserved and retained at a 
biorepository selected by the Sponsor for up to, but not longer than, 15 years or as required by 
applicable law to enable the conduct of exploratory, qualitative, metabolite identification studies 
or measurement of target related biomarkers, should the Sponsor decide these are informative. The 
Sponsor has put a system to protect the participants’ personal information to ensure optimal 
confidentiality and defined standard processes for sample and data collection, storage, analysis, 
and destruction. 
The sample will be labeled with a unique sample identifier similar to labeling in the main study 
but using a code different from the code attached to the health information and other clinical test 
results collected in the study. The sample and data are linked to personal health information with 
code numbers; the samples are stripped of all personally identifying information, but a key linking 
the samples to clinical analysis data exists. This link means that the participant may be identified 
but only indirectly. The code numbers will be kept secure by or on behalf of the Sponsor. 
9.5 
Blood Volume 
Direct venipuncture or intravenous cannula is the preferred method of blood collection. Any other 
method will need to be approved by the Sponsor. The maximum volume of blood on any single 
day is approximately 111 mL, with the maximum amount not to exceed 500mL for the duration of 
study participation. 
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9.6 
Definitions 
9.6.1 AE 
An AE is defined as any untoward medical occurrence in a clinical investigation participant 
administered a drug whether or not considered drug-related (CFR Title 21, Part 312.32(a)); it does 
not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a CS abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a drug whether or not it is 
considered related to the drug. 
A treatment-emergent adverse event (TEAE) is an AE than begins on or after administration of the 
first dose of trial medication or an increase in severity or frequency on or after administration of 
the first dose of trial medication. 
9.6.2 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered AEs) 
• Necessitate therapeutic intervention 
• Require an invasive diagnostic procedure 
• Require discontinuation or a change in dose of study medication or a concomitant medication 
• Be considered unfavorable by the investigator for any reason 
• AEs caused by a study procedure (e.g., a bruise after blood draw) should be recorded as an 
AE 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should NOT be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as an AE(s).  
Laboratory values and ECG findings: 
• Changes in laboratory values or ECG parameters are only considered to be AEs if they are 
judged to be CS (i.e., if some action or intervention is required or if the Investigator judges 
the change to be beyond the range of normal physiologic fluctuation). A laboratory re-test 
and/or continued monitoring of an abnormal value are not considered an intervention. In 
addition, repeated or additional noninvasive testing for verification, evaluation, or monitoring 
of an abnormality is not considered an intervention 
• If abnormal laboratory values or ECG findings are the results of pathology for which there is 
an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only should be 
reported appropriately as an AE 
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Pre-existing conditions: 
• Pre-existing conditions (present at the time of signing of the ICF) are considered concurrent 
medical conditions and should NOT be recorded as AEs. Baseline evaluations (e.g., 
laboratory tests, ECG, X-rays, etc.) should NOT be recorded unless related Study Procedures 
(Appendix A). 
• If a participant has a pre-existing episodic condition (e.g., asthma, epilepsy), any occurrence 
of an episode should only be captured as an AE if the episodes become more frequent, 
serious, or severe in nature; that is, Investigators should ensure that the AE term recorded 
captures the change in the condition from Baseline (e.g., “worsening of…”) 
• If a participant has a concurrent degenerative condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as an AE if occurring to a greater extent 
than that which would be expected. Again, Investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”) 
Worsening of AEs: 
• If the participant experiences a worsening or complication of an AE after starting 
administration of the study medication, the worsening or complication should be recorded 
appropriately as an AE. 
• If the participant experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. 
Changes in severity of AEs /Serious PTEs: 
• If the participant experiences changes in the severity of an AE, the event should be captured 
once, with the maximum severity recorded. 
Preplanned surgeries or procedures: 
• Preplanned procedures (surgeries or therapies) scheduled prior to the signing of the ICF are 
not considered AEs. However, if a preplanned procedure is performed early (e.g., as an 
emergency) due to a worsening of the pre-existing condition, the worsening of the condition 
should be captured appropriately as an AE. Complications resulting from any planned 
surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the participant’s medical 
condition should not be recorded as AEs but should be documented in the participant’s 
source documents. Complications resulting from an elective surgery should be reported as 
AEs. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are NOT considered 
AEs, but instead will be documented on an Overdose page of the eCRF. Any manifested side 
effects will be considered AEs and will be recorded on the AE page of the eCRF. 
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9.6.3 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH 
2. Is LIFE-THREATENING 
• The term “life threatening” refers to an event in which the participant was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it were more severe 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization 
4. Results in persistent or significant DISABILITY/INCAPACITY 
5. Leads to a CONGENITAL ANOMALY/CONGENITAL DISABILITY 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above 
• May expose the participant to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization 
o Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
AEs that fulfill 1 or more of the serious criteria above are also considered SAEs and should be 
reported and followed up in the same manner (see Section 9.7.1 and Section 9.7.2). 
9.6.4 Severity of AEs 
The different categories of intensity (severity) are characterized as follows: 
 
Mild:  
The event is transient and easily tolerated by the participant. 
Moderate:  
The event causes the participant discomfort and interrupts the participant’s 
usual activities. 
Severe:  
The event causes considerable interference with the participant’s usual  
 
 
activities. 
9.6.5 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Related:  
An AE that follows a reasonable temporal sequence from the 
administration of a drug (including the course after withdrawal of the 
drug), or for which possible involvement of the drug can be argued, 
although factors other than the drug, such as underlying diseases, 
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complications, concomitant drugs, and concurrent treatments, may also be 
responsible. 
Not Related:  An AE that does not follow a reasonable temporal sequence from the 
administration of a drug and/or that can reasonably be explained by other 
factors, such as underlying diseases, complications, concomitant drugs, 
and concurrent treatments. 
9.6.6 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all AEs. 
The relationship should be assessed as Related if the Investigator considers that there is a 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship should 
be assessed as Not Related. 
9.6.7 Start Date 
The start date of the AE is the date that the first signs/symptoms were noted by the participant 
and/or physician. 
9.6.8 Stop Date  
The stop date of the AE is the date at which the participant recovered, the event resolved but with 
sequelae, or the participant died. 
9.6.9 
Frequency  
Episodic AEs (e.g., vomiting) or those which repeatedly occur over a period of consecutive days 
are intermittent. All other events are continuous. 
9.6.10 
Action Concerning Study Medication  
• Drug withdrawn – a study medication is stopped due to the particular AE 
• Dose not changed – the particular AE did not require stopping a study medication 
• Unknown – only to be used if it has not been possible to determine what action has been 
taken 
• Not Applicable – a study medication was stopped for a reason other than the particular AE 
e.g., the study has been terminated, the participant died, dosing with study medication was 
already stopped before the onset of the AE 
9.6.11 
Outcome 
• Recovered/Resolved – Participant returned to first assessment status with respect to the AE 
• Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved but has not 
returned to the normal range or baseline; the participant died from a cause other than the 
particular AE with the condition remaining “recovering/resolving” 
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• Not recovered/not resolved – there is no change in the diagnosis, signs, or symptoms; the 
intensity of the diagnosis, signs/ symptoms, or laboratory value on the last day of the 
observed study period had got worse than when it started; is an irreversible congenital 
anomaly; the participant died from another cause with the particular AE/ state remaining 
“Not recovered/not resolved.” 
• Resolved with sequelae – the participant recovered from an acute AE/ but was left with 
permanent/significant impairment (e.g., recovered from a cardiovascular accident but with 
some persisting paresis) 
• Fatal – the AEs which are considered as the cause of death 
• Unknown – the course of the AE cannot be followed up due to hospital change or residence 
change at the end of the participant’s participation in the study 
9.7 
Procedures 
9.7.1 Collection and Reporting of AEs 
9.7.1.1 AE Collection Period 
Collection of AEs will commence from the time the participant signs the informed consent to 
participate in the study and continue until 14 days following last dose. 
9.7.1.2 AE Reporting 
At each study visit, the Investigator or designee will assess whether any subjective AEs have 
occurred. A neutral question, such as “How have you been feeling since your last visit?” may be 
asked. Participants may report AEs occurring at any other time during the study. Participants 
experiencing an AE must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline, or there is a satisfactory explanation for 
the change. All AEs will be documented on the AE page of the eCRF, whether or not the 
Investigator concludes that the event is related to the drug treatment. The following information 
will be documented for each event: 
1. Event term 
2. Start and stop date and time 
3. Frequency 
4. Severity 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (related or not related)  
6. Investigator’s opinion of the causal relationship to study procedure(s), including the 
details of the suspected procedure 
7. Action concerning study medication  
8. Outcome of event 
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9. Seriousness 
9.7.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period, it should be reported according to the 
following procedure: 
An SAE form must be completed in English and signed by the Investigator immediately or within 
24 hours of the first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as serious 
• Participant identification number 
• Investigator’s name 
• Name of the study medication(s) 
• Causality assessment 
The SAE form should be transmitted within 24 h to the attention of the contact listed in 
Section 1.0.  
Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation. 
9.7.3 Reporting of Abnormal LFT 
If a participant is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the 
abnormality should be recorded as an AE at the discretion of the PI. In addition, an LFT increases 
eCRF must be completed by providing additional information on relevant recent history, risk 
factors, clinical signs and symptoms, and results of any additional diagnostic tests performed. 
If a participant is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an 
alternative etiology has not been identified, the event should be recorded as an SAE and reported 
as per Section 9.7.2. The Investigator must contact the Medical Monitor to discuss the relevant 
participant details and possible alternative etiologies, such as acute viral hepatitis A or B or other 
acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory tests 
will be at the discretion of the Investigator. 
9.8 
Follow-up of SAEs 
If information is not available at the time of the first report becomes available at a later date, the 
Investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(e.g., ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee if requested. 
All SAEs should be followed up until resuspension or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
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9.8.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities  
The Sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities and IRBs, as applicable, in 
accordance with national regulations in the countries where the study is conducted. Relative to the 
first awareness of the event by/or further provision to the Sponsor or Sponsor’s designee, SUSARs 
will be submitted to the regulatory authorities as an expedited report within 7 days for fatal and 
life-threatening events and 15 days for other serious events, unless otherwise required by national 
regulations. The Sponsor will also prepare an expedited report for other safety issues that might 
materially alter the current benefit-risk assessment of an investigational medicinal product or that 
would be sufficient to consider changes in the investigational medicinal products administration 
or in the overall conduct of the trial. The investigational site also will forward a copy of all 
expedited reports to their IRB in accordance with national regulations. 
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10.0 
DATA HANDLING AND RECORDKEEPING 
AEs, medical history, and concurrent conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization 
(WHO) Drug Dictionary. All terms will be coded using the dictionary version available at the start 
of the study. 
10.1 
CRFs (Electronic) 
Completed eCRFs are required for each participant who signs an informed consent. 
The Sponsor or its designee will supply investigative sites with access to eCRFs. The Sponsor will 
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the Sponsor and regulatory 
authorities. eCRFs must be completed in English. Data are transcribed directly onto eCRFs. 
After completion of the entry process, computer logic checks will be run to identify items such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Sponsor 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, the identification of the person making the correction, the date the correction was 
made, and the reason for the change. Reasons for significant corrections should additionally be 
included.  
The Investigator must review the eCRFs for completeness and accuracy and must sign and date 
the appropriate eCRFs as indicated. Furthermore, the Investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs. 
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The Sponsor or its designee will be permitted to review the participant’s 
medical and hospital records pertinent to the study to ensure the accuracy of the eCRFs. The 
completed eCRFs are the sole property of the Sponsor and should not be made available in any 
form to third parties, except for authorized representatives of appropriate governmental health or 
regulatory authorities, without the written permission of the Sponsor. 
10.2 
Record Retention 
The investigator agrees to keep the records stipulated in Appendix B and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participants, medical records, temporary media such as thermal sensitive paper, source worksheets, 
all original signed and dated ICFs, participant authorization forms regarding the use of personal 
health information (if separate from the ICFs), an electronic copy of eCRFs, including the audit 
trail, and detailed records of drug disposition to enable evaluations or audits from regulatory 
authorities, the Sponsor or its designees. Any source documentation printed on degradable thermal 
sensitive paper should be photocopied by the site and filed with the original in the participant’s 
chart to ensure long-term legibility. Furthermore, ICH E6 Section 4.9.5 requires the Investigator 
to retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
approval of a marketing application for a specified drug indication being investigated or, if an 
application is not approved, until at least 2 years after the investigation is discontinued and 
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regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records 
should be retained until an amount of time specified by applicable regulatory requirements or for 
a time specified in the Clinical Study Site Agreement between the Investigator and the Sponsor. 
Refer to the Phase 1 Site Specifications document for the Sponsor’s requirements on record 
retention. The Investigator should contact and receive written approval from the Sponsor before 
disposing of such documents. 
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11.0 
STATISTICAL METHODS 
11.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of the 
participant’s treatment assignment. This document will provide further details regarding the 
definition of analysis variables and analysis methodology to address all study objectives. 
A targeted data review will be conducted prior to unblinding of the participant’s treatment 
assignment. This review will assess the accuracy and completeness of the study database, 
participant evaluability, and appropriateness of the planned statistical methods. 
11.1.1 Analysis Sets 
Safety Set 
The Safety Analysis Set will consist of all participants who are enrolled and receive study drug. 
Participants in this analysis set will be used for demographic, baseline characteristics, and safety 
summaries. 
PK Set 
The PK set will consist of all participants who receive study drug and have at least 1 measurable 
plasma concentration. 
If any participants are found to be non-compliant with the dosing schedule or with incomplete 
data, a decision will be made on a case-by-case basis as to their inclusion in the analysis but will 
be presented in the participant listings. 
11.1.2 Analysis of Demographics and Other Baseline Characteristics 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be generated for 
continuous demographic variables and baseline characteristics variables (age, height, weight, and 
BMI) CVN424 dose level, CVN424 overall, and overall. The number and percentage of 
participants in each class of the categorical demographic variables and baseline characteristics 
variables (gender, ethnicity, and race) will be tabulated for each CVN424 formulation, CVN424 
overall, and overall. Individual participant demographic and baseline characteristics data will be 
listed. 
Demographic variables of screen failure participants and reasons for screen failures will be 
summarized overall for participants who are screened but not enrolled in the study. Individual 
demographic characteristics, date of informed consent, and reason for screen failure will be listed. 
11.1.3 PK Analysis 
The concentration of CVN424 in plasma will be summarized by treatment over each scheduled 
sampling time using descriptive statistics. Individual concentration data versus time will be 
presented in a data listing. Individual and mean plasma concentration data will be presented 
graphically.  Descriptive statistics (arithmetic mean, SD, median, minimum and maximum) will 
be used to summarize the plasma PK parameters for CVN424. In addition, geometric mean and 
coefficient of variation will be computed. 
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The effect of formulation on PK and bioavailability of CVN424 will be assessed.   
The effect of fed/fasting state on PK and bioavailability of CVN424 will be characterized. 
Plots of Cmax and AUCs, as well as dose-normalized Cmax and AUCs, will be generated. 
A more detailed analysis will be presented in the SAP. 
11.1.4 Safety Analysis 
11.1.4.1 AEs 
All AEs will be coded by system organ class (SOC) and preferred term (PT) using MedDRA. 
Treatment-emergent AEs with onset occurring within 30 days (onset date – last date of dose +1 
≤30) after study drug administration will be listed and included in the summary tables. Treatment-
emergent AEs will be summarized by each CVN424 formulation, if in the fed or fasted state, and 
CVN424 overall by SOC and PT. The following summary tables will be included in the report: 
summary of TEAEs and drug-related AEs, relationship of AEs to study drug (related vs. not 
related), severity of AEs, and related AEs. AEs leading to study drug discontinuation and SAEs 
will be listed. Data listings will be provided for all AEs, TEAEs, AEs leading to study drug 
discontinuation, and SAEs. All AEs will be listed. 
11.1.4.2 Clinical Laboratory Evaluation 
Individual results of laboratory tests from hematology, chemistry, and urinalysis that are abnormal 
and CS will be summarized and listed. Baseline, post-dose, and change from baseline to post-dose 
laboratory data will be summarized for each CVN424 dose level and CVN424 overall. All clinical 
laboratory data will be listed. 
11.1.4.3 Vital Signs 
Individual results of vital signs that are abnormal and CS will be summarized and listed. Baseline, 
post-dose, and changes from Baseline in vital sign measurements will be summarized by each 
CVN424 dose level and CVN424 overall. All vital sign data will be provided in the data listings. 
11.1.4.4 ECGs 
Individual results of quantitative ECG parameters from the 12-lead safety ECGs that are abnormal 
and CS will be summarized and listed. Baseline, post-dose, and changes from baseline in 
quantitative ECG parameters will be summarized by each CVN424 dose level and CVN424 
overall. Shift tables may be generated for the Investigator’s ECG interpretations that changed from 
baseline to the post-dose collections by the above sequences. All ECG data will be provided in the 
data listings. 
11.1.4.5 Other Variables 
Physical exam findings and suicidal assessments will be presented in data listings. 
11.2 
Interim Analysis and Criteria for Early Termination 
Two interim analyses are planned, after dosing in the 2nd and 3rd periods. 
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11.3 
Determination of Sample Size 
It is planned to enroll up to 32 male or female participants for participation in this study. 
Based on previous PK studies with CVN424, it was determined 28 participants would be needed 
to show bioequivalence, assuming an intra-participant CV of 16% and an expected ratio of 1.10. 
32 participants will be enrolled to ensure at least 28 evaluable participants. 
 
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12.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The Investigator and institution guarantee access to source documents by the Sponsor or its 
designee (contract research organization) and by the IRB. 
All aspects of the study and its documentation will be subject to review by the Sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, participant medical records, informed consent documentation, documentation 
of participant authorization to use personal health information (if separate from the ICFs), and 
review of eCRFs and associated source documents. It is important that the Investigator and other 
study personnel are available during the monitoring visits and that sufficient time is devoted to the 
process. 
12.2 
Protocol Deviations 
The Investigator should not deviate from the protocol, except where necessary, to eliminate an 
immediate hazard to study participants. Should other unexpected circumstances arise that require 
deviation from protocol-specified procedures, the Investigator should consult with the Sponsor or 
designee (and IRB, as required) to determine the appropriate course of action. There will be no 
exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria. 
The site should document all protocol deviations in the participant’s source documents. In the 
event of a significant deviation, the site should notify the Sponsor or its designee (and IRB or EC, 
as required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the participant, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the Sponsor 
or designee for any significant deviation from the protocol. 
Every attempt will be made to collect each PK blood sample at the designated time point, and the 
actual time of each blood sample will be recorded on the source document and eCRF. Table 1 
defines the windows allowed for sample collections.  
Protocol Deviation Forms are to be completed for PK samples collected outside of the following 
intervals: 
Table 5  
Windows for PK Blood Sample Collection 
Minutes 
Nominal Sampling Time 
±5 
immediately post-dose to ≤6 hours 
±10 
>6 hours to 12 hours post-dose 
±15 
>12 hours to 24 hours 
±30 
>24 hours 
 
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12.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site may be subject to quality assurance audits by the Sponsor or designees. In this 
circumstance, the Sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies. If the 
study site is contacted for an inspection by a regulatory body, the Sponsor should be notified 
immediately. The Investigator and institution guarantee access for quality assurance auditors to all 
study documents as described in Section 12.1.  
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13.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
participants) according to the protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator 
will conduct the study according to applicable local or regional regulatory requirements and align 
his or her conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through appendices 
containing requirements for informed consent and investigator responsibilities. 
13.1 
IRB Approval 
IRBs must be constituted according to the applicable state and federal/local requirements of each 
participating region. The Sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from voting must 
also be obtained. Those Americas sites unwilling to provide names and titles of all members due 
to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services. 
The Sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the ICFs, 
and, if applicable, participant recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations must be submitted to a central or local IRB for 
approval. The IRB’s written approval of the protocol and participant informed consent must be 
obtained and submitted to the Sponsor or designee before the commencement of the study (i.e., 
before shipment of the Sponsor-supplied drug or study-specific screening activity). The IRB 
approval must refer to the study by exact protocol title, number, and version date; identify versions 
of other documents (e.g., ICF) reviewed; and state the approval date. The Sponsor will ship the 
drug/notify the site once the Sponsor has confirmed the adequacy of site regulatory documentation 
and, when applicable, the Sponsor has received permission from a competent authority to begin 
the trial. Until the site receives drug/notification, no protocol activities, including screening, may 
occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the ICF, recruitment materials 
intended for viewing by participants, local safety reporting requirements, reports, and updates 
regarding the ongoing review of the study at intervals specified by the respective IRB, and 
submission of the Investigator’s final status report to IRB. All IRB approvals and relevant 
documentation for these items must be provided to the Sponsor or designee. 
Participant incentives should not exert undue influence for participation. Payments to participants 
must be approved by the IRB and Sponsor. 
13.2 
Participant Information, Informed Consent, and Participant Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The ICF, participant authorization form (if applicable), and 
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participant information sheet (if applicable) describe the planned and permitted uses, transfers, and 
disclosures of the participant’s personal and personal health information for purposes of 
conducting the study. The ICF and the participant information sheet (if applicable) further explain 
the nature of the study, its objectives, and potential risks and benefits, as well as the date informed 
consent is given. The ICF will detail the requirements of the participant and the fact that he or she 
is free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the ICF and if 
applicable, the participant authorization form. The ICF, participant authorization form (if 
applicable), and participant information sheet (if applicable) must be approved by both the IRB 
and the sponsor prior to use. 
The ICF, participant authorization form (if applicable), and participant information sheet (if 
applicable) must be written in a language fully comprehensible to the prospective participant. It is 
the responsibility of the investigator to explain the detailed elements of the ICF, participant 
authorization form (if applicable), and participant information sheet (if applicable) to the 
participant. Information should be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB. In the event the participant is not capable of rendering 
adequate written informed consent, then the participant’s legally acceptable representative may 
provide such consent for the participant in accordance with applicable laws and regulations. 
The participant, or the participant’s legally acceptable representative, must be given ample 
opportunity to: (1) inquire about details of the study and (2) decide whether or not to participate in 
the study. If the participant, or the participant’s legally acceptable representative, determines he or 
she will participate in the study, then the ICF and participant authorization form (if applicable) 
must be signed and dated by the participant, or the participant’s legally acceptable representative, 
at the time of consent and prior to the participant entering into the study. The participant or the 
participant’s legally acceptable representative should be instructed to sign using their legal names, 
not nicknames, using blue or black ballpoint ink. The investigator must also sign and date the ICF 
and participant authorization (if applicable) at the time of consent and prior to participant entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law. 
Once signed, the original ICF, participant authorization form (if applicable), and participant 
information sheet (if applicable) will be stored in the investigator’s site file. The investigator must 
document the date the participant signs the informed consent in the participant’s medical record. 
Copies of the signed ICF, the signed participant authorization form (if applicable), and participant 
information sheet (if applicable) shall be given to the participant. 
All revised ICFs must be reviewed and signed by relevant participants or the relevant participant’s 
legally acceptable representative in the same manner as the original informed consent. The date 
the revised consent was obtained should be recorded in the participant’s objectives, and potential 
risks and benefits, as well as the date informed consent is given. The ICF will detail the 
requirements of the participant and the fact that they are free to withdraw at any time without 
providing a reason and without prejudice to their other medical care. 
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The Investigator is responsible for the preparation, content, IRB approval of the ICF and, if 
applicable, the participant authorization form. The ICF, participant authorization form (if 
applicable), and participant information sheet (if applicable) must be approved by the IRB and the 
Sponsor prior to use 
The ICF, participant authorization form (if applicable), and participant information sheet (if 
applicable) must be written in a language fully comprehensible to the prospective participant. It is 
the responsibility of the Investigator to explain the detailed elements of the ICF, participant 
authorization form (if applicable), and participant information sheet (if applicable) to the 
participant. Information should be given in both oral and written form whenever possible and in 
the manner deemed appropriate by the IRB. In the event the participant is not capable of rendering 
adequate written informed consent, the participant’s legally acceptable representative may provide 
such consent for the participant in accordance with applicable laws and regulations. 
The participant, or the participant’s legally acceptable representative, must be given medical 
record, and the participant should receive a copy of the revised ICF. 
13.3 
Participant Confidentiality 
The Sponsor and designees affirm and uphold the principle of the participant’s right to protection 
against invasion of privacy. Throughout this study, a participant’s source data will only be linked 
to the Sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited participant attributes, such as sex, age, or 
date of birth, and participant initials may be used to verify the participant and the accuracy of the 
participant’s unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the Sponsor 
requires the Investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (e.g., FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals, and Medical Devices Agency), the Sponsor’s designated auditors, and the 
appropriate IRBs to review the participant’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a participant’s study participation, and 
autopsy reports. Access to a participant’s original medical records requires the specific 
authorization of the participant as part of the informed consent process (see Section 9.1.1). 
Copies of any participant source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (i.e., participant name, address, and other identifier 
fields not collected on the participant’s eCRF). 
13.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
13.4.1 Publication and Disclosure 
The Investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the Investigator from the study. During and after the study, only the Sponsor may make study 
information available to other study Investigators or regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
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disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study, including data and information 
generated by the Investigator, without the consent of the Investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and review 
of the document. All publications and presentations must be prepared in accordance with this 
section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
The Sponsor may publish any data and information from the study (including data and information 
generated by the Investigator) without the consent of the Investigator. 
13.4.2 Clinical Trial Registration  
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations, and guidance, the Sponsor will register this clinical trial 
on ClinicalTrials.gov (and possibly on other publicly accessible websites) before the start of the 
study.   
Sponsor contact information, along with the Investigator’s city, state, country, and recruiting 
status, will be registered and available for public viewing. Once participants receive the 
Investigator's contact information, they may call the site and request enrollment into the trial. The 
investigative site(s) are encouraged to handle such trial inquiries according to their established 
participant screening process. If the caller asks additional questions beyond the topic of trial 
enrollment, they should be referred to the Sponsor. 
13.4.3 Clinical Trial Results Disclosure  
If required at the conclusion of the study, the Sponsor will post the results on ClinicalTrials.gov 
or other publicly accessible websites, as required by applicable national and local laws and/or 
regulations. 
13.5 
Insurance and Compensation for Injury 
Each participant in the study must be insured in accordance with the regulations applicable to the 
site where the participant is participating. If a local underwriter is required, then the Sponsor or 
Sponsor’s designee will obtain clinical study insurance against the risk of injury to clinical study 
participants. Refer to the Clinical Study Site Agreement regarding the Sponsor’s policy on 
participant compensation and treatment for an injury. If the Investigator has questions regarding 
this policy, they should contact the Sponsor or designee. 
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14.0 
REFERENCES 
 
American Parkinson Disease Association. https://www.apdaparkinson.org/what-is-parkinsons/, 
accessed on 26 Jan 2018. 
Assessing the Effects of Food on Drugs in Investigational New Drugs and New Drug Applications-
Clinical Pharmacology Considerations; Guidance for Industry; Availability (Jun 2022). 
Dunnett, C.W. (1964) New tables for multiple comparisons with a control, Biometrics Vol. 20, 
No. 3. 482-491. 
FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials 
for Therapeutics in Adult Healthy Volunteers. US Dept of Health and Human Services, Food 
and Drug Administration, Center for Drug Evaluation and Research. 06 July 2005. Publication 
No. 5541. 
Kaufmann P, Ort M, Golor G, Kornberger R, Dingemanse J. First-in-human study with ACT-
539313, a novel selective orexin-1 receptor antagonist. Br J Clin Pharmacol. 2020 
Jul;86(7):1377-1386. doi: 10.1111/bcp.14251. 
Kaufmann P, Ort M, Golor G, Kornberger R, Dingemanse J. Multiple-dose clinical pharmacology 
of the selective orexin-1 receptor antagonist ACT-539313. Prog Neuropsychopharmacol Biol 
Psychiatry. 2021 Jun 8;108:110166. doi: 10.1016/j.pnpbp.2020.110166.  
Salvadore G, Bonaventure P, Shekhar A, Johnson PL, Lord B, Shireman BT, Lebold TP, 
Nepomuceno D, Dugovic C, Brooks S, Zuiker R, Bleys C, Tatikola K, Remmerie B, Jacobs 
GE, Schruers K, Moyer J, Nash A, Van Nueten LGM, Drevets WC. Translational evaluation 
of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for 
panic in rodents and humans. Transl Psychiatry. 2020 Sep 7;10(1):308. doi: 10.1038/s41398-
020-00937-9. 
Wichmann T, DeLong MR, Guridi J, Obeso JA. Milestones in research on the pathophysiology of 
Parkinson's disease. Mov Disord. 2011 May;26(6):1032-41. doi: 10.1002/mds.23695. 
PMID: 21626548; PMCID: PMC4272856. 
 
 
 
 
 
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Appendix A: Schedule of Study Procedures 
 
1 Assessments to be completed on final in-patient day and will be repeated if AE requires in-person follow-up 
2 Once eligibility has been confirmed by Screening assessments 
3 Assessments to include HR, BP, and temperature 
4 Height only at screening 
5 Part of safety assessments (Pre and 24h post-dose) 
Overall Study Day # 
-28 to -2 
-1 
0 
1-4 
5-12 
13 
14 
15-18 
19-26 
27 
28 
29-32 
33 +/- 2 
Period 
 
 
1 
2 
3 
 
Day 
 
0 
1 
2-5 
6-13 
14 
1 
2-5 
6-13 
14 
1 
2-5 
15 +/- 2 
 
 
 
 
Washout 
 
Washout 
 
 
 
 
 
 
Inpatient 
 
Inpatient 
 
Inpatient 
 
 
Screening 
Check-
in 
Dosing 
 
 
Check-in 
Dosing 
Day 
 
 
Check-in 
Dosing  
Follow-
Up/ET1 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review ICF and I/E 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Participant Admission 
to CRU 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs3 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Weight, height, and 
BMI4  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Urinalysis5 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
Urine Drug Screen 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Cotinine Screen 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
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6 Full PE at Screening, Medical Assessment pre-dose (within 24 hours prior to dosing) and 24-hours post-dose 
7 Pre and Post dose Safety Labs, standard hematology with WBC differential, CRP, coagulation tests, lipase, amylase, albumin, and calcium. Predose labs do not need to be 
reviewed prior to dosing. Post dose to be done at 48 hours and EOT. Unscheduled as clinically indicated. 
8 Serum pregnancy test at Screening and urine pregnancy test at subsequent discharge and check-ins 
9 FSH level will be obtained on post-menopausal women (defined as continuous amenorrhea of at least 2 years and not surgically sterile) 
10 Screening, Check-in, 24 and 96-hour post dose 
11 Triplicate standard 12-lead ECG will be recorded at Screening and on Days 0, 10, and 20 pre-dose [within 1 h prior to dosing] and 3h (+/-15 minutes) post-dose. Triplicate 
standard 12-lead ECG will also be recorded at Early Termination (if applicable) 
12 Plasma Sampling: Predose (within 15 minutes prior to dosing; 60 minutes for the fed treatments), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 84 and 96h 
13 For tablet fasted sequence: Predose (for bioanalysis), 0-12, 12-24, 24-48, 48-96h.  Volume of urine collected needs to be recorded 
14 Sequences 1, 2, 4, 5  
15 Sequences 1, 3, 5, 6 
16 Sequences 2, 3, 4, 6 
17 Sequences 1, 4 will be dosed with suspension; 2,3,5,6 will be dosed with tablet per figure 1 
Physical Examination6 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
Hepatitis panel and 
HIV antibody test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory 
tests7 
X 
X 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
Pregnancy Test8 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
FSH9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS10 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
ECG11 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
PK Blood Collection12  
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
PK Urine13 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
Overnight Fasting 
 
X14 
 
 
 
X15 
 
 
 
X16 
 
 
 
CVN424 Dosing17 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
AE Assessment 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
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Appendix B: Responsibilities of the Investigator 
Clinical research studies Sponsored by the Sponsor are participant to ICH GCP and all the 
applicable local laws and regulations.  
The Investigator agrees to assume the following responsibilities. 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures, including study specific (non routine/nonstandard 
panel) screening assessments are NOT performed on potential participants, prior to the 
receipt of written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are 
informed of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB that conforms 
to local regulatory requirements. 
6. Ensure that the IRB will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB all changes in research activity and 
all anticipated risks to participants. Make at least yearly reports on the progress of the 
study to the IRB and issue a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in local regulations, are met. 
8. Obtain valid ICF from each participant who participates in the study and document the 
date of consent in the participant’s medical chart. Valid informed consent is the most 
current version approved by the IRB. Each ICF should contain a participant authorization 
section that describes the uses and disclosures of a participant’s personal information 
(including personal health information) that will take place in connection with the study. 
If an ICF does not include such a participant authorization, then the Investigator must 
obtain a separate participant authorization form from each participant or the participant’s 
legally acceptable representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, 
including eCRFs, hospital records, laboratory results, etc., and maintain these data for a 
minimum of 2 years following notification by the Sponsor that all investigations have 
been discontinued or that the regulatory authority has approved the marketing 
application. The Investigator should contact and receive written approval from the 
Sponsor before disposing of any such documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified 
essential documents. 
11. Maintain current records of the receipt, administration, and disposition of Sponsor-
supplied drugs, and return all unused Sponsor-supplied drugs to the Sponsor.  
12. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the 
Sponsor within 24 hours. 
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Appendix C: Investigator Consent to Use of Personal Information  
Cerevance will collect and retain personal information of Investigator, including his or her name, 
address, and other personally identifiable information. In addition, Investigator’s personal 
information may be transferred to other parties located in countries throughout the world (e.g., 
the United Kingdom, United States, and Japan), including the following: 
• Cerevance, its affiliates, and licensing partners 
• Business partners assisting Cerevance, its affiliates, and licensing partners 
• Regulatory agencies and other health authorities 
• IRBs  
• Investigator’s personal information may be retained, processed, and transferred by Cerevance 
and these other parties for research purposes including the following: 
• Assessment of the suitability of Investigator for the study and/or other clinical studies 
• Management, monitoring, inspection, and audit of the study 
• Analysis, review, and verification of the study results 
• Safety reporting and pharmacovigilance relating to the study 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may 
contain the same chemical compound present in the study medication 
• Inspections and investigations by regulatory authorities relating to the study 
• Self-inspection and internal audit within Cerevance, its affiliates, and licensing partners 
• Archiving and audit of study records 
• Posting Investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites 
• Investigator’s personal information may be transferred to other countries that do not have 
data protection laws that offer the same level of protection as data protection laws in 
Investigator’s own country. 
• Investigator acknowledges and consents to the use of his or her personal information by 
Cerevance and other parties for the purposes described above. 
 
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