Clinical trial NCT05413668
Conditions: Healthy
Sponsor: Reveal Pharmaceuticals Inc.
Start date: 2022-05-18; Completion date: 2022-08-22
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objectives of this trial are:

1. To evaluate the safety and tolerability of single ascending doses of RVP-001 in healthy adult volunteers
2. To determine the pharmacokinetics and elimination of RVP-001 in healthy adult volunteers.

Detailed description:
The first in human study is intended to evaluate the safety and tolerability of single ascending doses of RVP-001 in healthy adult volunteers, and to determine the pharmacokinetics and elimination of RVP-001 in healthy adult volunteers.

Arms: arm 1: 4 Cohorts of 6 subjects each will receive RVP-001 at doses of 2, 4, 7 and 12 mg Mn/kg. arm 2: 4 Cohorts of 2 subjects each will receive placebo (saline).
Interventions: intervention 1: RVP-001 intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous administration of RVP-001 intervention 2: Intravenous administration of saline placebo

Protocol documents:
Prot_SAP_000.pdf: 
Pr ot o c ol  N o.  R V P -1 0 1 -2 2  
A  Si n gl e  C e nt er,  D o u bl e -Bli n d e d  P h as e  1 a  R a n d o  miz e d  St u d y t o  E v al u at e  S af et y  a n d  P h ar  m a c o ki n e ti cs  of 
a  N e  w   M a n g a n es e  B as e d   M a g n e ti c  R es o n a n c e I  m a gi n g (  M RI)  C o ntr ast  A g e nt,  R V P  0 0 1, i n  H e alt h y  A d ult 
S u bj e cts  
N C T 0 5 4 1 3 6 6 8   
D at e  of  Pr ot o c ol:   M a y  9 , 2 0 2 2  
V ersi o n:  2. 0  
1. 0   Ori gi n al (  M ar c h  1 4,  2 0 2 2)  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 1  
Cli nic al St u d y Pr ot oc ol  
A Si n gl e C e nt er, D o u bl e -Bli n d e d P h as e 1 a R a n d o miz e d St u d y 
t o E v al u at e S af et y a n d P h ar m ac o ki n etics of a N e w M a n g a n es e 
B as e d M a g n etic R es o n a nc e I m a gi n g ( M RI ) C o ntr ast A g e nt, 
R V P -0 0 1 , i n H e alt h y A d ult S u bj ects 
R VL -1 0 1 -2 2  
A m e n d m e nt  1  
Q u oti e nt Sci e nc es St u d y N u m b er:    
Q S C 2 0 6 0 9 6  
I N D N u m b er:   
   
   
   
1 5 0 9 1 5  
Cli nic al St u dy Sit e:    
   
   
Q u oti e nt Sci e nc es –  Mi a mi, I nc.  
3 8 9 8 N W 7 Str e et  
Mi a mi, FL 3 3 1 2 6  
U S A  
T el: 3 0 5 -6 4 4 -9 9 0 3   
S p o ns or:     
   
   
   
R e v e al P h ar m ac e utic als I nc.  
A d dr ess :     
   
   
   
3 7 r e ar Pr e ntiss St  
 
   
   
   
   
   
C a m bri d g e, M A 0 2 1 4 9  
E m ail :    
   
   
   
   
i nf o @r e v e al p h ar m a.c o m 
P h o n e :  
   
   
   
   
+ 1( 6 1 7) 7 4 4 -9 2 0 9  
D at e of Pr ot oc ol:     
   
   
M ay 9.  2 0 2 2  
V ersi o n:  
   
   
   
   
2. 0  
 
   
   
   
   
   
1. 0 Ori gi n al  (M arc h 1 4, 2 0 2 2)  
 
 
C o nfi d e nti al  
T h e i nf or m ati o n pr ovi d e d i n t his d oc u m e nt is strictly c o nfi d e nti al a n d is i nt e n d e d s ol ely f or  
t h e g ui d a nc e of t h e cli nic al i nv esti g ati o n. R e pr o d ucti o n or discl os ur e of t his  
d oc u m e nt - w h et h er i n p art or i n f ull - t o p arti es n ot ass oci at e d wit h t h e cli nic al 
i nv esti g ati o n, or its us e f or a n y ot h er p ur p os e wit h o ut t h e pri or writt e n c o ns e nt of t h e  
s p o ns or is n ot p er mitt e d.  
 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 2  
St u d y C o nt acts  
Pri nci p al I nv esti g at or:  
   
M ari a B er m u d ez M D, C PI  
E m ail: m ari a. b er m u d ez @ q u oti e ntsci e nc es.c o m  
T el: ( d ay) 1 -3 0 5 -6 4 4 -9 9 0 3 ext. 1 1 5  
T el: ( o ut of h o urs e m er g e nc y) 1 -3 0 5 -6 4 4 -9 9 0 3  
  
  
  
 
 
  
 
 
 
  
 
 
 
 
    
 
 
 
 
 
  
 
 
 
 
 
 
    
 
 
   
   
   
 
  
 
   
   
   
 
 
 
 
 
 
 
 
 
 
 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3  
1  
T A B L E O F C O N T E N T S  
1  
T A B L E O F C O N T E N T S  ............................................................................... 3  
2  
A b br e vi ati o n s  ................................................................................................. 7  
3  
P R O T O C O L S U M M A R Y  ........................................................................... 1 1  
3. 1  
S y n o p si s    
 ...................................................................................... 1 1  
3. 2  
S c h e d ul e of A cti viti e s ( S o A)  ...................................................................... 1 8  
4  
I N T R O D U C TI O N......................................................................................... 2 2  
4. 1  
St u d y R ati o n al e  
 ...................................................................................... 2 2  
4. 2  
B a c k gr o u n d    
 ...................................................................................... 2 2  
4. 2. 1  
N o n -cli ni c al St u di e s  .................................................................................... 2 3  
4. 3  
Ri s k/ B e n efit A s s e s s m e nt  ........................................................................... 2 5  
4. 3. 1  
Ri s k a s s e s s m e nt   ...................................................................................... 2 5  
4. 3. 2  
K n o w n P ot e nti al B e n efit s  ........................................................................... 2 5  
4. 3. 3  
A s s e s s m e nt of P ot e nti al Ri s k s a n d B e n efit s  ........................................... 2 5  
4. 4  
St u d y O bj e cti v e s   ...................................................................................... 2 6  
4. 5  
St u d y e n d p oi nt s  
 ...................................................................................... 2 6  
5  
S T U D Y D E SI G N  ......................................................................................... 2 7  
5. 1  
O v er all D e si g n    
 ...................................................................................... 2 7  
5. 2  
J u stifi c ati o n f or D o s e  .................................................................................. 2 8  
5. 3  
E n d of St u d y D efi niti o n  ............................................................................... 2 9  
6  
S T U D Y P O P U L A TI O N  ............................................................................... 3 0  
6. 1  
J u stifi c ati o n  f or t h e St u d y  P o p ul ati o n  ....................................................... 3 0  
6. 2  
S a m pl e  Si z e    
 ...................................................................................... 3 0  
6. 3  
I n cl u si o n Crit eri a   ...................................................................................... 3 0  
6. 4  
E x cl u si o n  Crit eri a   ...................................................................................... 3 1  
6. 5  
C o ntr a c e pti o n a n d R e stri cti o n s  ................................................................. 3 3  
6. 5. 1  
S p er m D o n ati o n  
 ...................................................................................... 3 5  
6. 5. 2  
E g g D o n ati o n    
 ...................................................................................... 3 5  
6. 5. 3  
Pr e g n a n c y    
 ...................................................................................... 3 5  
6. 6  
Lif e s t yl e C o n si d er ati o n s ............................................................................. 3 5  
6. 7  
S cr e e n F ail ur e s  
 ...................................................................................... 3 6  
6. 8  
Str at e gi e s f or R e cr uit m e nt a n d R et e nti o n ................................................ 3 6  
7  
S T U D Y I N T E R V E N TI O N  ........................................................................... 3 7  
7. 1  
R V P -0 0 1    
 ...................................................................................... 3 7  
7. 1. 1  
Pl a c e b o    
 ...................................................................................... 3 7  
7. 1. 2  
A d mi ni str ati o n of St u d y Dr u g, M e al s, a n d  Fl ui d s  .................................... 3 7  
7. 1. 3  
M e al s a n d Fl ui d  
 ...................................................................................... 3 8  
7. 2  
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y  .......................................... 3 8  
7. 2. 1  
P a c k a gi n g, L a b eli n g  a n d  Di s p e n si n g  ....................................................... 3 8  
7. 2. 2  
St or a g e  a n d  H a n dli n g  ................................................................................. 3 9  
7. 2. 3  
F or m ul ati o n, A p p e ar a n c e, P a c k a gi n g, a n d L a b eli n g  ............................. 3 9  
7. 2. 4  
D o s e Pr e p ar ati o n   ...................................................................................... 4 0  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 4  
7. 3  
M e a s ur e s t o Mi ni mi z e Bi a s: R a n d o mi z ati o n  a n d  Bli n di n g  ..................... 4 1  
7. 3. 1  
S u bj e ct N u m b er s   ...................................................................................... 4 3  
7. 4  
St u d y I nt er v e nti o n C o m pli a n c e  ................................................................. 4 4  
7. 5  
C o n c o mit a nt T h e r a p y ................................................................................. 4 4  
8  
S T U D Y I N T E R V E N TI O N DI S C O N TI N U A TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ...................................................... 4 5  
8. 1  
B ef or e Fir st Tr e at m e nt A d mi ni str ati o n  ..................................................... 4 5  
8. 2  
Aft er Fir st Tr e at m e nt A d mi ni str ati o n  ......................................................... 4 5  
8. 3  
St o p pi n g R ul e s   
 ...................................................................................... 4 6  
8. 3. 1  
I n di vi d u al S u bj e ct St o p pi n g R ul e s ............................................................ 4 6  
8. 3. 2  
C o h ort St o p pi n g R ul e s  ............................................................................... 4 6  
8. 3. 3  
Tri al St o p pi n g R ul e s  ................................................................................... 4 7  
8. 4  
L o st t o F oll o w -U p   ...................................................................................... 4 7  
9  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................... 4 8  
9. 1  
S af et y a s s e s s m e nt s  ................................................................................... 4 8  
9. 1. 1  
S af et y M o nit ori n g   ...................................................................................... 4 8  
9. 1. 2  
Vit al  Si g n s    
 ...................................................................................... 4 8  
9. 1. 3  
E C G M e a s ur e m e nt s  ................................................................................... 4 9  
9. 1. 4  
P h y si c al  E x a mi n ati o n i n cl u di n g N e ur ol o gi c al a s s e s s m e nt  .................... 4 9  
9. 1. 5  
Dr u g , Al c o h ol  a n d C oti ni n e S cr e e n  ........................................................... 5 0  
9. 1. 6  
Pr e g n a n c y  T e st  
 ...................................................................................... 5 0  
9. 1. 7  
F olli cl e -Sti m ul ati n g H or m o n e T e st  ............................................................ 5 0  
9. 1. 8  
B o d y W ei g ht, h ei g ht, a n d B MI  ................................................................... 5 0  
9. 1. 9  
I nj e cti o n Sit e M o nit ori n g ............................................................................. 5 0  
9. 2  
L a b or at or y  A s s e s s m e nt s  ............................................................................ 5 2  
9. 2. 1  
Bi o c h e mi str y    
 ...................................................................................... 5 2  
9. 2. 2  
S er ol o g y    
 ...................................................................................... 5 3  
9. 2. 3  
H e m at ol o g y    
 ...................................................................................... 5 3  
9. 2. 4  
C o a g ul ati o n    
 ...................................................................................... 5 3  
9. 2. 5  
Uri n al y si s    
 ...................................................................................... 5 3  
9. 2. 6  
Bi o a n al yti c al S a m pl e  C oll e cti o n  a n d  Pr o c e s si n g  .................................... 5 3  
9. 3  
S cr e e ni n g    
 ...................................................................................... 5 6  
9. 3. 1  
R e -S cr e e ni n g    
 ...................................................................................... 5 6  
9. 4  
A d m i s si o n a n d Pr e-d o s e Pr o c e d ur e s  ....................................................... 5 7  
9. 5  
Ti mi n g of Pr o c e d ur e s  ................................................................................. 5 7  
9. 6  
Di s c h ar g e fr o m t h e Cli ni c al U nit  ................................................................ 5 7  
9. 7  
F oll o w -U p  Vi sit   
 ...................................................................................... 5 8  
9. 8  
D at a  C oll e cti o n  a n d  E v al u ati o n  ................................................................. 5 8  
9. 9  
S u bj e ct  Wit h dr a w al  a n d  R e pl a c e m e nt  ..................................................... 5 8  
9. 1 0  
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  ......................................... 5 9  
9. 1 0. 1  
D efi niti o n  of  a n  A d v er s e  E v e nt  ( A E) ......................................................... 5 9  
9. 1 0. 2  
D efi niti o n  of  a  S eri o u s  A d v er s e  E v e nt  ( S A E) .......................................... 5 9  
9. 1 0. 3  
D efi niti o n of S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s  ........ 6 0  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 5  
9. 1 0. 4  
R e c or di n g  of  A d v er s e  E v e nt s  .................................................................... 6 0  
9. 1 0. 5  
A d v er s e  E v e nt s  S e v erit y  ............................................................................ 6 0  
9. 1 0. 6  
A d v er s e E v e nt C a t e g ori e s f or D et er mi ni n g R el ati o n s hi p t o St u d y Dr u g
 
6 1  
9. 1 0. 7  
R e p orti n g S eri o u s A d v er s e E v e nt s  ........................................................... 6 3  
9. 1 0. 8  
S u s p e ct e d, U n e x p e ct e d, S eri o u s A d v er s e Dr u g R e a cti o n s ( S U S A R)  . 6 4  
9. 1 0. 9  
Ot h er s u s p e ct e d, u n e x p e ct e d, s eri o u s a d v er s e dr u g r e a c ti o n s ............ 6 4  
9. 1 0. 1 0  
R e p orti n g of Ur g e nt S af et y i s s u e s  ............................................................ 6 4  
9. 1 0. 1 1  
R e p orti n g Ot h er S eri o u s I m p ort a nt M e di c al E v e nt s  ............................... 6 4  
9. 1 0. 1 2  
p ot e nti al cl a s s s p e cifi c e v e nt s  ................................................................... 6 5  
9. 1 0. 1 3  
R e p ort a bl e di s e a s e  ..................................................................................... 6 5  
9. 1 1  
C o vi d R e s p o n s e Pl a n  ................................................................................. 6 5  
9. 1 1. 1  
C O VI D -1 9 R el at e d Ri s k s  a n d Ri s k Miti g ati o n M e a s ur e s  ....................... 6 5  
9. 1 2  
S A F E T Y R E VI E W C O m mitt e e ( S R C)  ...................................................... 6 6  
9. 1 2. 1  
D e ci si o n P oi nt s   
 ...................................................................................... 6 6  
9. 1 2. 2  
Crit eri a f or D o s e D e ci si o n s  ........................................................................ 6 6  
1 0  
S T A TI S TI C A L C O N S I D E R A TI O N S ......................................................... 6 7  
1 0. 1  
P o p ul ati o n s f or A n al y s e s  ........................................................................... 6 7  
1 0. 1. 1  
S af et y  P o p ul ati o n   ...................................................................................... 6 7  
1 0. 1. 2  
P h ar m a c o ki n eti c  P o p ul ati o n  ...................................................................... 6 7  
1 0. 2  
St ati sti c al A n al y s e s  ..................................................................................... 6 7  
1 0. 2. 1  
S af et y A n al y s e s  
 ...................................................................................... 6 7  
1 0. 2. 2  
S af et y  E n d p oi nt s   ...................................................................................... 6 7  
1 0. 2. 3  
S A F E T Y S T A TI S TI C A L M E T H O D O L O G Y  ............................................. 6 8  
1 0. 2. 4  
B a s eli n e  D e s cri pti v e St ati sti c s  .................................................................. 6 8  
1 0. 2. 5  
Pl a n n e d I nt eri m A n al y s e s  .......................................................................... 6 8  
1 0. 2. 6  
P h ar m a c o ki n eti c s A n al y si s c o n c e ntr ati o n  D at a:  ..................................... 6 8  
1 0. 2. 7  
P h ar m a c o ki n eti c  P ar a m et er s:  ................................................................... 6 8  
1 0. 2. 8  
P H A R M A C O KI N E TI C S T A TI S TI C A L M E T H O D O L O G Y  ...................... 7 0  
1 0. 2. 9  
D e s cri pti v e  St ati sti c s  .................................................................................. 7 1  
1 0. 2. 1 0  
St ati sti c al  A n al y si s   ...................................................................................... 7 1  
1 0. 2. 1 1  
Pl a n n e d I nt eri m  A n al y s e s  .......................................................................... 7 1  
1 0. 2. 1 2  
D et er mi n ati o n  of  S a m pl e  Si z e  ................................................................... 7 1  
1 1  
A p p e n di x 1: S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C o n si d er ati o n s  ............................................................................................ 7 2  
1 1. 1  
R e g ul at or y, Et hi c al, a n d St u d y O v er si g ht C o n si d er ati o n s  ..................... 7 2  
1 1. 1. 1  
R e g ul at or y a n d Et hi c al C o n si d er ati o n s  .................................................... 7 2  
1 1. 1. 2  
Fi n a n ci al Di s cl o s ur e  ................................................................................... 7 2  
1 1. 1. 3  
I nf or m e d C o n s e nt Pr o c e s s ........................................................................ 7 3  
1 1. 1. 4  
St u d y Di s c o nti n u ati o n a n d Cl o s ur e  .......................................................... 7 3  
1 1. 1. 5  
C o nfi d e nti alit y a n d Pri v a c y  ........................................................................ 7 4  
1 1. 1. 6  
F ut ur e U s e o f St or e d S p e ci m e n s a n d D at a ............................................. 7 6  
1 1. 1. 7  
K e y R ol e s a n d St u d y G o v er n a n c e ............................................................ 7 6  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 6  
1 1. 1. 8  
S af et y O v er si g ht  7 6  
1 1. 1. 9  
Cli ni c al M o nit ori n g  7 6  
1 1. 1. 1 0  
Q u alit y A s s ur a n c e a n d Q u alit y C o ntr ol  .................................................... 7 7  
1 1. 2  
D at a H a n dli n g a n d R e c or d K e e pi n g  ......................................................... 7 7  
1 1. 2. 1  
D at a C oll e cti o n a n d M a n a g e m e nt R e s p o n si biliti e s  ................................ 7 7  
1 1. 2. 2  
P u bli c ati o n a n d D at a S h ari n g P oli c y  ........................................................ 7 9  
1 1. 3  
R E F E R E N C E S   
8 0  
1 1. 4  
C Y P I n hi bit or s    
8 2  
 
LI S T O F T A BL E S 
T a bl e 1  
P h as e 1 a Pl a n n e d D os e Esc al ati o n  ......................................................................... 2 9  
T a bl e 2  
 B o d y W ei g ht ( B W) b as e d d osi n g c h art f or v ol u m e ( mL) of 3 5 m g M n/ mL R V P -0 0 1 
t o a d mi nist er f or e ac h c o h ort i n t h e P h as e 1 a st u dy R VL-1 0 1 -2 2.  ......................... 4 1  
T a bl e 3  
S u bj ect N u m b ers b y C o h ort  ................................................................................... 4 3  
T a bl e 4  
 I nj ecti o n Sit e Ex a mi n ati o n .................................................................................... 5 1  
T a bl e 5  
  Esti m at e d T ot al Bl o o d V ol u m e  ............................................................................. 5 5  
T a bl e 6  
N CI  C o m m o n T er mi n ol o gy Crit eri a A dv ers e Ev e nts ( C T C A E)  v ersi o n 5. 0. S ev erity 
Gr a d e  ..................................................................................................................... 6 1  
T a bl e 7  
 D et er mi ni n g  t h e R el ati o ns hi p  of  A dv ers e  Ev e nts  t o t h e St u dy  Dr u g  ..................... 6 3  
T a bl e 8  
P h ar m ac o ki n etic P ar a m et ers of R V P -0 0 1 i n Pl as m a  .............................................. 6 9  
 
LI S T O F FI G U R E S 
Fi g ur e 1  
 D os e Esc al ati o n Sc h e m a  ........................................................................................ 2 8  
 
 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7  
2  
A B B R E VI A TI O N S  
A D R  
A dv ers e dr u g r e acti o n 
A E  
A dv ers e Ev e nt  
AL T  
Al a ni n e A mi n otr a nsf er as e  
A nti -H Bs A g    
A nti b o d y H Bs A g  
A nti -H C V    
A nti b o di es a g ai nst H e p atitis C vir us  
A P T T  
Activ at e d p arti al t hr o m b o pl asti n ti m e  
A S T  
As p art at e A mi n otr a nsf er as e  
A U C  
Ar e a u n d er t h e c o nc e ntr ati o n-ti m e c ur v e 
B MI  
B o d y M ass I n d ex  
B U N  
Bl o o d ur e a nitr o g e n  
B P  
Bl o o d pr ess ur e  
C D E R  
C e nt er f or Dr u g Ev al u ati o n a n d R es e arc h  
C E  
C o ntr ast -e n h a nc e d  
C F R  
C o d e of F e d er al R e g ul ati o ns  
CI  
C o nfi d e nc e i nt er nv al  
CI O M S  
C o u ncil f or I nt er n ati o n al Or g a niz ati o ns of M e dic al Sci e nc es 
C K  
Cr e ati n e Ki n as e  
C m ax  
M axi m u m s er u m c o nc e ntr ati o n  
C N S  
C e ntr al N erv o us S yst e m  
C O VI D -1 9    
C or o n avir us Dis e as e 2 0 1 9  
C R F  
C as e R e p ort F or m  
C S P M  
Cli nic al s a m pl e pr oc essi n g m a n u al  
C Y P  
c yt oc hr o m e P 4 5 0 
C R O  
Cli nic al R es e arc h Or g a niz ati o n  
C S R  
Cli nic al st u d y r e p ort  
C T C A E  
N CI  C o m m o n T er mi n ol o gy Crit eri a A dv ers e Ev e nts  
C V  
C ar di ov asc ul ar  
C V %  
C o effici e nt  of v ari ati o n  
D DI  
Dr u g -dr u g i nt er acti o n  
D M P  
D at a m a n a g e m e nt pl a n  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 8  
D N A  
D e ox yri b o n ucl eic Aci d  
D S M P  
D at a S af et y M o nit ori n g Pl a n  
e C R F  
El ectr o nic C as e R e p ort F or ms  
E C G  
El ectr oc ar di o gr a m  
e G F R  
Esti m at e d gl o m er ul ar filtr ati o n r at e  
F D A  
F o o d a n d Dr u g A d mi nistr ati o n  
FI H  
First I n H u m a n  
F S H  
F ollicl e sti m ul ati n g h or m o n e  
G B C A  
G a d oli ni u m -B as e d C o ntr ast A g e nt  
G C P  
G o o d Cli nic al Pr actic e  
G d  
G a d oli ni u m  
GL P  
G o o d L a b or at or y Pr actic es  
G M P  
G o o d M a n uf act uri n g Pr actic es  
H Bs A g  
S urf ac e a nti g e n of t h e  h e p atitis B vir us  ( H B V) 
h C G  
H u m a n C h ori o nic G o n a d otr o pi n  
H C V  
H e p atitis C vir us  
H C V A b  
H e p atitis C vir us a nti b o di es  
h E R G  
H u m a n Et h er -a -g o -g o -r el at e d G e n e 
HI V  
H u m a n i m m u n o d efici e nc y vir us  
H R  
H e art r at e  
I B 
I nv esti g at or’s Br oc h ur e 
I C5 0 
H alf m axi m al i n hi bit or y c o nc e ntr ati o n  
I C F 
I nf or m e d c o ns e nt f or m  
I C H 
I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n  
I C P-M S  
I n d uctiv el y C o u pl e d Pl as m a M ass S p ectr o m etr y 
I E C 
I nt er n ati o n al Et hics C o m mitt e e 
I N D 
I nv esti g ati o n al N e w Dr u g A p plic ati o n 
I N R 
I nt er n ati o n al N or m aliz e d R ati o 
I P 
I nv esti g ati o n al Pr o d uct 
I R B 
I nstit uti o n al R evi e w B o ar d 
I S F 
I nv esti g at or Sit e Fil e 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 9  
I V 
I ntr av e n o us 
K g  
Kil o gr a m  
L C 
Li q ui d C hr o m at o gr a p h y 
LL N 
L o w er li mit of n or m al 
LL O Q 
l o w er li mit of  q u a ntit ati o n  
M e d D R A    
M e dic al Dicti o n ar y f or R e g ul at or y Activiti es  
mL  
Millilit er  
M n  
M a n g a n es e  
M n -D P D P    
M a n g af o di pir tris o di u m  
M R  
M a g n etic R es o n a nc e  
M RI  
M a g n etic R es o n a nc e I m a gi n g  
M S  
M ass S p ectr o m etr y  
ms ec  
Millis ec o n d  
M S S D  
M axi m u m S af e St arti n g D os e  
N O A EL  
N o -O bs erv e d -A dv ers e -Eff ect -L ev el 
N S F  
N e p hr o g e nic S yst e mic Fi br osis  
O A T 3  
Or g a nic a ni o n tr a ns p ort er 3  
O A T P 1 B 1    
Or g a nic a ni o n tr a ns p orti n g p ol y p e pti d e 1 B 1  
P -g p  
P -gl yc o pr ot ei n  
PI  
Pri nci p al I nv esti g at or  
P K  
P h ar m ac o ki n etic(s)  
P T  
Pr ef err e d t er m  
Pt  
Pr ot hr o m bi n ti m e  
Q C  
Q u alit y C o ntr ol  
Q Tc F  
Fri d erici a -c orr ect e d Q T i nt erv al 
R B C  
R e d bl o o d c ell  
R N A  
Ri b o n ucl eic Aci d  
S A D  
Si n gl e Asc e n di n g D os e  
S A E  
S eri o us A dv ers e Ev e nt  
S A P  
St atistic al A n al ysis Pl a n  
S A R S -C o V -2    
S ev er e ac ut e r es pir at or y s y n dr o m e c or o n avir us 2; t h e vir us t h at c a us es C O VI D-
1 9  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 1 0  
S D  
St a n d ar d d evi ati o n  
S O A  
Sc h e d ul e of Activiti es  
S O C  
S yst e m Or g a n Cl ass  
S O P  
St a n d ar d O p er ati n g Pr oc e d ur e  
S R C  
S af et y R evi e w C o m mitt e e  
S U S A R  
S us p ect e d U n ex p ect e d S eri o us A dv ers e R e acti o n  
T B D  
T o b e d et er mi n e d  
U S  
U nit e d St at es  
UL N  
U p p er Li mit of N or m al  
U. S.  
U nit e d St at es  
W B C  
W hit e bl o o d c ell  
W H O  
W orl d H e alt h Or g a niz ati o n  
W H O -D D    
W orl d H e alt h Or g a niz ati o n dr u g dicti o n ar y  
W O C B P  
W o m e n of C hil d b e ari n g P ot e nti al  
 
 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 1 1  
3  
P R O T O C O L S U M M A R Y  
3. 1  
S Y N O P SI S  
Titl e:  
A Si n gl e C e nt er, D o u bl e -Bli n d e d P h as e 1 a R a n d o miz e d St u d y t o Ev al u at e 
S af et y a n d P h ar m ac o ki n etics of a N e w M a n g a n es e B as e d  M a g n etic 
R es o n a nc e I m a gi n g ( M RI ) C o ntr ast A g e nt, R V P -0 0 1 , i n H e alt h y A d ult S u bj ects 
O bj ectiv es:  
 
Pri m ar y o bj ectiv es:  
•  
T o ev al u at e t h e s af et y a n d t ol er a bilit y of si n gl e asc e n di n g d os es  
( S A Ds) of R V P -0 0 1 i n h e alt h y a d ult v ol u nt e ers.  
S ec o n d ar y o bj ectiv es:  
•  
T o d et er mi n e t h e p h ar m ac o ki n etics a n d eli mi n ati o n of R V P -0 0 1 i n 
h e alt h y a d ult v ol u nt e ers .  
 
E n d p oi nts:  
S af et y:  
S af et y will b e ev al u at e d t hr o u g h o ut t h e st u d y b y ass essi n g t h e f oll o wi n g 
p ar a m et ers: a dv ers e ev e nts, p h ysic al ex a mi n ati o ns, i nj ecti o n sit e 
m o nit ori n g, el ectr oc ar di o gr a ms ( E C Gs), vit al si g ns, cli nic al l a b or at or y 
ev al u ati o ns, m e dic al hist or y, a n d pri or a n d c o nc o mit a nt m e dic ati o ns.  
 
P h ar m ac o ki n etic s a n d Eli mi n ati o n : 
Pl as m a a n d uri n e will b e a n al yz e d b y hi g h p erf or m a nc e li q ui d 
c hr o m at o gr a p h y wit h t a n d e m m ass s p ectr o m etr y ( L C-M S/ M S ) t o m e as ur e 
t h e c o nc e ntr ati o n of i nt act R V P-0 0 1 a n d t o ass ess pl as m a p h ar m ac o ki n etics.  
U ri n e a n d f ec es will b e a n al yz e d b y i n d uctiv el y c o u pl e d pl as m a m ass 
s p ectr o m etr y (I C P-M S ) f or t ot al m a n g a n es e ( M n ) c o nt e nt t o q u a ntif y 
eli mi n ati o n of i nj ect e d M n a n d fr a cti o n al excr eti o n.   
A d diti o n al ass ess m e nts of  bi otr a nsf or m ati o n pr o d ucts a n d m et a b olis m m ay 
b e p erf or m e d . 
 
St u d y D esi g n :   
T his is a P h as e 1 a, si n gl e c e nt er, r a n d o miz e d, d o u bl e -bli n d e d, S A D -c o h ort 
st u d y t o ass ess t h e s af et y, t ol er a bilit y, p h ar m ac o ki n etics, a n d eli mi n ati o n of 
R V P -0 0 1 at f o ur d os es: 
 
 
 
 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 1 2  
 
 
D uri n g P h as e 1 a, n o m e dic al i m a gi n g will b e p erf or m e d.  
S u bj ects will b e c o nfi n e d t o t h e P h as e 1 f acility fr o m 2 4 h o urs pri or t o d os e 
a d mi nistr ati o n ( D a y -1) u ntil 1 2 0 h o urs ( D a y 6) f oll o wi n g d os e 
a d mi nistr ati o n.  T h e pl a n is t o e nr oll 4 d os e c o h orts of 8 h e alt h y v ol u nt e ers 
e ac h, wit h t w o s u bj ects r ec eivi n g pl ac e b o a n d six s u bj ects r ec eivi n g 
R V P -0 0 1.  F or all c o h orts, a st a g g er e d d osi n g sc h e d ul e will i ncl u d e 2 s e nti n el 
su bj ects ( 1 activ e, 1 pl ac e b o) d os e d i niti all y, wit h t h e r e m ai ni n g 6 s u bj ects 
d os e d at l e ast 2 4 h o urs l at er.  
If t his i niti al d os e is s af e a n d w ell t ol er at e d, as d efi n e d i n t h e crit eri a t o 
pr oc e e d t o t h e n ext d os e l ev el, t h e n t h e s ec o n d d os e c o h ort gr o u p wi ll b e 
a d mi nist er e d. T his cycl e will pr oc e e d as d escri b e d t o e ac h s ucc essiv e d os e 
l ev el.  
D e p e n di n g o n s af et y a n d t ol er a bility d at a as w ell as o n av ail a bl e  
p h ar m ac o ki n etic  (P K ) d at a u p t o D a y 6 ( 1 2 0 h o urs), t h e esc al ati o n sc h e m e 
m a y b e m o difi e d s uc h t h at a n ot h er i nt er m e di at e d os e l ev el or a r e p e at d os e 
is a d mi nist er e d. T his a d diti o n al c o h ort will b e o pti o n al a n d m ay b e a d d e d 
d e p e n di n g o n t h e o utc o m e of t h e s af et y, t ol er a bilit y, a n d P K ass ess m e nts i n 
t h e pr evi o us c o h orts.  
S u bj ects w h o wit h dr a w or ar e wit h dr a w n fr o m t h e st u d y aft er d osi n g f or 
r e as o ns ot h er t h a n s af et y a n d t ol er a bilit y m a y b e r e pl ac e d aft er c o ns ult ati o n 
b et w e e n t h e S af et y C o m mitt e e m e m b ers. I n s uc h c as e, t h e t ot al n u m b er of 
s u bj ects d os e d will r e m ai n wit hi n a m axi m u m of 1 0 s u bj ects p er c o h ort.  
S u bj ects wit h dr a w n d u e t o a  st u d y dr u g -r el at e d a dv ers e ev e nt (A E ) will n ot 
b e r e pl ac e d.  
 
I ncl usi o n/ Excl usi o n 
 
S u bj ects e nr oll e d i n t his st u d y will b e fr o m t h e c o m m u nit y at l ar g e. T h e 
r ecr uit m e nt a dv ertis e m e nts m a y us e v ari o us m e di a ty p es ( e. g. , r a di o, 
n e ws p a p er, Cli nic al R es e arc h Or g a niz ati o n [ C R O ] W e b sit e, C R O v ol u nt e er  
d at a b as e).   
S u bj ects  m ust  m e et  all  of  t h e f oll o wi n g crit eri a t o b e i ncl u d e d  i n t h e st u dy: 
1)  M al e or f e m al e  
2)  N o n -s m o k er ( n o us e of t o b acc o pr o d ucts, e-ci g ar ett es or nic oti n e 
r e pl ac e m e nt pr o d ucts wit hi n 1 2 m o nt hs pri or t o scr e e ni n g) 
3)  ≥ 1 8 a n d ≤ 5 5 y e ars of a g e at t h e ti m e of si g ni n g i nf or m e d c o ns e nt  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 1 3  
4)  B o d y M ass I n d ex ( B MI ) > 1 8. 0 a n d < 3 2. 0  k g/ m 2 at scr e e ni n g  
5)  B o d y w ei g ht ≥ 5 5. 0 k g f or m al es a n d f e m al es at scr e e ni n g  
6)  S u bj ect m ust b e i n g o o d g e n er al h e alt h c o n diti o n (i. e., f ull p h ysic al 
ex a mi n ati o ns, m e dic al hist or y, vit al si g ns, 1 2 -l e a d E C G, a n d cli nic al 
l a b or at or y t ests p erf or m e d at scr e e ni n g) as d et er mi n e d b y t h e 
i nv esti g at or. N or m al E C G is d efi n e d as n or m al c ar di ac c o n d uctio n 
p ar a m et ers i ncl u di n g r esti n g h e art r at e  ( H R) b et w e e n 5 0 a n d 1 0 0 
b p m, Fri d erici a -c orr ect e d Q T i nt erv al ( Q Tc F) ≤ 4 5 0 ms, a n d Q R S 
i nt erv al < 1 2 0 ms  
7)  S u bj ect s h o ws n or m al bi oc h e mistr y t est r es ults ( wit hi n n or m al r a n g e 
or c o nsi d er e d n ot cli nic all y si g nific a nt b y t h e cli nic al i nv esti g at or) at 
scr e e ni n g or a d missi o n, i ncl u di n g it e ms list e d b el o w: 
a.  Bl o o d ur e a nitr o g e n ( B U N), a n d cr e ati ni n e  
b.  Al b u mi n a n d t ot al pr ot ei n  
c. Al k ali n e p h os p h at as e, Al a ni n e A mi n otr a nsf er as e  (AL T ), 
As p art at e A mi n otr a nsf er as e (A S T ), an d t ot al bilir u bi n  
d.  H u m a n i m m u n o d efici e nc y vir us ( HI V), A nti b o d y H Bs A g ( a nti -
H Bs A g) a n d a nti b o di es a g ai nst H e p atitis C vir us ( H C V ) ( a nti-
H C V).  
8)  S u bj ect s h o ws n or m al h e m at ol o g y t est r es ults ( wit hi n n or m al r a n g e 
or c o nsi d er e d n ot  cli nic all y si g nific a nt b y t h e cli nic al i nv esti g at or) at 
scr e e ni n g or a d missi o n i ncl u di n g it e ms list e d b el o w: 
a.  
R e d bl o o d c ell ( R B C) c o u nt  
b.  
W hit e bl o o d c ell ( W B C) c o u nt wit h diff er e nti al  
c. 
H e m o gl o bi n a n d h e m at ocrit  
d.  
Pl at el et c o u nt  
9)  S u bj ect s h o ws n or m al uri n al ysis t est r es ults ( wit hi n n or m al r a n g e or 
c o nsi d er e d n ot cli nic all y si g nific a nt b y t h e cli nic al i nv esti g at or) at 
scr e e ni n g or a d missi o n i ncl u di n g it e ms list e d b el o w: 
a)  p H a n d s p ecific gr avit y (r ef er t o S ecti o n  9. 2 ) 
b)  bl o o d, l e u k oc yt e, gl uc os e, pr ot ei n, k et o n es, a n d nitrit e  
c) Dr u g a n d alc o h ol a b us e scr e e ni n g t est ( dr u gs of a b us e ar e list e d i n 
S ecti o n  9. 1. 5 ). 
1 0)  S u bj ect s h o ws n or m al c o a g ul ati o n t est r es ults ( wit hi n n or m al r a n g e 
or c o nsi d er e d n ot cli nic all y si g nific a nt b y t h e cli nic al i nv esti g at or) at 
scr e e ni n g or a d missi o n i ncl u di n g pr ot hr o m bi n ti m e ( Pt), 
I nt er n ati o n al N or m aliz e d R ati o (I N R) a n d activ at e d p arti al 
t hr o m b o pl asti n ti m e ( A P T T). 
1 1)  S u bj ect m ust a gr e e t o us e a n a d e q u at e m et h o d of c o ntr ac e pti o n ( as 
d efi n e d i n S ecti o n  6. 5 ) 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 1 4  
1 2)  S u bj ect m ust b e a bl e t o u n d erst a n d a writt e n i nf or m e d c o ns e nt, 
w hic h m ust b e o bt ai n e d pri or t o i niti ati o n of st u d y pr oc e d ur es  
1 3)  S u bj ect m ust b e willi n g a n d a bl e t o c o m pl y wit h all st u d y 
r e q uir e m e nts. 
E xcl usi o n Crit eri a  
S u bj ects t o w h o m a n y of t h e f oll o wi n g a p pli es will b e excl u d e d fr o m t h e 
st u d y: 
1)  A n y cli nic all y si g nific a nt a b n or m alit y or a b n or m al l a b or at or y t est 
r es ults f o u n d d uri n g m e dic al scr e e ni n g; p ositiv e t est f or h e p atitis B, 
h e p atitis C, or HI V f o u n d d uri n g m e dic al scr e e ni n g  
2)  Hist or y of cli ni c all y si g nific a nt c ar di o v asc ul ar  ( C V), r e n al, h e p atic, 
c hr o nic r es pir at or y or g astr oi nt esti n al dis e as e ( exc e pt 
c h ol ecyst ect o m y); n e ur ol o gic al or ps yc hi atric dis or d er, as j u d g e d by 
t h e i nv esti g at or 
3)  Evi d e nc e of cli nic all y si g nific a nt h e p atic i m p air m e nt at sc r e e ni n g a n d 
a d missi o n i ncl u di n g  a n y of : 
a)  Al b u mi n a b o v e 1. 3 × t h e u p p er li mit of n or m al ( UL N) or b el o w 0. 7 
x t h e l o w er li mit of n or m al (LL N)  
b)  AL T a b ov e 1. 5 × UL N  
c) A S T a b ov e 2. 5 × UL N  
d)  t ot al bilir u bi n a b ov e 2. 0 ×  UL N (t ot al bilir u bi n acc e pt e d u p t o 2 ×  
UL N if di r ect bilir u bi n is wit hi n n or m al li mits) 
4)  Evi d e nc e of cli nic all y si g nific a nt r e n al i m p air m e nt at scr e e ni n g 
i ncl u di n g esti m at e d g l o m er ul ar filtr ati o n r at e ( e G F R) of < 6 0 mL/ mi n or 
cr e ati ni n e gr e at er t h a n 1. 5 m g/ dL.  ( T h e e G F R c alc ul ati o ns will b e 
p erf or m e d usi n g t h e C K D -E PI 2 0 2 1 R efit E q u ati o n)  
5)  Cli nic all y si g nific a nt c ar di ac fi n di n gs at scr e e ni n g or a d missi o n 
i ncl u di n g r esti n g H R  b el o w 5 0 or a b o v e 1 0 0 b p m, or E C G a b n or m ality  
or Q Tc F  a b o v e 4 5 0 ms  
6)  K n o w n all er gi es t o a n y c o m p o n e nt of R V P -0 0 1  
7)  K n o w n dr u g all er gi es or s e nsitiviti es  w hic h h av e  r es ulte d  i n E m er g e ncy 
R o o m visits, h os pit aliz ati o ns , or n e e d t o c arr y r esc u e E pi p e ns as a 
m att er of r o uti n e pr actic e ; m o d er at e or s ev er e all er gi es t o a n y 
i ntr av e n o us (I V) c o ntr ast a g e nts; se as o n al all er gi es r e q uiri n g 
m e dic ati o n  
8)  Hist or y of ast h m a  
9)  S u bj ects w h o h av e t a k e n str o n g C Y P i n hi bit ors 1 4 d a ys pri or t o first 
d os e of st u d y A list of t h es e i n hi bit ors is pr ovi d e d i n S ecti o n  1 1. 4  C Y P  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 1 5  
I n hi bit ors (F o o d a n d Dr u g A d mi nistr ati o n [ F D A] T a bl e of S u bstr at es, 
I n hi bit ors, a n d I n d uc ers 2 0 2 0 ). 
1 0) S u bj ects wit h d i ets t h at ar e hi g h i n M n c o nt e nt (> 2. 5 m g/ d a y).  F o o ds
k n o w n  t o h av e hi g h M n  c o nt e nt, i ncl u di n g s h ellfis h (i. e., m uss els,
cl a ms, o yst ers), h az el n uts, p ec a ns, bl u e b erri es, pi n e a p pl e , a n d/ or
s u p pl e m e nts c o nt ai ni n g M n.
1 1) Vit al si g n a b n or m aliti es at scr e e ni n g or a d missi o n (s yst olic bl o o d
pr ess ur e [ B P] l o w er t h a n 9 0 or ov er 1 4 0  m m H g, di ast olic B P  l o w er
t h a n 5 0 or ov er 9 0 m m H g)
1 2) Hist or y of si g nific a nt alc o h ol a b us e wit hi n t w o y e ars pri or t o scr e e ni n g
a)
or r e g ul ar us e of alc o h ol wit hi n six m o nt hs pri or t o t h e scr e e ni n g
visit ( i n m al es m or e t h a n 2 1 u nits p er w e e k a n d f e m al es m or e t h a n
1 4 u nits p er w e e k ( 1 u nit = 1 2 oz 1 b ottl e/c a n of b e er, 1  oz 4 0 %
s pirit, or 5 oz gl ass of wi n e)
b)
or a c o nf irm e d p ositiv e alc o h ol uri n e t est at scr e e ni n g or
a d missi o n .
1 3) Hist or y of si g nific a nt dr u g a b us e or us e of s oft dr u gs or h ar d dr u gs
(dr u gs of a b us e ar e list e d i n S ecti o n 9. 1. 5 ) wit hi n 1 y e ar pri or t o
scr e e ni n g.
1 4) A c o nfir m e d p ositiv e uri n e c oti ni n e t est at scr e e ni n g or a d missi o n.
1 5) S u bj ects w h o h av e r ec eiv e d a n y i nv esti g ati o n al pr o d uct (I P) i n a
cli nic al res e arc h st u d y wit hi n 5 h alf -liv es or wit hi n 3 0 d a ys pri or t o first
d os e. H o w ev er, i n n o ev e nt s h all t h e ti m e b et w e e n l ast r ec ei pt of I P
a n d first d os e b e l ess t h a n 3 0 d a ys.
1 6) Us e of m e dic ati o n ot h er t h a n t o pic al pr o d ucts wit h o ut si g nific a nt
s yst e mic a bs or pti o n:
a)
pr escri pti o n m e dic ati o n wit hi n 1 4  d a ys pri or t o (t h e first) d osi n g
b)
o v er -t h e-c o u nt er pr o d ucts i ncl u di n g n at ur al h e alt h pr o d ucts ( e. g. ,
f o o d s u p pl e m e nts a n d h er b al s u p pl e m e nts) wit hi n 1 4 d a ys pri or t o
(t h e first) d osi n g, wit h t h e exc e pti o n of t h e occ asi o n al us e of
ac et a mi n o p h e n ( u p t o 2  g d ail y)
c)
a d e p ot i nj ecti o n or a n i m pl a nt of a n y dr u g (i ncl u di n g
c o ntr ac e pti o n) wit hi n 3 m o nt hs pri or t o (t h e first) d osi n g
d)
C or o n avir us Dis e as e 2 0 1 9 (C O VI D -1 9 ) v acci n es ar e acc e pt e d
c o nc o mit a nt m e dic ati o ns.
1 7) D o n ati o n of pl as m a wit hi n 7 d a ys pri or t o d osi n g. D o n ati o n or l oss of
bl o o d ( excl u di n g v ol u m e dr a w n at scr e e ni n g) of 5 0  mL t o 4 9 9 mL of
bl o o d wit hi n 3 0 d a ys, or m or e t h a n 4 9 9  mL wit hi n 5 6 d a ys pri or t o t h e
first d osi n g.


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 1 6  
1 8)  P ositiv e hi g hl y s e nsitiv e pr e g n a nc y t est at scr e e ni n g or at a d missi o n 
f or w o m e n  of c hil d b e ari n g p ot e nti al  ( W O C B P). 
1 9)  H av e p o or v e n o us acc ess t h at li mits p hl e b ot o m y at scr e e ni n g a n d 
a d missi o n  
2 0)  Evi d e nc e of c urr e nt s ev er e ac ut e r es pir at or y s y n dr o m e c or o n avir us 2 
(S A R S -C o V -2 ; t h e vir us t h at c a us es C O VI D-1 9 ) i nf ecti o n  
2 1)  M al e s u bj ects wit h pr e g n a nt or l act ati n g p art n ers  
2 2)  S u bj ects w h o ar e, or ar e i m m e di at e f a mil y m e m b ers of, a st u d y sit e or 
s po ns or e m pl o y e e  
2 3)  A n y r e as o n w hic h, i n t h e o pi ni o n of t h e Pri nci p al I nv esti g at or, w o ul d 
pr ev e nt t h e s u bj ect fr o m p artici p ati n g i n t h e st u d y.  
P h as e:  
1 a  
St u d y P o p ul ati o n:  
N u m b er of s u bj ects
   
 
H e at h y a d ult m al e a n d f e m al e v ol u nt e ers will b e e nr oll e d i n t his st u d y. 
T hirt y -t w o ( 3 2) s u bj ects ( + 8 s u bj ects f or p ot e nti al r e pl ac e m e nt if a p plic a bl e) 
will b e e nr oll e d i n t his st u d y i n 4 d os e c o h orts of 8 s u bj ects e ac h ( 6 R V P -0 0 1, 
2 pl ac e b o  p er c o h ort ). 
D e p e n di n g o n s af et y a n d t ol er a bility as w ell as o n av ail a bl e P K d a t a, t h e 
esc al ati o n sc h e m e m a y b e m o difi e d s uc h t h at a n a d diti o n al i nt er m e di at e 
d os e l ev el or a r e p e at d os e is a d mi nist er e d.   T his a d diti o n al c o h ort will b e 
o pti o n al a n d m a y b e a d d e d d e p e n di n g o n t h e o utc o m e of t h e s af et y, 
t ol er a bilit y, a n d P K ass ess m e nts i n t h e pr evi o us c o h orts.  
S u bj ects w h o wit h dr a w or ar e wit h dr a w n fr o m t h e st u d y aft er d osi n g f or 
r e as o ns ot h er t h a n s af et y a nd t ol er a bilit y m a y b e r e pl ac e d aft er c o ns ult ati o n 
b et w e e n t h e S af et y C o m mitt e e m e m b ers.   I n s uc h c as e, t h e t ot al n u m b er of 
s u bj ects d os e d will r e m ai n wit hi n a m axi m u m of 1 0 s u bj ects p er c o h ort.  
S u bj ects wit h dr a w n d u e t o a st u d y dr u g-r el at e d A E will n ot b e r e pl ac e d.  
A s a m pl e siz e of 8 s u bj ects p er c o h ort r a n d o miz e d i n a 3: 1 r ati o t o t h e st u dy 
dr u g vs pl ac e b o r e pr es e nts a t y pic al p a n el f or a first -i n-h u m a n st u d y.  T h is 
n u m b er of s u bj ects is j u d g e d a d e q u at e t o ac hi ev e t h e st u d y o bj ectiv es.  
D escri pti o n of 
Sit es/ F aciliti es E nr olli n g 
P artici p a nts:  
T his st u d y will b e c o n d uct e d at a si n gl e sit e. 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 1 7  
St u d y Dr u g , D os e, a n d 
M o d e of  
A d mi nistr ati o n:  
 
  
At t h e cli nic al sit e a pr e d et er mi n e d d os e of t h e dr u g pr o d uct will b e dr a w n 
fr o m t h e vi al i nt o a s yri n g e affix e d wit h a n e e dl e, f or us e as a n I V b ol us, 
b as e d o n t h e dir ecti o ns i n t h e pr ot oc ol.  
Pl ac e b o, D os e,  a n d  
M o d e of  
A d mi nistr ati o n:  
R V P -0 0 1 is a h y p ert o nic s ol uti o n t h at is cl e ar, c ol orl ess t o p al e y ell o w, a n d  is 
i nt e n d e d t o b e a d mi nist er e d t hr o u g h t h e I V r o ut e vi a b ol us i nj ecti o n.  Giv e n 
t h e l ac k of exci pi e nts i n t h e f or m ul ati o n, n or m al s ali n e will b e us e d as  a n 
a p pr o pri at e pl ac e b o.  A m b er ti nt e d s yri n g es a n d I V t u bi n g as w ell as p o w er 
i nj ect ors will b e us e d t o pr es erv e bli n di n g a m o n gst t h e st u d y st aff, b y 
c o nc eali n g sli g ht c ol or a n d e as e of i nj ect a bility diff er e nc es b et w e e n t h e 
activ e p h ar m ac e utic al a n d pl ac e b o (s ali n e).   
W ei g ht b as e d d osi n g will b e us e d b y p h ar m ac y st aff t o pr e p ar e s yri n g es  
c o nt ai ni n g R V P-0 0 1 or pl ac e b o  f or I V a d mi nistr ati o n b y t h e st u d y st aff.  
P o w er i nj ect ors will b e us e d t o st a n d ar diz e i nj ecti o n ti m es of t h e b ol us a n d 
t h e s ali n e fl us h t h at f oll o ws.   
St u d y D ur ati o n:    
T his st u d y is esti m at e d t o t a k e a p pr oxi m at el y 9  m o nt hs fr o m first -s u bj ect-i n 
t o t h e c o m pl eti o n of t h e cli nic al st u d y r e p ort ( C S R). 
P artici p a nt D ur ati o n:    
E ac h s u bj ect will b e c o nfi n e d t o a P h as e 1 f acilit y fr o m  2 4 h o urs  ( D a y -1)  
pri or t o d os e a d mi nistr ati o n u ntil 1 2 0 h o urs  f oll o wi n g d os e a d mi nistr ati o n.  
S u bj ects will b e r e q uir e d t o p artici p at e i n a f oll o w -u p p h o n e c all o n D a y 8  t o 
m o nit or f or a dv ers e ev e nts , a n d t o s elf-r e p ort a n y A Es u p t o D a y 3 0.  Ov er all 
d ur ati o n of i n divi d u al s u bj ect p artici p ati o n (i ncl u di n g scr e e ni n g) will b e u p t o 
5 8 d a ys.  










R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 2 2  
4  
 
I N T R O D U C TI O N 
4. 1  
S T U D Y R A TI O N A L E   
C o ntr ast -e n h a nc e d ( C E) M a g n etic R es o n a nc e I m a gi n g (M RI ) is a vit al t o ol i n di a g n ostic m e dici n e.  R V P -0 0 1 
is b ei n g d ev el o p e d as a g a d oli ni u m ( G d)-fr e e alt er n ati v e t o c urr e ntl y av ail a bl e g e n er al p ur p os e M RI 
c o ntr ast a g e nts, all of w hic h b el o n g t o a cl ass of c o m p o u n ds k n o w n as g a d oli ni u m -b as e d c o ntr ast a g e nts 
( G BC As).  G e n er al p ur p os e M RI c o ntr ast a g e nts ar e n o n -s p ecific i n t h eir bi o distri b uti o n a n d distri b ut e i n 
t h e bl o o d p o ol a n d i n t h e extr ac ell ul ar fl ui d (Ai m e & C ar av a n 2 0 0 9 ).  T h e y ar e ess e nti al f or r o uti n e 
di a g n ostic p ur p os es a n d ar e us e d t o h el p d et ect a n d st a g e a wi d e r a n g e of dis e as es, as w ell as t o m o nit or 
dis e as e pr o gr essi o n a n d r es p o ns e t o tr e at m e nt ( Kl ei n et al. 2 0 1 8 ).  H o w ev er, s eri o us b ut r ar e si d e eff ects 
c a n occ ur wit h G B C As, li miti n g t h eir us e.  T h e U nit e d St at es ( U. S.) F o o d a n d Dr u g A d mi nistr ati o n ( F D A) 
a dvis es t h at all G B C As i ncr e as e t h e ris k f or n e p hr o g e nic s yst e mic fi br osis ( N S F) a m o n g p ati e nts wit h 
i m p air e d r e n al eli mi n ati o n of t h e dr u gs a n d r e q uir es a ‘ bl ac k b ox w ar ni n g” dir ecti n g p h ysici a ns t o av oi d 
t h e us e of G B C As i n t h es e p ati e nts if p ossi bl e; F D A  l at er r e q uir e d ot h er l a b el u p d at es t o mi ni miz e t h e ris k 
of N S F ( F D A Dr u g S af et y C o m m u nic ati o n 2 0 1 0 ).  S af et y c o nc er ns c o nti n u e t o e m er g e as m or e b ec o m es 
k n o w n a b o ut t h e l o n g -t er m eff ects of G B C As.  It is est a blis h e d t h at r esi d u al G d, i n s o m e c h e mic al f or m, is 
r et ai n e d i n t h e br ai n a n d b o d y f or l o n g p eri o ds ( y e ars) aft er a d mi nistr ati o n of G B C As; F D A h as r e act e d 
wit h a d diti o n al w ar ni n gs r e q uir e d o n dr u g l a b els ( F D A Dr u g S af et y C o m m u nic ati o n 2 0 1 8 ).  T h e 
i n dis p e ns a bl e r ol e of G B C As is r efl ect e d i n t h e f act t h at t h e y ar e a d mi nist er e d o v er 8 milli o n ti m es p er 
y e ar i n t h e U. S. ( F D A MI D A C M  2 0 1 7 ).   
M a n g a n es e  ( M n), u nli k e  G a d oli ni u m, is a n or m al el e m e nt al c o m p o n e nt of t h e h u m a n b o d y.   T h er ef or e, 
R V P -0 0 1 w as d esi g n e d t o act i n a f u ncti o n all y si mil ar m a n n er t o G B C As b ut t o  c o nt ai n t h e bi oc o m p ati bl e  
ess e nti al  tr ac e el e m e nt  M n  a n d  n ot  c o nt ai n t h e g a d oli ni u m  i o n. 
T his hi g hli g hts t h e hi g h u n m et m e dic al n e e d f or a G d -fr e e alt er n ativ e t h at c a n b e us e d t o pr o vi d e 
im p ort a nt C E  di a g n ostic M RI sc a ns.  I nst e a d of G d, R V P-0 0 1 utiliz es c h el at e d m a n g a n es e i o n ( M n 2 +) t o 
pr o d uc e c o ntr ast i n M RI sc a ns.  B y av oi di n g G d alt o g et h er i n t h e c o ntr ast a g e nt, s af et y c o nc er ns b as e d 
u p o n G d w o ul d b e pr ecl u d e d.  
T h e g o al of t his first cli nic al tri al, R VL --2 2, is t o ev al u at e t h e s af et y, t ol er a bilit y, p h ar m ac o ki n etics, a n d 
eli mi n ati o n of si n gl e asc e n di n g d os es ( S A Ds) of R V P -0 0 1 w h e n i nj ect e d as a si n gl e i ntr av e n o us (I V) b ol us 
a d mi nistr ati o n i n n or m al, h e alt h y a d ults .    
4. 2  
B A C K G R O U N D   
R V P -0 0 1 is a l o w m ol ec ul ar  w ei g ht c h el at e of M n
2 + th at w as d esi g n e d a n d d ev el o p e d t o pr ovi d e a G d -fr e e 
alt er n ativ e t o G B C As f or I V us e i n C E  M RI.  R V P -0 0 1, als o k n o w n i n t h e sci e ntific lit er at ur e as M n-P y C 3 A, 
c o m pris es a r ati o n all y d esi g n ed h y dr o p hilic, a ni o nic h ex a d e nt at e c h el at or c o m pl ex e d t o div al e nt 
m a n g a n es e ( M n
2 +).  T his r es ults i n a c h el at e t h at si m ult a n e o usl y pr ovi d es hi g h r el axivit y, is l ar g el y 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 2 3  
c o nfi n e d to t h e extr ac ell ul ar s p ac e, a n d is hi g hl y r esist a nt t o M n  diss oci ati o n ( G a l e et al. 2 0 1 8 , Erst a d e t al. 
2 0 1 9 ).   
T h e m ec h a nis m of act i o n of M RI c o ntr ast a g e nts is t o r e d uc e t h e r el ax ati o n ti m es, T 1 a n d T 2, of w at er 
m ol ec ul es i n tiss u e.  F or ex a m pl e, i n T 1- w ei g ht e d M R i ma g es, tiss u e t h a t h as a s h ort er T 1 v al u e h as hi g h er 
si g n al a n d a p p e ars bri g ht er c o m p ar e d t o tissu e th at h as a l o n g er T 1.  P ar a m a g n etic s p eci es s uc h as G d 3 + (i n 
G B C As) or M n 2 + str o n gl y re d uc e t h e T 1 of w at er m ol ec u l es i n cl os e pr oxi mit y t o th e m et al i o n, a n d as a 
r es ult i ncr e as e t h e M RI si g n al i n a T 1- w ei g ht e d i m a g e.  T h e ext e nt t o w hich a c o ntr ast a g e nt c a n c h a n g e 
t h e r el ax ati o n tim e is ch ar act eriz e d b y its r el axivit y a n d i s d e n ot e d r 1 or r 2 d e p e n di n g o n w h e t h er it r ef ers 
t o c h a n gi n g th e T 1 tim e or T 2 ti m e.  R el axivit y is a n i n h er e nt pr o p e rt y of t h e c o ntr as t a g e nt.  C o ntr ast 
a g e nts wi t h a hi g h er r 1 r el axivit y will ca us e a l ar g er T 1 c h a n g e at a give n c o nc e ntr ati o n t h a n a c o ntr ast 
a g e nt wit h a l o w er r el axivity.  T h e a m o u nt of si g n al c h a n g e g e n er at e d b y a c o ntr as t a g e nt is pr o p orti o n al 
t o b ot h its r el axivit y a n d its co nc e ntr ati o n wit hi n a n a n at o mic al r e gi on.  T h e pr es e nc e or a bs e nc e of si g n al 
e n h a nc e m e n t is us e d b y p h ysici a ns to i d e ntif y w h e t h er p at h ol o g y is a bs e nt or pr es e nt (Kl ei n et al. 2 0 1 8 ).  
T h e m ost wi d el y us e d i n dic ati o n f or M RI co ntr ast a g e nts is f or t h e d et ecti o n of c e ntr al n e rv o us s yst e m 
( C N S) l esi o ns.  F or ex a m pl e, m a n y pri m ar y a n d m et ast atic br ai n tu m ors ca us e disr u pti o n o f th e bl o o d-
br ai n b arri er, r es ulti n g i n c o nc e ntr ati o n of t h e c o ntr ast a g e nt wit hi n t h e l esi o n b e d.  T his r es ults i n l oc al 
e n h a nc e m e nt m a ki n g t h e t u m or hi g hl y c o ns pic u o us o n M RI sc a ns ( Kl ei n et al. 2 0 1 8 ). 
T h e M R c o ntr as t eff ects of a n M n 2 + b as e d c o ntr ast a g e nt ar e ex e m plifi e d i n t h e ex p eri e nc e wit h 
m a n g af o di pir tris o di u m ( M n- D P D P; T esl asc a n ®), a n a g e nt t h at w as F D A- a p pr o v e d f or us e i n c o ntr ast 
e n h a nc e d h e p at o bili ar y M R i m a gi n g.  I n h u m a ns a n d a ni m als, M n- D P D P diss o ci at es i n t h e b o d y 
i m m e di at el y aft er I V a d mi nistr ati o n, wit h a b o u t 8 0 % of t h e a d mi nist er e d M n b ei n g r el e as e d fr o m its 
c h el at or i n h u m a ns ( T oft et al. 1 9 9 7 ), w h er e as R V P- 0 0 1 w as d e si g n e d a n d h as b e e n d e m o nstr at e d t o 
r e m ai n i nt act a n d t o b e excr et e d i nt act.  T his str o n g M n 2 + c h el ati ng pr o p ert y of R V P- 0 0 1 v ers us M n - DP D P 
is r efl ect e d i n co n diti o n al st a bility co nst a nts f or t h e 2 co m p o u n ds at p H 7. 4: R V P- 0 0 1 ut iliz es a c h el at or 
t h at h as ov er 1 0 0, 0 0 0 ti m es hi g h er affi ni ty t o M n 2 + t h a n M n- D P D P (G al e et al. 2 0 1 5 ).  T his l o w er st a bility 
of M n- D P D P l ea ds to g r e at er M n 2 + r el e as e a n d c o ns e q u e ntl y t o g r e at er r et e nti o n of i nj ect e d M n in t h e 
b o d y, wit h 1 5 % of t h e i nj ec t e d M n fr o m M n- D P D P r e mai ni n g i n r ats 5 d a ys aft er I V a d mi nistr ati o n ( Gr a nt 
et al. 1 9 9 4 ) c o m p ar e d t o 0. 0 5 8 ± 0. 0 5 1 % of M n fr o m I V i nj ect e d R V P- 0 0 1 r e m ai ni n g i n r ats at 7 d a ys aft er 
i nj ecti o n (Erst a d et al. 2 0 1 9 ).  U nli k e M n- D P D P w hic h diss oci at es u p o n i nj ecti o n, R V P- 0 0 1 w as d esi g n e d t o 
b e c h e mic all y st a bl e a n d n ot r el e as e fr e e M n 2 + i o n i n t h e b od y.  Bi o a n al ytic al st u di es s h o w e d th at R V P- 0 0 1 
is r a pi dl y eli mi n at e d i nt act wi t h o ut u n d er g oi n g m et a b olis m or d e gr a d ati o n i n rats, m ic e, a n d m o n k eys.  
4. 2. 1  N O N -C LI NI C A L S T U DI E S  
N o ncli nic al p h ar m ac ol o g y d at a i n dic at e t h at R V P -0 0 1 is a u ni q u e, eff ectiv e i m a gi n g a g e nt b as e d o n M RI 
st u di es i n mic e a n d b a b o o ns.  T h e eff ectiv e n ess of R V P-0 0 1 i n t h es e st u di es w as g e n er all y e q uiv al e nt t o 
t h at of c o m p ar at or G B C As.  T h e ac ut e s afet y of R V P -0 0 1  w as  ass ess e d i n a st a n d ar d G o o d L a b or at ory 
Pr actic es ( GL P )-c o m pli a nt b att ery of s af ety p h ar m ac ol o g y st u di es of C N S, r es pir at or y , a n d C V f u ncti o n.  
R V P -0 0 1 is t h e N -m et h yl -D -gl uc a mi n e  ( m e gl u mi n e) s alt of t h e M n c o m pl ex.  S o m e e arl y st u di es use d t h e 
s o di u m s alt f or m w hic h is d e n ot e d R V P-0 0 1 -3 0.  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 2 4  
I n n o ncli nic al st u di es R V P- 0 0 1 w as s h ow n t o b e c h e mic all y st a bl e w it h a r el axivit y co m p ar a bl e to G B C As, 
a n d t o pr o vi d e eff ect iv e c o ntr ast e n h a nc e m e nt i n a ni m al m o d els.  R V P- 0 0 1 h as t h e d esir e d 
p h ar m ac o ki n etic ( P K) attri b ut es of r a pi d eli mi n ati o n, l o w tiss u e r et e nti o n a n d r esist a nc e t o m et a b olic 
d e gr a d ati o n (G al e at al. 2 0 1 5 , G al e at al. 2 0 1 8 , Erst a d et al. 2 0 1 9 , Z h o u et al. 2 0 2 1 ).  R V P- 0 0 1 w as s h o w n 
t o u n d er g o mix e d h e p at o bili ar y a n d r en al eli mi n a ti o n i n mic e, b a b o o ns, a n d r ats (G al e at al. 2 0 1 8, Erst a d 
et al. 2 0 1 9, Z h o u et al. 2 0 2 1), wit h i ncr e as e d fr acti o n al h e p at o bili ar y eli mi n ati o n i n a r at m od el of r e n al 
i m p air m ent ( Z h o u et al. 2 0 2 1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
R ef er t o t h e I nv esti g at or B r oc h ur e f or d et ails of all no n-cli nic al st u di es t o d at e .  T h e pr o p os e d P h as e 1 a 
st u d y will co nstit ut e t h e first in h u m a n ( FI H) st u d y of R V P- 0 0 1 to a ss ess s afet y a n d P K usi n g a r a n d o miz e d 
S A D sc h e m e. 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 2 5  
4. 3  
RI S K / B E N E FI T A S S E S S M E N T 
4. 3. 1  RI S K  A S S E S S M E N T  
R V P -0 0 1 h as n ot y et b e e n ev al u at e d i n h u m a ns. 
I n n o ncli nic al t oxic ol o g y st u di es i n r ats ( St u di es 1 7 3 7-1 9 0 0 8 a n d G D 6 4L N) a n d c y n o m ol g us m o n k e ys 
( St u di es 1 7 3 7-1 9 0 2 1 a n d MJ 9 5 Q X), R V P -0 0 1 w as f o u n d t o b e s af e a n d w ell t ol er at e d at pr oj ect e d cli nic ally 
us ef ul d os es.  
 
 
 
 
   
 
  
 
 
 
 
 
 
 
 
 
4. 3. 2  K N O W N P O T E N TI A L B E N E FI T S 
As t h e st u dy tr e at m e nt is n ot b ei n g giv e n t o s u bj ects t o tr e at a n y s y m pt o ms or ill n ess, t h er e will b e n o dir ect 
m e dic al b e n efit fr o m p artici p ati o n i n t his tri al. 
4. 3. 3  A S S E S S M E N T O F P O T E N TI A L R I S KS  A N D B E N E FI T S 
M n h as a w ell u n d erst o o d t oxicit y pr ofil e.   K n o w n eff ects fr o m M n t oxicity i nf or m p ot e nti al s af et y 
c o nc er ns f or t h e e ntir e cl ass of M n -c o nt ai ni n g M RI c o ntr ast a g e nts i ncl u d e t h e p ossi biliti es of M n 
r et e nti o n i n t h e br ai n s u bs e q u e nt t o c hr o nic ov er ex p os ur e, h y p ers e nsitivit y r e acti o ns, l o w eri n g of s eiz ur e 
t hr es h ol d, a n d tr a nsi e nt c h a n g es i n C V  f u ncti o n as a c o ns e q u e nc e of ac ut e o v er ex p os ur e t o fr e e M n 2 +.  T o 
miti g at e ris k fr o m M n ex p os ur e, R V P -0 0 1 w as d esi g n e d t o st a bl y c h el at e M n 2 +, t o r e m ai n i nt act w hil e i n 
t h e b o d y, a n d t o b e excr et e d i nt act.  N o n e t h el ess F D A h as r e q u est e d R ev e al s u b mit ex p e dit e d I N D s af et y 
r e p orts f or a n y r e p orts of s eiz ur e, str o k e, c er e br al v e n o us t hr o m b osis, Q Tc > 4 8 0 ms ec, or Q Tc i ncr e as e of 
6 0 ms ec ov er b as eli n e, r e g ar dl ess of ass ess m e nt of c a us alit y.   


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 2 6  
M or e d et ail e d i nf or m ati o n a b o ut t h e k n o w n a n d ex p ect e d b e n efits a n d ris ks a n d r e as o n a bl y ex p ect e d 
a dv ers e ev e nts ( A Es) of R V P -0 0 1  m a y b e f o u n d i n t h e i nv esti g at or’s br oc h ur e (I B). 
4. 4  
S T U D Y O BJ E C TI V E S  
T h e o bj ectiv e s of t his st u d y ar e as f oll o ws:  
Pri m ar y  o bj ectiv e:  
• 
T o ev al u at e t h e s af et y a n d t ol er a bility of S A D s of R V P-0 0 1 i n h e alt h y a d ult v ol u nt e ers.
S ec o n d ar y  o bj ectiv e:  
•
T o d et er mi n e t h e p h ar m ac o ki n etics a n d eli mi n ati o n of R V P -0 0 1 i n h e alt h y a d ult v ol u nt e ers.
4. 5  
S T U D Y E N D P OI N T S  
S af et y:  
S af et y will b e ev al u at e d t hr o u g h o ut t h e st u d y b y ass essi n g t h e f oll o wi n g p ar a m et ers: A Es , p h ysic al 
ex a mi n ati o ns, i nj ecti o n sit e m o nit ori n g, E C Gs, vit al si g ns, cli nic al l a b or at or y ev al u ati o ns, m e dic al hist ory, 
a n d pri or a n d c o nc o mit a nt m e dic ati o ns.  
P h ar m ac o ki n etic s a n d Eli mi n ati o n: 
Pl as m a a n d uri n e will b e a n al yz e d b y  li q ui d c hr o m at o gr a p h y wit h t a n d e m m ass s p ectr o m etr y (L C-M S/ M S ) 
t o m e as ur e t h e c o nc e ntr ati o n of i nt act R V P-0 0 1 a n d t o ass ess pl as m a p h ar m ac o ki n etics.  U ri n e a n d f ec es 
will b e a n al yz e d b y i n d ucti v el y c o u pl e d pl as m a m ass s p ectr o m etr y (I C P-M S ) f or t ot al M n c o nt e nt t o 
q u a ntif y eli mi n ati o n of i nj ect e d M n vi a t h e uri n e a n d f ec es.  A d diti o n al ass ess m e nts of  bi otr a nsf or m ati o n 
pr o d ucts m a y b e p erf or m e d.  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 2 7  
5  
S T U D Y D E SI G N 
5. 1  
O V E R A L L  D E SI G N  
T his is a P h as e 1 a, si n gl e c e nt er, r a n d o miz e d, d o u bl e- bli n d e d, S A D-c o h ort st u d y t o ass ess t h e s af et y, 
t ol er a bilit y, p h ar m ac o ki n etics, a n d el i mi n ati o n of R V P- 0 0 1 at f our d os es: 
 
 
 
 
 
D uri n g P h as e 1 a, n o m e dic al i m a gi n g will b e p erf or m e d. 
S u bj ects will b e c o nfi n e d t o th e P h as e 1 f acility fr o m 2 4 h o urs pri or t o d os e a d mi nistr ati o n ( D a y - 1) u ntil 
1 2 0 h o urs ( Da y 6) f oll owi n g d os e a d mi nistr ati o n.  T h e pl a n is t o e nr oll 4 d os e c o h orts of 8 h e alt h y 
v ol u nt e ers e ac h, wit h t w o s u bj ects r ec ei vi n g pl ac e b o a n d six s u bj ects r ec eivi n g R V P- 0 0 1.  F or all c o h orts, a 
st a g g er e d d o si n g sc h e d ul e will i ncl ud e 2 s e nti n el s u bj ects ( 1 activ e, 1 pl ac e b o) d os e d i nit i all y, wit h 
r e m ai ni n g 6 s u bj ects d os e d at l e ast 2 4 h o urs l at er.  
If t his i niti al d os e is s af e a n d w ell t ol er at e d, as d efi n e d i n t h e crit eri a t o pr oc e e d to t h e n ex t d os e l ev el, 
t h e n t h e s ec o n d d os e c o h ort gr o u p will b e a d mi nist ere d.  T his c ycl e will pr oc e e d as d e scri b e d t o e ac h 
s ucc essiv e d os e l ev el.  
D e p e n di n g o n s af et y a n d t ol er a bility as w ell as o n av ail a bl e P K d at a u p t o D a y 6 ( 1 2 0 h o urs), t h e esc al ati o n 
sc h e m e m a y b e m o difi e d s uc h t h at a n ot h er i nt er m e di at e d os e l ev el or a r e p e at d os e is a d mi nist er e d.  T his 
a d diti o n al c o h ort will b e o pti o n al a n d m a y b e a d d e d d e p e n di n g o n t h e o utc o m e of t h e s af et y, t ol er a bility, 
a n d P K ass ess m e nts i n t h e pr evi o us c o h orts.  
S u bj ects w h o wit h dr a w or ar e wit h dr a w n fr o m t h e st u d y aft er d os i n g f or r e as o ns ot h er t h a n s afet y a n d 
t ol er a bilit y m a y b e r e pl ac e d aft er co ns ult ati o n b et w e e n t h e S af et y C o m mitt e e m e m b ers.  I n s uc h c as e, t h e 
t ot al n u m b er of s u bj ects d os e d will r e m ai n wit hi n a m axi m u m of 1 0 s u bj ects p er c o h ort.  S u bj ects 
wit h dr a w n d u e t o a st u d y dr u g-r el at e d A E will n ot b e r e pl ac e d.  
T h e  d os e esc al ati o n sc h e m a is s h o w n i n Fi g ur e 1 . 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 2 8  
Fi g ur e 1    
 D os e Esc al ati o n Sc h e m a 
5. 2  
J U S TI FI C A TI O N F O R D OS E  
P h as e 1 a will b e a n esc al ati n g si n gl e- d os e, s af et y, t ol er a nc e, a n d p h ar m ac o ki n etic st u d y of R V P- 0 0 1 i n 
d os e c o h ort gr o u ps of h e alt h y a d ult m al e a n d f e m al e v ol u nt e ers ( T a bl e 1 ).  T h e st arti n g cli nic al d os e is 
b as e d o n n o ncli nic al s af et y, t oxicit y, a n d p h ar m ac o ki n etic d at a, i n acc or d a nc e wit h F D A g ui d a nc e 
(G ui d a nc e f or I n d ustr y Esti m ati n g t h e M axi m u m S af e St arti n g D os e i n I niti al Cli nic al Tri als f or T h er a p e utics 
i n A d ult H e alt h y V ol u nt e ers, F D A 2 0 0 5) a n d i n c o nj u ncti o n wit h pr ecli nic al i m a gi n g d at a g e n er at e d wit h 
R V P- 0 0 1 .  
 
 
 
 
 
 
 
 
C o h ort 1 a 1  D os e 
(s e e i ns et) 
 
S af et y R e vi e w 
C o m mitt e e  
C o h ort 1 a 3 : D os e  
 
C o h ort 1 a 4: D os e  
 
S af et y R e vi e w 
C o m mitt e e  
C o h ort 1 a 5 : D os e  
(if n e e d e d) 
S af et y R e vi e w 
C o m mitt e e  
C o h ort   S e nti n el s 
( 1 + 1) 
 
C o h ort 1 a 2 : D os e 
 
S af et y R e vi e w 
C o m mitt e e  
PI R e vi e w  
C o h ort  M ai n  
Gr o u p ( 5 + 1)  
 




R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3 0  
6  
S T U D Y P O P U L A TI O N  
6. 1  
J U S TI FI C A TI O N F O R  T H E  S T U D Y  P O P U L A TI O N  
T his is a FI H st u d y. A h e alt h y v ol u nt e er p o p ul ati o n h as b e e n s el ect e d f or t h e st u d y b ec a us e  h e alt h y 
s u bj ects wit h n o c o nc o mit a nt dis e as es a n d usi n g n o c o nc o mit a nt m e dic ati o ns r e pr es e nt a  h o m o g e n e o us 
p o p ul ati o n all o wi n g f or pr o p er ev al u ati o n of t h e s af et y, t ol er a bilit y, a n d P K of a  dr u g  wit h o ut c o nf o u n di n g  
f act ors. 
Si nc e t h e ris k t o t h e d ev el o pi n g h u m a n f et us f oll o wi n g ex p os ur e t o R V P -0 0 1 is u n k n o w n a t t his ti m e, 
f e m al e s u bj ects will b e e nr oll e d i n t his tri al o nl y if t h e y m e et all i ncl usi o n crit eri a a n d n o ne of  t h e excl usi o n 
crit eri a.  T o e ns ur e t h at f e m al e s u bj ects ar e n ot pr e g n a nt or li k el y t o b ec o m e  pr e g n a nt d uri n g t h e st u dy, 
c o nfir m ati o n will b e o bt ai n e d by s er u m a n d uri n e  t ests pri or t o  st u d y dr u g a d mi nistr ati o n.   I n a d diti o n, 
f e m al e s u bj ects of c hil d b e ari n g p ot e nti al a n d n o n-s ur gic all y st eril e m al e s u bj ects will b e r e q uir e d t o us e 
eff ectiv e c o ntr ac e ptiv e m et h o ds f or a n a p pr o pri at e  d ur ati o n (r ef er t o S ecti o n 6. 5  f or acc e pt a bl e 
c o ntr ac e ptiv e m et h o ds)  
6. 2  
S A M P L E  SI Z E  
T hirt y -t w o ( 3 2) s u bj ects ( + 8 s u bj ects f or p ot e nti al r e pl ac e m e nt if a p plic a bl e) will b e e nr oll e d i n t his st u dy 
i n 4 d os e c o h orts of 8 s u bj ects e ac h ( 6 R V P-0 0 1, 2 pl ac e b o).  
D e p e n di n g o n s af et y a n d t ol er a bility as w ell as o n av ail a bl e P K d at a, t h e esc al ati o n sc h e m e m a y b e 
m o difi e d s uc h t h at a n a d diti o n al i nt er m e di at e d os e l ev el or a r e p e at d os e is a d mi nist er e d.  T his a d diti o n al 
c o h ort will b e o pti o n al a n d m a y b e a d d e d d e p e n di n g o n t h e o utc o m e of t h e s af et y, t ol er a bilit y, a n d P K 
ass ess m e nts i n t h e pr evi o us c o h orts.  
S u bj ects w h o wit h dr a w or ar e wit h dr a w n fr o m t h e st u d y aft er d osi n g f or r e as o ns ot h er t h a n s af et y a n d 
t ol er a bilit y m a y b e r e pl ac e d aft er c o ns ult ati o n b et w e e n t h e S af et y C o m mitt e e m e m b ers.  I n s uc h c as e, t h e 
t ot al n u m b er of s u bj ects d os e d will r e m ai n wit hi n a m axi m u m of 1 0 s u bj ects p er c o h ort.  S u bj ects 
wit h dr a w n d u e t o a st u d y dr u g -r el at e d A E will n ot b e r e pl ac e d. 
A s a m pl e siz e of 8 s u bj ects p er c o h ort r a n d o miz e d i n a 3: 1 r ati o t o t h e st u d y dr u g vs pl ac e b o  r e pr es e nts a 
t y pic al p a n el f or a first-i n-h u m a n st u d y.  T h at n u m b er of s u bj ects is j u d g e d a d e q u at e  t o ac hi ev e t h e st u dy 
o bj ectiv es.  
6. 3  
I N C L U SI O N C RI T E RI A  
S u bj ects e nr oll e d i n t his st u d y will b e fr o m t h e c o m m u nit y at l ar g e.   T h e r ecr uit m e nt  a dv ertis e m e nts m a y 
us e v ari o us m e di a t y p es ( e. g. , r a di o, n e ws p a p er, Cli nic al R es e arc h Or g a niz ati o n [ C R O ] W e b sit e, C R O 
v ol u nt e er  d at a b as e).   
S u bj ects  m ust  m e et  all  of  t h e f oll o wi n g crit eri a t o b e i ncl u d e d  i n t h e st u d y: 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3 1  
1)  H e alt h y a d ults  
2)  N o n -s m o k er ( n o us e of t o b acc o pr o d ucts, e -ci g ar ett es or  nic oti n e r e pl ac e m e nt pr o d ucts wit hi n 1 2 
m o nt hs pri or t o scr e e ni n g)  
3)  ≥ 1 8 a n d ≤ 5 5 y e ars of a g e  at t h e ti m e of si g ni n g i nf or m e d c o ns e nt 
4)  B o d y M ass I n d ex ( B MI ) > 1 8. 0  a n d < 3 2 . 0 k g/ m 2 at scr e e ni n g  
5)  B o d y w ei g ht ≥ 5 5. 0 k g f or m al es a n d f e m al es at scr e e ni n g  
6)  S u bj ect m ust b e i n g o o d g e n er al h e alt h c o n diti o n (i. e., f ull p h ysic al ex a mi n ati o ns, m e dic al hist ory, 
vit al si g ns, 1 2 -l e a d E C G, a n d cli nic al l a b or at or y t ests p erf or m e d at scr e e ni n g) as d et er mi n e d b y t h e 
i nv esti g at or.  N or m al E C G is d efi n e d as n or m al c ar di ac  c o n d ucti o n p ar a m et ers i ncl u di n g r esti n g H R  
b et w e e n 5 0 a n d 1 0 0 b p m, Fri d erici a -c orr ect e d Q T i nt erv al ( Q Tc F) ≤ 4 5 0 ms , a n d Q R S i nt erv al < 1 2 0 
ms  
7)  S u bj ect s h o ws n or m al bi oc h e mistr y t est r es ults ( wit hi n n or m al r a n g e or c o nsi d er e d n ot cli nic ally 
si g nific a nt b y t h e cli nic al i n v esti g at or) at scr e e ni n g or a d missi o n i ncl u di n g it e ms list e d b el o w: 
a.  Bl o o d ur e a nitr o g e n ( B U N), a n d cr e ati ni n e 
b.  Al b u mi n a n d t ot al pr ot ei n  
c. Al k ali n e p h os p h at as e,  Al a ni n e A mi n otr a nsf er as e  (AL T ), As p art at e A mi n otr a nsf er as e (A S T ), 
a n d t ot al bilir u bi n  
d.  H u m a n i m m u n o d efici e nc y vir us ( HI V), A nti b o d y H Bs A g ( a nti -H Bs A g ) a n d a nti b o di es 
a g ai nst H e p atitis C vir us ( H C V ) ( a nti-H C V)  
8)  S u bj ect s h o ws n or m al h e m at ol o g y t est r es ults ( wit hi n n or m al r a n g e or c o nsi d er e d n ot  cli nic ally 
si g nific a nt b y t h e cli nic al i n v esti g at or) at scr e e ni n g or a d missi o n i ncl u di n g it e ms list e d b el o w: 
e.  
R e d bl o o d c ell ( R B C) c o u nt  
f.  
W hit e bl o o d c ell ( W B C) c o u nt wit h diff er e nti al  
g.  
H e m o gl o bi n a n d h e m at ocrit  
h.  
Pl at el et c o u nt  
9)  S u bj ect s h o ws n or m al uri n al ysis t est r es ults ( wit hi n n or m al r a n g e or c o nsi d er e d n ot cli nic all y 
si g nific a nt b y t h e cli nic al i n v esti g at or) at scr e e ni n g or a d missi o n i ncl u di n g it e ms list e d b el o w: 
a)  p H a n d s p ecific gr avit y  (r ef er t o S ecti o n 9. 2 ) 
b)  bl o o d , l e u k oc yt e, gl uc os e, pr ot ei n, k et o n es, a n d nitrit e 
c) Dr u g a n d alc o h ol a b us e scr e e ni n g t est (dr u gs of a b us e ar e list e d i n S ecti o n 9. 1. 5 ) 
1 0)  S u bj ect s h o ws n or m al c o a g ul ati o n t est r es ults ( wit hi n n or m al r a n g e or c o nsi d er e d n ot cli nic ally 
si g nific a nt b y t h e cli nic al i n v esti g at or) at scr e e ni n g or a d missi o n , i ncl u di n g pr ot hr o m bi n ti m e ( Pt), 
I nt er n ati o n al N or m aliz e d R ati o (I N R), a n d activ at e d p arti al t hr o m b o pl asti n ti m e ( A P T T).  
1 1)  S u bj ect m ust a gr e e t o us e a n a d e q u at e m et h o d of c o ntr ac e pti o n ( as d efi n e d i n S ecti o n  6. 5 ) 
1 2)  S u bj ect m ust b e a bl e t o u n d erst a n d a writt e n i nf or m e d c o ns e nt, w hic h m ust b e o bt ai n e d pri or t o 
i niti ati o n of st u d y pr oc e d ur es 
1 3)  S u bj ect m ust b e willi n g a n d a bl e t o c o m pl y wit h all st u d y r e q uir e m e nts   
6. 4  
E X C L U SI O N  C RI T E RI A  
S u bj ects t o w h o m a n y of t h e f oll o wi n g a p pli es will b e excl u d e d fr o m t h e st u d y:  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 3 2  
1)
A n y cli nic all y si g nific a nt a b n or m ality or a b n or m al l a b or at or y t est r es ults f o u n d d uri n g m e dic al  
scr e e ni n g; p ositiv e t est f or h e p atitis B, h e p atitis C, or HI V f o u n d d uri n g m e dic al scr e e ni n g
2)
Hist or y of cli nic all y si g nific a nt C V , r e n al, h e p atic, c hr o nic r es pir at or y or g astr oi nt esti n al dis e as e
( exc e pt c h ol ec yst ect o m y); n e ur ol o gic al or ps yc hi atric dis or d er, as j u d g e d b y t h e i nv esti g at or
3)
Evi d e nc e of cli nic all y si g nific a nt h e p atic i m p air m e nt at scr e e ni n g a n d a d missi o n i ncl u di n g a n y of:
a)
Al b u mi n a b ov e 1. 3 × t h e u p p er li mit of n or m al ( UL N) or b el o w 0. 7 x t h e l o w er li mit of n or m al
(LL N)
b)
AL T a b ov e 1. 5 × UL N
c)
A S T a b ov e 2. 5  × UL N
d)
t ot al bilir u bi n a b ov e 2. 0 × UL N (t ot al bilir u bi n acc e pt e d u p t o 2 × UL N  if dir ect bilir u bi n is wit hi n  
n or m al li mits)
4)
Evi d e nc e of cli nic all y si g nific a nt r e n al i m p air m e nt at scr e e ni n g i ncl u di n g esti m at e d Gl o m er ul ar  
filtr ati o n r at e ( e G F R) of < 6 0 mL/ mi n or cr e ati ni n e gr e at er t h a n 1. 5 m g/ dL.  ( T h e e G F R c alc ul ati o ns  will 
b e p erf or m e d usi n g t h e C K D- E PI 2 0 2 1 R efit E q u ati o n)
5)
Cli nic all y si g nific a nt c ar di ac fi n di n gs at scr e e ni n g or a d missi o n i ncl u di n g r esti n g H R  b el o w 5 0 or  
a b ov e 1 0 0  b p m, or E C G  a b n or m alit y or  Q Tc F ov er 4 5 0 ms
6)
K n o w n all er gi es t o a n y c o m p o n e nt of R V P- 0 0 1
7)
K n o w n dr u g all er gi es or s e nsitiviti es w hic h h av e r es ult ed  i n E m er g e nc y R o o m visits, h os pit aliz ati o ns,  
or n e e d t o c arr y r esc u e E pi p e ns as a m att er of r o uti n e pr actic e;  m o d er at e or s ev er e all er gi es t o a ny  
I V c o ntr ast a g e nts; s e as o n al all er gi es r e q uiri n g m e dic ati o n
8)
Hist or y of ast h m a
9)
S u bj ects w h o h av e t a k e n str o n g C Y P i n hi bit ors 1 4 d a ys pri or t o first d os e of st u d y A list of t h es e  
i n hi bit ors is pr ovi d e d i n S ecti o n 1 1. 4 C Y P I n hi bit ors (F D A T a bl e of S u bstr at es, I n hi bit ors, a n d  I n d uc ers 
2 0 2 0 ).
1 0) S u bj ects wit h di ets t h at ar e hi g h i n M n c o nt e nt ( > 2. 5 m g/ d a y).  F o o ds k n o w n wit h hi g h M n  c o nt e nt 
i ncl u d e s h ellfis h (i. e., m uss els, cl a ms, o yst ers), h az el n uts, p ec a ns, bl u e b erri es, pi n e a p pl e, a n d/ or 
s u p pl e m e nts c o nt ai ni n g M n
1 1) Vit al si g n a b n or m aliti es at scr e e ni n g or a d missi o n (s yst olic B P  l o w er t h a n 9 0 or ov er 1 4 0 m m H g, 
di ast olic B P  l o w er t h a n 5 0 or ov er 9 0 m m H g)
1 2) Hist or y of si g nific a nt alc o h ol a b us e wit hi n t w o y e ars pri or t o scr e e ni n g
a)
or r e g ul ar us e of alc o h ol wit hi n six m o nt hs pri or t o t h e scr e e ni n g visit (i n m al es ov er 2 1 u nits p er 
w e e k a n d f e m al es ov er 1 4 u nits p er w e e k [ 1 u nit = 1 2 oz 1 b ottl e/c a n of b e er, 1 oz 4 0 % s pirit, or 
5 oz gl ass of wi n e])
b)
or a c o nfi rm e d p ositiv e alc o h ol uri n e t est at scr e e ni n g or a d missi o n
1 3) Hist or y of si g nific a nt dr u g a b us e or us e of s oft dr u gs or h ar d dr u gs ( dr u gs of a b us e ar e list e d i n 
S ecti o n Dr u g,  Alc o h ol a n d C oti ni ne Scree n 9. 1. 5 ) wit hi n 1 y e ar pri or t o scr e e ni n g
1 4) A c o nfir m e d p ositiv e uri n e c oti ni n e t est at scr e e ni n g or a d missi o n.


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3 3  
1 5)  S u bj ects w h o h av e r ec eiv e d a n y i nv esti g ati o n al pr o d uct (I P) i n a cli nic al r es e arc h st u d y w it hi n 5 h alf-
liv es or wit hi n 3 0 d a ys pri or t o first d os e. H o w ev er, i n n o ev e nt s h all t h e ti m e b et w e e n l ast r ec ei pt of 
I P a n d first d os e b e l ess t h a n 3 0 d a ys.  
1 6)  Us e of m e dic ati o n ot h er t h a n t o pic al pr o d ucts wit h o ut si g nific a nt s yst e mic a bs or pti o n:  
a)  pr escri pt i o n m e dic ati o n wit hi n 1 4 d a ys pri or t o (t h e first) d osi n g  
b)  o v er -t h e-c o u nt er pr o d ucts i ncl u di n g n at ur al h e alt h pr o d ucts ( e. g. , f o o d s u p pl e m e nts a n d h er b al 
s u p pl e m e nts) wit hi n 1 4  d a ys pri or t o (t h e first) d osi n g , wit h t h e exc e pti o n of t h e occ asi o n al us e 
of ac et a mi n o p h e n ( u p t o 2  g d ail y )  
c) a  d e p ot i nj ect io n or a n i m pl a nt of a n y dr u g  (i ncl u di n g c o ntr ac e pti o n) wit hi n 3  m o nt hs pri or t o 
(t h e first) d osi n g  
d)  C or o n avir us Dis e as e 2 0 1 9 (C O VI D -1 9 ) v acci n es ar e acc e pt e d c o nc o mit a nt m e dic ati o ns  
1 7)  D o n ati o n of pl as m a wit hi n 7 d a ys pri or t o d osi n g ; do n ati o n or l oss of bl o o d ( excl u di n g v ol u m e dr a w n 
at scr e e ni n g) of 5 0  mL t o 4 9 9 mL of bl o o d wit hi n 3 0 d a ys, or m or e t h a n 4 9 9  mL wit hi n 5 6 d a ys pri or 
t o t h e first d osi n g 
1 8)  P ositiv e hi g hl y s e nsitiv e pr e g n a nc y t est at scr e e ni n g  or a d missi o n  f or W O C B P . 
1 9)  H av e p o or v e n o us acc ess t h at li mits p hl e b ot o m y  at scr e e ni n g  a n d a d missi o n  
2 0)  Evi d e nc e of c urr e nt s ev er e ac ut e r es pir at or y s y n dr o m e c or o n avir us 2 (S A R S -C o V -2 ; t h e vir us t h at 
c a us es C O VI D-1 9 ) i nf ecti o n  
2 1)  M al e s u bj ects wit h pr e g n a nt or l act ati n g p art n ers  
2 2)  S u bj ects w h o ar e, or ar e i m m e di at e f a mil y m e m b ers of, a st u d y sit e or s p o ns or e m pl o y e e  
2 3)  A n y r e as o n w hic h, i n t h e o pi ni o n of t h e Pri nci p al I nv esti g at or, w o ul d pr ev e nt t h e s u bj ect fr o m 
p artici p ati n g i n t h e st u d y.  
6. 5  
C O N T R A C E P TI O N A N D R E S T RI C TI O N S  
 
M al e S u bj ects wit h P art n ers of C hil d b e ari n g P ot e nti al  
M al e s u bj ects w h o ar e s ex u all y activ e wit h a p art n er of c hil d b e ari n g p ot e nti al m ust us e, wit h t h eir p art n er, 
a c o n d o m pl us a n a p pr o v e d m et h o d of hi g hl y eff ectiv e c o ntr ac e pti o n fr o m t h e ti m e of i nf or m e d c o ns e nt 
u ntil 9 7  d a y s aft er l ast st u d y dr u g a d mi nistr a ti o n.  T his is b as e d o n 9 0 d a ys ( o n e c ycl e of s p er m at o g e n esis) 
pl us 5 h alf -liv es of t h e I P.  T h e h alf -lif e of t h e  R V P -0 0 1  is u n k n o w n i n h u m a ns.  T h er ef or e, t h e d ur ati o n fr o m 
fi n al d os e t o t h e l ast f oll o w-u p visit/ p h o n e c all will  b e us e d.  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3 4  
T h e f oll o wi n g m et h o ds ar e acc e pt a bl e:  
•  
P art n er’s us e of c o m bi n e d ( estr o g e n a n d pr o g est o g e n -c o nt ai ni n g) h or m o n al c o ntr ac e pti o n ass oci at e d 
wit h i n hi biti o n of ov ul ati o n:  
− or al  
− i ntr av a gi n al  
− tr a ns d er m al  
•  
P art n er’s us e of pr o g est o g e n -o nl y h or m o n al c o ntr ac e pti o n ass oci at e d wit h i n hi biti o n of ov ul ati o n:  
− or al  
− i nj ect a bl e/i m pl a nt a bl e 
− i ntr a ut eri n e h or m o n e-r el e asi n g s yst e m  
•  
P art n er’s us e of i ntr a ut eri n e d evic e  
•  
V as ect o miz e d  
•  
P art n er’s  bil at er al t u b al occl usi o n  
M al es wit h P art n ers of N o n -c hil d b e ari n g P ot e nti al 
T h er e is a si g nific a nt ris k of dr u g ex p os ur e t hr o u g h t h e ej ac ul at e ( w hic h als o a p pli es t o v as ect o miz e d m al es) 
t h at mi g ht b e h ar mf ul t o s ex u al p art n ers.  T h er ef or e, ev e n if a m al e is s ex u all y activ e wit h a p art n er of n o n -
c hil d b e ari n g p ot e nti al, t h e y will b e r e q uir e d t o us e a c o n d o m fr o m first a d mi nistr ati o n of st u d y dr u g u ntil 
t h e f oll o w-u p visit/ p h o n e c all.  
F e m al e S u bj ects of C hil d b e ari n g P ot e nti al  
F e m al e s u bj ects w h o ar e s ex u all y activ e a n d of c hil d b e ari n g p ot e nti al m ust us e, wit h t h eir p art n er, a n 
a p pr o v e d m et h o d of hi g hl y eff ectiv e c o ntr ac e pti o n fr o m t h e ti m e of i nf or m e d c o ns e nt u ntil 3 7  d a ys aft er 
l ast st u d y dr u g a d mi nistr ati o n.  T his h as b e e n c a lc ul at e d b as e d o n 3 0 d a ys ( o n e f e m al e m e nstr u al c ycl e) pl us 
5 h alf -liv es of t h e st u d y dr u g.  T h e h alf -lif e of t h e R V P-0 0 1 is u n k n o w n i n h u m a ns.  T h er ef or e, t h e d ur ati o n 
fr o m fi n al d os e t o t h e l ast f oll o w-u p visit/ p h o n e will b e us e d.  
T h e f oll o wi n g hi g hl y e ff ecti v e m et h o ds ar e acc e pt a bl e: 
•  
I ntr a ut eri n e d evic e  
•  
V as ect o miz e d p art n er  
•  
Bil at er al t u b al occl usi o n  
F e m al e su bj ects ar e n ot r e q uir e d t o us e a n y of t h e a b ov e c o ntr ac e ptiv e m et h o ds if t h eir s ex u al p art n er is 
f e m al e. 
All S u bj ects ( M al e a n d F e m al e S u bj ects of  C hil d b e ari n g P ot e nti al)  
Alt er n ativ el y, s ex u al a bsti n e nc e is c o nsi d er e d a hi g hl y eff ectiv e m et h o d o nl y if d efi n e d as r efr ai ni n g fr o m 
i nt erc o urs e d uri n g t h e e ntir e p eri o d of ris k ass oci at e d wit h t h e st u d y tr e at m e nts.  T h e r eli a bilit y of s ex u al 
a bsti n e nc e n e e ds t o b e ev al u at e d i n r el ati o n t o t h e d ur ati o n of t h e cli nic al tri al a n d t h e pr ef err e d a n d us u al 
lif est yl e of t h e s u bj ect. 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3 5  
F e m al es of N o n -C hil d b e ari n g P ot e nti al  
F e m al e s u bj ects w h o ar e n ot of c hil d b e ari n g p ot e nti al d o n ot n e e d t o us e a n y m et h o ds of c o ntr ac e pti o n.   A 
w o m a n is c o nsi d er e d a W O C B P u nl ess p ost -m e n o p a us al or p er m a n e ntl y st eril e.  P er m a n e nt st eriliz ati o n 
m et h o ds i ncl u d e h yst er ect o m y, bil at er al s al pi n g ect o m y , a n d bil at er al o o p h or ect o m y.   A p ost -m e n o p a us al 
st at e is d efi n e d as n o m e ns es f or 1 2 m o nt hs wit h o ut a n alt er n ativ e m e dic al c a us e a n d c o nfir m e d by a F S H 
r es ult of ≥4 0 I U/L. 
6. 5. 1  S P E R M D O N A TI O N  
M al e s u bj ects s h o ul d n ot d o n at e s p er m f or t h e d ur ati o n of t h e st u d y a n d f or 9 7  d a ys aft er l ast st udy dr u g  
a d mi nistr ati o n.  
6. 5. 2  E G G D O N A TI O N  
F e m al e s u bj ects s h o ul d n ot p artici p at e i n e g g d o n ati o n f or t h e d ur ati o n of t h e st u d y a n d f or at l e ast 9 7 d ays 
aft er l ast st u d y dr u g a d mi nistr ati o n.  
6. 5. 3  P R E G N A N C Y  
S u bj ects will b e i nstr uct e d t h at if t h e y/t h eir p art n er b ec o m es pr e g n a nt d uri n g t h e st u d y t his s h o ul d b e 
r e p ort e d t o t h e i nv esti g at or.  T h e i nv esti g at or s h o ul d als o b e n otifi e d of pr e g n a nc y occ urri n g d uri n g t h e 
st u d y b ut c o nfir m e d aft er c o m pl eti o n of t h e stu d y. I n t h e ev e nt t h at a s u bj ect/s u bj ect’s p art n er is 
s u bs e q u e ntl y f o u n d t o b e pr e g n a nt aft er t h e s u bj ect is i ncl u d e d i n t h e st u d y, t h e n c o ns e nt will b e s o u g ht 
fr o m t h e s u bj ect/ p art n er a n d, if gr a nt e d, a n y pr e g n a nc y will b e f oll o w e d a n d t h e st at us of m ot h er a n d/ or 
c hil d(r e n) will b e r e p ort e d t o t h e s p o ns or aft er d eliv er y.  A n y s u bj ect r e p orti n g a pr e g n a nc y d uri n g t h e st u dy 
will b e disc o nti n u e d fr o m t h e st u d y tr e at m e nt a n d ev er y r e as o n a bl e eff ort will b e m a d e b y Q u oti e nt t o 
f oll o w u p t h e pr e g n a nc y u ntil d eliv er y.  
A pr e g n a nc y n otific ati o n f or m a n d f oll o w -u p will b e c o m pl et e d.  
6. 6  
LI F E S T Y L E C O N SI D E R A TI O N S  
 
D uri n g t his st u d y , p artici p a nts ar e as k e d t o a bst ai n  fr o m: 
•  f o o d c o nt ai ni n g p o p p y  s e e ds d uri n g t h e 4 8 h o urs pri or t o scr e e ni n g a n d t h e 4 8  h o urs 
pri or  t o a d missi o n  u ntil disc h ar g e f r om t h e cli nic al sit e 
•  f o o d or b ev er a g es c o nt ai ni n g x a nt hi n e d eriv ativ es or x a nt hi n e-r el at e d c o m p o u n ds or 
e n er gy   dri n ks  fr o m 4 8 h o urs pri or t o t h e first d osi n g u ntil disc h ar g e f r om t h e cli nic al sit e 
•  f o o d or b ev er a g es c o nt ai ni n g gr a p efr uit, st arfr uit, p o m e gr a n at e, pi n e a p pl e, p o m el o, 
a n d bl u e b erri es fr o m 2 4 h o urs  pri or t o t h e first d osi n g u ntil disc h ar g e f r om t h e cli nic al 
sit e 
•  
t a ki n g p art i n a n y u n acc ust o m e d str e n u o us ex ercis e fr o m 7 2 h o urs  b ef or e t h e scr e e ni n g visit 
a n d t h e n fr o m 7 2  h o urs  pri or t o a d missi o n u ntil disc h ar g e fr o m t h e st u d y  
•  
d o n ati n g bl o o d or pl as m a ( o utsi d e of t his st u d y) fr o m cli nic al u nit a d missi o n t hr o u g h o ut  t h e 
st u d y d ur ati o n a n d f or at l e ast 3 0 d a ys f oll o wi n g l ast d os e of st u d y m e dic ati o n  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3 6  
•  
C o ns u m pti o n of alc o h olic pr o d ucts : t his will b e pr o hi bit e d fr o m 2 4 h o urs  pri or t o scr e e ni n g a n d 
2 4 h o urs pri or t o a d missi o n  u ntil disc h ar g e f r om t h e cli nic al u nit  
T h e a d diti o n al r estricti o ns a b o v e ar e n ot excl usi o n crit eri a; if n o n -c o m pli a nc e occ urs, t h e s p o ns or will b e 
c o nt act e d, a n d e ac h d evi ati o n will b e ass ess e d o n a c as e-b y -c as e b asis.   
6. 7  
S C R E E N F AI L U R E S  
Scr e e n  f ail ur es ar e  d efi n e d  as  p artici p a nts  w h o  c o ns e nt t o p artici p at e  i n t h e cli nic al tri al b ut  ar e n ot  
s u bs e q u e ntl y r a n d o ml y assi g n e d  t o t h e st u d y i nt erv e nti o n or  e nt er e d i n  t h e st u dy. 
T h e r e as o n(s) f or t h e scr e e n f ail ur e will b e d oc u m e nt e d a n d m a y i ncl u d e d e m o gr a p h y, scr e e n f ail ur e 
d et ails, eli gi bilit y crit eri a, a n d a n y s eri o us a dv ers e ev e nt ( S A E).  
6. 8  
S T R A T E GI E S F O R R E C R UI T M E N T A N D R E T E N TI O N  
T h e i nv esti g at or or d el e g at e d, q u alifi e d st u d y st aff m e m b er will ex pl ai n a n d r evi e w t h e I nstit uti o n al 
R evi e w B o ar d  (I R B) a p pr o v e d i nf or m e d c o ns e nt f or m (I C F) wit h e ac h s u bj ect.  S u bj ects will t h e n b e giv e n 
t h e o p p ort u nit y t o as k q u esti o ns a n d will b e i nf or m e d of t h eir ri g ht t o wit h dr a w fr o m t h e st u d y wit h o ut 
pr ej u dic e.  Aft er t his ex pl a n ati o n a n d b ef or e a n y st u d y s p ecific pr oc e d ur es ar e p erf or m e d, t h e s u bj ect will 
v ol u nt aril y si g n a n d d at e t h e I R B a p pr o v e d I C F.  
 
 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 3 7  
7  
S T U D Y I N T E R V E N TI O N 
7. 1  
R V P -0 0 1  
T h e  cli nic al f or m ul ati o n of  R V P -0 0 1 will  b e  pr e p ar e d  f or I V i nj ecti o n.  At t h e cli nic al sit e a pr e d et er mi n e d d os e 
of t h e dr u g pr o d uct will b e dr a w n fr o m t h e vi al i nt o a  s yri n g e affix e d  wit h  a  n e e dl e,  f or us e  as a n  I V b ol us,  
b as e d o n  t h e dir ecti o ns  i n t h e pr ot oc ol.  
T his  pr o d uct  is f or si n gl e-us e  o nl y a n d  will  n ot  c o nt ai n a  pr es erv ativ e.  
St u dy dr u g  pr e p ar ati o ns , m et h o ds of a d mi nistr ati o n, a n d fi n al v ol u m es will b e d et ail e d i n t h e st u d y-
s p ecific p h ar m ac y  m a n u al.  
7. 1. 1  P L A C E B O  
A v ol u m e of n or m al s ali n e e q u al t o t h e d os e v ol u m e  of R V P -0 0 1 will b e a d mi nist er e d I V a n d f oll o w e d wit h 
t h e a p pr o pri at e v ol u m e of s ali n e fl us h.  Giv e n t h e l ac k of exci pi e nts i n t h e f or m ul ati o n, n or m al s ali n e is a n 
a p pr o pri at e pl ac e b o.  R V P -0 0 1 is cl e ar , c ol orl ess t o p al e y ell o w s ol uti o n, a n d h as a hi g h er visc osit y t h a n 
n or m al s ali n e.  T h er ef or e, a ll dr u g a n d pl ac e b o s yri n g es a n d I V t u b es us e d f or a d mi nistr ati o n  will b e a m b er 
ti nt e d, a n d a p o w er i nj ect or will b e us e d t o a d mi nist er t h e I V b ol us a n d s ali n e c h as e t o pr ot ect bli n di n g. 
7 .1 .2  A D M IN IS T R A T IO N O F S T U D Y D R U G , M E AL S, A N D FL UI DS 
All i nj ect a bl es will b e pr e p ar e d i n th e l ab or at or y a n d a d mi nist er e d usi n g a m b er ti nt e d s yri n g es a n d I V 
t u bi n g.  P o w er i nj ect ors wil l b e us e d t o st a n d ar diz e i nj ecti o n tim es of t h e b ol us a n d t h e s ali n e fl us h t h at 
f oll o ws.  S p ec ific d et ails of st u d y dr u g a n d d os es to b e a d mi ni st er e d ar e pr ovi d e d i n S ecti o n 7. 2. 3 a n d 
S ecti o n 5. 2 , r es p ectiv el y.  S u bj ects will b e d os e d o n t h e m or ni n g of D a y 1.  
T h e ex act ti m e of d osi n g w ill b e d eci d e d b as e d o n l o gistics a n d will b e d oc u m e nt e d in El ectr o nic C as e 
R e p ort F or ms ( e C R F). D et ails of t h e pr oc e d ur es a d o pt e d f or m ai nt ai ni n g t h e st ud y bli n d d uri n g d os i n g ar e 
pr o vi d e d i n S ecti o n 7. 3 .  If a p p e ar anc e m atc hi n g of t h e pl ac e b o is n ot p os si bl e t h e n m aski n g a n d/ or 
u n bli n d e d d osi n g t e a ms will b e us e d t o pr es erv e t h e st u d y bli n d. F urt h er d et ails of t h es e st e ps will b e 
c o nt ai n e d i n t h e st u d y s p ecific bli n di n g pl a n, w hic h will b e a p pr ov e d pri or t o d osi n g (s e e als o  S ecti o n 7. 3 ).  
F or e ac h s u bj ect, all sc h e d ul e d p ost d os e activiti es a n d ass ess m e nts will b e  p erf or m e d r el ativ e t o t h e ti m e 
of  st u d y dr u g a d mi nistr ati o n (s e e S ecti o n 9. 5 f or f urt h er d et ails).  R ef er e nc e tim e f or all p ost- d os e activiti es 
will b e ti m e of b e gi n ni n g of b ol us d os e i nj ecti o n. 
A st a g g er e d d osi n g sc h e d ul e will b e  us e d .  I n e ac h c o h ort 2 s e nti n el s u bj ects ( 1 activ e a n d 1 pl ac e b o) will 
b e d os e d first a n d t h e r e m ai ni n g 6 s u bj ects ( 5 activ e a n d 1 pl ac e b o) will b e d os e d  2 4 h o urs l at er. All 
c o h orts will b e  d os e d i n a si mil ar m a n n er.  S e e S ecti o n 7. 3 f or f urt h er d et ails.  
T o ass ess t ol er a bility of t h e I V a d mi nistr ati o n, t h e first s u bj ect will b e d os e d at l e ast 3 0 mi n pri or t o d osi n g 
t h e s ec o n d s u bj ect.  All s u bs e q u e nt d osi n g of t h e st u d y dr u g will b e st a g g er e d b y at l e ast 1 5 mi n.  T o all o w 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3 8  
f or p ot e nti al i nt err u pti o ns a n d i nj ect or v ari ati o ns, u p t o a 2 0 % diff er e nc e i n d ur ati o n of t h e i nf usi o n will 
n ot b e c o nsi d er e d as a pr ot oc ol d evi ati o n pr ovi d e d t h at f ul l pl a n n e d d os e is a d mi nist er e d.  A n y s uc h mi n or 
discr e p a nci es s h o ul d n ot h av e a si g nific a nt i m p act o n t h e ov er all st u d y o bj ecti v es.  
T h e pl a n n e d i n j ecti o n ti m e will b e a p pr oxi m at el y 5 -1 5  s ec ( d e p e n di n g u p o n p ati e nt w ei g ht/ d os e) ; t h e 
act u al i nf usi o n st art a n d st o p ti m e will b e r ec or d e d i n t h e s o urc e  d oc u m e nts . I n all c as es, t h e st u d y dr u g 
i nj ecti o n will b e f oll o w e d b y 2 0 s ec o n d i nj ecti o n of n or m al s ali n e.  
A 2 0 g a u g e  I V will b e st art e d i n t h e ri g ht a nt ec u bit al f oss a, w h er e p ossi bl e , a n d  m ust d e m o nstr at e e as y 
fl us h. A n  I V b ol us i nj ecti o n of R V P-0 0 1 will b e a d mi nist er e d vi a a  p o w er i nj ect or  at a fl o w r at e of u p t o 2 
mL/s ec f oll o w e d b y b ol us a d mi nistr ati o n of u p t o 4 0  cc of n or m al s ali n e als o a d mi nist er e d at u p t o 2 
mL/s ec.  Pr ecis e v ol u m es a n d  r at es of i nj ecti o n of b ot h R V P -0 0 1 a n d s ali n e fl us h will b e r ec or d e d.  
F urt h er d et ails of pr oc e d ur e s f or i nj ecti o n c a n b e f o u n d i n t h e st u d y dr u g i nj ecti o n g ui d eli n es. 
I V bl o o d s a m pl es will b e o bt ai n e d fr o m t h e o p p osit e ar m  t o t h e b ol us, w h er e p ossi bl e . 
7. 1. 3  M E A L S A N D F L UI D  
S u bj ects will b e all o w e d w at er u p t o 1 h o ur  b ef or e t h e sc h e d ul e d d osi n g ti m e.  S u bj ects will b e r e q uir e d t o 
dri n k 2 5 0 mL of w at er at 1 h o ur  p ost -d os e t o e ns ur e a d e q u at e h y dr ati o n a n d  a n a d diti o n al 2 5 0 mL of 
w at er 1 -2 h o urs  p ost d os e.  T h er e aft er, w at er will b e all o w e d a d li bit u m.   S u bj ects will b e str o n gl y 
e nc o ur a g e d t o dri n k all o w e d fl ui ds t hr o u g h o ut st u d y.  D ec aff ei n at e d fl ui ds will b e all o w e d a d li bit u m fr o m 
l u nc h ti m e o n t h e d a y of d osi n g.  
T h e c al oric/f at c o nt e nt of m e als ar e n ot r e q uir e d t o b e c o ntr oll e d.  S u bj ects will b e pr o vi d e d wit h a 
st a n d ar diz e d m e n u t h at d o es n ot c o nt ai n f o o ds hi g h i n M n  c o nt e nt.  
S u bj ects will b e pr o vi d e d wit h a li g ht s n ac k a n d t h e n f ast fr o m all f o o d a n d dri n k ( exc e pt w at er) f or a 
mi ni m u m of 8 h o urs pri or t o d osi n g u ntil a p pr oxi m at el y 4  h o urs p ost -d os e  at w hic h ti m e l u nc h will b e 
pr o vi d e d.   A n ev e ni n g m e al will b e pr o vi d e d at a p pr oxi m at el y 1 0  h o urs p ost -d os e a n d a n ev e ni n g s n ac k at 
a p pr oxi m at el y 1 4  h o u rs p ost-d os e.   O n s u bs e q u e nt d a ys, m e als will b e pr ovi d e d at a p pr o pri at e ti m es.  
7. 2  
P R E P A R A TI O N / H A N D LI N G / S T O R A G E / A C C O U N T A BI LI T Y  
7. 2. 1  P A C K A GI N G, L A B E LI N G  A N D  DI S P E N SI N G  
T h e  S p o ns or  will  b e  r es p o nsi bl e f or e ns uri n g  t h at t h e st u d y dr u g is m a n uf act ur e d  i n acc or d a nc e  wit h 
a p plic a bl e c urr e nt G o o d  M a n uf act uri n g  Pr actic e ( G M P) r e g ul ati o ns  a n d  r e q uir e m e nts. 
T h e  st u d y dr u g will  b e  l a b el e d acc or di n g  t o t h e r e q uir e m e nts of  l oc al l a w a n d l e gisl ati o n.   T h e  st u dy dr u g 
will  b e  pr e p ar e d a n d dis p e ns e d acc or di n g t o t h e p h ar m acy m a n u al by t h e  cli nic al sit e’s p h ar m acy . 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 3 9  
B as e d o n t h e s u bj ect s el ecti o n list, t h e a p pr o pri at e d os e of R V P-0 0 1 or m atc hi n g pl ac e b o will b e pr e p ar e d 
a n d dis p e ns e d b y a n u n bli n d e d p h ar m acist at t h e cli nic al sit e . 
7. 2. 2  S T O R A G E  A N D  H A N D LI N G  
At t h e st u d y sit e, st u d y dr u g m ust b e k e pt i n a s ec ur e, l oc k e d ar e a or l oc k e d c a bi n et wit h acc ess r estrict e d 
t o d esi g n at e d st u d y sit e p ers o n n el.  Vi als s h o ul d b e st or e d at r o o m t e m p er at ur e of 2 5° C ( 7 7° F), exc ursi o ns 
p er mitt e d b et w e e n 1 5° C t o 3 0° C ( 5 9° F t o 8 6° F) i n a dr y ar e a, pr ot ect e d fr o m li g ht.  T h e l ot n u m b ers a n d 
ex pir ati o n d at es ( w h er e av ail a bl e) of t h e st u d y dr u gs s u p pli e d will b e r ec or d e d i n t h e fi n al Cli nic al St u dy 
R e p ort ( C S R).  R ec or ds will b e m a d e of t h e r ec ei pt a n d dis p e nsi n g of t h e st u d y dr u gs  s u p pli e d.  At t h e 
c o ncl usi o n of t h e st u d y a n y u n us e d st u d y dr u gs will b e r et ai n e d b y C R O, r et ur n e d t o t h e S p o ns or or 
d esi g n e e, or d estr o y e d, as p er S p o ns or i nstr ucti o ns.  If n o s u p pli es r e m ai n, t his f act will b e d oc u m e nt e d i n 
t h e p h ar m ac y pr o d uct acc o u nt ability r ec or ds.  All st u d y dr u g will b e tr a ns p ort e d, r ec eiv e d, st or e d, a n d 
h a n dl e d strictl y i n acc or d a nc e wit h t h e c o nt ai n er or pr o d uct l a b el, t h e i nstr ucti o ns s u p pli e d t o t h e cli nic al 
sit e a n d its d esi g n at e d p h ar m ac y, t h e sit e’s st a n d ar d o p er ati n g pr oc e d u r es ( S O Ps), a n d a p plic a bl e 
r e g ul ati o ns. A p pr o pri at e st or a g e t e m p er at ur e a n d tr a ns p ort ati o n c o n diti o ns will b e m ai nt ai n e d f or t h e 
st u d y dr u g fr o m t h e p oi nt of m a n uf act ur e u ntil d eliv er y t o t h e sit e.  T h e p h ar m ac y st aff will ex a mi n e t h e 
s hi p m e nt t o v erif y t hat t h e st u d y dr u gs w er e r ec eiv e d i n acc e pt a bl e c o n diti o n.  O nc e i ns p ect e d, t h e st u dy 
dr u gs  will b e st or e d i n a s ec ur e ar e a wit h acc ess r estrict e d o nl y t o a ut h oriz e d st aff, u n d er p h ysic al 
c o n diti o ns c o nsist e nt wit h t h e st u d y dr u g r e q uir e m e nts.  T h e sit e p h a r m acist or d el e g at e is r es p o nsi bl e f or 
e ns uri n g t h at all st u d y dr u gs r ec eiv e d at t h e sit e ar e i nv e nt ori e d a n d acc o u nt e d f or t hr o u g h o ut t h e st u dy, 
acc or di n g t o t h e a p plic a bl e r e g ul ati o ns a n d t h e sit e’s S O Ps.  D et ails of t h e r ec ei pt, st or a g e, dis p e nsi n g, a n d  
d estr ucti o n will b e r ec or d e d a n d m ai nt ai n e d i n t h e p h ar m ac y l o g b o o k b y t h e p h ar m ac y st aff.  T h e S p o ns or 
will pr ovi d e writt e n i nstr ucti o ns r e g ar di n g t h e fi n al dis p ositi o n of t h e u n us e d st u d y tr e at m e nts.  C o pi es of 
t h e st u d y tr e at m e nt acc o u nt a bility r ec or ds will b e pr o vi d e d t o t h e S p o ns or at t h e c o m pl eti o n of t h e st u d y 
a n d will b e m a d e av ail a bl e f or r evi e w b y t h e Sit e M o nit or, if a p plic a bl e, d uri n g t h e c o urs e of t h e st u dy.  
7. 2. 3  F O R M U L A TI O N, A P P E A R A N C E, P A C K A GI N G, A N D L A B E LI N G  
T h e  S p o ns or  will  b e  r es p o nsi bl e f or e ns uri n g  t h at t h e st u d y dr u g is m a n uf act ur e d  i n acc or d a nc e  wit h  
a p plic a bl e c urr e nt G M P r e g ul ati o ns a n d  r e q uir e m e nts. 
T h e  st u d y dr u g wil l b e pr e p ar e d a n d dis p e ns e d i n a m b er syri n g es acc or di n g t o t h e p h ar m acy m a n u al by t h e 
cli nic al sit e’s p h ar m acy, u nl ess  t h e S p o ns or  s u p pli es t h e p h ar m ac y wit h  pr el a b el e d  i n divi d u al d osi n g  
s a m pl es. 
 
 
R V P -0 0 1 dr u g pr o d uct is pr o vi d e d i n cl e ar gl ass vi als (t y p e 1 U S P) wit h br o m o b ut yl r u b b er  st o p p ers a n d 
al u mi n u m  fli p-a n d -t e ar t y p e s e al. 




R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 4 1  
  
 
 
  
Pr e p ar e d s yri n g es m a y b e st or e d at r o o m t e m p er at ur e pri or t o d osi n g f or u p t o 6 0 mi n ut es.  A si mil ar 
v ol u m e of n or m al s ali n e will b e dis p e ns e d f or s u bj ects r ec eivi n g pl ac e b o.  All s yri n g es a n d I V t u bi n g will b e 
a m b er ti nt e d t o pr ot ect bli n di n g.  F urt h er i nf or m ati o n will b e pr o vi d e d i n t h e p h ar m ac y m a n u al.  
F urt h er i nf or m ati o n will b e pr o vi d e d i n t h e P h ar m ac y M a n u al.  
7. 3  
M E A S U R E S T O MI NI MI Z E BI A S: R A N D O MI Z A TI O N  A N D  B LI N DI N G  
S u bj ects eli gi bl e f or p artici p ati o n will b e r a n d o miz e d t o r ec eiv e eit h er  R V P -0 0 1 or t h e pl ac e b o  i m m e di at el y 
pri or t o d osi n g .  
A s u bj ect s el ecti o n list will b e pr o d uc e d pri or t o d osi n g usi n g t h e r a n d o miz ati o n sc h e d ul e a n d will b e 
r et ai n e d i n t h e I nv esti gat or Sit e Fil e (I S F).  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 4 2  
F or all c o h orts , a s e nti n el gr o u p of 2  s u bj ects will b e d os e d a h e a d of t h e r e m ai ni n g s u bj ects i n e ac h c o h ort. 
F or e ac h c o h ort i n w hic h s e nti n el d osi n g is or m a y b e us e d, usi n g a c o m p ut er ‑g e n er at e d r a n d o mis ati o n 
sc h e d ul e, t h e first 2  s u bj ect n u m b ers will b e all oc at e d t o activ e or pl ac e b o i n a 1 : 1 r ati o (i. e., 1  s u bj ect will 
b e r a n d o ml y assi g n e d t o r ec eiv e  R V P -0 0 1 a n d 1  s u bj ect will b e r a n d o ml y assi g n e d t o r ec eiv e pl ac e b o).  
T h e r e m ai ni n g 6  s u bj ect n u m b ers will b e all oc at e d t o activ e or pl ac e b o i n a 5: 1  r ati o (i. e., 5  s u bj ects will b e 
r a n d o ml y assi g n e d t o r ec eiv e R V P -0 0 1 a n d 1  s u bj ect will b e r a n d o ml y assi g n e d t o r ec eiv e pl ac e b o). 
T his is a d o u bl e -bli n d st u d y. S u bj ects a n d t h e cli nic al p ers o n n el i nv olv e d i n t h e c oll ecti o n,  m o nit ori n g, 
r evisi o n, or ev al u ati o n of A E s, p ers o n n el of t h e bi o a n al ytic al d e p art m e nt , a n d p ers o n n el w h o c o ul d h a v e 
a n i m p act o n t h e o utc o m e of t h e st u d y will b e bli n d e d wit h  r es p ect t o t h e s u bj ect’s tr e at m e nt assi g n m e nt 
( R V P-0 0 1 or pl ac e b o).   Bli n di n g wil l b e m ai nt ai n e d at l e ast u ntil t h e cli nic al p h as e of t his p art of t h e st u d y 
is c o m pl et e d (i. e., w h e n i n v esti g ati o n a n d  r e p orti n g of all  A E s h as  b e e n  c o m pl et e d f or all c o h orts). 
T h e r a n d o miz ati o n sc h e d ul e a n d discl os ur e e nv el o p es will b e g e n er at e d b y a n u n b li n d e d st atistici a n at 
Q u oti e nt acc or di n g t o Q u oti e nt’s S O Ps.  T h e u n bli n d e d st atistici a n will n ot b e i nv olv e d i n a n y d ecisi o ns 
r el ati n g t o p o p ul ati o ns f or a n al ysis pri or t o u n bli n di n g.  Pri or t o d at a b as e l oc k a n d u n bli n di n g, all ori gi n al 
r a n d o miz ati o n m ateri als, i ncl u di n g t h e ori gi n al fi n al si g n e d a n d d at e d r a n d o miz ati o n sc h e d ul e, will b e h el d 
b y t h e Q u alit y Ass ur a nc e ( Q A) d e p art m e nt at Q u oti e nt.   T h e D at a Sci e nc es d e p art m e nt will n ot h av e 
acc ess t o t h e r a n d o miz ati o n sc h e d ul e b ef or e d at a b as e l oc k a n d u n bli n di n g.  
I nt eri m P K p ar a m et er esti m ati o ns will b e p erf or m e d usi n g bi o a n al ytic al d at a a p pli e d wit h s u bj ect ali as es i n 
or d er t o m ai nt ai n t h e st u d y bli n d.  
T h er e m a y b e i nst a nc es w h er e i nt eri m P K d at a h av e t h e p ot e nti al t o b e tr e at m e nt r ev e ali n g (e. g. , miss e d 
b l o o d s a m pli n g occ asi o ns).  I n t h es e c as es, ev er y eff ort will b e m a d e b y t h e p h ar m ac o ki n eticist t o 
m ai nt ai n t h e st u d y bli n d b y a p pr o pri at e pr es e nt ati o n of d at a t o t h e st u d y t e a m.   D at a d e m o nstr ati n g 
extr e m es of ex p os ur e will al w a ys b e pr es e nt e d, r e g ar dl ess of t h e p ot e nti al t o r ev e al t h e st u d y bli n d.  T o 
p er mit s el ecti o n of t h e d os e l ev el , i n divi d u al d at a m a y b e m a d e av ail a bl e i n f ull if j u d g e d n ec ess ar y by t h e 
i nv esti g at or or s p o nsor  r e g ar dl ess of t h e p ot e nti al t o r ev e al st u d y bli n d. W h er e p ossi bl e t his s h o ul d b e t o a 
s u b-gr o u p of t h e r evi e w c o m mitt e e w h o ar e r es p o nsi bl e f or  d os e l ev el s el ecti o n. 
D esi g n at e d p h ar m ac y p ers o n n el at t h e cli nic al sit es n ot dir ectl y i nv olv e d wit h t h e cli nic al as p ects  of t h e  
tri al will  pr e p ar e  a n d  dis p e ns e  t h e st u d y m e dic ati o n  a n d  will  b e  a w ar e  of  t h e r a n d o miz ati o n c o d e.  A c o py 
of t h e r a n d o mi zati o n sc h e d ul e or c orr es p o n di n g discl os ur e e nv el o p es will als o b e m a d e av ail a bl e  t o t h e 
p h ar m ac o vi gil a nc e pr o vi d er f or a n al ysis of p h ar m ac o vi gil a nc e.  
T h e  st u d y dr u g  a n d  pl ac e b o  will h av e t h e s a m e  vis u al  a p p e ar a nc e  i n or d er t o av oi d c o m pr o misi n g t h e 
st u d y b li n di n g. If a p p e ar a nc e m atc hi n g of t h e pl ac e b o is n ot p ossi bl e t h e n us e of m as ki n g a n d/ or 
u n bli n d e d d osi n g t e a ms will b e us e d t o pr es erv e t h e st u d y bli n d.  F urt h er d et ails of t h es e st e ps will b e 
c o nt ai n e d i n t h e st u d y s p ecific p h ar m ac y m a n u al w hic h will b e  a p pr o v e d pri or t o d osi n g.  
I n t h e ev e nt of a n e m er g e nc y, or r e pl ac e m e nt of s u bj ect, a n e nv el o p e f or e ac h s u bj ect c o nt ai ni n g his/ h er 
tr e at m e nt assi g n m e nt will b e av ail a bl e fr o m cli nic al p ers o n n el i nv olv e d wit h t h e pr e p ar ati o n of t h e st u dy 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 4 3  
m e dic ati o n.  T w o s ets of discl os ur e e nv el o p es (i. e., s e al e d e nv el o p es c o nt ai ni n g i n divi d u al s u bj ect 
r a n d o miz ati o n d et ails) will b e pr o vi d e d.  O n e s et will b e h el d i n t h e cli nic al ar e a a n d t h e ot h er r et ai n e d i n 
t h e I S F. 
T h es e m a y b e us e d i n t h e ev e nt of a n e m er g e nc y b y t h e i nv esti g at or.  A n y r e q u est f or i nf or m ati o n o n t h e 
r a n d o miz ati o n sc h e d ul e aft er i niti al iss u e m ust b e m a d e usi n g a r a n d o miz ati o n discl os ur e f or m, exc e pt i n 
t h e c as e of e m er g e nc y u n bli n di n g, w hic h m ust b e r ec or d e d o n t h e e m er g e nc y u n bli n di n g f or m.  Acc ess t o  
st u d y dr u g assi g n m e nt will b e i m m e di at el y av ail a bl e if t h e i nv esti g at or d e e ms it n ec ess ar y t o br e a k t h e 
st u d y bli n d i n t h e i nt er est of a s u bj ect’s m e dic al s af et y, i n c as e of a m e dic al e m er g e ncy, or if w arr a nt e d 
d uri n g sc h e d ul e d s af et y r e vi e ws.   T h e m e dic a l m o nit or m ust b e c o nt act e d wit hi n 2 4 h f oll o wi n g discl os ur e 
of st u d y dr u g assi g n m e nt.  
D et ails of a n y discl os ur e of t h e r a n d o miz ati o n sc h e d ul e will b e d oc u m e nt e d a n d r et ai n e d i n t h e I S F.  T h e 
s p o ns or will b e n otifi e d if t h e st u d y bli n d is br o k e n. 
T h e st u d y bli n d will b e br o k e n aft er t h e st u d y d at a b as e h as b e e n l oc k e d a n d t h e s af et y p o p ul ati o n h as 
b e e n d efi n e d .  A n y s u bs e q u e nt r e q u est f or iss u e of t h e r a n d o miz ati o n sc h e d ul e pri or t o u n bli n di n g m ust 
b e m a d e usi n g a r a n d o miz ati o n discl os ur e f or m.  
T h e r a n d o miz ati o n c o d e will n ot b e av ail a bl e t o t h e bi o a n al ytic al l a b pri or t o  t h e a n al ysis of t h e pl as m a 
s a m pl es fr o m e ac h c o h ort.  
7 .3 .1  S U B JE C T N U M B E R S 
S u bj ects will b e assi g n e d a t hr e e- di git scr e e ni n g n u m b er aft er i nf or m e d c o ns e nt is o bt ai n e d (e. g. , 0 0 1, 
0 0 2, 0 0 3, et c.).  F o ur- di git s u bj ect n u m b ers will b e all oc at e d o n t he m or ni n g o f d os i n g acc or di n g t o t h e 
c o d e 1 0 0 1 t o 1 0 4 0  usi n g t h e l ow est n u m b er av ail a bl e.  R e pl ac e m e n t s u bj ects will b e all o c at e d s u bj ect 
n u m b ers 9 0 0 1 t o 9 0 4 0 , w h er e t h e l ast t hr e e di gits ar e t he s a m e as t h os e of t h e ori gi n al s u bj ect (e. g., if 
S u bj ec t 1 0 0 5 wit h dr a ws, t h e r e pl ac e m ent will h av e S u bj ec t N u m b er 9 0 0 5 a n d will r ec eiv e t h e s a m e 
r e gi m e n as S u bj ec t 1 0 0 5 wit h t h e exc e pti o n of a n y st u d y dr u gs d os e d i n a pr e vi o us r e gi m e n t h a t h av e 
b e e n d e e m e d s u b- o pti m al). 
S u bj ect n u m b eri n g b y c o h ort is pr ovi d e d i n  T a bl e 3.  
T a bl e 3 S u bj ec t N u m b ers b y C o h ort 
C o h ort  
S u bj ect N u m b ers  
R e pl ac e m e nt N u m b ers  
1 a. 1  
1 0 0 1 -1 0 0 8  
9 0 0 1 -9 0 0 8  
1 a. 2  
1 0 0 9 -1 0 1 6  
9 0 0 9 -9 0 1 6  
1 a. 3  
1 0 1 7 -1 0 2 4  
9 0 1 7 -9 0 2 4  
1 a. 4  
1 0 2 5 -1 0 3 2  
9 0 2 5 -9 0 3 2  
1 a. 5 (if n e e d e d)  
1 0 3 3 -1 0 4 0  
9 0 3 3 -9 0 4 0  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 4 4  
7. 4  
S T U D Y IN T E R V E N TI O N  C O M P LI A N C E  
D uri n g all cli nic al p h as es of t h e st u d y, s u bj ects will b e o bs erv e d b y st u d y st aff t o ass ur e c o m pli a nc e t o all 
st u d y pr oc e d ur es, i ncl u di n g d os e a d mi nistr ati o n.  
T h e I V d os e will b e a d mi nist er e d b y tr ai n e d st aff t o e ns ur e d osi n g c o m pli a nc e.  
T h e d at e a n d ti m e t h at e ac h s u bj ect is d os e d will b e r ec or d e d i n t h e s u bj ect’s e C R F.  A n y vi ol ati o n of 
c o m pli a nc e will r e q uir e e v al u ati o n b y t h e i nv esti g at or a n d s p o ns or t o d et er mi n e if t h e s u bj ect c a n 
c o nti n u e i n t h e st u d y. 
7. 5  
C O N C O MI T A N T T H E R A P Y  
Pr escri pt i o n a n d ov er-t h e-c o u nt er m e dic ati o ns will b e pr o hi bi t e d wit hi n 1 4 d ays pri or t o (t h e first) d os i n g 
a n d t hr o u g h o ut t h e st u d y.  Ov er-t h e-c o u nt er pr o d u cts i ncl u di n g n at ur al h e alt h pr o d ucts ( e. g., f o o d 
s u p pl e me nts a n d h er b al s u p pl e m e nts) w it hi n 1 4  d a ys pri or to (t h e first) d osi n g , wit h t h e exc e pti o n of t h e 
occ asi o n al us e of ac et a mi n o p h e n ( u p t o 2 g d ail y) ar e als o pr o hi bit e d. 
T h e m et a b olic p at h w a y of R V P- 0 0 1 is n o t f ull y u n d ers t o o d, a n d n o f or m al dr u g-dr u g i nt er acti o n ( D DI) 
st u di es h av e b e e n co n d uct e d wit h R V P- 0 0 1 .  T h er ef or e, i n a n eff or t t o pr ev e n t th e occ urr e nc e of a ny D DIs, 
t h e us e of c yt oc hr o m e P 4 5 0 ( C Y P) i n hi bit ors is pr o hi bit e d f or us e u p t o 1 4 d a ys pri or to us e of R V P- 0 0 1  as 
st at e d i n excl usi o n crit eri a (s e e S ecti o n 6. 4 ). Als o a t a bl e listi n g a d diti o n al C Y P i n hi bit ors is pr ovi d e d i n 
S ecti o n 1 1. 4 C Y P I n hibit ors ( F D A T a bl e of S u bstr at es, I n hi bit ors a n d I n d uc ers 2 0 2 0 ).  
S u bj ects als o c a n n ot h av e d e p ot i nj ecti o n or a n i m pl a nt (i ncl u di n g co ntr ac e pti o n) of a n y dr u g wit hi n 3 
m o nt hs pri or t o (t h e first) d osi n g. 
C O VI D- 1 9 v acci n es ar e ac c e pt e d co nc o mit a nt m e dic ati o ns. 
All c o nc o mit a nt m e dic ati o n us e w ill b e d oc u m e nt e d. 
M e dic ati o ns t o b e r ep ort e d i n t h e C a s e R e p ort F or m ( C R F) ar e c o nc o mit a nt pr e scri pti o n m e dic ati o ns, 
o v er-t h e-c o u nt er m e dic ati o ns, a n d s u p pl e m e nts.  M e dic ati o ns wil l b e c o d e d usi n g W orl d H e a lt h 
Or g a niz at i o n ( W H O) Dr u g Dicti o n ar y Gl o b al Dr u g R ef er e nc e. 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 4 5  
8  
S T U D Y I N T E R V E N TI O N DI S C O N TI N U A TI O N  A N D P A R TI CI P A N T  
DI S C O N TI N U A TI O N / WI T H D R A W A L  
8. 1  
B E F O R E FI R S T T R E A T M E N T A D MI NI S T R A TI O N  
B ef or e t h e first tr e at m e nt a d mi nistr ati o n, i ncl usi o n/ excl usi o n cri t eri a will g o v er n t h e s u bj ects t o b e d os e d. 
S u bj ects wit h dr a w n b ef or e first tr e at m e nt a d mi nistr ati o n will n ot b e f oll o w e d u p a n d will n ot u n d er g o 
E n d -of -St u d y/ E arl y T er mi n ati o n ass ess m e nts.  
S u bj ects ar e fr e e t o wit h dr a w t h eir c o ns e nt t o p artici p at e i n t h e st u d y at a n y ti m e, wit h o ut pr ej u dic e.  T h e 
r e as o n f or t h eir wit h dr a w al or f or d eci di n g t o e n d t h eir p artici p ati o n will b e d oc u m e nt e d. 
8. 2  
A F T E R FI R S T T R E A T M E N T A D MI NI S T R A TI O N  
S u bj ects m a y, at a n y ti m e, v ol u nt aril y wit h dr a w fr o m t h e st u d y or b e r e m ov e d fr o m t h e st u d y at t h e 
discr eti o n of a n i nv esti g at or or t h e s p o ns or.  A n i nv esti g at or m a y wit h dr a w a s u bj ect at a n y ti m e if it is 
d et er mi n e d t h at c o nti n ui n g t h e st u d y w o ul d r es ult i n a s af et y ris k t o t h e s u bj ect or if t h eir b e h avi or is 
d el et eri o us t o t h e st u d y e n vir o n m e nt.  
If s uc h wit h dr a w al occ urs, or if t h e s u bj ect f ails t o r et ur n f or visits, a n i nv esti g at or s h o ul d d et er mi n e t h e 
pri m ar y r e as o n f or a s u bj ect’s pr e m at ur e wit h dr a w al fr o m t h e st u d y a n d r ec or d t h e r e as o n i n t h e s u bj ect’s 
st u d y d oc u m e nts.  Att e m pts s h o ul d b e m a d e t o h av e t h e s u bj ect c o m pl et e t h e E n d -of -St u d y/ E arl y 
T er mi n ati o n ass ess m e nts.  
A n i nv esti g at or m a y r e m o v e a s u bj ect fr o m t h e st u d y, f oll o wi n g c o ns ult ati o n wit h t h e s p o ns or d u e t o a n 
u n a ntici p at e d ev e nt t h at c o ul d r es ult i n a n i n a d e q u at el y c h ar ac t eriz e d P K pr ofil e, s uc h as a miss e d bl o o d 
dr a w or uri n e c oll ecti o n, a n A E, m e al d evi ati o n or c o nc o mit a nt m e dic ati o n i nt a k e.  
Att e m pts s h o ul d b e m a d e t o h av e s uc h s u bj ects c o m pl et e t h e E n d -of -St u d y/ E arl y T er mi n ati o n 
ass ess m e nts.   E n d -of -St u d y/ E arl y T er mi n ati o n ass ess m e nts s h o ul d b e p erf or m e d as s o o n as p ossi bl e aft er 
t h e l ast st u d y tr e at m e nt a d mi nistr ati o n. 
D et ails of r e as o ns f or r e m ov al of s u bj ects will b e r ec or d e d, r e p ort e d t o t h e S p o ns or a n d d oc u m e nt e d i n 
t h e C S R . 
E arl y wit h dr a w al is d efi n e d as t h e d at e of t h e d ecisi o n t o wit h dr a w t h e s u bj ect fr o m t h e st u d y.  S u bj ect 
c o m pl eti o n is d efi n e d as t h e d at e of t h e l ast pr oc e d ur e c o n d uct e d or l ast c o nt act ( e .g ., p h o n e c all or 
u nsc h e d ul e d visit) f or t h at s u bj ect.  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 4 6  
8. 3  
S T O P PI N G R U L E S  
8. 3. 1  I N DI VI DU A L S U BJ E C T S T O P PI N G R U L E S  
P artici p ati o n i n t h e cli nic al st u d y m a y b e disc o nti n u e d b y t h e p h ysici a n i n c h ar g e of t h e st u d y or b y t h e 
s p o ns or f or a n y of t h e f oll o wi n g r e as o ns, b ut n ot li mit e d t o:  
1)
A E s (i ncl u di n g if a s u bj ect d ev el o ps a n y si g nific a nt ill n ess or n e e ds t o u n d er g o a n y m aj or
s ur g er y d uri n g c o urs e of t h e st u d y i ncl u di n g s eiz ur e, str o k e, c er e br al v e n o us t hr o m b osis)
2)
S u bj ect n o n -c o m pli a nc e (i ncl u di n g a n y vi ol ati o n of pr ot oc ol r e q uir e m e nts w hic h m a y aff ect t h e
st u d y o utc o m e)
3)
S u bj ect s will b e disc o nti n u e d fr o m t h e cli nic al st u d y f or a n y of t h e f oll o wi n g r e as o ns, b ut n ot
li mit e d t o:
a)  
M e ets eit h er of t h e f oll o wi n g crit eri a b as e d o n E C G r e a di n gs:
1)  
Q Tc F > 4 8 0 ms ec
2)  
Q Tc F c h a n g e fr o m b as eli n e > 6 0 ms ec
4)
A 7 -d a y or 1 5 -d a y I N D S af et y r e p ort will b e s u b mitt e d f or a n y tr e at m e nt e m er g e nt c as e of
s eiz ur e, str o k e, c er e br al v e n o us, t hr o m b osis, Q Tc gr e at er t h a n 4 8 0 ms ec or Q T C i ncr e as e of
m or e t h a n 6 0 ms ec ov er b as eli n e
F or t h e p ur p os e of wit h dr a w al crit eri a, b as eli n e will b e c o nsi d er e d as t h e l ast av ail a bl e ass ess m e nt 
pri or t o first d os e . 
8. 3. 2  C O H O R T S T O P PI N G R U L E S  
If a n y of t h e f oll o wi n g s af et y c o nc er ns ar e o bs erv e d, d osi n g of all s u bj ects at t h e giv e n d os e l e v el or hi g h er 
will b e s us p e n d e d/ h alt e d a n d all av ail a bl e d at a will b e ev al u at e d b y t h e S af et y R evi e w  C o m mitt e e ( S R C ).  
1)
If o n e ( 1 ) R V P -0 0 1 -r el at e d S A E occ urs i n a c o h ort
2)
M o d er at e or s ev er e A Es i n 5 0 % of t h e s u bj ects i n t h e c o h ort or m or e
3)
Cli nic all y si g nific a nt l a b or at or y a b n or m aliti es of t h e s a m e c h ar act er i n 3 or m or e s u bj ects ( e. g. ,
AL T > 3 UL N)
4)
Cli nic all y si g nific a nt c h a n g es i n vit al si g ns of t h e s a m e c h ar act er i n 3 or m or e s u bj ects: B P
c o nsist e ntl y gr e at er t h a n 1 6 0 m m H g ass oci at e d wit h a n i ncr e as e fr o m b as eli n e gr e at er t h a n 2 0
m m H g
5)
Cli nic all y si g nific a nt c h a n g es i n E C Gs of t h e s a m e c h ar act er i n 3 or m or e s u bj ects: Q Tc F gr e at er
t h a n 4 8 0  ms ec wit h a n i ncr e as e fr o m b as eli n e gr e at er t h a n 6 0 ms ec
D os e c o nti n u ati o n (r e m ai ni n g s u bj ects wit hi n a c o h ort or r e m ai ni n g d osi n g f or a s u bj ect) or esc al ati o n 
d ecisi o n will b e m a d e f oll o wi n g ev al u ati o n of t h e ev e nt b y t h e S R C.  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 4 7  
Pri or t o st arti n g a n e w d os e/c o h ort, d os e esc al ati o n will b e disc uss e d d uri n g t h e S R C m e eti n g a n d m ay b e 
m o difi e d or st o p p e d d e p e n di n g o n t he i nv esti g at or’s or s p o ns or’s d ecisi o n, b as e d o n b ut n ot li mit e d t o t h e 
f oll o wi n g: 
1)
N e w cl i nic all y si g nific a nt a b n or m aliti es i n p hysic al ex a mi n ati o n, 1 2-l e a d E C G or vit al si g ns i n 2
or m or e s u bj ects
2)
Ov er all p att er n of cli nic al c h a n g es or s y m pt o ms t h at m a y h av e a p p e ar e d mi n or i n t er ms of a n
i n divi d u al A E or s u bj ect, b ut w hic h c oll ectiv el y pr es e nt a s af et y c o nc er n
3)
Cli nic all y si g nific a nt c h a n g es i n or g a n -s p ecific l a b or at or y p ar a m et ers ( e. g., liv er f u ncti o n
e nz y m es, r e n al f u ncti o n st u di es i n o n e or m or e s u bj ects)
4)
P att er n of l a b or at or y c h a n g es ( e. g. , a c o nsist e nt i ncr e as e or d ecr e a s e wit hi n 2 or m or e s u bj ects
or wit hi n or acr oss d osi n g gr o u ps) w hic h mi g ht i n dic at e a n ov er all s af et y c o nc er n
I n t h e ev e nt t h at a c o h ort is st o p p e d d u e t o n o n-dr u g -r el at e d ev e nts, a n e w c o h ort of a d diti o n al s u bj ects 
m a y b e e nr oll e d t o r e pl ac e t h e st o p p e d c o h ort.  
8. 3. 3  T RI A L S T O P PI N G R U L E S  
D osi ng a n d/ or r ecr uit m e nt will b e i nt err u pt e d u ntil t h e S R C h as c o m pl et e d a t h or o ug h  r evi e w of all 
av aila bl e  d at a,  f or a ny  of  t h e f oll o wi n g r e as o ns, b ut  n ot  li mit e d t o: 
•
If 1  s u bj ect ex p eri e nc es  a n S A E
Cli nical  trial st o p pi ng r ul es: 
•
If 2  R V P -0 0 1 r el at e d  S A Es  occ ur  i n a  c o h ort
•
If 2  s u bj ects ex p eri e nc e  s ev er e R V P -0 0 1 r el at e d  A Es
•
Occ urr e nc e  of  a n  R V P -0 0 1  r el at e d A E  or  S A E  w hic h  r es ults i n d e at h
R el at e d n ess t o st u d y dr u g will b e d et er mi n e d b y t h e i nv esti g at or. 
If t h e st u d y is h alt e d, t h e I R B will b e n otifi e d.  T h e st u d y m a y b e r es u m e d or t er mi n at e d; h o w ev er, it will 
n ot b e r es u m e d u ntil a f urt h er n otic e t o r es u m e t h e st u d y is s u b mitt e d a n d a p pr o v e d b y t h e I R B.  
8. 4  
L O S T T O F O L L O W -U P  
F or s u bj ects w h o ar e l ost t o f oll o w -u p (i. e. , t h os e s u bj ects w h os e st at us is u ncl e ar b ec a us e t h e y f ail t o b e 
av ail a bl e f or  st u d y visits wit h o ut st ati n g a n i nt e nti o n t o wit h dr a w), a n i nv esti g at or s h o ul d s h o w “d u e 
dili g e nc e ” b y d oc u m e nti n g i n t h e s o ur c e d oc u m e nts st e ps t a k e n t o c o nt act t h e s u bj ect, e. g. , d at es of 
t el e p h o n e c alls, r e gist er e d l ett ers, etc.  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 4 8  
9  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
9. 1  
S A F E T Y A S S E S S M E N T S  
9. 1. 1  S A F E T Y M O NI T O RI N G 
S u bj ects will b e m o nit or e d t hr o u g h o ut t h e st u d y b y cli nic al sit e st aff f or A E s.  A p h ysici a n will b e 
r es p o nsi bl e f or t h e cli nic al as p ects of t h e st u d y a n d will b e av ail a bl e at all ti m es d uri n g t h e st u d y.  If 
n ec ess ar y, a p h ysici a n, eit h er at t h e cli nic al sit e or i n a  n e ar b y  h os pit al will a d mi nist er  tr e at m e nt f or a ny  
A E (s). 
A d diti o n al n o n -i nv asiv e pr oc e d ur es t h at ar e alr e a d y s p ecifi e d i n t h e pr ot oc ol m a y b e p erf or m e d, if it is 
b eli ev e d t h at a n i m p ort a nt eff ect of t h e I P(s) is occ urri n g or m a y occ ur at a ti m e w h e n n o m e as ur e m e nts 
ar e sc h e d ul e d, or if extr a pr oc e d ur es ar e n e e d e d i n t h e i nt er ests of s af et y.  
A d diti o n al bl o o d s a m pl es, uri n e s a m pl es or ot h er di a g n ostic t ests f or s af et y ass ess m e nts m a y b e t a k e n if 
r e q uir e d b y t h e i nv esti g at or or s u b-i nv esti g at or at a n y p oi nt. 
9. 1. 2  VI T A L  SI G N S  
B P , r es pir at or y r at e, H R , a n d b o d y t e m p er at ur e will b e m e as ur e d i n a su pi n e  p ositi o n ( exc e pt f or s af ety 
r e as o ns) at t h e ti m e p oi nts d escri b e d i n S ecti o n 3. 2  ( S 0 A).  H R  a n d p uls e oxi m etr y will b e m o nit or e d 
c o nti n u o usl y f or 4 h o urs p ost d os e.  
S u bj ect s h o ul d b e i n s u pi n e p ositi o n at l e ast 5 mi n ut es pri or t o m e as ur e m e nts.  
T h e acc e pt a bl e d evi ati o ns fr o m t h e n o mi n al vit al si g ns m e as ur e m e nt ti m e p oi nts ar e:  
• 
T h e pr e -d os e vit al si g ns m e as ur e m e nts will b e t a k e n ≤2 h b ef or e d osi n g.
• 
P ost -d os e vit al si g ns m e as ur e m e nts will b e t a k e n ±  2  mi n fr o m t h e n o mi n al p ost -d os e ti m e p oi nts
f or t h e first h o ur.  P ost -d os e vi t al si g ns m e as ur e m e nts will b e t a k e n ± 1 5 mi n fr o m all ot h er
n o mi n al p ost -d os e ti m e p oi nts.
• 
Disc h ar g e vit al si g ns m e as ur e m e nts will b e t a k e n ±  1  h fr o m t h e n o mi n al ti m e p oi nt.
If a s u bj ect s h o ws a n a b n or m al ass ess m e nt at a n y st a g e, r e p e at m e as ur e m e nts m a y b e m a d e a n d t h e 
a b n or m alit y f oll o w e d t o r es ol uti o n if r e q uir e d.  A d diti o n al m e as ur e m e nts m a y b e t a k e n as d e e m e d 
n ec ess ar y b y t h e i nv esti g at or or s u b-i nv esti g at or. 
A n y cli nic all y si g nific a nt a b n or m alit y, i ncl u di n g c h a n g es fr o m b as eli n e, m ust b e r e p ort e d as a n A E.  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 4 9  
9. 1. 3  E C G M E A S U R E M E N T S  
S u pi n e (si n gl e) 1 2 -l e a d E C Gs will b e t a k e n at 1, 3 a n d 8 mi n ut es p ost d os e  aft er t h e s u bj ect h as b e e n i n t h e 
s upi n e p ositi o n f or a mi ni m u m of 5 mi n .  S u pi n e tri plic at e 1 2 -l e a d E C G s ( 3 E C Gs t a k e n a p pr oxi m at ely 1 
mi n ut e a p art) aft er t h e s u bj ect h as b e e n i n t h e s u pi n e p ositi o n f or a mi ni m u m of 5 mi n will b e p erf or m e d 
at t h e n o mi n al ti m e p oi nts i n S ecti o n 3. 2  ( S o A).  F or tri plic at e E C Gs, t h e m e a n of t h e t hr e e r ec or di n gs will 
b e  r e p ort e d. 
• 
T h e pr e -d os e E C G m e as ur e m e nts will b e t a k e n ≤2  h b ef or e d osi n g
• 
P ost -d os e  si n gl e E C G m e as ur e m e nts ( mi n ut es 1, 3  a n d 8 ) will b e t a k e n ±  2  mi n fr o m t h e n o mi n al
p ost -d os e ti m e p oi nt
• 
All ot h er E C Gs will b e t a k e n ± 1 0  mi n f or first 3 h o urs ( excl u di n g a b ov e) p ost d os e a n d ±  3 0 mi n
t h er e aft er.
• 
Disc h ar g e E C G m e as ur e m e nts will b e t a k e n ±  1  h fr o m t h e n o mi n al ti m e p oi nt.
If a s u bj ect s h o ws a n a b n or m al ass ess m e nt at a n y st a g e, r e p e at m e as ur e m e nts m a y b e m a d e a n d t h e 
a b n or m alit y f oll o w e d t o r es ol uti o n if r e q uir e d.  A d diti o n al m e as ur e m e nts m a y b e t a k e n as d e e m e d 
n ec ess ar y b y t h e i nv esti g at or or s u b -i nv esti g at or. 
A n y cli nic all y si g nific a nt a b n or m alit y, i ncl u di n g c h a n g es fr o m b as eli n e, will b e r e p ort e d as a n A E.  
9 .1 .4  P H Y S IC A L E X A M IN A T IO N IN C L U D IN G N E U R O L O G IC A L A S S E S S M E N T 
A c o m pl et e p h ysic al ex a mi n ati o n will b e p erf or m e d a t a d missi o n.  H ei g ht a n d b o d y w ei g h t w ill b e 
m e as ur e d, a n d B MI will b e c alc ul at e d at scr e e ni n g.  A c o m pl et e p h ysic al ex a mi n ati o n i ncl u d es 
ass ess m e nts of t h e f oll o wi n g: h e a d, e y es, e ars, n os e, t hr o at, n ec k, c h est, l u n gs, a b d o m e n, extr e miti es, 
m usc ul os k el et al, d er m at ol o gic al, C V / p eri p h er al v asc ul ar, a n d n e ur ol o gic al ex a mi n ati o n.  
A c o m pl et e n e ur ol o gic al ex a m (i ncl u di n g m e nt al st at us ex a m, cr a ni al n erv es, c o or di n ati o n, a n d p eri p h er al 
m ot or, s e ns or y a n d r efl ex ex a mi n ati o ns of all extr e miti es)  will b e p erf or m e d as i n dic at e d i n S ecti o n 3. 2 
( S o A).  
If a s u bj ect r e p orts or d ail y ex a mi n ati o n i d e ntifi es a n y tr e at m e nt e m er g e nt m o d er at e or s ev er e 
n e ur ol o gic al si g ns/s y m pt o ms,  a c o m pl et e n e ur ol o gic al ex a mi n ati o n will b e p erf or m e d. 
C h a n g es fr o m b as eli n e a b n or m aliti es will b e r ec or d e d at e ac h s u bs e q u e nt p h ysic al ex a mi n ati o n.  N e w  or 
w ors e n e d a b n or m aliti es s h o ul d b e r ec or d e d as A E s, if j u d g e d a p pr o pri at e by t h e Pri nci p al I nv esti g at or or  
M e dic al S u b-I nv esti g at or. 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 5 0  
9. 1. 5  D R U G , A L C O H O L  A N D C O TI NI N E S C R E E N  
A uri n e dr u g scr e e n ( A m p h et a mi n es  [ref ers t o a gr o u p of dr u gs t h at i ncl u d es m et h a m p h e t a mi n e/ M D M A 
{c o m m o nl y k n o w n as Ecst as y}], B ar bit ur at es, B e nz o di az e pi n es , C oc ai n e , Et h a n ol , M arij u a n a/ C a n n a bis , 
M et h a d o n e , M or p hi n e/ O pi at es , p H , P h e ncycli di n e  a n d Tric yclic A nti d e pr ess a nts ) a n d a n alc o h ol uri n e t est 
a n d uri n e  coti ni n e t est will b e p erf or m e d at scr e e ni n g. A uri n e dr u g scr e e n , alc o h ol t est a n d c oti ni n e t est 
will als o b e  p erf or m e d  at a d missi o n.   
9. 1. 6  P R E G N A N C Y  T E S T  
A  hi g hl y s e nsitiv e  uri n e pr e g n a nc y t est will b e p erf or m e d at scr e e ni n g f or all f e m al e s u bj ects.  F or  W O C B P , 
a hi g hl y s e nsitiv e uri n e pr e g n a nc y t est will als o b e p erf or m e d b ef or e disc h ar g e.   A hi g hl y s e nsitiv e s er u m 
pr e g n a nc y t est will b e p erf or m e d at a d missi o n.   T h e s a m pl es will b e c oll ect e d a n d pr oc ess e d as d et ail e d i n 
t h e cli nic al s a m pl e pr oc essi n g m a n u al ( CS P M).  
9. 1. 7  F O L LI C L E -S TI M U L A TI N G H O R M O N E T E S T  
S er u m F S H t ests will b e p erf or m e d as d et ail e d i n S ecti o n  3. 2  ( S o A).  T h e s a m pl es will b e c oll ect e d a n d 
pr oc ess e d acc or di n g t o t h e C S P M.  
9 .1 .8  B O D Y W E IG H T , H E IG H T , A N D B M I 
T h e s u bj ect’s b o d y w ei g ht a n d h ei g ht will b e m e as ur e d, a n d t h eir B MI will b e c alc ul at e d acc or di n g t o t h e 
ti m e sc h e d ul e pr es e nt e d i n S ecti o n 3. 2 ( S o A). 
9 .1 .9  IN JE C T IO N S IT E M O N IT O R IN G 
A n ass ess m e nt of e ac h i nj ecti o n sit e will b e m a d e b y a n urs e, n urs e pr actiti o n er, p h ysici a n ’s assist a nt or 
p h ysici a n acc or di n g t o t h e sc h e d ul e i n S ecti o n 3. 2 ( S o A). 
T h e acc e pt a bl e d evi ati o ns fr o m t h e n o mi n al ti m e p oi nts ar e: 
• 
P ost -d os e (i ncl u di n g disc h ar g e) ex a mi n ati o ns will b e c arri e d o ut ±  1 h o ur  fr o m t h e n o mi n al
p ost -d os e ti m e p oi nt
T h e i nj ecti o n sit e will b e ass ess e d a n d r ec or d e d acc or di n g t o t h e gr a di n g s yst e m i n  T a bl e 4 . 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 5 1  
T a bl e 4   I nj ecti o n Sit e E x a mi n ati o n 
N A = n ot a p plic a bl e 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 5 2  
9. 2  
L A B O R A T O R Y  A S S E S S M E N T S  
R ef er t o C S P M  f or d et ail e d i nstr ucti o ns f or all s a m pl e h a n dli n g. 
T h e acc e pt a bl e d evi ati o ns fr o m t h e n o mi n al bl o o d s a m pli n g ti m e p oi nts f or bi oc h e mistr y, 
h e m at ol o g y, s er ol o g y a n d c o a g ul ati o n ar e:  
•  
T h e pr e -d os e bl o o d s a m pl e will b e t a k e n u p t o 2 h o urs  b ef or e d osi n g  
•  
2  t o 1 2 ho ur  p ost -d os e bl o o d s a m pl es will b e t a k e n wit hi n ±  1 0 mi n ut es  of t h e n o mi n al 
p ost -d os e s a m pli n g ti m e  
•  
2 4 t o 1 2 0 h o ur  p ost -d os e bl o o d s a m pl es will b e t a k e n wit hi n ±  3 0 mi n ut es  of t h e n o mi n al 
p ost -d os e s a m pli n g ti m e  
T h e acc e pt a bl e d evi ati o ns fr o m t h e n o mi n al uri n e s a m pli n g ti m e p oi nts f or uri n al ysis ar e:  
•  
T h e pr e -d os e uri n e s a m pl e will b e t a k e n fr o m t h e 2 4 h o ur ( d ay-1) uri n e c oll ecti o n wit hi n 1 h o ur  
of n o mi n al ti m e p oi nt).  
•  
P ost -d os e ur i n e s a m pl es will b e t a k e n ± 1  h o ur  fr o m t h e n o mi n al uri n e s a m pli n g ti m e 
T h e acc e pt a bl e d evi ati o ns f or P K bl o o d a n d bi o a n al ytic al uri n e s a m pl es c a n b e f o u n d i n S ecti o n 9. 2. 6 . 
I n c as es w h er e l a b or at or y fi n di n gs ar e o utsi d e t h e n or m al r a n g e a n d t h e i nv esti g at or b eli ev es t h at t h e 
r es ults m a y b e of cli nic al si g nific a nc e, r e p e at s a m pli n g m a y b e r e q u est e d as cli nic all y i n dic at e d.  If t h e 
a b n or m al fi n di n g is cli nic all y si g nific a nt, a p pr o pri at e acti o ns will b e t a k e n e. g. , t h e s u bj ect will n ot b e 
e nt er e d i nt o t h e st u d y, or t h e s u bj ect m a y b e wit h dr a w n fr o m t h e st u d y.  T h e s u bj ect will b e r ef err e d t o 
t h eir pri m ar y c ar e pr ovi d er or ot h er a p pr o pri at e pr o vi d er f or f urt h er c ar e if n ec ess ar y.  T h e s a m e will 
a p pl y if t h e r es ults of t h e H Bs A g, H C V  A b , or HI V t est ar e p ositiv e a n d i n a d diti o n t h e i nv esti g at or will 
e ns ur e t h at a d e q u at e c o u ns elli n g is av ail a bl e if r e q u est e d.  
A b n or m al r es ults at f oll o w -u p ass ess m e nts will als o r e q uir e r e p e at t esti n g if t h e i nv esti g at or b eli ev es t h e 
r es ults m a y b e of cli nic al si g nific a nc e. 
A n y cli nic all y si g nific a nt a b n or m alit y, i ncl u di n g c h a n g es fr o m b as eli n e, m ust b e r e p ort e d as a n A E.  
A d diti o n al bl o o d a n d/ or uri n e s a m pl es m a y b e t a k e n f or s af et y t ests.  F urt h er m or e, a d diti o n al ass a ys 
o utsi d e t h os e s p ecifi e d i n t h e pr ot oc ol m a y b e p erf or m e d f or s af et y r e as o ns as r e q u est e d b y t h e 
i nv esti g at or. 
9. 2. 1  BI O C H E MI S T R Y  
Bi oc h e mistr y will b e p erf or m e d at  t h e ti m e p oi nts s p ecifi e d i n S ecti o n 3. 2  ( S o A).  T h e f oll o wi n g will b e 
ass ess e d:  Al a ni n e A mi n otr a nsf er as e ( AL T), Al b u mi n, Al k ali n e P h os p h at as e, As p art at e A mi n otr a nsf er as e 
( A S T), Bilir u bi n ( T ot al), Bilir u bi n ( Dir ect), B U N, C alci u m, C ar b o n Di oxi d e, C hl ori d e, Cr e ati n e Ki n as e ( C K), 
s er u m Cr e ati ni n e, e G F R  will b e c alc ul at e d at scr e e ni n g usi n g C K P -E PI 2 0 2 1 R efit  e q u ati o n f or eli gi bili ty 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 5 3  
p ur p os e s, F ollicl e Sti m ul ati n g H or m o n e ( F S H; p ost-m e n o p a us al f e m al e s u bj ects o nl y w h e n i n dic at e d), 
Gl uc os e ( u nsc h e d ul e d ti m e p oi nts), Gl uc os e ( F asti n g), H u m a n C h ori o nic G o n a d otr o pi n ( h C G) (f e m al e 
s u bj ects w h e n i n dic at e d), P ot assi u m, P h os p h at e (I n or g a nic), Pr ot ei n ( T ot al), S o di u m , a n d Li pi d pr ofil e 
(c h ol est er ol, H DL, L DL, tri gl yc eri d es). 
9. 2. 2  S E R O L O G Y  
H e p atitis B ( H Bs A g)  a nti g e n , H C V a nti b o d y , a n d HI V a nti b o d y d et ecti o n will b e p erf or m e d at  scr e e ni n g. 
9. 2. 3  H E M A T O L O G Y  
H e m at ol o g y will b e p erf or m e d at scr e e ni n g, o n a d missi o n, a p pr oxi m at el y at 2 4 h o urs p ost -d os e , a n d 
b ef or e disc h ar g e . T h e f oll o wi n g will b e ass ess e d: B as o p hils , E osi n o p hils , H e m at ocrit , H e m o gl o bi n , 
L y m p h oc yt es, M e a n C ell H e m o gl o bi n , M e a n C ell H e m o gl o bi n C o nc e ntr ati o n , M e a n C ell V ol u m e , 
M o n oc yt es , N e utr o p hils , Pl at el et C o u nt , R B C C o u nt , R e d C ell Distri b uti o n Wi dt h, M e a n Pl at el et V ol u m e, 
a n d W B C C o u nt . 
9. 2. 4  C O A G U L A TI O N  
P t, I N R, a n d A P T T will b e p erf or m e d at scr e e ni n g, o n a d missi o n, a n d a p pr oxi m at el y at 2 4 h o urs p ost - d os e.  
9. 2. 5  U RI N A L Y SI S  
Uri n al ysis will b e p erf or m e d at scr e e ni n g, a n d o n a d missi o n .  Sm all s p ot uri n e s a m pl e c oll ecti o ns f or 
uri n al ysis will b e c oll ect e d at t h e e n d of e ac h 2 4 h o ur uri n e c oll ecti o n  i nt erv al f or eli mi n ati o n st u di es.  T h e 
f oll o wi n g will b e ass ess e d:  p H, s p ecific gr avit y, pr ot ei n, gl uc os e, k et o n es, bilir u bi n, bl o o d, nitrit e,  
ur o bili n o g e n, a n d l e u k oc yt es.  U nl ess ot h er wis e s p ecifi e d, micr osc o pic ex a mi n ati o n will b e  p erf or m e d  o n  
a b n or m al  fi n di n gs. 
I n a d diti o n, an ali q u ot of uri n e fr o m e ac h  2 4 h o ur c oll ecti o n will b e a n al yz e d f or 2 4 h o ur uri n e cr e ati ni n e  
 
.  T h e 2 4 h o ur uri n e cr e ati ni n e , 2 4 h o ur uri n e v ol u m e, a n d c orr es p o n di n g s er u m cre ati ni n e wil l b e us e d t o 
c alc ul at e 2 4 h o ur uri n e cr e ati ni n e cl e ar a nc e.  
9. 2. 6  B I O A N A L Y TI C A L S A M P L E  C O L L E C TI O N  A N D  P R O C E S SI N G  
Pl as m a a n d uri n e will b e a n al yz e d b y hi g h p erf or m a nc e L C-M S/ M S t o m e as ur e t h e c o nc e ntr ati o n of i nt act 
R V P -0 0 1 i n or d er t o ass ess pl as m a p h ar m ac o ki n etics at I n otiv . S e p ar at e uri n e a n d f ec es s a m pl es will b e 
a n al yz e d b y I C P -M S f or t ot al M n c o nt e nt t o q u a ntif y eli mi n ati o n of i nj ect e d M n a n d fr acti o n al excr eti o n  at 
Q u oti e nt Bi o a n al ytic al .  S e p ar at e pl as m a a n d uri n e s a m pl es will b e s e nt t o M ass ac h us etts G e n er al H os pit al 
f or ex pl or at or y st u di es.  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 5 4  
A t ot al of 1 6 bl o o d s a m pl es will b e dr a w n fr o m e ac h s u bj ect f or P K a n al ys es .  V e n o us bl o o d will b e 
c oll ect e d pri or t o ( wit hi n 2 h o urs pri or t o d ose) a n d at 2, 5, 1 0, 2 0 , a n d 3 0 mi n ut es aft er t h e e n d of t h e 
b ol us d os e a n d  at  1,  2,  4,  8,  1 2,  2 4,  4 8,  7 2, 9 6 , a n d 1 2 0 h o urs p ost -d os e ( 6 mL f or e ac h s a m pli n g ti m e).  
T h e acc e pt a bl e d evi ati o ns fr o m t h e n o mi n al bl o o d s a m pli n g ti m es ar e as f oll o ws:  
• 
T h e pr e -d os e s a m pl es will b e t a k e n u p t o 2  h o urs  b ef or e d osi n g
• 
0 t o 1 h o ur  p ost -d os e s a m pl es will b e t a k e n wit hi n ±  2 mi n ut es  of t h e n o mi n al p ost -d os e
s a m pli n g ti m e
• 
2  t o 1 2 ho ur  p ost -d os e s a m pl es will b e t a k e n wit hi n ±  1 0 mi n ut es  of t h e n o mi n al p ost -d os e
s a m pli n g ti m e
• 
2 4 t o 1 2 0 h o ur  p ost -d os e s a m pl es will b e t a k e n wit hi n ±  3 0 mi n ut es  of t h e n o mi n al p ost -
d os e s a m pli n g ti m e
T h e t ot al bl o o d v ol u m e wit h dr a w n fr o m e ac h s u bj ect wi ll n ot exc e e d 5 5 0 mL i n a n  8 w e e k p eri o d 
( b as e d o n a r e pr es e nt ativ e h e alt h y s u bj ect w ei g hi n g at l e ast 1 1 0 p o u n ds). T h e bl o o d v ol u m e t a k e n 
d uri n g t h e st u d y is pr es e nt e d i n T a bl e 5 .  T h e n u m b er a n d ti mi n g of s a m pl es m a y b e a m e n d e d 
f oll o wi n g a n y i nteri m P K p ar a m et er esti m ati o ns. 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 5 5  
T a bl e 5      
Esti m at e d T ot al Bl o o d V ol u m e  
St u d y Visit  
S a m pl e T y p e  
N u m b er of 
S a m pl es  
S a m pl e V ol u m e   
T ot al V ol u m e  
Scr e e ni n g  
S af et y l a b or at or y 
ass ess m e nts 
( bi oc h e mistr y [i ncl u di n g 
F S H], h e m at ol o g y, 
c o a g ul ati o n a n d s er ol o g y) 
1  
2 2. 7 mL    
2 2. 7 mL  
A d missi o n ( D a y -1)  
S af et y l a b or at or y 
ass ess m e nts 
( bi oc h e mistr y [i ncl u di n g 
pr e g n a nc y], h e m at ol o g y, 
a n d c o a g ul ati o n)  
1  
1 5. 2  mL    
1 5. 2  mL  
D a y 1  
S af et y l a b or at or y 
ass ess m e nts 
( bi oc h e mistr y, 
h e m at ol o g y,  a n d 
c o a g ul ati o n) 
2  
1 4. 2  mL    
2 8. 4  mL  
D a y 1 t o D a y 6  
P h ar m ac o ki n etic 
ass ess m e nts  
1 6  
6. 0 mL    
9 6. 0 mL  
D a y 2  t o D a y 6  
S af et y l a b or at or y 
ass ess m e nts 
( bi oc h e mistr y, 
h e m at ol o g y,  a n d 
c o a g ul ati o n) 
5  
1 4. 2  mL    
7 1. 0 mL  
T ot al Bl o o d V ol u m e p er S u bj ect p er C o h ort:    
2 3 3. 3  mL  
F S H = f ollicl e sti m ul ati n g h or m o n e  
Act u al s a m pli n g ti m es will b e us e d f or st atistic al a n al ys es.  B l o o d s a m pl es will b e c oll ect e d b y dir ect 
v e ni p u nct ur e  as p er cli nic al sit e o p er ati o n al pr actic e. 
D evi ati o ns of bl o o d v ol u m e will b e r e p ort e d o nl y w h e n t h e t ot al v ol u m e of t h e w h ol e st u d y is  
exc e e d e d.  
Pl as m a s a m pl es will b e c oll ect e d a n d pr oc ess e d as p er t h e a gr e e d u p o n pr oc e d ur es of t h e 
bi o a n al ytic al l a b (s).  E ac h s a m pl e will b e s plit i nt o t h e f oll o wi n g c o m p o n e nts: (i) P K ev al u ati o n t o b e 
a n al yz e d   
, (ii) D ev el o p m e nt al a n al ysis b y 
, (iii) 
B a n ki n g: St or e d at -8 0 ° C  at    
 p er G LP st a n d ar ds . 
T h e acc e pt a bl e d evi ati o ns fr o m t h e n o mi n al uri n e  s a m pli n g ti m es ar e as f oll o ws: 
•  
T h e -2 4 h o urs  t o 0 h o urs uri n e c oll ecti o n will  b e c oll ect e d wit hi n -1 8 0 mi n ut es t o + 6 0 
mi n ut es of t h e n o mi n al d os e s a m pli n g ti m e  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 5 6  
•  
T h e s u bs e q u e nt 2 4 h o ur uri n e c oll ecti o ns will b e c oll ect e d wit hi n ±  6 0 mi n ut es  of t h e 
n o mi n al p ost -d os e s a m pli n g ti m e  
Uri n e s a m pl es will b e c oll ect e d as i n divi d u al s a m pl es a n d c o m bi n e d i n t h e f oll o wi n g ti m e i nt erv als: -
2 4 -0 h o urs, 0 -2 4 h o urs, 2 4 -4 8 h o urs, 4 8 -7 2 h o urs, 7 2 -9 6 h o urs, 9 6 -1 2 0 h o urs.  E ac h s a m pl e will b e 
w ei g h e d pri or t o c o m bi n i ng.  Aft er fi n al c oll ecti o n f or e ac h c o nt ai n er, t ot al  s a m pl e will b e w ei g h e d,  
a n d  uri n e v ol u m e m e as ur e d.   Ali q u ots will b e r e m o v e d f or uri n al ysis a n d a d diti o n al ali q u ots  will b e 
s e nt f or f oll o wi n g a n al ys es: (i) Eli mi n ati o n ev al u ati o n R V P-0 0 1: s hi p t o    
 (i) Eli mi n ati o n  ev al u ati o n  
t ot al M n: s hi p t o 
 (iii) D ev el o p m e nt al A n al ysis : 
, (iv ) 
B a n ki n g: St or e d at -8 0 ° C  at    
 p er G LP st a n d ar ds.  
F ec es s a m pl es will b e c oll ect e d i n t h e f oll o wi n g i nt erv als: -2 4 -0 h o urs,  0 -2 4 h o urs, 2 4 -4 8 h o urs, 4 8 -7 2 
h o urs, 7 2 -9 6 h o urs, 9 6 -1 2 0 h o urs.  I n di vi d u al s a m pl es will b e c oll ect e d, l a b el e d, a n d st or e d . S a m pl es 
will b e pr e p ar e d  as p er t h e a gr e e d u p o n pr oc e d ur es of t h e bi o a n al ytic al l a b or at or y  a n d C S P M , a n d 
t h e n s hi p p e d t o 
. 
9. 3  
S C R E E NI N G  
Wit hi n t h e  2 8  d a ys pr ec e di n g first d os e, all s u bj ects will b e r e q uir e d t o u n d er g o a scr e e ni n g visit.  
Scr e e ni n g pr oc e d ur es will b e c arri e d o ut i n acc or d a nc e wit h t h e sc h e d ul e of ass ess m e nts i n  S ecti o n  3. 2  
( S o A). 
If t h e st art of t h e st u d y is d el a y e d f or a n y r e as o n s o t h at t h e i nt erv al b et w e e n scr e e ni n g a n d first d os e 
exc e e ds  2 8  d a ys, all or p art of t h e scr e e ni n g pr oc e d ur es will b e r e p e at e d at t h e discr eti o n of t h e 
i nv esti g at or. 
Scr e e ni n g s af et y pr oc e d ur es s uc h as s af et y bl o o ds, E C Gs, vit al si g ns, uri n e alc o h ol, uri n e c oti ni n e, uri n e 
dr u g scr e e n a n d uri n al ysis c a n b e r e p e at e d as cli nic all y i n dic at e d u n d er t h e discr eti o n of t h e i nv esti g at or 
or s u b -i nv esti g at or if t h er e is a c o nc er n r e g ar di n g a s u bj ect’s s af et y or eli gi bilit y t o p artici p at e i n t h e tri al. 
9. 3. 1  R E -S C R E E NI N G  
T his st u d y p er mits t h e r e -scr e e ni n g of a s u bj ect w h o h as disc o nti n u e d t h e st u d y as a pr e-tr e at m e nt f ail ur e 
(i.e ., s u bj ect h as n ot b e e n r a n d o miz e d); t h e r e as o n f or f ail ur e m ust b e t e m p or ar y a n d ex p ect e d t o r es olv e.  
If r e-scr e e n e d, t h e s u bj ect m ust b e r e-c o ns e nt e d. 
 
 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 5 7  
9. 4  
A D MI S SI O N A N D P R E -D O S E  P R O C E D U R E S  
T h e i d e ntity of t h e s u bj ects will b e c o nfi r m e d a t a d missi o n a n d pr e- d os e. 
I n a d diti o n, t h e o n g oi ng eli gi bil it y of s u bj ect s will b e r e- ass ess e d at a d missi o n/ pr e- d os e, as d escri b e d i n 
S ect i o ns 6. 3 a n d 6. 4 . 
A d missi o n/ pr e- d os e s af et y pr oc e d ur es s uc h as s afet y bl o o ds, E C Gs, vit al si g ns, uri n al ysis , a n d dr u gs of 
a b us e t ests c a n b e r e p e at e d as cli nic all y i n dic at e d u n d er t h e discr eti o n of i nv e sti g at or or s u b-i nv esti g at or 
if t h er e is a c o nc er n r e g ardi n g a s u bj ect’s s af et y or eli gi bilit y to p artici p a t e i n t h e cli nical tri al.  
Alt er n ativ e s u bj ects f or th e first d o s e occ as i o n, i n a n y gr o u p, will n ot r e q uir e a d missi o n pr oc e d ur es t o b e 
r e p e at e d if d osi n g is wit hi n 2 d a ys.  
If d osi n g is d el a y e d, s u bj ects w h o h av e c om pl et e d a d missi o n pr oc e d ur es d o n o t n e e d a d missi o n 
pr oc e d ur es t o b e r e p e at e d if d os i n g is wit hi n 2 d a ys a n d t h e s u bject s h av e r e m a i n e d r esi de nt in t h e cli nic al 
u nit. 
T h e s u bj ects will b e a d mitt e d t o t h e cli nic al u nit i n t h e m or ni n g o n t h e d a y b ef or e d osi n g ( D a y - 1).  
T h e a d missi o n a n d pr e- d os e pr oc e d ur es ar e pr es e nt e d i n S ecti o n 3. 2 ( S o A). 
9. 5  
TI MI N G O F P R O C E D U R E S  
T h er e ar e ti m es w h er e t h e pr ot oc ol r e q uir es m or e t h a n o n e pr oc e d ur e t o b e c o m pl et e d at t h e s a m e ti m e 
p oi nt. I n t h es e i nst a nc es, t h e f oll o wi n g will a p pl y t o p ost -d os e ti m e p oi nts:  
• 
S e q u e nci n g: E C Gs s h o ul d b e t a k e n pri or t o vit al si g ns w h e n b ot h m e as ur e m e nts ar e sc h e d ul e d at t h e
s a m e ti m e p oi nt.
• 
Pri orit y f or pr ecis e ti mi n g: P K s a m pl es s h o ul d t a k e pri orit y (i. e. , t a k e n at t h e n o mi n al ti m e p oi nt) o v er
ot h er pr oc e d ur es sc h e d ul e d at t h e s a m e ti m e p oi nt
• 
Ot h er ass ess m e nts, e. g. , p h ysic al ex a mi n ati o ns, will b e p erf or m e d wit hi n t h e r e q uir e d ti m e wi n d o ws.
As g ui d a nc e, t h e pr ef err e d or d er of ass ess m e nts is:  
E C Gs  
 
Vit als  
P K bl o o d 
s a m pli n g 
( n o mi n al 
ti m e) 
Ot h er ass ess m e nts 
e .g ., p h ysic al
e x a mi n ati o ns
All s af et y ass ess m e nts will b e ti m e d a n d p erf or m e d r el ativ e t o t h e st art of d osi n g. 
9. 6  
DI S C H A R G E F R O M T H E C LI NI C A L U NI T  
S u bj ects will b e disc h ar g e d fr o m t h e cli nic al u nit f oll o wi n g c o m pl eti o n of st u d y -s p ecific pr oc e d ur es at 
1 2 0  h p ost -d os e ( D a y 6) . H o w ev er, t h e i nv esti g at or m a y as k a s u bj ect t o r e m ai n d o micil e d f or a d diti o n al 
s af et y o bs erv ati o n a n d m o nit ori n g (e. g. , as i n di c at e d f or a n A E). 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 5 8  
9. 7  
F O L L O W -U P  VI SI T  
S u bj ects will r ec eiv e a f oll o w -u p c all 7 d a ys f oll o wi n g d os e a d mi nistr ati o n t o ass ess f or a n y n e w A Es si nc e 
disc h ar g e.   A q u esti o n n air e will b e f oll o w e d f or t h e f oll o w -u p i nt ervi e w.  
9. 8  
D A T A  C O L L E C TI O N  A N D  E V A L U A TI O N  
All cli ni c al r a w d at a will b e r ec or d e d pr o m ptl y, acc ur at el y, a n d l e gi bl y; eit h er dir ectl y i nt o t h e  e -s o urc e 
d at a or i n d eli bl y o n p a p er ( e. g. , E C G r e a di n gs).  A d et ail e d list of t h e t y p e ( el ectr o nic or p a p er) a n d l oc ati o n 
f or all s o urc e d at a will b e i ncl u d e d i n t h e Tri al M ast er Fil e.  All r a w d at a will b e c o ns erv e d i n or d er t o 
m ai nt ai n d at a  i nt e grit y.  A p h ysici a n a n d/ or t h e cli nic al st aff will ass u m e t h e r es p o nsi bilit y of e ns u ri n g t h e 
c o m pl et e n ess a n d  acc ur ac y  of  t h e cli nic al d at a. 
9. 9  
S U BJ E C T  WI T H D R A W A L  A N D  R E P L A C E M E N T  
S u bj ects will b e a dvis e d t h at t h e y ar e fr e e t o wit h dr a w fr o m t h e st u d y at a n y ti m e.  Ov er t h e  c o urs e of t h e 
st u d y, t h e S p o ns or a n d t h e I nv esti g at or(s) or a d el e g at e m a y wit h dr a w a n y s u bj ect   fr o m t h e st u d y f or n o n-
c o m pli a nc e wit h pr ot oc ol r e q uir e m e nts or si g nific a nt pr ot oc ol d evi ati o n.  S u bj ects m a y als o b e wit h dr a w n 
b y t h e I nv esti g at or(s) or a  d el e g at e  f or: 
•  
Pr e g n a nc y [if a p plic a bl e] 
•  
T er mi n ati o n of t h e st u d y b y t h e s p o ns or, r e g ul at or y a g e nc y, or I R B  
•  
U p o n t h e s u bj ect’s r e q u est ( wit h dr a w al of c o ns e nt)  
•  
Si g nific a nt d evi ati o n fr o m t h e pr ot oc ol  
•  
Si g nific a nt c o nc urr e n t ill n ess or r e q uir e m e nt f or pr o hi bit e d m e dic ati o n  
•  
Evi d e nc e of c urr e nt S A R S -C o V -2 i nf ecti o n  
•  
S u bj ect n o n -c o m pli a nc e  
•  
At t h e discr eti o n of t h e i nv esti g at or  
Cli nic al l a b or at or y r es ults will b e r evi e w e d b y a M e dic al S u b -I nv esti g at or pri or t o d osi n g, w h e n a p plic a bl e; 
s u bj ects will b e wit h dr a w n fr o m t h e st u d y if it is d e e m e d t h at t h e s u bj ect’s s af et y  m a y b e at ri s k o n t h e 
b asis of t h es e t est r es ults.  
S u bj ects w h o wit h dr a w or ar e wit h dr a w n fr o m t h e st u d y aft er d osi n g will n ot b e s yst e m atic all y  r e pl ac e d.  
H o w ev er, at l e ast 7 ( o ut of 8) s u bj ects fr o m a s a m e d os e l ev el s h o ul d h av e c o m pl et e d t h e d osi n g p eri o d, 
a n d s af et y a n d t ol er a bilit y d at a c oll ect e d u p t o t h e  f oll o w u p visit s h o ul d b e av ail a bl e f or t h es e s u bj ects 
b ef or e t h e S R C c a n d eci d e  o n d os e esc al ati o n.   T h er ef or e, s u bj ects w h o wit h dr a w or ar e wit h dr a w n fr o m 
t h e st u d y aft er d osi n g f or r e as o ns ot h er t h a n s af et y a n d t ol er a bilit y  m a y b e r e pl ac e d aft er c o ns ult ati o n  
b et w e e n t h e S af et y C o m mitt e e m e m b ers.   I n s uc h c as e, t h e t ot al n u m b er of s u bj ects d os e d will r e m ai n 
wit hi n a  m axi m u m of  1 0 s u bj ects p er  c o h ort. 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 5 9  
S u bj ects wit h dr a w n f or s af et y r e as o ns will b e as k e d t o r e m ai n at t h e cli nic u ntil t h e I nv esti g at or(s) or a 
d el e g at e a gr e es t h at t h e s u bj ect is fi n e a n d c a n b e disc h ar g e d.  As s o o n  as s u bj ect  wit h dr a w al is 
c o nfir m e d, bl o o d s a m pli n g will b e st o p p e d. 
T h e mi ni m u m n u m b er of ev al u a bl e  s u bj ects is 7 p er c o h ort.  A n e v al u a bl e s u bj ect is d efi n e d as a s u bj ect 
w h o h as p h ar m ac o ki n etic, s af et y , a n d t ol er a bilit y d at a o ut t o 1 2 0 h o urs p ost d os e , f or ev al u ati o n of t h e 
pri m ar y o bj ectiv e . 
9. 1 0  A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S  
9. 1 0. 1  D E FI NI TI O N  O F  A N  A D V E R S E  E V E N T  ( A E) 
A n A E is a n y u nt o w ar d m e dic al occ urr e nc e i n a s u bj ect w h o h as  b e e n a d mi nist er e d a p h ar m ac e utic al 
pr o d uct or n ot, w hic h d o es n ot n ec ess aril y h av e a c a us al  r el ati o ns hi p wit h t his tr e at m e nt.  A n A E c a n 
t h er ef or e b e a n y u nf av or a bl e a n d u ni nt e n d e d si g n (i ncl u di n g a n a b nor m al l a b or at or y fi n di n g j u d g e d 
cli nic all y si g nific a nt), s y m pt o m, or dis e as e  t e m p or all y ass oci at e d wit h t h e us e of a m e dici n al 
(i nv esti g ati o n al) pr o d uct (st u dy dr u g) or cli nic al pr oc e d ur e,   w h et h er  or  n ot  it is r el at e d t o t h e m e dici n al  
(i nv esti g ati o n al) p r o d uct (st u d y dr u g) or  cli nic al pr oc e d ur e. A n  a dv ers e dr u g r e acti o n ( A D R) is a n y A E 
w h er e a c a us al r el ati o ns hi p wit h t h e st u dy dr u g is at l e ast a r e as o n a bl e p ossi bilit y ( p ossi bl y r el at e d or 
pr o b a bl y r el at e d).  
9. 1 0. 2  D E FI NI TI O N  O F  A  S E RI O U S  A D V E R S E  E V E N T  ( S A E) 
A  S A E  is a n y A E  t h at at a n y  d os e:  
•  
R es ults  i n d e at h  
•  Is lif e-t hr e at e ni n g (i. e., i n t h e o pi ni o n of t h e pri nci p al i nv esti g at or  ( PI) t h e s u bj ect is at 
i m m e di at e risk of d e at h fr o m t h e A E)  
•  R e q uir es  i n p ati e nt h os pit aliz ati o n  or  pr ol o n g ati o n of  existi n g  h os pit aliz ati o n  
•  R es ults i n p ersist e nt or si g nific a nt dis a bility/i nc a p acity ( a s u bst a nti al disr u pti o n of t h e 
s u bj ect’s a bilit y  t o c o n d uct n or m al lif e f u ncti o ns) 
•  R es ults  i n a  c o n g e nit al a n o m al y/ birt h d ef ect  
•  C o nstit ut es  a n  i m p ort a nt m e dic al  ev e nt:  
o  T h es e m ay n ot r es ult i n d e at h, b e lif e -t hr e at e ni n g, or r e q uir e h os pit aliz ati o n, b ut   
m a y b e c o nsi d er e d s eri o us w h e n t h e y j e o p ar diz e t h e h e alt h of t h e s u bj ect a n d  
r e q uir e m e dic al  or  s ur gic al i nt er v e nti o n t o pr e v e nt  o n e  of  t h e o utc o m es  list e d. 
o  A n y ot h er ev e nt ( e. g. , all er gic br o nc h os p as m r e q uiri n g i nt e nsiv e tr e at m e nt i n a n  
e m er g e nc y r o o m or at h o m e, bl o o d dyscr asi as, c o nv ulsi o ns t h at d o n ot r es ult i n  
i n p ati e nt h os pit aliz ati o n, or t h e d ev el o p m e nt of dr u g d e p e n d e ncy or dr u g a b us e) 
t h o u g ht t o b e s eri o us by th e  P ri nci p al Inv esti g at or  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 6 0  
Ev e nts  n ot  c o nsi d er e d t o b e  s eri o us ar e  h os pit aliz ati o ns  t h at: 
• 
W er e  pl a n n e d  b ef or e e ntr y  i nt o t h e cli nic al tri al
• 
Ar e f or el ectiv e tr e at m e nt of a c o n diti o n u nr el at e d t o t h e st u di e d i n dic ati o n or its
tr e at m e nt
• 
Occ ur o n a n e m er g e nc y o ut p ati e nt b asis a n d d o n ot r es ult i n a d missi o n ( u nl ess f ulfilli n g
ot h er  crit eri a a b o v e)
• 
Ar e p arts of t h e n or m al tr e at m e nt or m o nit ori n g of  t h e st u di e d i n dic ati o n a n d ar e n ot
ass oci at e d  wit h a n y  d et eri or ati o n i n c o n diti o n
9. 1 0. 3  D E FI NI TI O N O F S U S P E C T E D U N E X P E C T E D S E RI O U S A D V E R S E R E A C TI O N S  
S us p ect e d U n ex p ect e d S eri o us A dv ers e R e acti o n S  ( S U S A Rs) ar e A Es t h at ar e b eli ev e d t o b e r el at e d t o a 
t est pr o d uct a n d ar e b ot h u n ex p ect e d ( i. e., t h e n at ur e or s ev erit y is n ot ex p ect e d fr o m t h e i nf or m ati o n 
pr o vi d e d i n t h e I B) a n d s eri o us.   S U S A Rs ar e s u bj ect t o ex p e dit e d r e p orti n g t o t h e I R B (s e e S ecti o n  9. 1 0. 8  
f or d et ails o n r e p orti n g S U S A Rs). 
9 .1 0 .4  R E C O R D IN G O F  A D V E R S E E V E N T S 
A E s will b e r ec or d e d a n d e v al u at e d f or t h eir s eri o us n ess, s ev erit y, a n d r el ati o nshi p t o t h e st u d y tr e at m e nt.  
A E s will b e c oll ecte d a n d d oc u m e n t e d fr om t h e ti m e of pr ovi di n g writt e n i nf or m e d c o ns e nt (scr e e ni n g) 
u ntil 7 d a ys a ft er st u d y dr ug a d mi nistr ati o n.  S u bj ects will b e as k e d to s elf-r e p ort b et w e e n d a y 8 (f oll o w u p 
c all) a n d d a y 3 0 f o ll o wi n g dr u g a d mi nis tr ati o n.  If e m er gi n g or o n g o i n g A Es ar e r e p ort e d at t h e f oll o w- u p 
p h o n e c all o r aft er f oll o w- u p, a d diti o n a l visits a n d p h o n e c alls will b e arr a n g e d as u nsc h e d ul e d visits.  
D uri n g e a c h st u d y vis it t h e s u bj ect will b e q u esti o n e d dir ectl y r e g ar di n g t h e oc c urr e nc e of a n y a dv ers e 
m e dic al ev e n t acc or di n g t o th e sc h e d ule i n e C R F .  All A E s, w h et h er ascri b e d to st u d y pr oc e d ur es or n ot, 
will b e d oc u m e nt e d i m m e di at e l y i n t h e s u bj ect’s e C R F.  A E s will b e f oll o w e d- u p u ntil c o m pl et e r es ol uti o n, 
or u ntil t h e I nv esti g at or j u d g es it s af e t o disc o nti n u e f oll o w- u p. T h e r el ati o ns hi p t o t h e st u d y m e dic ati o n 
will b e cl assifi e d acc or di n g t o t h e c at e g ori es d escri b e d i n  S ecti o n 9. 1 0. 6 .  Cl assific ati o n of A Es will b e 
p erf or m e d b y S yst e m Or g a n Cl ass ( S O C) a n d Pr ef err e d T er m ( P T) u si n g t h e M e dic al Dicti o n ar y f or 
R e g ul at or y Activiti es ( M e d D R A), v ers i o n 2 4. 0 or hi g h er. 
C o nc o mit a nt m e dic ati o ns will b e c o d e d usi n g th e W orl d H e alt h Or g a niz ati o n d r u g dicti o n ar y ( W H O- D D E 
M a rc h 2 0 2 1  or l at er).  
9 .1 0 .5  A D V E R S E E V E N T S S E V E R IT Y 
T h e  s ev erit y of A Es will b e  gr a d e d acc or di n g t o crit eri a fr o m t h e N CI C o m m o n T er mi n ol o g y Crit eri a 
A dv ers e Ev e nts ( C T C A E) v ersi o n 5. 0. ( T a bl e 6 ). 
T h e  C T C A E dis pl a ys Gr a d es 1 t hr o u g h 5 wit h u ni q u e cli nic al d escri pti o ns of  s ev erit y f or e ac h  A E  b as e d 
o n t his g e n er al g ui d eli n e: 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 6 1  
T a bl e 6  N CI  C o m m o n T er mi n ol og y Crit eri a A dv ers e E v e nts ( C T C A E)  v ersi o n 5. 0. S e v erit y Gr a d e  
G R A D E    
D E S C RI P TI O N  
Gr a d e  1    
Mil d;  as y m pt o m atic  or  mil d  sy m pt o ms; cli nic al or  di a g n ostic o bs erv ati o ns  
o nly;  i nt er v e nti o n n ot  i n dic at e d. 
Gr a d e  2    
M o d er at e; mi ni m al, l oc al or n o n -i nv asiv e i nt erv e nti o n i n dic at e d;  li miti n g a g e-
a p pr o pri at e i nstr u m e nt al activiti es of d aily livi n g  
(i nstr u m e nt al activiti es of d aily livi n g r ef er t o pr e p ari n g 
m e als,  s h o p pi n g f or gr oc eri es or  cl ot h es, usi n g  t h e 
t el e p h o n e, m a n a gi n g  m o n ey, etc.).  
Gr a d e  3    
S e v er e or m e dic ally si g nific a nt b ut n ot i m m e di at ely lif e -t hr e at e ni n g; 
h os pit aliz ati o n  or  pr ol o n g ati o n  of  h os pit aliz ati o n  i n dic ate d;  
dis a bli n g;  li miti n g s elf-c ar e activiti es of d aily livi n g (s elf-c ar e 
activiti es of d aily  livi n g r ef er t o b at hi n g,  dr essi n g  a n d  
u n dr essi n g, f e e di n g  s elf, usi n g t h e t oil et, t a ki n g 
m e dic ati o ns,  a n d  n ot  b e dri d d e n).  
Gr a d e  4    
Lif e-t hr e at e ni n g c o ns e q u e nc es; ur g e nt  i nt er v e nti o n i n dic at e d. 
Gr a d e  5    
D e at h  r el at e d t o A E.  
* Gr a d e  5  ( d e at h) is n ot  a p pr o pri at e  f or s o m e A Es  a n d  t h er ef or e is n ot  a n 
o pti o n.  
A E = a dv ers e ev e nt  
9. 1 0. 6  A D V E R S E E V E N T C A T E G O RI E S F O R D E T E R MI NI N G R E L A TI O N S HI P T O S T U D Y D R U G  
P R O B A BL E  (first t hr e e c o n diti o ns m ust a p ply)  
T his  c at e g or y a p pli es  t o t h os e A E s t h at ar e  c o nsi d er e d, wit h  a hi g h  d e gr e e of c ert ai nt y,  t o b e  r el at e d t o t h e 
st u d y dr u g.  A n A E  m a y  b e  c o nsi d er e d pr o b a bl e, if:  
•  It f oll o ws a r e as o n a bl e t e m p or al s e q u e nc e fr o m a d mi nistr ati o n  of  t h e dr u g.  
•  It c a n n ot b e r e as o n a bly ex pl ai n e d by t h e k n o w n c h ar act eristics of t h e s u bj ect’s cli nic al 
st at e, e nvir o n m e nt al , or  t oxic f act ors or  ot h er  m o d es  of  t h er a py a d mi nist er e d  t o th e 
s u bj ect. 
•  It dis a p p e ars or d ecr e as es o n c ess ati o n or r e d ucti o n of t h e d os e.   ( T h er e ar e i m p ort a nt 
exc e pti o ns w h e n a n A E  d o es n ot dis a p p e ar u p o n disc o nti n u ati o n of t h e dr u g,  y et  dr u g  
r el at e d n ess cl e arl y exists,  e. g.,  ( 1) b o n e  m arr o w  d e pr essi o n,  ( 2) t ar div e dys ki n esi as.)  
•  It f oll o ws a  k n o w n  p att er n  of  r es p o ns e t o t h e s us p ect e d dr u g.  
•  It r e a p p e ars u p o n r e -c h all e n g e. 
P O S SI BL E  (first t w o c o n diti o ns m ust  a p pl y)  
T his c at e g or y a p pli es t o t h os e A E s i n w hic h t h e c o n n ecti o n wit h t h e st u d y dr u g a d mi nistr ati o n a p p e ars 
u nli k el y b ut c a n n ot b e r ul e d o ut wit h c ert ai nt y.  A n A E  m a y b e  c o nsi d er e d p ossi bl e  if, or w h e n:  


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 6 2  
• 
It f oll o ws a r e as o n a bl e t e m p or al s e q u e nc e fr o m a d mi nistr ati o n  of  t h e dr u g.
• 
It m a y  h av e  b e e n  pr o d uc e d  b y  t h e s u bj ect’s cli nic al st at e, e nvir o n m e nt al  or  t oxic f act ors
or ot h er  m o d es of  t h er a p y a d mi nist er e d t o t h e  s u bj ect.
• 
It f oll o ws a  k n o w n  p att er n  of  r es p o ns e t o t h e s us p ect e d dr u g.
R E M O T E  (first t w o c o n diti o ns m ust  a p pl y)  
I n g e n er al, t his c at e g or y is a p plic a bl e  t o a n  A E  t h at m e ets  t h e f oll o wi n g crit eri a: 
• 
It d o es  n ot  f oll o w a  r e as o n a bl e t e m p or al s e q u e nc e fr o m a d mi nistr ati o n  of  t h e dr u g.
• 
It m a y  r e a dil y h av e  b e e n  pr o d uc e d  by  t h e s u bj ect’s cli nic al st at e, e nvir o n m e nt al  or  t oxic
f act ors, or  ot h er  m o d es of  t h er a py a d mi nist er e d t o  t h e s u bj ect.
• 
It d o es  n ot  f oll o w a  k n o w n  p att er n  of r es p o ns e  t o t h e s us p ect e d dr u g.
• 
It d o es  n ot  r e a p p e ar or  w ors e n  w h e n  t h e st u dy dr u g  is r e-a d mi nist er e d.
U N R EL A T E D 
T his  c at e g ory is a p plic a bl e t o t h os e A E s w hic h ar e j u d g e d t o b e  cl e arl y a n d i nc o ntr ov erti bly d u e o nly t o 
extr a n e o us c a us es ( dis e as e, e nvir o n m e nt, etc.) a n d d o n ot m e et t h e crit eri a f or st u d y dr u g r el ati o ns hi p 
list e d u n d er r e m ot e, p ossi bl e, or pr o b a bl e. 
R ef er t o  T a bl e 7 f or d et er mi ni n g r el ati o ns hi p of A E s. 


R V L-1 0 1 -2 2  
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
V ersi o n 2 . 0: 9 M a y 2 0 2 2 
 C o nfi d e nti al  
 P a g e 6 3  
T a bl e 7   D et er mi ni n g  t h e R el ati o ns hi p  of  A d v ers e  E v e nts  t o t h e St u d y  Dr u g  
Pr o b a bl e    
P ossi bl e    
R e m ot e    
U nr el at e d  
Cl e arl y d u e t o extr a n e o us   c a us es   
–  
–  
–  
+  
R e as o n a bl e  t e m p or al ass oci ati o n  wit h  
dr u g   a d mi nistr ati o n  
+  
+  
–  
–  
M a y b e pr o d uc e d b y s u bj ect  cli nic al 
st at e, etc. 
–  
+  
+  
+  
K n o w n r es p o ns e p att er n t o   s us p ect e d 
dr u g  
+  
+  
–  
–  
Dis a p p e ars or d ecr e as es o n  c ess ati o n 
or  r e d ucti o n of  t h e 
d os e  
+  
–  
–  
–  
R e a p p e ars  o n  r e-c h all e n g e   
+  
–  
–  
–  
9. 1 0. 7  R E P O R TI N G S E RI O U S A D V E R S E E V E N T S  
A n y S A E will b e r e p ort e d t o t h e S p o ns or vi a t el e p h o n e, f ax, e -m ail , or i n p ers o n, wit hi n 2 4 h o urs of 
k n o wl e d g e b y t h e I nv esti g at or.  T his will b e m a n a g e d acc or di n g t o t h e S af e t y M a n a g e m e nt M o nit ori n g 
Pl a n.  T h e n otific ati o n m ust b e dir ect e d t o:  
 
S A Es m ust b e r e p ort e d t o t h e I R B wit hi n 2 4 h o urs  of sit e a w ar e n ess.  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 6 4  
9. 1 0. 8  S U S P E C T E D, U N E X P E C T E D, S E RI O U S A D V E R S E D R U G R E A C TI O N S  ( S U S A R)  
It is t h e r es p o nsi bility of t h e s p o ns or t o d et er mi n e w h et h er a r e p ort e d S A E fits t h e cl assific ati o n of a 
S U S A R a n d t o n otif y t h e i n v esti g at or of t h eir d ecisi o n as s o o n as p ossi bl e. 
T h e i nv esti g at or a n d s p o ns or ar e  r es p o nsi bl e f or n otif yi n g r e g ul at or y a g e nci es of f at al or lif e-t hr e at e ni n g 
s eri o us, u n ex p ect e d A D Rs  ( b y t el e p h o n e, f acsi mil e tr a ns missi o n or i n writi n g) as s o o n as p ossi bl e, b ut n o 
l at er t h a n 7 c al e n d ar d a ys aft er b ec o mi n g a w ar e of t h e i nf or m ati o n. 
A d diti o n all y, wit hi n 8 d a ys aft er h a vi n g i nf or m e d t h e a g e nc y(i es), a c o m pl et e r e p ort m ust b e s u b mitt e d, 
i ncl u di n g a n ass ess m e nt of t h e i m p ort a nc e a n d i m plic ati o n of a n y fi n di n gs. 
It is t h e r es p o nsi bility of t h e i nv esti g at or a n d s p o ns or t o r e p ort S A Es t o t h e I R B r es p o nsi bl e f or t h e st u dy 
f oll o wi n g t h e l oc al pr oc e d ur e. T h e t as k of r e p orti n g ot h er S U S A Rs m a y b e d el e g at e d t o t h e 
p h ar m ac o vi gil a nc e pr o vi d er.  
9. 1 0. 9  O T H E R S U S P E C T E D, U N E X P E C T E D, S E RI O U S A D V E R S E D R U G R E A C TI O N S  
T h e S p o ns or is r es p o nsi bl e f or n otif yi n g r e g ul at or y a g e nci es of all ot h er s us p ect e d, u n ex p ect e d, s eri o us 
A D R s t h at ar e n eit h er f at al n or lif e-t hr e at e ni n g as s o o n as p ossi bl e, b ut n o l at er t h a n 1 5 c al e n d ar d ays 
aft er b ec o mi n g a w ar e of t h e i nf or m ati o n.  
It is t h e r es p o nsi bility of t h e i nv esti g at or a n d s p o ns or t o r e p ort t o t h e I R B r es p o nsi bl e f or t h e st u dy all 
ot h er s us p ect e d, u n ex p ect e d, s eri o us A D R s t h at ar e n eit h er f at al n or lif e-t hr e at e ni n g, as s o o n as p ossi bl e, 
b ut n o l at er t h a n 1 5 c al e n d ar d a ys aft er first k n o wl e d g e b y t h e I n v esti g at or.   T h e t as k of r e p ort i n g ot h er 
S U S A Rs m a y b e d el e g at e d t o t h e p h ar m ac ovi gil a nc e pr o vi d er.  
9. 1 0. 1 0    
R E P O R TI N G O F U R G E N T S A F E T Y I S S U E S  
T h e s p o ns or is r e q uir e d t o i nf or m t h e a p pr o pri at e r e g ul at or y a ut h oriti es a n d i nv esti g at ors a n d t h e 
i nv esti g at or is r es p o nsi bl e f or i nf or mi n g t h e I R B, withi n 3 c al e n d ar d a ys of t h e ur g e nt s af et y iss u e . 
9. 1 0. 1 1    
R E P O R TI N G O T H E R S E RI O U S I M P O R T A N T M E DI C A L E V E N T S  
R e p ort w h e n t h e ev e nt d o es n ot fit t h e ot h er o utc o m es, b ut t h e ev e nt m a y j e o p ar diz e t h e s u bj ect a n d 
m a y r e q uir e m e dic al or s ur gic al i nt erv e nti o n (tr e at m e nt) t o  pr ev e nt o n e of t h e ot h er o utc o m es.   Ex a m pl es 
i ncl u d e all er gic br o nc h os p as m ( a s eri o us pr o bl e m wit h br e at hi n g) r e q uiri n g tr e at m e nt i n a n e m er g e ncy 
r o o m, s eri o us bl o o d d yscr asi as ( bl o o d dis or d ers), or s eiz ur es/c o n v ulsi o ns t h at d o n ot r es ult i n 
h os pit aliz ati o n.  T h e d ev el o p m e nt of dr u g d e p e n d e nc e or dr u g a b us e w o ul d als o b e ex a m pl es of m e dic al 
ev e nts.  
 
 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 6 5  
9. 1 0. 1 2    
P O T E N TI A L C L A S S S P E CI FI C E V E N T S   
B as e d o n F D A r evi e w of a v ail a bl e d at a, t h er e ar e p ot e nti al s af et y c o nc er ns f or t h e e ntir e cl ass of M n 
c o nt ai ni n g M RI c o ntr ast a g e nts.  T h e se i ncl u d e t h e p ossi biliti es of M n r et e nti o n i n t h e br ai n, 
h y p ers e nsitivit y r e acti o ns, l o w eri n g of s eiz ur e t hr es h ol d , a n d tr a nsi e nt c h a n g es i n C V  f u ncti o n.   
T h er ef or e, s p o ns or will s u b mit a 7 - or 1 5 -d a y  I N D s af et y r e p ort f or a n y e m er g e nt tr e at m e nt of s eiz ur e, 
str o k e, c er e br al v e n o us t hr o m b osis, QT c a b o v e 4 8 0 ms ec, or Q T c i ncr e as e of 6 0 ms ec o v er b as eli n e, 
r e g ar dl ess of ass ess m e nt of c a us alit y. 
9. 1 0. 1 3    
R E P O R T A B L E DI S E A S E  
I n t h e c as e a s u bj ect h as or m a nif est e d a n y cli nic al si g ns c h ar act eristic of a r e p ort a bl e dis e as e ( e. g., 
t u b erc ul osis, S A R S -C o V -2) it is t h e r es p o nsi bilit y of t h e M e dic al Dir ect or t o n otif y t h e P u blic H e alt h 
a ut h oriti es wit hi n 4 8 h o urs aft er b ec o mi n g a w ar e  of t h e i nf or m ati o n  or p er l oc al g ui d eli n es . 
A d diti o n al d et ails c a n b e f o u n d i n t h e s af et y m a n a g e m e nt pl a n.  
9. 1 1  C O VI D R E S P O N S E P L A N  
9. 1 1. 1  C O VI D -1 9 R E L A T E D RI S K S A N D RI S K MI TI G A TI O N M E A S U R E S  
T h e f oll o wi n g ris ks a n d ris k miti g ati n g m e as ur es a p pl y t o t h e ti m e i n w hic h t h e st u d y is c o n d uct e d d uri n g 
t h e C O VI D-1 9 p a n d e mic.  
9. 1 1. 1. 1  S T U D Y D R U G  R E L A T E D RI S K  
A g ai nst t h e b ac k gr o u n d of t h e C O VI D -1 9 p a n d e mic, t h e p ot e nti al ris k of a s u bj ect d ev el o pi n g C O VI D -1 9 
h as b e e n c o nsi d er e d i n t er ms of t h e ris k -b e n efit ev al u ati o n.  R V P -0 0 1 is n ot b i ol o gic all y activ e.  B as e d o n   
av ail a bl e n o n -cli nic al a n d cli nic al d at a (i ncl u di n g cl ass eff ects) , it is c o nsi d er e d t h at a s u bj ect w o ul d n ot b e 
at i ncr e as e d ris k of eit h er b ec o mi n g i nf ect e d wit h S A R S -C o V -2 or ex p eri e nci n g a m or e s ev er e ill n ess.  T h at 
is, t h e st u d y dr u g h as n o k n o w n i m m u n o m o d ul at or y eff ect t h at w o ul d c o nf er a n i ncr e as e d ris k t o h e alt hy 
s u bj ects e nr oll e d i n t h e st u d y. 
9. 1 1. 1. 2  G E N E R A L C O VI D -1 9 R E L A T E D RI S K S A N D RI S K MI TI G A TI O N M E A S U R E S  
G e n er al ris k miti g ati o n a g ai nst C O VI D -1 9 will b e i m pl e m e nt e d i n acc or d a nc e wit h Q u oti e nt’s m o nit ori n g 
a n d pr ev e nti o n c o ntr ol m e as ur es.  
T h e ris k miti g ati o n m e as ur es,  w h er e a p plic a bl e, will b e a m e n d e d b as e d o n e m er gi n g g ov er n m e nt 
g ui d a nc e.  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 6 6  
9. 1 1. 1. 3  C O VI D -1 9 V A C CI N E -R E L A T E D RI S K  
A p pr o v e d (i ncl u di n g h e alt h a ut h orit y c o n diti o n al m ar k eti n g a ut h oriz ati o n) C O VI D -1 9 v acci n es e .g ., kill e d, 
i n activ at e d, p e pti d e, d e ox yri b o n ucl eic aci d ( D N A ), a n d ri b o n e ucl eic aci d (R N A ) v acci n es m a y b e p er mitt e d 
acc or di n g t o t h e i nv esti g at or’s discr eti o n a n d as p er l oc al g ui d a nc e.  
D u e t o l ac k of bi ol o gic al activit y of R V P -0 0 1 , t h er e is n o p erc eiv e d i m p act o n t h e s af et y of t h e st u d y 
s u bj ects or o n t h e st ud y o bj ectiv es f or s u bj ects w h o m a y r ec eiv e t h es e v acci n es ( eit h er first, s ec o n d, or 
b o ost er d os es).  It is als o v er y u nli k el y t h at a d mi nistr ati o n of t h e st u d y dr u g w o ul d i nt erf er e wit h 
C O VI D -1 9 v acci n ati o n r es p o ns e; h o w ev er, n o s p ecific pr e -cli nic al or clinic al i nv esti g ati o ns h av e b e e n 
c o n d uct e d at t his p oi nt wit h R V P -0 0 1 .  
T h e e m er gi n g s af et y a n d effic acy d at a fr o m milli o ns of v acci n at e d p e o pl e i n dic at e t h at t h es e v acci n es h av e 
a n exc ell e nt s af et y a n d effic ac y r ec or d.   I n t h e br o a d er i nt er ests of s oci et y an d t o li mit t h e ext e nt of t h e 
gl o b al p a n d e mic, it is i m p ort a nt t h at s u bj ects s h o ul d r ec eiv e a v acci n e w h e n it is off er e d t o t h e m.  
9. 1 2  S A F E T Y R E VI E W C O M MI T T E E  ( S R C) 
9. 1 2. 1  D E CI SI O N P OI N T S  
T h e f oll o wi n g i n -st u d y d ecisi o ns will b e m a d e d uri n g t his st u d y: 
•  
D os e s el ecti o n f or C o h orts 2 t o  4.  
•  
Pr o gr essi o n fr o m s e nti n el gr o u p t o m ai n gr o u p  
•  
C h a n g es t o s af et y a n d/ or P K ti m e p oi nts, if t h er e is r e as o n t o b eli ev e t h at t h e c h a n g e mi g ht 
i m pr ov e t h e q u alit y of t h e d at a as a c o ns e q u e nc e of r evi e w of e m er gi n g d at a.  
9. 1 2. 2  C RI T E RI A F O R D O S E D E CI SI O N S  
C o h orts will b e d os e d s e q u e nti all y i n a n asc e n di n g f as hi o n.   
F oll o wi n g c o m pl eti o n of e ac h S A D c o h ort, a S R C will c o nv e n e t o r evi e w all av ail a bl e bli n d e d  s af et y, 
t ol er a bilit y a n d av ail a bl e P K/ ex p os ur e ass ess m e nts u p t o D a y 6 ( 1 20 h o urs) p erf or m e d f or e ac h S A D 
c o h ort, a n d t o g et h er wit h  att e m pts  t o c orr el at e ex p os ur e  l ev els wit h o bs erv e d  A Es  t o ev al u at e  
pr o gr essi o n  to t h e n ext d os e  c o h ort. 
T h e  S R C  will  b e  c o m pris e d of  t h e Pri nci p al  I nv esti g at or at  t h e cli nic al sit e a n d  t h e S p o ns or’s  m e dic al   
p ers o n n el,  at a  mi ni m u m.  
Crit eri a f or S e nti n el D osi n g D ecisi o n (s) 
F or all c o h orts f oll o wi n g a s e nti n el d esi g n t h e d ecisi o n t o pr oc e e d wit h t h e m ai n gr o u p will b e m a d e by t h e 
i nv esti g at or, b as e d o n s af et y d at a u ntil 2 4 ho urs  p ost -d os e of t h e l ast s e nti n el s u bj ect.   T h e i nv esti g at or 
will i nf or m t h e s p o ns or of a n y s af et y c o nc er ns.  
F or a d diti o n al d et ails r ef er t o D at a S af et y M o nit ori n g Pl a n ( D S M P) . 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 6 7  
1 0  S T A TI S TI C A L C O N SI D E R A TI O N S   
1 0. 1  P O P U L A TI O N S F O R A N A L Y S E S  
P o p ul ati o ns a n d a n al ysis s e ts will b e d et er mi n e d f or s af et y a n d P K aft er d at a b as e l oc k usi n g t h e crit eri a 
d efi n e d i n t h e st atistic al a n al ysis pl a n ( S A P); t h e S A P will b e si g n e d off pri or t o d at a b as e l oc k.   T h e s af ety 
p o p ul ati o n a n d s af et y a n al ysis s et will b e d efi n e d aft er d at a b as e l oc k b ut pri or t o st u d y u n bli n di n g; all 
ot h er p o p ul ati o ns will b e d efi n e d aft er d at a b as e l oc k w h e n t h e r el ev a nt d at a ar e av ail a bl e.  
1 0. 1. 1  S A F E T Y  P O P U L A TI O N  
T h e  s af et y p o p ul ati o n  will i ncl u d e  all  s u bj ects w h o r ec eiv e d at l e ast  1  d os e  of  R V P -0 0 1  or pl ac e b o.  
T h e  n u m b er  of  s u bj ects w h o  w er e  i ncl u d e d, w h o  disc o nti n u e d,  a n d w h o c o m pl et e d  t h e st u dy wil l  b e  
t a b ul at e d.  T h e  pri m ary  r e as o ns f or disc o nti n u ati o n  will  b e  pr o vi d e d.  
1 0. 1. 2  P H A R M A C O KI N E TI C  P O P U L A TI O N  
T h e P K p o p ul ati o n will c o nsist of all tr e at e d s u bj ects w h o h av e s uffici e nt d at a t o c alc ul at e at  l e ast o n e  of  t h e 
P K  p ar a m et ers.   H o w ev er,  t h e P K  a n alysis  d at as et  will  excl u d e  d at a ass oci at e d wit h pr ot oc ol vi ol ati o ns 
a n d/ or m aj or  pr ot oc ol d evi ati o ns (s u bj ect s h o ul d n ot h av e vi olat e d a ny m aj or  e ntry crit eri o n li k el y t o i m p act 
t h e P K a n al ysis a n d  s h o ul d n ot h av e d evi at e d si g nific a ntl y fr o m t h e pr ot oc ol b et w e e n  e nr oll m e nt  a n d  
s uccessf ul st u dy c o m pl eti o n ). 
T h e  P K p o p ul ati o n will  b e  f urt h er d escri b e d  i n a S A P. 
St atistics  f or d e m o gr a p hic  a n d b as eli n e  d at a  will b e  d et ail e d  i n t h e S A P.  
1 0. 2  S T A TI S TI C A L A N A L Y S E S  
1 0. 2. 1  S A F E T Y A N A L Y S E S  
T h e  cli nic al l a b or at or y t ests, m e as ur e m e nts of vit al si g ns, p uls e oxi m etr y , E C Gs, p hysic al  ex a mi n ati o n,  a n d  
ot h er  s af ety p ar a m et ers  will  b e  us e d  t o p erf or m  t h e s af ety st atistic al a n alysis.  
1 0. 2. 2  S A F E T Y  E N D P OI N T S  
T h e  s af et y e n d p oi nts  ar e  t h e fr e q u e nc y, t y p e a n d s e v erit y of  A Es,  cli nic al l a b or at or y r es ults, vit al   si g ns, 
E C G, p uls e  oxi m etr y, p h ysic al ex a mi n ati o n , a n d n e ur ol o gic al ass ess m e nt  fi n di n gs, a n d b o d y w ei g ht.  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 6 8  
1 0. 2. 3  S A F E T Y S T A TI S TI C A L M E T H O D O L O G Y  
All  s af et y d at a  ( A Es, cli nic al l a b or at or y r es ults, vit al  si g ns, p uls e oxi m etr y  a n d  E C Gs)  will  b e  list e d.  S af ety 
d at a will b e s u m m ariz e d wit h d escri ptiv e st atistics a n d fr e q u e nc y t a bl es.   If r e q u est e d b y t h e  S p o ns or  
a n d/ or S R C  a d diti o n al a n al ysis m a y b e  p erf or m e d.  
St atistics  f or s u m m ar y of A Es  a n d  s af et y r es ults will b e  d et ail e d  i n a S A P . 
1 0. 2. 4  B A S E LI N E D E S C RI P TI V E S T A TI S TI C S  
Listi ngs a n d d escri ptiv e s u m m ar y st atistics of d e m o gr a p hic ( a g e, h ei g ht, w ei g ht, a n d B MI) a n d  b as eli n e  
d at a  will  b e  pr es e nt e d.  
1 0. 2. 5  P L A N N E D I N T E RI M A N A L Y S E S  
I nt eri m P K a n al ysis will b e p erf or m e d aft er e ac h c o h ort ( d os e s el ecti o n a n d s af e t y ass ess m e nt) . 
T h e  S A P  will  d escri b e  t h e pl a n n e d i nt eri m  a n al ys es  i n gr e at er  d et ail.  
1 0. 2. 6  P H A R M A C O KI N E TI C S A N A L Y SI S  C O N C E N T R A TI O N  D A T A:  
Pl as m a  c o nc e ntr ati o n d at a  will  b e  s u m m ariz e d b y  tr e at m e nt a n d occ asi o n  ( as a p plic a bl e) usi n g  t h e f oll o wi ng 
d escri ptiv e  st atistics: S a m pl e  siz e ( N), mi ni m u m  ( mi n), arit h m etic  m e a n,  m e di a n,  m axi m u m ( m ax), st a n d ar d 
d evi ati o n  ( S D), a n d c o effici e nt  of v ari ati o n  ( C V %).  D escri ptiv e  st atistics will  b e  c alc ul at e d at  e ac h  i n divi d u al 
ti m e p oi nt.   C o nc e ntr ati o ns  t h at ar e  b el o w  t h e l o w er li mit of  q u a ntit ati o n  (LL O Q) will  b e  tr e at e d as  z er o f or 
d escri ptiv e  st atistics. 
T h e i n divi d u al pl as m a c o nc e ntr ati o n/ti m e pr ofil es will b e pr es e nt e d usi n g  t h e act u al s a m pli n g ti m es w h er e as 
t h e m e a n  pl as m a  c o nc e ntr ati o n-ti m e pr ofil es  will  b e  pr es e nt e d  usi n g  t h e n o mi n a l s a m pli n g ti mes.  
C o nc e ntr ati o n  pr ofil es  will  b e  pr es e nt e d  o n  b ot h  li n e ar a n d l o g arit h mic  sc al es. 
1 0. 2. 7  P H A R M A C O KI N E TI C  P A R A M E T E R S:  
Pl as m a R V P -0 0 1 c o nc e ntr ati o n -ti m e d at a will b e a n alyz e d by n o n -c o m p art m e nt al a p pr o ac h c o nsist e nt wit h 
t h e I V r o ut e of a d mi nistr ati o n  usi n g  P h o e nix Wi n N o nli n v 8. 0 or hi g h er .  N o mi n al  ti m es m ay b e us e d  f or 
i nt eri m a n alys es;  h o w ev er,  act u al  s a m pli n g ti m es will  b e  us e d  f or fi n al c alc ul ati o ns. 
T h e  p ar a m et ers  pr es e nt e d i n  T a bl e  8  will  b e  d et er mi n e d, b ut  n ot  li mit e d t o, f or e ac h pl as m a  
c o nc e ntr ati o n-ti m e pr ofil e  f or t h os e s u bj ects t h at r ec eiv e d tr e at m e nt as  t h e d at a  all o ws:  
   
 




R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 0  
 
 
 
 
 
  
 
 
 
 
   
 
 
 
   
 
 
 
 
  
 
 
 
 
A d diti o n al  d et ails  c a n b e f o u n d i n t h e S A P.  
1 0. 2. 8  P H A R M A C O KI N E TI C S T A TI S TI C A L M E T H O D O L O G Y  
Listi n gs a n d  fi g ur es of  i n divi d u al R V P -0 0 1  pl as m a  c o nc e ntr ati o ns a n d  s u m m ari es will  b e   b as e d o n t h e 
r a n d o miz e d s af et y p o p ul ati o n. R V P-0 0 1 pl as m a c o nc e ntr ati o ns will b e  s u m m ariz e d d escri ptiv el y  at  e ac h  
ti m e p oi nt  f or e ac h d os e  gr o u p  usi n g  t h e r a n d o miz e d s af et y p o p ul ati o n.   P h ar m ac o ki n etic m etrics will b e 
s u m m ariz e d d escri ptiv el y f or e ac h d os e gr o u p usi n g t h e f ull a n al ysis p o p ul ati o n.  C u m ul ativ e   a m o u nts of 
R V P -0 0 1 excr et e d i n uri n e b y c oll ecti o n i nt erv al w ill b e s u m m ariz e d d escri ptiv el y.  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 1  
1 0. 2. 9  D E S C RI P TI V E  S T A TI S TI C S  
D escri ptiv e  st atistics will  b e  c alc ul at e d f or e ac h  tr e at m e nt gr o u p.   Pl as m a  P K  p ar a m et ers  will  b e   s u m m ariz e d 
by tr e at m e nt a n d occ asi o n ( as a p plic a bl e)  usi n g  t h e f oll o wi n g d escri ptiv e st atistics:  N, mi n, arit h m etic 
m e a n, g e o m etric m e a n, m e di a n, m ax, S D, C V %, 9 5 % c o nfi d e nc e i nt erv al  ( CI) ( g e o m etric m e a n),  a n d  
g e o m etric  m e a n  C V %.  
1 0. 2. 1 0    
S T A TI S TI C A L  A N A L Y SI S  
F or m al st atistic al a n al ysis will b e p erf or m e d o n t h e l o g -tr a nsf or m e d P K p ar a m et ers m axi m u m s er u m 
c o nc e ntr ati o n (C m ax ), ar e a u n d er t h e  c o nc e ntr ati o n-ti m e  c urv e ( A U C )( 0-t), a n d A U C ( 0-i nf) t o ass ess d os e 
pr o p orti o n alit y. T his will b e ass ess e d usi n g t h e f oll o wi n g p o w er m o d el:  
l o ge ( A U C or C m ax) = µ + βx l o ge ( D os e) 
T h e esti m at e o bt ai n e d f or b  is a m e as ur e of d os e pr o p orti o n alit y.  T h e esti m at e of b  t o g et h er wit h its 9 0 % 
CI ( b l,b u) will b e pr es e nt e d t o q u a ntif y t h e d e gr e e of n o n -pr o p orti o n alit y.  
F urt h er d et ails r el ati n g t o t h e st atistic al a n al ysis will b e i ncl u d e d i n t h e S A P i ncl u di n g t h e f oll o wi n g:  
•  
Crit eri a t o b e us e d t o d efi n e e ac h of t h e p o p ul ati o ns a n d  a n al ysis s ets  
•  
A d diti o n al d et ail c ov eri n g t h e a n al ys es a n d/ or d escri pti o n of pri m ary a n d s ec o n d ar y a n al ys es a n d 
s af et y d at a 
•  
H a n dli n g of missi n g d at a, u n us e d or s p uri o us d at a  
•  
H a n dli n g of d at a fr o m wit h dr a w n s u bj ects  
•  
U n bli n di n g pr oc e d ur es a n d m ai nt ai ni n g t h e bli n d  
F urt h er d et ail o n t h e st atistic al a n al ysis will b e i ncl u d e d i n t h e S A P.  
1 0. 2. 1 1    
P L A N N E D I N T E RI M  A N A L Y S E S  
I nt eri m P K a n al ysis will b e p erf or m e d aft er e ac h c o h ort ( d os e s el ecti o n a n d s af et y ass ess m e nt)  . 
T h e  S A P  will  d escri b e  t h e pl a n n e d i nt eri m  a n al ys es  i n gr e at er  d et ail.  
1 0. 2. 1 2    
D E T E R MI N A TI O N  O F  S A M P L E  SI Z E  
T his  st u dy is ex pl or at ory  a n d  t h er ef or e t h e s a m pl e siz e is n ot  b as e d  o n  st atistic al c o nsi d er ati o ns. T h e  c o h ort siz e 
is a  c o m m o n siz e f or p h as e  1  st u di es. 
 
 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 2  
1 1  A P P E N DI X 1: S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L  C O N SI D E R A TI O N S  
1 1. 1  R E G U L A T O R Y, E T HI C A L , A N D S T U D Y O V E R SI G H T C O N SI D E R A TI O N S  
1 1. 1. 1  R E G U L A T O R Y A N D E T HI C A L C O N SI D E R A TI O N S  
•  
T his st u d y will b e c o n d uct e d i n acc or d a nc e wit h t h e pr ot oc ol a n d wit h t h e f oll o wi n g:  
o  C o ns e ns us et hic al pri nci pl es d eriv e d fr o m i nt er n ati o n al g ui d eli n es i ncl u di n g t h e 
D ecl ar ati o n of H elsi n ki a n d C o u ncil f o r I nt er n ati o n al Or g a niz ati o ns of M e dic al Sci e nc es 
( CI O M S) i nt er n ati o n al et hic al g ui d eli n es 
o  A p plic a bl e I nt er n ati o n al C o nf er e nc e o n H ar m o niz ati o n (I C H) G o o d Cli nic al Pr actic e ( G C P) 
g ui d eli n es  
o  A p plic a bl e l a ws a n d r e g ul ati o ns  
•  
T h e pr ot oc ol, pr ot oc ol a m e n d m e nts, I C F, I B, a n d ot h er r el ev a nt d oc u m e nts (e. g. , a dv ertis e m e nts) 
m ust b e s u b mitt e d t o a n I R B/I E C by t h e i nv esti g at or a n d r evi e w e d a n d a p pr o v e d b y t h e I R B/I E C 
b ef or e t h e st u d y is i niti at e d.  
•  
A n y a m e n d m e nts t o t h e pr ot oc ol will r e q uir e I R B/I E C a p pr o v al b ef or e i m pl e m e nt ati o n of c h a n g es 
m a d e t o t h e st u d y d esi g n, exc e pt f or c h a n g es n ec ess ar y t o eli mi n at e a n i m m e di at e h az ar d t o 
st u d y p artici p a nts.  
•  
Pr ot oc ols a n d a n y s u bst a nti al a m e n d m e nts t o t h e pr ot oc ol will r e q uir e h e alt h a ut h orit y  a p pr o v al 
pri or t o i niti ati o n exc e pt f or c h a n g es n ec ess ar y t o eli mi n at e a n i m m e di at e h az ar d t o st u dy 
p artici p a nts.  
•  
T h e i nv esti g at or will b e r es p o nsi bl e f or t h e f oll o wi n g:  
o  Pr o vi di n g writt e n s u m m ari es of t h e st at us of t h e st u d y t o t h e I R B/I E C a n n u all y or m or e 
fr e q u e ntl y i n acc or d a nc e wit h t h e r e q uir e m e nts, p olici es, a n d pr oc e d ur es est a blis h e d by 
t h e I R B/I E C 
o  N otif yi n g t h e I R B/I E C of S A Es or ot h er si g nific a nt s af et y fi n di n gs as r e q uir e d b y I R B/I E C 
pr oc e d ur es  
o  Pr o vi di n g o v ersi g ht of t h e c o n d uct of t h e st u d y at t h e sit e a n d a d h er e nc e t o r e q uir e m e nts 
of 2 1 C F R, I C H g ui d eli n es, t h e I R B/I E C, E ur o p e a n r e g ul ati o n 5 3 6/ 2 0 1 4 f or cli nic al st u di es (if 
a p plic a bl e), E ur o p e a n M e dic al D evic e R e g ul ati o n 2 0 1 7/ 7 4 5 f or cli nic al d evic e r es e arc h (if 
a p plic a bl e), a n d all ot h er a p plic a b l e l oc al r e g ul ati o ns 
1 1. 1. 2  FI N A N CI A L DI S C L O S U R E  
I nv esti g at ors a n d s u b-i nv esti g at ors will pr o vi d e t h e s p o ns or wit h s uffici e nt, acc ur at e fi n a nci al i nf or m ati o n 
as r e q u est e d t o all o w t h e s p o ns or t o s u b mit c o m pl et e a n d acc ur at e fi n a nci al c ertific ati o n or discl os ur e 
st at e m e nts t o t h e a p pr o pri at e r e g ul at or y a ut h oriti es.  I nv esti g at ors ar e r es p o nsi bl e f or pr ovi di n g 
i nf or m ati o n o n fi n a nci al i nt er ests d uri n g t h e c o urs e of t h e st u d y a n d f or 1 y e ar aft er c o m pl eti o n of t h e 
st u d y. 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 3  
1 1. 1. 3  I N F O R M E D C O N S E N T P R O C E S S 
1 1. 1. 3. 1  C O N S E N T/ A S S E N T A N D O T H E R I N F O R M A TI O N A L D O C U M E N T S P R O VI D E D T O 
P A R TI CI P A N T S  
C o ns e nt f or ms d escri bi n g i n d et ail t h e st u d y i nt erv e nti o n, st u d y pr oc e d ur es, a n d ris ks ar e giv e n t o t h e 
p artici p a nt , a n d writt e n d oc u m e nt ati o n of i nf or m e d c o ns e nt is r e q uir e d pri or t o st arti n g 
i nt erv e ntio n/ a d mi nist eri n g st u d y i nt erv e nti o n.  T h e f oll o wi n g c o ns e nt m at eri als ar e s u b mitt e d wit h t his 
pr ot oc ol : 
•  
I R B a p pr ov e d I nf or m e d C o ns e nt 
1 1. 1. 3. 2  C O N S E N T P R O C E D U R E S A N D D O C U M E N T A TI O N  
 
•  
T h e i nv esti g at or or his/ h er r e pr es e nt ati v e will ex pl ai n t h e n at ur e of t h e st u d y, i ncl u di n g t h e ris ks 
a n d b e n efits, t o t h e p artici p a nt [ or t h eir l e g all y a ut h oriz e d r e pr es e nt ativ e], a n d a ns w er all 
q u esti o ns r e g ar di n g t h e st u d y.  
•  
P artici p a nts m ust b e i nf or m e d t h at t h eir p artici p ati o n is v ol u nt ar y.  P artici p a nts [ or t h eir l e g ally 
a ut h oriz e d r e pr es e nt ativ es]  will b e r e q uir e d t o si g n a st at e m e nt of i nf or m e d c o ns e nt t h at m e ets 
t h e r e q uir e m e nts of 2 1 C F R 5 0, l oc al r e g ul ati o ns, I C H g ui d eli n es, priv ac y, a n d d at a pr ot e cti o n 
r e q uir e m e nts, w h er e a p plic a bl e, a n d t h e I R B/I E C or st u d y c e nt er. 
•  
T h e m e dic al r ec or d m ust i ncl u d e a st at e m e nt t h at writt e n i nf or m e d c o ns e nt w as o bt ai n e d b ef or e 
t h e p artici p a nt w as e nr oll e d i n t h e st u d y a n d t h e d at e t h e writt e n c o ns e nt w as o bt ai n e d.  T h e 
a ut h oriz e d p ers o n o bt ai ni n g t h e i nf or m e d c o ns e nt m ust als o si g n t h e I C F.  
•  
P artici p a nts m ust b e r ec o ns e nt e d t o t h e m ost c urr e nt v ersi o n of t h e I C F(s) d uri n g t h eir 
p artici p ati o n i n t h e st u d y.  
•  
A c o p y of t h e I C F(s) m ust b e pr o vi d e d t o t h e p artici p a nt [ or t h eir l e g all y a ut h oriz e d 
r e pr es e nt ativ e]. 
T h e I C F will c o nt ai n a s e p ar at e s ecti o n t h at a d dr ess es t h e us e of r e m ai ni n g m a n d at or y s a m pl es f or 
o pti o n al ex pl or at or y r es e arc h.  T h e i nv esti g at or or a ut h oriz e d d esi g n e e will ex pl ai n t o e ac h p artici p a nt t h e 
o bj ectiv es  of t h e ex pl or at or y r es e arc h.   P artici p a nts will b e t ol d t h at t h e y ar e fr e e t o r ef us e t o p artici p at e 
a n d m a y wit h dr a w t h eir c o ns e nt at a n y ti m e a n d f or a n y r e as o n d uri n g t h e st or a g e p eri o d.  A s e p ar at e 
si g n at ur e will b e r e q uir e d t o d oc u m e nt a p artici p a nt’s a gr e e m e nt t o all o w a n y r e m ai ni n g s p eci m e ns t o b e 
us e d f or ex pl or at or y r es e arc h. P artici p a nts w h o d ecli n e t o p artici p at e i n t his o pti o n al r es e arc h will n ot 
pr o vi d e t his s e p ar at e si g n at ur e . 
1 1. 1. 4  S T U D Y DI S C O N TI N U A TI O N A N D C L O S U R E  
T his st u d y m a y b e t e m p or aril y s us p e n d e d or pr e m at ur el y t er mi n at e d if t h er e is s uffici e nt r e as o n a bl e 
c a us e.  Writt e n n otific ati o n, d oc u m e nti n g t h e r e as o n f or st u dy s us p e nsi o n or t er mi n ati o n, will b e pr ovi d e d 
b y t h e s us p e n di n g or t er mi n ati n g p art y t o st u d y p artici p a nts, i nv esti g at or, f u n di n g a g e nc y, t h e 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 4  
I nv esti g ati o n al N e w Dr u g (I N D) s p o ns or, a n d r e g ul at or y a ut h oriti es.  If t h e st u d y is pr e m at ur el y t er mi n at e d 
or s us p e n d e d, t h e  P ri nci p al Inv esti g at or ( PI ) will pr o m ptl y i nf or m st u d y p artici p a nts  a n d  t h e I R B, a nd 
s p o ns or will pr o vi d e t h e r e as o n(s) f or t h e t er mi n ati o n or s us p e nsi o n.  St u d y p artici p a nts will b e c o nt act e d, 
as a p plic a bl e, a n d b e i nf or m e d of c h a n g es t o st u d y visit sc h e d ul e.  
Circ u mst a nc es t h at m a y w arr a nt t er mi n ati o n or s us p e nsi o n i ncl u d e, b ut ar e n ot li mit e d t o: 
•  
D et er mi n ati o n of u n ex p ect e d, si g nific a nt, or u n acc e pt a bl e ris k t o p artici p a nts  
•  
D e m o nstr ati o n of effic ac y t h at w o ul d w arr a nt st o p pi n g    
•  
I ns uffici e nt c o m pli a nc e t o pr ot oc ol r e q uir e m e nts 
•  
D at a t h at ar e n ot s uffici e ntl y c o m pl et e a n d/ or ev al u a bl e  
•  
D e t er mi n ati o n t h at t h e pri m ar y e n d p oi nt h as b e e n m et 
•  
D et er mi n ati o n of f utilit y  
(St u d y m a y r es u m e o nc e c o nc er ns a b o ut s af et y, pr ot oc ol c o m pli a nc e, a n d d at a q u ality ar e a d dr ess e d a n d 
s atisf y t h e s p o ns or, I R B, a n d/ or F D A. ) 
1 1. 1. 5  C O N FI D E N TI A LI T Y A N D P RI V A C Y  
P artici p a nt c o nfi d e nti alit y a n d priv ac y is strictl y h el d i n tr ust b y t h e p artici p ati n g i nv esti g at ors, t h eir st aff, 
a n d t h e s p o ns or(s) a n d t h eir r e pr es e nt ativ es.  T his c o nfi d e nti alit y is ext e n d e d t o c o v er t esti n g of bi ol o gic al 
s a m pl es a n d g e n etic t ests i n a d diti o n to t h e cli nic al i nf or m ati o n r el ati n g t o p artici p a nts.   T h er ef or e, t h e 
st u d y pr ot oc ol, d oc u m e nt ati o n, d at a, a n d all ot h er i nf or m ati o n g e n er at e d will b e h el d i n strict c o nfi d e nc e.  
N o i nf or m ati o n c o nc er ni n g t h e st u d y, or t h e d at a will b e r el e as e d t o a n y u n a ut h oriz e d t hir d p art y wit h o ut 
pri or writt e n a p pr o v al of t h e s p o ns or.  
All r es e arc h activiti es will b e c o n d uct e d i n as priv at e a s etti n g as p ossi bl e.  
T h e st u d y m o nit or, ot h er a ut h oriz e d r e pr es e nt ativ es of t h e s p o ns or,  r e pr es e nt ativ es of t h e I R B, r e g ul at or y 
a g e nci es , s p o ns or, or p h ar m ac e utic al c o m p a n y s u p pl yi n g st u d y pr o d uct m a y i ns p ect all d oc u m e nts a n d 
r ec or ds r e q uir e d t o b e m ai nt ai n e d b y t h e i nv esti g at or, i ncl u di n g b ut n ot li mit e d t o, m e dic al r ec or ds 
( offic e, cli nic, or h os pit al) a n d p h ar m ac y r ec or ds f or t h e p artici p a nts i n t his st u d y.  T h e cli nic al st u d y sit e 
will p er mit acc ess t o s uc h r ec or ds.  
T h e st u d y p artici p a nt’s c o nt act i nf or m ati o n will b e s ec ur el y st or e d at e ac h cli nic al sit e f or i nt er n al us e 
d uri n g t h e st u d y.   At t h e e n d of t h e st u d y all r ec or ds will c o nti n u e t o b e k e pt i n a s ec ur e l oc ati o n f or as 
l o n g a p eri o d as dict at e d b y t h e r evi e wi n g I R B, I nstit uti o n al p olici es, or s p o ns or r e q uir e m e nts. 
St u d y p artici p a nt r es e arc h d at a w hic h is c oll ect e d f or p ur p os es of st atistic al a n al ysis a n d sci e ntific 
r e p orti n g will b e tr a ns mitt e d t o a n d st or e d at Q u oti e nt Sci e nc es.  T his will n ot i ncl u d e t h e p artici p a nt’s 
c o nt act or i d e ntif yi n g i nf or m ati o n.  R at h er, i n divi d u al p artici p a nts a n d t h eir r es e arc h d at a will b e 
i d e ntifi e d b y a u ni q u e st u d y i d e ntific ati o n n u m b er.   T h e st u d y d at a e ntr y a n d st u d y m a n a g e m e nt s yst e ms 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 5  
us e d b y t h e cli nic al sit e a n d b y Q u oti e nt  r es e arc h st aff will be s ec ur e d  a n d p ass w or d pr ot ect e d.  At t h e 
e n d of t h e st u d y, all st u d y d at a b as es will b e d e -i d e ntifi e d an d arc hiv e d at Q u oti e nt Sci e nc es . 
P ers o n al d at a will b e  s ec ur el y st or e d t o pr ev e nt u n a ut h oriz e d acc ess, discl os ur e, diss e mi n ati o n, alt er ati o n 
or l oss of i nf or m ati o n a n d u n a ut h oriz e d p ers o n al d at a pr oc essi n g.  
Acc ess t o p ers o n al i nf or m ati o n is r estrict e d s o  t h at o nl y p ers o n n el w h o ar e r e q uir e d t o acc ess p ers o n al 
d at a as p art of t h eir j o b r ol e c a n d o s o. All p ers o n n el w h o acc ess p ers o n al i nf or m ati o n ar e b o u n d b y a d uty 
of c o nfi d e nti alit y.  
T ec h nic al arr a n g e m e nts s urr o u n di n g t h e el ectr o nic st or a g e a n d us e of d a t a ar e as f oll o ws: 
•  
C o m p ut ers st ori n g el ectr o nic p ers o n al d at a ar e pr ot ect e d b y a ntivir us s oft w ar e , a n d t h e n et w or k s 
o n w hic h c o m p ut ers ar e li n k e d ar e pr ot ect e d b y i n d ustr y gr a d e fir e w alls  
•  
Off -sit e p ers o n n el c a n o nl y acc ess n et w or k e d c o m p ut ers t hr o u g h a vir t u al priv at e n et w or k 
•  
El ectr o nic acc ess t o d at a is li mit e d acc or di n g t o us er r ol es  
•  
All d at a ar e st or e d o n p ass w or d pr ot ect e d c o m p ut ers  
Or g a niz ati o n al arr a n g e m e nts ar e as f oll o ws:  
•  
All b uil di n gs ar e s ec ur e d b y k e y -c ar d acc ess 
•  
M a n u al fil es of p ers o n al d at a ar e st or e d wit hi n r estrict e d ar e as of t h e cli nic al u nit t h at c a n o nly b e 
acc ess e d b y a ut h oriz e d p ers o n n el  
•  
D at a s ec urity a n d/ or c o nfi d e nti alit y pr ovisi o ns ar e utiliz e d i n a gr e e m e nts wit h t hir d p arti es  
•  
D oc u m e nt e d b ac k -u p a n d dis ast er r ec o v er y pr oc e d ur es ar e i n pl ac e 
•  
I nt er n al a u dit a n d c o m pli a nc e f u ncti o ns pr ovi d e r e g ul at or y ov ersi g ht 
T h e s p o ns or s h all b e t h e d at a c o ntr oll er i n r es p ect of t h e p ers o n al d at a of t h e st u d y s u bj ects c oll ect e d i n 
c o n n ecti o n wit h t h e st u d y a n d s h all act i n acc or d a nc e wit h t h e r el e v a nt d at a pr ot ecti o n l a ws i n r el ati o n t o 
t h e c oll ecti o n a n d pr oc essi n g of t h os e p ers o n al d at a.  R ec or ds i d e ntif yi n g t h e s u bj ect will b e k e pt 
c o nfi d e nti al a n d, t o t h e ext e nt p er mitt e d b y t h e a p plic a bl e l a ws a n d/ or r e g ul ati o ns, will n ot b e m a d e 
p u blicl y av ail a bl e.  A n o n y miz e d p ers o n al d at a s h all b e c oll ect e d a n d pr oc ess e d f or t h e p ur p os es of t h e 
st u d y a n d m a y als o b e a d d e d t o r es e arc h d at a b as es a n d us e d i n t h e f ut ur e b y t h e s p o ns or a n d its affili at es 
f or c ert ai n a d diti o n al cli nic al r es e arc h, f or pr o d uct r e g ul ati o n a n d s af et y r e p orti n g p ur p os es, a n d f or 
e ns uri n g c o m pli a nc e wit h l e g al r e q uir e m e nts.  T h e s t u d y s u bj ects’ a n o n y miz e d p ers o n al d at a m a y b e 
pr oc ess e d f or s uc h p ur p os es b y ot h er p arti es i ncl u di n g: t h e s p o ns or’s affili at es a n d lic e nsi n g p art n ers ; t h e 
s p o ns or’s b usi n ess p art n ers ; r e g ul at or y a g e nci es a n d ot h er h e alt h a ut h oriti es; a n d I R B.  T h e st u d y 
su bj ects’ a ut h oriz ati o n f or s uc h us e a n d discl os ur e s h all b e o bt ai n e d b y t h e st u d y s u bj ects si g ni n g t h e I C F 
f or t h e st u d y. 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 6  
A d diti o n all y, Q u oti e nt p ers o n n el ar e c o ntr act u all y b o u n d b y a d ut y of c o nfi d e nti ality a n d r ec eiv e tr ai ni n g 
o n t his m att er.  
1 1. 1. 6  F U T U R E U S E O F S T O R E D S P E CI M E N S A N D D A T A  
D at a c oll ect e d f or t his st u d y will b e a n al yz e d a n d st or e d at Q u oti e nt Sci e nc es . Aft er t h e st u d y is c o m pl et e d 
t h e d e-i d e ntifi e d, arc hiv e d d at a will b e tr a ns mitt e d t o a n d st or e d at Q u oti e nt Sci e nc es  f or us e b y ot h er 
r es e arc h ers i ncl u di n g t h os e o utsi d e of t h e st u d y.  P er missi o n t o tr a ns mit d at a t o  Q u oti e nt Sci e nc es will b e 
i ncl u d e d i n t h e i nf or m e d c o ns e nt.  
Wit h t h e p artici p a nt’s a p pr o v al a n d as a p pr ov e d b y l oc al I R Bs, d e -i d e ntifi e d bi ol o gic al s a m pl es m a y b e 
utiliz e d f or f urt h er e x pl or at or y r es e arc h.  T h es e s a m pl es m a y b e h el d i n st or a g e b y Q u oti e nt a n d R ev e al 
P h ar m ac e utic als a n d t h eir p art n ers f or u p t o 1 0 y e ars.  
D uri n g t h e c o n d uct of t h e st u dy, a n i n di vi d u al p artici p a nt c a n c h o os e t o wit h dr a w c o ns e nt t o h av e 
bi ol o gic al s p eci m e ns  st or e d f or f ut ur e r es e arc h.  H o w ev er, wit h dr a w al of c o ns e nt wit h r e g ar d t o 
bi os a m pl e st or a g e m a y n ot b e p ossi bl e aft er t h e st u d y is c o m pl et e d.  
W h e n t h e st u d y is c o m pl et e d, acc ess t o st u d y d at a a n d/ or s a m pl es will b e pr o vi d e d t hr o u g h t h e s p o ns or. 
1 1. 1. 7  K E Y R O L E S  A N D S T U D Y G O V E R N A N C E  
Pri nci p al I n v esti g at or  
S p o ns or M e dic al R e pr es e nt ati v e  
M ari a B er m u d ez M D , C PI  
Q u oti e nt Sci e nc es   
3 8 9 8 N W 7t h Str e et  
Mi a mi, FL 3 3 1 2 6  
P h o n e N u m b er : ( d a y) 1-3 0 5 -6 4 4 -9 9 0 3 ext. 1 1 5  
( o ut of h o urs e m er g e nc y) 1-3 0 5 -6 4 4 -9 9 0 3  
E m ail : m ari a. b er m u d ez @ q u oti e ntsci e nc es .c o m 
1 1. 1. 8  S A F E T Y O V E R SI G H T  
T h e pri nci p al i nv esti g at or is r es p o nsi bl e f or t h e d a y -t o-d a y s af et y o v ersi g ht acti viti es.  
R ef er t o S ecti o n 8. 3  St o p pi n g R ul es a n d S ecti o n 9. 8  S af et y R evi e w C o m mitt e e.  
M or e d et ails of s af et y m o nit ori n g of st u d y c a n b e f o u n d i n t h e s af et y pl a n.  
1 1. 1. 9  C LI NI C A L M O NI T O RI N G  
Cli nic al sit e m o nit ori n g is c o n d uct e d t o e ns ur e t h at t h e ri g hts a n d w ell-b ei n g of tri al p artici p a nts ar e 
pr ot ect e d ; t h at t h e r e p ort e d tri al d at a ar e acc ur at e, c o m pl et e, a n d v erifi a bl e; a n d t h at t h e c o n d uct of t h e 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 7  
tri al is i n c o m pli a nc e wit h t h e c urr e ntl y a p pr ov e d pr ot oc ol/ a m e n d m e nt(s), wit h I C H G C P, a n d wit h 
a p plic a bl e r e g ul at or y r e q uir e m e nt(s).  
T h e  S p o ns or  or  its r e pr es e nt ativ e m a y visit  t h e st u d y f aciliti es at a n y  ti m e i n or d er  t o m ai nt ai n  c urr e nt a n d 
p ers o n al k n o wl e d g e of t h e st u d y t hr o u g h r evi e w of t h e r ec or ds, c o m p aris o n wit h  s o urc e d oc u m e nts, a n d 
o bs erv ati o n a n d disc ussi o n of t h e c o n d uct a n d pr o gr ess of t h e st u d y.  T h e  cli nic al sit e will p er mit tri al-
r el at e d m o nit ori n g, a u dits, I R B/I E C r evi e w, a n d r e g ul at or y i ns p ecti o n(s) b y pr ovi di n g dir ect acc ess t o  
s o urc e d at a/ d oc u m e nts.  
1 1. 1. 1 0    
Q U A LI T Y A S S U R A N C E A N D Q U A LI T Y C O N T R O L  
E ac h cli nic al sit e will p erf or m i nt er n al q u ality m a n a g e m e nt of st u d y c o n d uct, d at a a n d bi ol o gic al s p eci m e n  
c oll ecti o n, d oc u m e nt ati o n,  a n d c o m pl eti o n.  A n i n divi d u aliz e d q u alit y m a n a g e m e nt pl a n will b e d ev el o p e d 
t o d escri b e a sit e’s q u ality m a n a g e m e nt.] 
Q u alit y c o ntr ol ( Q C ) pr oc e d ur es will b e i m pl e m e nt e d b e gi n ni n g wit h t h e d at a e ntr y s yst e m , a n d d at a Q C 
c h ec ks t h at will b e r u n o n t h e d at a b as e will b e g e n er at e d.  A n y missi n g d at a or d at a a n o m ali es will b e 
c o m m u nic at e d t o t h e sit e(s) f or cl arific ati o n/r es ol uti o n.  
F oll o wi n g writt e n S O Ps, t h e m o nit ors will v erif y t h at t h e cli nic al tri al is c o n d uct e d, a n d d at a ar e g e n er at e d  
a n d bi ol o gic al s p eci m e ns ar e c oll ect e d , d oc u m e nt e d (r ec or d e d), a n d r e p ort e d i n c o m pli a nc e wit h t h e 
pr ot oc ol, I C H G C P, a n d a p plic a bl e r e g ul at or y r e q uir e m e nts ( e. g.,  GL P, G M P).  
T h e i nv esti g ati o n al sit e will pr ovi d e dir ect acc ess t o all tri al r el at e d  sit es, s o urc e d at a/ d oc u m e nts, a n d 
r e p orts f or t h e p ur p os e of m o nit ori n g a n d a u diti n g b y t h e s p o ns or, a n d i ns p ecti o n b y l oc al a n d r e g ul at ory 
a ut h oriti es.  
1 1. 2  D A T A  H A N D LI N G  A N D R E C O R D  K E E PI N G   
1 1. 2. 1  D A T A C O L L E C TI O N A N D  M A N A G E M E N T R E S P O N SI BI LI TI E S  
1 1. 2. 1. 1  C A S E  R E P O R T F O R M S  
T h e  d at a  r e q uir e d b y  t h e pr ot oc ol is o bt ai n e d  i n t w o w a ys.   S o urc e  D oc u m e nts  ar e  us e d  i n t h e cli nic 
r ec or di n g d evic es  d uri n g  pr oc e d ur es.   T h e  d at a  ar e  tr a nscri b e d fr o m s o urc e i nt o t h e s ec ur e, v ali d at e d 
e C R F  f or e ac h s u bj ect i ncl u d e d i n a cli nic al tri al (i. e., e ac h s u bj ect w h o r ec eiv e d a st u d y dr u g tr e at m e nt).  
Scr e e n F ail ur e d at a will als o b e tr a nscri b e d i nt o t h e e C R F a n d r e p ort e d at  t h e discr eti o n  of  t h e S p o ns or.  
D at a  ass e m bl e d  o utsi d e  t h e cli nic s o urc e (i. e., s af et y l a b d at a a n d P K  c o nc e ntr ati o n d at a) will  b e r ec eiv e d 
fr o m a s p ecifi e d ext er n al v e n d or vi a a n el ectr o nic d at a fil e.  T h e fil e  will b e  r ec eiv e d e ncr y pt e d ( or p ost e d  t o 
a s ec ur e Fil e Tr a nsf er Pr ot oc ol) a n d st or e d i n a s ec ur e f ol d er o n a s erv er.  T h e  el ectr o nic d at a fil e(s) ar e 
i n d e p e n d e nt of t h e e C R F  d at a d uri n g t h e  c o n d uct of  t h e st u d y. 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 8  
T h e e C R F  cl e a n e d d at a will b e r evi e w e d, a p pr o v e d , a n d el ectr o nic all y si g n e d b y t h e  Pri nci p al I nv estig at or or 
d el e g at e.  T h e e C R F  d at a a n d  ext er n al  d at a  fil es will  b e  o ut p ut  i n S A S ® d at as ets.  All  d at a  will  b e  i ncl u d e d wit h  
t h e fi n al r e p ort t o b e pr o vi d e d t o t h e S p o ns or.  
1 1. 2. 1. 2  D A T A  M A N A G E M E N T  A N D  P R O C E S SI N G  
D at a M a n a g e m e nt activiti es p erf or m e d d uri n g t h e d at a  m a n a g e m e nt c o n d uct of t h e st u d y tri al  will b e 
d oc u m e nt e d i n t h e D at a M a n a g e m e nt Pl a n ( D M P) .  T h e e C R F  s yst e m is t h e t o ol us e d t o c o n d uct all d at a 
cl e a ni ng activiti es, m o nit ori ng activiti es, a n d r evi e w/ a p pr ov al activiti es  f or cli nic c oll ect e d d at a a n d pr oc e d ur e  
d at a.   T h e  ext er n al  d at a  fil es ar e  r ec o ncil e d (t o c o m p ar e t h e ext er n al  v e n d or d at a  a n d e C R F s a m pl e 
c oll ecti o n d at a).  D at a M a n a g e m e nt acti viti es ar e p erf or m e d i n acc or d a nc e  wit h  t h e D at a  M a n a g e m e nt  
S O Ps.  
I n a d diti o n t o t h e cl e a ni n g activiti es,  d at a  e nt er e d  i n t h e e C R F  d at a b as e will  b e  c h eck e d f or acc ur ac y   vi a  
pr o gr a m m e d a n d m a n u al c h ecks .  W h e n t h e d at a b as e d at a is d ecl ar e d t o b e c o m pl et e a n d acc ur at e, t h e  
d at a b as e  will b e  l oc k e d, a n d all us ers  writ e acc ess r e m ov e d.  
1 1. 2. 1. 3  S T U D Y R E C O R D S R E T E N TI O N  
St u d y d oc u m e nts s h o ul d b e r et ai n e d f or a mi ni m u m of 2 y e ars aft er t h e l ast a p pr o v al of a m ar k eti n g 
a p plic ati o n i n a n  I C H r e gi o n a n d u ntil t h er e ar e n o p e n di n g or c o nt e m pl at e d m ar k eti n g a p plic ati o ns i n a n 
I C H r e gi o n or u ntil at l e ast 2 y e ars h av e el a ps e d si nc e t h e f or m al disc o nti n u ati o n of cli nic al d e v el o p m e nt 
of t h e st u d y i nt erv e nti o n.  T h es e d oc u m e nts s h o ul d b e r et ai n e d f or a l o n g er p eri o d, h o w ev er, if r e q uir e d 
b y l oc al r e g ul ati o ns.   N o r ec or ds will b e d estr o y e d wit h o ut t h e writt e n c o ns e nt of t h e s p o ns or, if 
a p plic a bl e. It is t h e r es p o nsi bilit y of t h e s p o ns or t o i nf or m t h e i nv esti g at or w h e n t h es e d oc u m e nt s n o 
l o n g er n e e d t o b e r et ai n e d. 
All d oc u m e nt ati o n a n d c orr es p o n d e nc e p ert ai ni n g t o t h e st u d y ( e C R F, r a w d at a, l ett ers etc .) will b e k e pt i n 
acc or d a nc e wit h 2 1 C F R a n d t h e I C H g ui d eli n es f or G C P :  G ui d a nc e f or I n d ustry E 6( R 2) G o o d Cli nic al 
Pr actic e: I nt e gr at e d A d d e n d u m t o I C H E 6( R 1) 2 0 1 8.  
All st u d y r el at e d d oc u m e nts will b e r et ai n e d f or a p eri o d of at l e ast 2 y e ars f oll o wi n g t h e d at e a m ar k eti n g 
a p plic ati o n is a p pr o v e d f or t h e i n dic ati o n f or w hic h it is b ei n g i nv esti g at e d; or, if n o a p plic at i o n is t o b e 
fil e d or if t h e a p plic ati o n is n ot a p pr o v e d f or s uc h i n dic ati o n, u ntil 2 y e ars aft er t h e i nv esti g ati o n is 
disc o nti n u e d a n d r e g ul at or y a ut h oriti es h av e b e e n n otifi e d; or 8 y e ars aft er c o m pl eti o n of t h e st u d y, 
w hic h ev er is l o n g er.  Aft er t his ti m e, t h e s p o ns or will b e c o nt act e d t o asc ert ai n w h et h er c o nti n u e d st or a g e 
or d estr ucti o n is r e q uir e d i n acc or d a nc e wit h c urr e nt r e g ul ati o ns.  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 7 9  
1 1. 2. 2  P U B LI C A TI O N A N D D A T A S H A RI N G P O LI C Y  
T h e r es ults of t his st u d y m a y b e p u blis h e d or pr es e nt e d at sci e ntific m e eti n gs.  If t his is f or es e e n, t h e 
i nv esti g at or a gr e es t o s u b mit all m a n uscri pts or a bstr acts t o t h e s p o ns or b ef or e s u b missi o n.  T his all o ws 
t h e s p o ns or t o pr ot ect pr o pri et ar y i nf or m atio n a n d t o pr ovi d e c o m m e nts.  
T h e d et ails of t h e pr oc ess es of pr o d uci n g a n d r evi e wi n g r e p orts, m a n uscri pts, a n d pr es e nt ati o ns b as e d o n 
t h e d at a fr o m t his tri al will b e d escri b e d i n t h e Cli nic al St u d y A gr e e m e nt. 


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 8 0  
1 1. 3  R E F E R E N C E S  
Ai m e S, C ar av a n P. Bi o dist ri b uti o n of g a d oli ni u m-b as e d c o ntr ast a g e nts, i ncl u di n g g a d oli ni u m 
d e p ositi o n. J M a g n R e as o n I m a gi n g. 2 0 0 9; 3 0: 1 2 5 9-1 2 6 7.  
A m os -Kr o o hs R M, Us ac h V, Pi ñ er o G, et al. M et al b as hi n g: ir o n d efici e nc y a n d m a n g a n es e ov er ex p os ur e 
i m p act o n p eri p h er al n erv es. J T oxic ol E nvir o n H e alt h A. 2 0 1 9; 8 2( 2): 9 9-1 1 2. 
d oi: 1 0. 1 0 8 0/ 1 5 2 8 7 3 9 4. 2 0 1 9. 1 5 6 6 1 0 5  
Erst a d D, R a ms a y I, J or d a n V, et al. T u m or c o ntr ast e n h a nc e m e nt a n d w h ol e -b o d y eli mi n ati o n of t h e 
m a n g a n es e -b as e d m a g n etic r es o n a nc e i m a gi n g c o ntr ast a g e nt M n -P y C 3 A. I nv est R a di ol. 2 0 1 9. 
5 4( 1 1): 6 9 7 -7 0 3. d oi: 1 0. 1 0 9 7/ RLI. 0 0 0 0 0 0 0 0 0 0 0 0 0 5 9 3.  
F o o d a n d Dr u g A d mi nistr ati o n  ( F D A). Dr u g D ev el o p m e nt a n d Dr u g I nt er acti o ns | T a bl e of S u bstr at es, 
I n hi bit ors a n d I n d uc ers. U p d at e d M arc h 2 0 2 0.  Av ail a bl e vi a: htt ps:// w w w.f d a. g ov/ dr u gs/ dr u g -
i nt er acti o ns-l a b eli n g/ dr u g-d ev el o p m e nt -a n d -dr u g -i nt er acti o ns-t a bl e-s u bstr at es-i n hi bit ors-a n d -i n d uc ers. 
F D A. G ui d a nc e f or I n d ustr y: Esti m ati n g t h e m axi m u m s af e st arti n g d os e i n i niti al cli nic al tri als f or 
t h er a p e utics i n a d ult h e alt h y v ol u nt e ers. Iss u e d J ul y 2 0 0 5.  C e nt er f or Dr u g Ev al u ati o n a n d R es e arc h 
( C D E R). 
F D A . M e dic al I m a gi n g Dr u gs A dvis or y C o m mitt e e M e eti n g.  Bri efi n g D oc u m e nt, S e pt e m b er 8, 2 0 1 7.  
Av ail a bl e vi a: htt ps:// w w w.f d a. g ov/ a dvis ory -c o m mitt e es/ a dvis ory-c o m mitt e e-c al e n d ar/ u p d at e d-st art-
ti m e-a n d -p u bl ic-p artici p ati o n -i nf or m ati o n-s e pt e m b er-8 -2 0 1 7 -m e eti n g -m e dic al -i m a gi n g. 
F D A Dr u g S af et y C o m m u nic ati o n: N e w w ar ni n gs f or usi n g g a d oli ni u m -b as e d c o ntr ast a g e nts i n p ati e nts 
wit h ki d n e y d ysf u ncti o n.  Ori gi n all y p ost e d S e pt e m b er 9, 2 0 1 0; u p d at e d F e br u ar y 6, 2 0 1 8.  Av ail a bl e vi a: 
htt ps:// w w w.f d a. g o v/ dr u gs/ dr u g -s af et y-a n d -av ail a bilit y/f d a -dr u g -s af et y-c o m m u nic ati o n-n e w -w ar ni n gs -
usi n g -g a d oli ni u m -b as e d -c o ntr ast-a g e nts -p ati e nts -ki d n e y . 
F D A Dr u g S af et y C o m m u nic ati o n: F D A w ar ns t h at g a d oli ni u m -b as e d c o ntr ast a g e nts ( G B C As) ar e 
r et ai n e d i n t h e b o d y; r e q uir es n e w cl ass w ar ni n gs.  Ori gi n all y p ost e d D ec e m b er 1 9, 2 0 1 7; u p d at e d M ay 
1 6, 2 0 1 8.  Av ail a bl e vi a: htt ps:// w w w.f d a. g ov/ dr u gs/ dr u g -s af ety-a n d -av ail a bility/f d a -dr u g -s af ety-
c o m m u nic ati o n-f d a-w ar ns -g a d oli ni u m -b as e d -c o ntr ast-a g e nts -g bc as -ar e -r et ai n e d-b o dy . 
G al e E M, At a n as o v a I P, Bl asi F, A y I, C ar av a n P. A m a n g a n es e alt er n ativ e t o g a d oli ni u m f or M RI c o ntr ast. 
J A m C h e m S oc. 2 0 1 5; 1 3 7: 1 5 5 4 8-1 5 5 5 7.  
G al e E, W e y H Y, R a ms a y I, et al. A m a n g a n es e -b as e d  alt er n ativ e t o g a d oli ni u m: c o ntr ast -e n h a nc e d M R 
a n gi o gr a p h y, excr eti o n, p h ar m ac o ki n etics, a n d m et a b olis m. R a di ol o gy . 2 0 1 8. 2 8 6: 8 6 5-8 7 2. d oi: 
1 0. 1 1 4 8/r a di ol. 2 0 1 7 1 7 0 9 7 7.  
Gr a nt D, Z ec h K, H oltz E. Distri b uti o n a n d i n viv o st a bilit y of m a n g a n es e di p yri d ox yl d i p h os p h at e i n 
r el ati o n t o i m a gi n g effic ac y. I nv est R a di ol. 1 9 9 4; 2 9: S 2, S 2 4 9-S 2 5 0.  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 8 1  
I nstit ut e of M e dici n e. F o o d a n d N utriti o n B o ar d. Di et ar y R ef er e nc e I nt a k es f or Vit a mi n A, Vit a mi n K, 
Ars e nic, B or o n, C hr o mi u m, C o p p er, I o di n e, Ir o n, M a n g a n es e, M ol y b d e n u m, N ic k el, Silic o n, V a n a di u m, 
a n d Zi nc W as hi n gt o n, D C: N ati o n al Ac a d e m y Pr ess; 2 0 0 1.  
Kl ei n J S, Br a nt W E, H el ms C A, Vi ns o n E N. Br a nt a n d H el ms’ F u n d a m e nt als of Di a g n ostic R a di ol o gy. 5 t h e d. 
Li p pi nc ott Willi a ms & Wil ki ns; 2 0 1 8. 
M UL TI T R A C E -5 (tr ac e el e m e nts 5 i nj ecti o n) Pr escri bi n g I nf or m ati o n.  S hirl e y, N Y: A m eric a n R e g e nt, I nc. 
R evis e d A pril 2 0 1 9.  
R a d br uc h A, Ric ht er H, B üc k er P, et al. Is S m all Fi b er N e ur o p at h y I n d uc e d b y G a d oli ni u m -B as e d C o ntr ast 
A g e nts ?. I nv est R a di ol. 2 0 2 0; 5 5( 8): 4 7 3-4 8 0. d oi: 1 0. 1 0 9 7/ RLI. 0 0 0 0 0 0 0 0 0 0 0 0 0 6 7 7.  
T oft K, H ustv e dt S, Gr a nt D, et al. M et a b olis m a n d p h ar m ac o ki n etics of M n D P D P i n m a n. Act a 
R a di ol o gic a . 1 9 9 7; 3 8: 6 7 7-6 8 9. d oi. or g/ 1 0. 1 0 8 0/ 0 2 8 4 1 8 5 9 7 0 9 1 7 2 4 0 0  
Z h o u I Y, R a ms a y I A, A y I, et al. P ositr o n E missi o n T o m o gr a p h y -M a g n etic R es o n a nc e I m a gi n g 
P h ar m ac o ki n etics, I n Viv o Bi o distri b uti o n, a n d W h ol e -B o d y Eli mi n ati o n of M n -P y C 3 A. I nv est R a di ol. 
2 0 2 1; 5 6: 2 6 1 -2 7 0.  


R V L-1 0 1 -2 2  
 
R ev e al P h ar m ac e utic als  
P h as e 1 a Cli nic al St u d y Pr ot oc ol  
 
 
 
V ersi o n 2 . 0: 9 M a y 2 0 2 2  
 C o nfi d e nti al  
 P a g e 8 2  
1 1. 4  C Y P I N HI BI T O R S  
Ex a m pl es of str o n g a n d m o d er at e cli nic al i n d ex i n hi bit ors f or P 4 5 0 -m e di at e d m et a b olis ms:  
 
Str o n g I n d e x I n hi bit ors 
M o d er at e I n d e x I n hi bit ors  
C Y P 1 A 2    
Fl uv ox a mi n e a 
-- 
C Y P 2 B 6 b   
-- 
-- 
C Y P 2 C 8    
Cl o pi d o gr el c, g e mfi br ozil d  
-- 
C Y P 2 C 9    
-- 
Fl uc o n az ol e e 
C Y P 2 C 1 9    
Fl uv ox a mi n e a 
-- 
C Y P 2 D 6    
Fl u ox eti n e f, p ar ox eti n e 
Mir a b e gr o n  
C Y P 3 A    
Cl arit hr o m yci n g, itr ac o n az ol e g   
Er yt hr o m yci n, fl uc o n az ol e e, v er a p a mil g 
A U C  =  ar e a u n d er t h e c o nc e ntr ati o n -ti m e c urv e; C Y P =  cyt oc hr o m e P 4 5 0; D DI =  dr u g -dr u g i nt er acti o n; O A T P 1 B 1  =  
or g a nic a ni o n tr a ns p orti n g p ol y p e pti d e 1 B 1; O A T 3  =  or g a nic a ni o n tr a ns p ort er 3; P -g p  =  P -glyc o pr ot ei n  
a    
Str o n g i n hi bit or of C Y P 1 A 2 a n d C Y P 2 C 1 9, a n d m o d er at e i n hi bit or of C Y P 2 D 6 a n d C Y P 3 A.  
b    
W e c urr e ntl y d o n ot h av e i n d ex i n hi bit ors f or C Y P 2 B 6.  
c   
Str o n g i n hi bit or of C Y P 2 C 8, w e a k i n hi bit or of C Y P 2 B 6, a n d i n hi bit or of O A T P 1 B 1.  T h e gl uc or o ni d e  
m et a b olit e is als o a n i n hi bit or f or C Y P 2 C 8 a n d O A T P 1 B 1.  
d    
Str o n g i n hi bit or of C Y P 2 C 8 a n d i n hi bit or of O A T P 1 B 1 a n d O A T 3.  T h e gl uc or o ni d e m et a b olit e is als o a n 
i n hi bit or f or C Y P 2 C 8 a n d O A T P 1 B 1. 
e    
Str o n g i n hi bit or of C Y P 2 C 1 9 a n d m o d er at e i n hi bit or of C Y P 2 C 9  a n d C Y P 3 A.  
f   
Str o n g i n hi bit ors of C Y P 2 C 1 9 a n d C Y P 2 D 6. ( g) I n hi bit or of P -g p ( d efi n e d as t h os e i ncr e asi n g A U C of di g oxi n t o 
≥1. 2 5 -f ol d). 
S o urc e:  F D A T a bl e of S u bstr at es, I n hi bit ors a n d I n d uc ers 2 0 2 0  


R VL- 1 0 1- 2 2 
R ev e al P h ar m ac e utic als
P h as e 1 a Cli nic al St u dy Pr ot oc ol
V ersi o n 2. 0: 9 M ay 2 0 2 2 
C o nfi d e nti al
P a g e 8 3
Si g n at ur es f or S p o ns or
S p o ns or St u dy N u m b er: R VL- 1 0 1- 2 2
Q u oti e nt Sci e nc es St u dy N u m b er: 
Q S C 2 0 6 0 9 6
D at e of Pr ot oc ol:  M ay 9, 2 0 2 2
V ersi o n 2. 0 ( A m e n d m e nt 1)