A Randomised, Controlled, Examiner Blind, Methodology Development Study to Evaluate the Effect of a Stannous Fluoride Toothpaste on the Oral Microbiome
Phase: NA
Conditions: Oral Health
Sponsor: HALEON

Hale o n  
Cli nical Pr ot oc ol  
Pr ot oc ol N u m ber : 3 0 0 1 0 1  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1  of 5 8  
C LI NI C A L P R O T O C O L  
A r a n d o mi s e d, c o ntr oll e d, e x a mi n er bli n d, m et h o d ol o g y 
d e v el o p m e nt st u d y t o e v al u at e t h e  eff e ct  of a st a n n o u s fl u ori d e 
t o ot h p a st e o n t h e or al mi cr o bi o m e  
Pr ot o c ol N u m b er:  
3 0 0 1 0 1  
C o m p o u n d/ Pr o d u ct N a m e:  
St a n n o u s Fl u ori d e  
U nit e d St at e s ( U S) I n v e sti g ati o n al 
N e w Dr u g (I N D) N u m b er:  
N A  
E ur o p e a n Cli ni c al Tri al s D at a b a s e 
( E u dr a C T) N u m b er: 
N A  
Ot h er R e g ul at or y A g e n c y I d e ntifi e d 
N u m b er:  
N A  
P h a s e:  
N A  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
T his d oc u me nt c o ntai ns c o nfi de ntialit y state me nts t hat are n ot rele va nt
f or t his p u blicl y a vaila ble versi o n
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2  of 5 8  
 
S p o n s or I nf or m ati o n 
 
S p o n s or N a m e & L e g al 
R e gi st er e d A d dr e s s  
 
H al e o n  ( U K)  
St G e or g e s A v e n u e,  
W e y bri d g e,  
S urr e y,  
K T 1 3 0 D E,  
U nit e d Ki n g d o m ( U K)  
S p o n s or C o nt a ct D et ail s  
 
H al e o n  
H ol di n g s ( U S) L L C  
1 8 4 Li b ert y C or n er R d,  
W arr e n, N e w J er s e y ( N J) 0 7 0 5 9,  
U nit e d St at e s ( U S) 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3  of 5 8  
D o c u m e nt Hi st or y  
 
D o c u m e nt  
V er si o n  S u m m ar y of C h a n g e s  
Ori gi n al pr ot o c ol  
1. 0  
N ot a p pli c a bl e ( N/ A)  
N e w V er si o n  
2. 0  
•  O n e of t h e ar e a s of t h e m o ut h ( c h e e k) h a s b e e n 
r e m o v e d fr o m t h e s a m pl e c oll e cti o n t hr o u g h o ut t h e 
d o c u m e nt.  
•  R e m o v e d a r ef er e n c e i n S e cti o n 3. 2 a n d r ef er e n c e 
li st. 
•  T y p o s c orr e ct e d t hr o u g h o ut t h e d o c u m e nt . 
 
 
 
 
 
 
A me n d me nts i nc or p orate all re visi o ns t o dat e, i ncl u di n g a me n d m e nts ma de at t he re q u est of 
c o u ntr y h ealt h a ut h orities, i nstit uti o nal re vie w b oar ds/et hics c o m mittees (I R Bs/ E Cs), etc.   
 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4  of 5 8  
Pri n ci p al I n v e sti g at or Pr ot o c ol A gr e e m e nt P a g e  
•  I c o nfir m a gree m e nt t o c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a n d a n y 
a me n d me nts acc or di n g t o t he c urre nt I nter n ati o nal C o nfere nce o n Har m o nisati o n G o o d 
Cli nical Practice (I C H G C P ) g ui deli nes. 
•  I ac k n o wle d ge t hat I a m res p o nsi ble f or o verall st u d y c o n d u ct. I a gree t o p ers o nall y 
c o n d uct or s u per vise t he descri be d st u d y.  
•  I a gree t o e ns ure t hat all ass ociates, c ollea g ues a n d e m pl o yees assisti n g i n t he c o n d uct of 
t he st u d y are i nf or m e d a b o ut t heir o bli gati o ns. Mec ha nis ms are i n place t o e ns ure site staff 
recei v es all a p pr o priate i nf or mati o n t hr o u g h o ut t h e st u d y. 
•  I a gree t o c o n d uct t his st u d y i n f ull c o nf or ma nce wit h t he la ws a n d re g ul ati o ns of t he 
c o u ntr y i n w hic h t he researc h is c o n d u ct e d a n d t he Declarati o n of Helsi n ki.  
 
I n v esti gat or Na me: 
I n v esti gat or Q ualificati o ns: 
I n v esti gat or Si g nat ure: 
Date of Si g nat ure/ A gree me nt:  
D D -M m m -Y Y Y Y  
 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
P P D
P P D
P P D
P P D

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5  of 5 8  
T a bl e of C o nt e nt s  
S p o ns or I nf or mati o n  ............................................................................................................ 2  
D oc u me nt Hist or y  ............................................................................................................... 3  
Pri nci pal I n v esti gat or Pr ot oc ol A gree me nt Pa ge  ................................................................ 4  
Ta ble of C o nte nts  ................................................................................................................ 5  
1  
I N T R O D U C TI O N ............................................................................................................. 1 0  
1. 1  
St u d y R ati o nale  ...................................................................................................... 1 0  
1. 2  
Bac k gr o u n d  ............................................................................................................ 1 0  
1. 3  
Be nefit/ Ris k Assess me nt  ....................................................................................... 1 1  
1. 4  
Mec ha nis m of Acti o n/I n dicati o n  ........................................................................... 1 1  
2  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S  .................................................................... 1 2  
3  
S T U D Y D E SI G N  .............................................................................................................. 1 2  
3. 1  
O verall Desi g n  ....................................................................................................... 1 2  
3. 2  
Scie ntific Rati o nale f or St u d y Desi g n  ................................................................... 1 3  
3. 3  
J ustificati o n f or D ose ............................................................................................. 1 4  
3. 4  
E n d of St u d y Defi niti o n  ......................................................................................... 1 5  
4  
S T U D Y P O P U L A TI O N  .................................................................................................... 1 5  
4. 1  
T y pe a n d Pla n ne d N u m b er of S u bjects  ................................................................. 1 5  
4. 2  
I n cl usi o n Criteria ................................................................................................... 1 5  
4. 3  
E x cl usi o n Criteria  .................................................................................................. 1 6  
4. 4  
Ra n d o mizati o n Criteria  .......................................................................................... 1 8  
4. 5  
Lif est yle C o nsi derati o ns  ........................................................................................ 1 8  
4. 5. 1  
De ntal Pr o d uct/ Treat me nt a n d Oral H y gie ne Restricti o ns  ................... 1 8  
4. 5. 2  
Meals a n d Dietar y Restri cti o ns  ............................................................. 1 9  
4. 5. 3  
C o ntrace pti o n  ........................................................................................ 1 9  
4. 6  
Scree n Fail ures ....................................................................................................... 1 9  
4. 7  
S p o ns or’s Q ualifie d Me dical Pers o n nel  ................................................................ 1 9  
5  
S T U D Y P R O D U C T S  ........................................................................................................ 2 0  
5. 1  
I n v esti gati o nal/ St u d y Pr o d uct S u p plies ................................................................. 2 0  
5. 1. 1  
D osa ge F or m a n d Pac k a gi n g  ................................................................. 2 2  
5. 1. 2  
Pre parati o n a n d Dis pe nsi n g ................................................................... 2 2  
5. 2  
A d mi nistrat i o n ....................................................................................................... 2 2  
5. 2. 1  
Pr o d uct D osi n g Err ors  ........................................................................... 2 2  
5. 2. 2  
O ver d ose  ............................................................................................... 2 3  
5. 3  
St u d y Pr o d uct St ora ge  ........................................................................................... 2 3  
5. 4  
St u d y Pr o d uct Acc o u nta bilit y  ................................................................................ 2 4  
5. 4. 1  
Destr ucti o n of St u d y Pr o d uct S u p plies  ................................................. 2 4  
5. 5  
Bli n di n g a n d All oca ti o n/ Ra n d o mizati o n ............................................................... 2 4  
5. 6  
Brea ki n g t he Bli n d  ................................................................................................. 2 5  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6  of 5 8  
5. 7  
C o m plia nce  ............................................................................................................ 2 5  
5. 8  
C o nc o mita nt Me dicati o n/ Treat me nt(s)  .................................................................. 2 6  
6  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D S U BJ E C T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ......................................................................... 2 7  
6. 1  
S u bject Disc o nti n uati o n/ Wit h dra wal  ..................................................................... 2 7  
6. 2  
L ost t o F oll o w u p  ................................................................................................... 2 7  
7  
S T U D Y P R O C E D U R E S  ................................................................................................... 2 8  
7. 1  
Visit 1/ Scree ni n g  ................................................................................................... 2 9  
7. 1. 1  
I nf or me d C o nse nt .................................................................................. 2 9  
7. 1. 2  
De m o gra p hics  ....................................................................................... 2 9  
7. 1. 3  
Me dical Hist or y a n d Pri or Me dicati o n/ Treat me nt  ................................ 3 0  
7. 1. 4  
Cli nical E x a mi nati o ns a n d Assess me nts  ............................................... 3 0  
7. 1. 5  
I n cl usi o n/ E x cl usi o n Criteria ................................................................. 3 0  
7. 1. 6  
S u bject Eli gi bilit y  ................................................................................. 3 0  
7. 1. 7  
S u per vise d Br us hi n g wit h Lea d -in T o ot h paste  ..................................... 3 0  
7. 2  
St u d y Peri o d  .......................................................................................................... 3 1  
7. 2. 1  
Visit 2/ Da y 1  ......................................................................................... 3 1  
7. 2. 2  
Visit 3/ Da y 4 3 ± 4  ................................................................................. 3 2  
7. 3  
St u d y C o n cl usi o n  ................................................................................................... 3 3  
7. 4  
F oll o w -u p Visit / P h o ne Call  ................................................................................. 3 3  
8  
S T U D Y A S S E S S M E N T S  ................................................................................................. 3 3  
8. 1  
Scree ni n g Assess me nts  .......................................................................................... 3 3  
8. 1. 1  
M o difie d Gi n gi val I n d e x ( M GI)  ........................................................... 3 4  
8. 1. 2  
Blee di n g I n d e x ( BI) ............................................................................... 3 4  
8. 1. 3  
T ures k y M o dificati o n of t he Q ui gle y Hei n I n de x ( T PI)  ....................... 3 4  
8. 2  
Safet y a n d Ot her Assess me nts  ............................................................................... 3 5  
8. 2. 1  
Oral S oft Tiss ue ( O S T) E x a mi nati o n  .................................................... 3 5  
8. 2. 2  
Oral Har d Tiss ue ( O H T) E x a mi nati o n  .................................................. 3 6  
8. 2. 3  
Sa m pli n g a n d La b orat or y Pr oce d ures  ................................................... 3 6  
8. 2. 4  
Pre g n a nc y T esti n g  ................................................................................. 3 6  
9  
A D V E R S E E V E N T A N D S E RI O U S A D V E R S E E V E N T S  ........................................... 3 6  
9. 1  
Defi niti o n of a n A d verse E ve nt ( A E)  .................................................................... 3 6  
9. 2  
Defi niti o n of  a Seri o us A d verse E ve nt ( S A E)  ....................................................... 3 7  
9. 3  
Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A E a n d S A E I nf or mati o n  .................. 3 8  
9. 4  
Re p orti n g Pr oce d ures ............................................................................................. 3 9  
9. 4. 1  
Re p orti n g of a n A d verse E ve nt  ............................................................. 4 0  
9. 4. 2  
Re p orti n g of a Seri o us A d verse E ve nt  .................................................. 4 0  
9. 5  
E val uati n g A d v erse E ve nts  .................................................................................... 4 1  
9. 5. 1  
Assess me nt of I nte nsit y  ........................................................................ 4 1  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 7  of 5 8  
9. 5. 2  
Assess me nt of Ca usalit y  ....................................................................... 4 1  
9. 6  
F oll o w -u p of A Es a n d S A Es .................................................................................. 4 2  
9. 7  
Wit h dra wal D ue t o a n A d verse E ve nt  ................................................................... 4 2  
9. 8  
Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ...................................................... 4 2  
9. 9  
Pre g n a nc y  .............................................................................................................. 4 3  
9. 9. 1  
Ti me Peri o d f or C ollecti n g Pre g n a nc y I nf or m ati o n.............................. 4 3  
9. 9. 2  
Acti o n t o be Ta ke n if Pre g na n c y Occ urs  .............................................. 4 3  
9. 1 0  
Me dica l De vic e I n ci de nts ...................................................................................... 4 3  
9. 1 0. 1  
Defi niti o n of a n I nci d e nt  ....................................................................... 4 3  
9. 1 1  
Re p orti n g of I nci de nts a n d Malf u ncti o ns  .............................................................. 4 4  
9. 1 2  
F oll o w -u p of Me di cal De vice I nci de nts  ................................................................ 4 5  
9. 1 3  
Re g ulat or y Re p orti n g Re q uire me nts f or Me dical De vice I n ci de nts ...................... 4 5  
1 0  D A T A M A N A G E M E N T  .................................................................................................. 4 5  
1 0. 1  
Case Re p ort F or m  .................................................................................................. 4 5  
1 0. 2  
Data Ha n dli n g  ........................................................................................................ 4 6  
1 0. 2. 1  
Data Q ueries  .......................................................................................... 4 6  
1 0. 2. 2  
E xter nal data .......................................................................................... 4 7  
1 1  S T A TI S TI C A L C O N SI D E R A TI O N S A N D D A T A A N A L Y S E S  .................................. 4 7  
1 1. 1  
Sa m ple Siz e Deter mi nati o n  ................................................................................... 4 7  
1 1. 2  
P o p ulati o ns f or A nal ysis  ........................................................................................ 4 7  
1 1. 2. 1  
Defi niti o ns of A nal ysis P o p ulati o ns  ..................................................... 4 7  
1 1. 3  
Statistical A nal yses  ................................................................................................ 4 7  
1 1. 3. 1  
Micr o bi o me Pr ofili n g ( 1 6 S r R N A ge n e a m plic o n a nal ysis)  ................. 4 8  
1 1. 3. 2  
F u ncti o nal Pr ofili n g  .............................................................................. 4 9  
1 1. 3. 3  
Safet y A nal yses  ..................................................................................... 4 9  
1 1. 3. 4  
De m o gr a p hic a n d Baseli ne C haracteristics  ........................................... 4 9  
1 1. 3. 5  
St u d y Pr o d uct C o m plia nce a n d Us e of Ot her T hera pies.  ..................... 5 0  
1 1. 3. 6  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  .............................................. 5 0  
1 1. 3. 7  
I nteri m A nal ysis .................................................................................... 5 0  
1 2  S T U D Y G O V E R N A N C E C O N SI D E R A TI O N S .............................................................. 5 0  
1 2. 1  
Q ualit y C o ntr ol  ...................................................................................................... 5 0  
1 2. 2  
Q ualit y Ass ura nce  .................................................................................................. 5 1  
1 2. 3  
Re g ulat or y a n d Et hical C o nsi derati o ns  ................................................................. 5 1  
1 2. 3. 1  
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee..................................... 5 1  
1 2. 3. 2  
Et hical C o n d uct of t he St u d y  ................................................................ 5 1  
1 2. 3. 3  
S u bject I nf or mati o n a n d C o nse nt  .......................................................... 5 2  
1 2. 3. 4  
S u bject Recr uit me nt  .............................................................................. 5 2  
1 2. 3. 5  
Re p orti n g of Safet y Iss ues a n d Seri o us Breac hes of t he Pr ot oc ol or 
I C H G C P ............................................................................................... 5 2  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 8  of 5 8  
1 2. 4  
P osti n g of I nf or m ati o n o n P u blicl y A vaila ble Cli nical Trial Re gisters  ................. 5 3  
1 2. 5  
Pr o visi o n of St u d y Res ults t o I n vesti gat ors  ........................................................... 5 3  
1 2. 6  
Rec or ds Rete nti o n  .................................................................................................. 5 3  
1 2. 7  
Micr o bial a n d F u n cti o nal Pr ofili n g Data Ret e nti o n  .............................................. 5 4  
1 2. 8  
C o n diti o ns f or Ter mi nati n g t he St u d y  ................................................................... 5 4  
1 3  R E F E R E N C E S  .................................................................................................................. 5 5  
1 4  A P P E N DI CI E S .................................................................................................................. 5 7  
1 4. 1  
A B B R E VI A TI O N S  ............................................................................................... 5 7  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 9  of 5 8  
Li st of i n t e xt t a bl e s  
Ta ble 3 -1  
St u d y O bjecti ves a n d E n d p oi nts  ........................................................... 1 2  
Ta ble 6 -1  
St u d y Pr o d uct S u p plies  ......................................................................... 2 0  
Ta ble 6 -2  
Lea d -I n Pr o d uct S u p plies ...................................................................... 2 1  
Ta ble 6 -3  
S u n dr y Ite ms  ......................................................................................... 2 1  
Ta ble 7 -1  
Sc he d ule of Acti vities  ........................................................................... 2 8  
Ta ble 1 5 -1  
A b bre viati o ns  ........................................................................................ 5 7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 0  of 5 8  
1  
I N T R O D U C TI O N 
1. 1  
St u d y R ati o n al e  
T he  s p o ns or c urre ntl y de m o nstrate d t he effect of sta n n o us fl u ori de (S n F 2) o n t he oral micr o bial 
ec os yste m  i n a ne w, v ali date d i n vitr o bi ofil m m o del s yste m w hic h us es a sali va -d eri ve d 
i n oc ul u m t o ge n erate c o m ple x oral bacterial bi ofil ms. T his m o del, c o m bi ne d wit h 1 6 S 
se q ue nci n g a n d meta ge n o mics a nal ys es, has bee n s uccessf ull y use d t o ge nerate  data  f or a dee p er 
u n dersta n di n g o n  the m ec ha nis m of acti o n of st a n n o us o n t he micr o bi o me , s pecificall y its 
i n hi biti o n of bi ofil m re gr o wt h b y affecti n g b acteria meta b olis m. 
F urt her m ore, i n a rece nt Hale o n m al o d o ur st u d y ( Hale o n cli nical st u d y  3 0 0 0 2 5, 2 0 2 3) a 
t o ot h paste c o ntai ni n g 0. 4 5 4 % S n F2 s h o we d statisticall y si g nifi ca nt i m pr o ve me nts i n oral 
mal o d o ur i n all e n d p oi nts c o m pare d t o a sta n dar d fl u ori de t o ot h paste. Gi ve n t he mai n 
aeti ol o gic al fact or of oral mal o d o ur is t he v olatile s ul p h ur c o m p o u n ds ( V S C) pr o d uce d b y oral 
bacteria, a n d data fr o m t his st u d y h a ve b ee n ge nerate d i n a p o p ulati o n wit h cli nical dia g n os e d 
gi n gi vitis, it is rati o nal t o h y p ot hesize t hat t he efficac y of a f or m ulati o n c o nt ai ni n g 0. 4 5 4 % S n F 2 
is li n ke d t o its a bilit y t o m o d ulate t he oral micr o bi o me. 
Ta k i n g all t his i nf or mati o n t o get her, t he c o n d uct of a met h o d ol o g y cli nical de vel o p me nt st u d y 
usi n g a t o ot h paste c o ntai ni n g 0. 4 5 4 % S n F 2 will ge nerat e i nf or mati o n o n h o w it ma y m o d ulate 
t he o verall oral b acteria c o m p ositi o n a n d acti vit y. T he res ults will t he n fee d i nt o t he desi g n of 
f ut ure micr o bi o me cli nic al st u dies.  
F urt her m ore, t his met h o d ol o g y st u d y will i ncl u d e n o vel tec h n ol o gi es s uc h as 1 6 S se q ue n ci n g 
a n d meta-tra ns cri pt o mics a n d/ or meta ge n o mics , w hic h will gi ve a clear c haracterizati o n  of t he 
o verall oral b acterial s pecies (micr o bial pr ofili n g) a n d t heir esse ntial i nterli n k wit h f u ncti o n  
(f u ncti o nal pr ofili n g). 
1. 2  
B a c k gr o u n d  
T he oral b acterial c o m m u nities are hi g hl y c o m pl e x wit h ar o u n d 1 0 0 0 s pecies pres e nt a n d h as 
bee n s h o w n t o be t he s ec o n d m ost c o m ple x i n t he b o d y, aft er t he c ol o n. T he relati o ns hi p 
bet wee n t h ese c o m m u nities ( or micr o bi o me) a n d t he h ost is d y na mic, ca n be i nf l ue nce d b y 
ma n y as pects of m o der n lifest yle, s u c h as diet, t o bacc o c o ns u m pti o n a n d stress, a n d it 
c o nstit utes a n i m p orta nt li n k bet wee n healt h a n d disease.  
T o date, t here is n o cle ar defi niti o n of a healt h y micr o bi o me. It has bee n s h o w n t hat t he 
c o m p ositi o n of micr o bi o me s h o ws great di versit y bet wee n c o m part me nts i n t he b o d y, a n d it is 
hi g hl y varia bl e wit hi n a n d bet wee n p e o ple. H o we ver, des pite t his variati o n i n t he c o m p ositi o n, 
t he o verall f u ncti o ns of t he micr o bi ome  are relati vel y c o nsiste nt a n d resilie n t t o s mall 
pert ur bati o ns. T his hel ps pre ve nt t he s hift fr o m s y m bi otic state (e q uili bri u m bet wee n t he hi g hl y 
di verse micr o bial c o m m u nit y) t o d ys bi osis ( o ut gr o wt h a n d o veracti vit y of a n y si n gl e or fe w 
s pecies w hic h mi g ht lea d t o e x cee d t he pat h ol o gical t hresh ol d; Wa de 2 0 1 3 ). 
Gi ve n t he c o m ple xit y of t he micr o bial c o m m u nit y, it mi g ht be c o nsi dere d i m p ossi ble t o clearl y 
assi g n a r ole f or eac h micr o or ga nis m wit hi n t he c o m m u nit y a n d li n k its prese nce or a bse n ce t o 
a partic ular diseas e state. T here is e mer gi n g e vi de nce i n t he literat ure of p ote ntial bacterial 
gr o u ps w hic h c o ul d be ass ociate d wit h healt h or disease, as s h o w n i n a rece nt st u d y b y A da ms 
a n d c ollea g ues w h o re p orte d s o me e x a m ples of t he ass ociati o n of t heir i de ntifie d ta xa wit h g u m 
healt h a n d/ or disease ( A d a ms S E et al. 2 0 1 7 ). H o we ver, n o wa da ys it is acce pte d t hat t he bacteri a 
hist oricall y c o nsi dere d as oral ‘ pat h o ge ns’ ca n b e f o u n d i n l o w n u m bers at healt h y sites, a n d 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 1  of 5 8  
oral disease occ urs d ue t o ne gati ve c h a n ges t o t he nat ural bala nce of t he o verall micr o bi ota 
( d ys bi osis) a n d n ot t o a si n gle s pecies ( Killia n 2 0 1 6 ). 
T he a d v e nt of hi g h t hr o u g h p ut s e q ue nci n g tec h n ol o gies s u c h as 1 6 S se q u e nci n g (c o m m u nit y 
pr ofili n g), m eta ge n o mics ( ge n etic c o m p ositi o n  –  f u ncti o nal pr ofili n g), meta-tra nscri pt o mic 
( ge nes tra nscri be d –  f u ncti o nal pr ofili n g) has i m pr o ve d t he c haracterisati o n of t he o verall oral 
bacterial s peci es, i ncl u di n g t h os e w hic h are diffic ult t o gr o w i n la b orat or y c o n diti o ns usi n g wit h 
c o n ve nti o nal micr o bi ol o g y met h o ds (i.e., plati n g ) (Ere n A M, et al. 2 0 1 4 ). F urt her m ore, t h e y 
ha ve hel p e d t o u n dersta n d t he esse ntial i nterli n k bet wee n t he bacteri al c o m p ositi o n a n d t he 
f u ncti o n i n or der t o e xpl ore t he c o ntri b uti o n of i n di vi d ual s pecies t o t he o verall c o m m u nit y 
f u ncti o n (G u m ber  H K, et al. 2 0 2 2 ). 
A nti micr o bial i n gre die nts li ke sta n n o us, te n d t o i m pact t he bacterial c o m m u nit y i n hi biti n g t he 
bi ofil m re gr o wt h b y affec ti n g bacteria meta b olis m. Usi n g t he a b o ve tec h ni q ues, Hale o n ha v e 
ge n erat e d data t o s h o w its m o de of acti o n i n vitr o; it is t he n nat ural pr o gressi o n t o e x pl ore t his 
effect o n t he micr o bi o me  i n a cli nical st u d y.  
T he ai m of t his st u d y is t o e val uate t h e eff ect of a t o ot h paste c o ntai ni n g sta n n o us fl u ori de o ver 
ti me o n t he oral b acterial c o m p ositi o n a n d acti vit y a n d t o e x pl ore its effect i n c o m paris o n t o a 
re g ular fl u ori de t o ot h paste. A n y c ha n ges o bser ve d fr o m t his met h o d ol o g y de vel o p me nt st u d y 
will pr o vi de i n si g hts t o ge n erat e h y p ot h eses o n t he p ote ntial effect  of a sta n n o us c o ntai ni n g 
t o ot h paste o n t he o verall c o m m u nit y s hift t o war ds a str o n ger ass o ciati o n t o healt h a n d li miti n g 
d ys bi osis ( o ver gr o wt h of p ote ntial pat h o ge nic s pecies).  
1. 3  
B e n efit/ Ri s k A s s e s s m e nt  
T his st u d y will use c o m merciall y a vaila ble f or m ulati o ns. C o m plete i nf or mati o n f or t h es e 
pr o d ucts  ma y be f o u n d i n t he  c o m merciall y a v aila ble pac k .   
1. 4  
M e c h a ni s m of A cti o n/I n di c ati o n  
Sta n n o us fl u ori de ( S n F 2) is a well-k n o w n c he m ot hera pe utic a ge nt, i nc or p orate d i nt o de ntifrices 
si nce t he 1 9 4 0s f or its a nti-caries, a nti -de nti n h y perse nsiti vit y a n d a nti -pla q ue/a nti -gi n gi vitis 
be nefits ( Ma ki n, 2 0 1 3; Miller et al, 1 9 9 4; Va n L o vere n, 2 0 0 1; V a n L o vere n, 1 9 9 0 b ).  
T he sta n n o us i o n ( S n [II ]) is a br oa d-s p ectr u m a nti micr o bial wit h bacteri ost atic a n d bacterici dal 
pr o perties ( Arc hila et al, 2 0 0 4; Bella m y et al, 2 0 1 2; He et al, 2 0 1 2; Ti na n off, 1 9 9 5 ). It h as bee n 
s h o w n t o i nterfere wit h t he de v el o p me nt a n d mat uratio n of t h e pla q ue bi ofil m, i n hi biti n g 
bacterial a d here nce a n d c ol o nizati o n of t he oral s urfaces, a n d pe n etrati n g t he cell wall t o 
i nterfere wit h bacterial meta b olis m (Ti na n off, 1 9 9 0; Wils o n a n d Pratte n, 1 9 9 9 ). T hese effects 
ha ve bee n s h o w n t o carr y t hr o u g h t o i n vi v o effects o n a ra n ge of micr o bial acti vities, res ulti n g 
i n a nti-pla q ue be nefits ( Bacca et al, 1 9 9 7; Kast uri et al, 1 9 9 5; W hite et al, 1 9 9 5 ). 
 
 
 
 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 2  of 5 8  
2  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
T a bl e 2 -1  
St u d y O bj e cti v e s a n d E n d p oi nt s  
O bj e cti v e( s)  
E n d p oi nt( s)  
Pri m ar y  
T o d e s cri b e t h e o v er all or al b a ct eri al 
c o m p o siti o n f oll o wi n g 6 w e e k s u s e of a 0. 4 5 4 % 
St a n n o u s fl u ori d e ( S n F2 ) t o ot h p a st e a n d r e g ul ar 
fl u ori d e t o ot h p a st e ( c o ntr ol) u si n g mi cr o bi o m e 
pr ofili n g  
•  
C h a n g e s i n r el ati v e a b u n d a n c e s of 
b a ct eri al gr o u p s at W e e k 6 c o m p ar e d t o 
B a s eli n e b y tr e at m e nt  
E x pl or at or y  
T o c o m p ar e t h e o v er all or al b a ct eri al 
c o m p o siti o n f oll o wi n g  6 w e e k s u s e of t h e 
0. 4 5 4 % S n F 2  t o ot h p a st e t o a r e g ul ar fl u ori d e 
t o ot h p a st e ( c o ntr ol) u si n g mi cr o bi o m e pr ofili n g 
•  
Diff er e n c e s i n r el ati v e a b u n d a n c e s of 
b a ct eri al gr o u p s at w e e k 6 c o m p ar e d t o 
c o ntr ol  
T o d e s cri b e a n d c o m p ar e t h e or al b a ct eri al 
c o m p o siti o n f oll o wi n g 6 w e e k s u s e of a 0. 4 5 4 % 
S n F 2  t o ot h p a st e a n d r e g ul ar fl u ori d e t o ot h p a st e 
( c o ntr ol) f or diff er e nt ar e a s of t h e m o ut h (t o n g u e, 
s u pr a gi n gi v al, s u b gi n gi v a  a n d s ali v a ) u si n g 
mi cr o bi o m e pr ofili n g  
F or e a c h of t h e diff er e nt ar e a s of t h e m o ut h:  
•  
C h a n g e s i n R el ati v e a b u n d a n c e s of 
b a ct eri al gr o u p s at W e e k 6 c o m p ar e d t o 
B a s eli n e b y tr e at m e nt  
•  
Diff er e n c e s i n t h e r el ati v e a b u n d a n c e s 
of b a ct eri al gr o u p s at w e e k 6 c o m p ar e d 
t o c o ntr ol   
T o d e s cri b e a n d c o m p ar e  t h e o v er all or al 
b a ct eri al f u n cti o n alit y f oll o wi n g 6 w e e k s u s e of a 
0. 4 5 4 % S n F 2  t o ot h p a st e a n d r e g ul ar fl u ori d e 
t o ot h p a st e ( c o ntr ol), o v er all a n d f or diff er e nt 
ar e a s of t h e m o ut h (t o n g u e, s u pr a gi n gi v al, 
s u b gi n gi v a a n d s ali v a ), u si n g f u n cti o n al pr ofili n g 
O v er all a n d f or e a c h of t h e diff er e nt ar e a s of t h e 
m o ut h:  
•  
C h a n g e s i n b a ct eri al a cti vit y at W e e k 6 
c o m p ar e d t o B a s eli n e b y tr e at m e nt  
•  
Diff er e n c e s i n b a ct eri al a cti vit y at w e e k 
6 c o m p ar e d t o c o ntr ol  
N o f or mal s uccess criteri o n has bee n d efi ne d f or t his met h o d ol o g y de vel o p me nt st u d y; h o we v er, 
a n y c ha n ges o bser ve d fr o m t his met h o d ol o g y d e vel o p me nt st u d y will pr o vi de i nsi g hts t o 
ge n erat e h y p ot heses o n t he p ote ntial effect  of a st a n n o us c o ntai ni n g t o ot h paste o n t he o verall 
c o m m u nit y s hift t o war ds a str o n ger ass o ciati o n t o healt h a n d li miti n g d ys bi osis . 
3  
S T U D Y D E SI G N  
3. 1  
O v er all D e si g n  
T his will be a si n gle -ce nt er, 6 -w ee k, ra n d o mize d, c o ntr olle d, a nal yst a n d e x a mi ner -bli n d , t w o-
treat me nt, parallel gr o u p desi g n, met h o d ol o g y d e vel o p me nt cli nical st u d y, i n vesti gati n g t he 
effic ac y of a  t o ot h paste c o ntai ni n g 0.4 5 4 % S n F 2 i n healt h y a d ult v ol u nteers  wit h mil d -m o derat e 
gi n gi vitis .  
At Scree ni n g ( Visit 1), s u bjects will pr o vi de t h eir writte n i nf or me d c o nse nt t o partici pat e i n t h e 
st u d y. D e m o gra p hics, m e dical hist or y a n d c urre nt me dicati o ns will t he n be rec or de d, f oll o we d 
b y a n oral e x a mi nati o n, w hic h will i ncl u de O H T a n d O S T e x a mi nati o ns , a n d gi n gi val healt h 
will be assesse d wit h M GI a n d BI assess me nt s. S u bjects will t he n use a  discl osi n g s ol uti o n, a n d 
s u pra-gi n gi val pla q ue ( T PI) assess m e nts will be c o m plete d . S u bjects will be c o nsi dere d eli gi ble 
wit h  a mi ni m u m of 2 0 nat ural teet h, at least 4 0 e val ua ble s urfaces , wit h 1 0 % < B S  < 3 0 %  
( B S = ble e di n g sites) a n d o verall mea n T PI ≥ 1. 5  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 3  of 5 8  
T o sta n dar dize oral h y gi e ne practice, eli gi ble s u bjects will c o m plete a lea d -i n peri o d pri or t o 
Visit  2 d uri n g w hic h t h e y will br us h wit h t he t o ot h br us h a n d re g ular fl u ori de t o ot h paste 
pr o vi de d . S u bjects will ret ur n t o t he st u d y site f or Baseli ne visit ( Visit 2)  ha vi n g a bstai ne d fr o m 
oral h y gie n e f or t he past 1 2 -1 8  h o urs i.e., wit h o ver ni g ht pla q ue acc u m u lati o n. F oll o wi n g a n 
O S T e x a mi nati o n , sa m ples will be c ollecte d fr o m 4  differe nt areas of t he m o ut h  (sali va, t o n g ue, 
s u pra gi n gi v al pla q ue a n d s u bgi n gi val s urface) .  
F oll o wi n g sa m ple c ollecti o n, ra n d o mize d s u bjects will recei ve t heir assi g n e d st u d y t o ot h past e 
a n d t he y will be i nstr ucte d t o br us h t wice dail y ( m or ni n g a n d e ve ni n g) i n t heir us ual ma n ner, 
f or 1-ti me d mi n ute, f or t he ne xt 6  wee ks a n d t o rec or d eac h br us hi n g  i n t he diar y pr o vi d e d. 
T he y will c o m plete t he first br us hi n g at t he st u d y site, u n der s u per visi o n . 
S u bjects will ret ur n t o t h e st u d y site aft er 6  wee ks ( Visit 3) of tr eat me nt, ha vi n g a bst ai ne d fr o m 
oral h y gie n e f or 1 2 -1 8 h bef ore st u d y visit. 
W here ver p ossi ble, re mai ni n g visit s h o ul d b e 
sc he d ule d at a p pr o xi matel y t he sa me ti me of da y as t he s u bject’s Baseli ne visit ( Visit 2). At 
Visits 3 , st u d y pr o d uct usa ge a n d t he c o m plete d diar y will be re vie we d f or c o m plia nce wit h 
st u d y re q uir e me nts, a n d c ha n ges i n healt h/c o nc o mita nt me dicati o ns a n d A Es will be rec or de d. 
F oll o wi n g a n O S T a n d O H T e x a mi nati o n, sa m ples will be c ollecte d (as Visit 2). At Visit 3 , 
s u bjects will ret ur n all st u d y materials.  
3. 2  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  
Se veral Hal e o n cli nical st u dies (Hale o n cli nical st u dies  2 0 7 0 1 4, Par ki ns o n et al. 2 0 1 4, 
Ac he r k o u k et al. 2 0 2 1, Par ki ns o n et al. 2 0 1 8 b, Par ki ns o n et al 2 0 1 8 a, P ar ki ns o n et al. 2 0 2 0) 
ha ve de m o nstrate d t he efficac y of sta n n o us o n gi n gi vitis a n d pla q ue re m o val acr oss differe nt 
i nter ve nti o n peri o ds (s h ort ter m –  u p t o 3  wee ks; l o n g ter m –  u p t o 6 m o nt hs). T his is t he first 
ti me Hale o n is e val u ati n g t he i m pact of S n F 2  o n t he oral micr o bi o me a n d a  6 -wee k st u d y peri o d 
was selecte d as de e m e d s ufficie nt f or t his met h o d ol o g y d e vel o p me nt st u d y t o see c ha n ges i n 4  
differe nt areas of t he m o ut h . 
A parallel gr o u p desi g n has bee n selecte d as t he m ost a p pr o priate t o o bser ve t he a ntici pate d 
differe ntial c ha n ges i n t h e micr o bial c o m p ositi o n a n d acti vit y fr o m b aseli n e a n d  b et wee n t he 
treat me nt gr o u ps, a v oi di n g t he p ote ntial f or carr y o ver effects ha d a cr oss o ver e x peri me ntal 
desi g n bee n e m pl o ye d.   
Acc or di n g t o t he I C H -G C P g ui deli nes, f or a st u d y t o be classifie d as tr ul y d o u ble bli n d neit her 
t he s ubject n or t he i n vesti gat or, st u d y staff i n v ol ve d i n t he treat me nt or cli nical e val uati o n of 
t he s u bjects, m o nit ors or data a nal ysts s h o ul d be a ware of t he treat me nt recei ve d. T his i ncl u des 
a n y o n e deter mi ni n g s u bj ect eli gi bilit y, e val uati n g e n d p oi nts, or as sessi n g c o m plia nce wit h t he 
pr ot oc ol. F urt h er m ore, t h e pr o d ucts u n der test s h o ul d be i de ntical (c ol or, fla v or, a p peara n ce a n d 
pac ka gi n g). Gi ve n t hat t his st u d y will be usi n g c o m merciall y a v aila ble t o ot h pastes, it is al m ost 
i m p ossi ble t o e ns ure i de ntical a ppeara n ce, t aste a n d pac ka gi n g,  t heref ore t h e le vel of bli n d ness 
f or t his st u d y is descri be d as ‘a nal yst a n d e x a mi ner bli n d’. 
W hilst t he st u d y pr o d ucts are n ot c o ntr a -i n dicate d f or pre g na n c y a n d breastfee di n g , pre g na nt 
a n d/ or lactati n g fe males will be e x cl ude d fr o m t his st u d y d ue t o t he i ncrease d pre v ale nce a n d 
se verit y of gi n gi vitis a n d peri o d o ntal disease o bser ve d d uri n g pre g na nc y ( Sa ma nt et al., 1 9 7 6 ) 
a n d breastfee di n g ( A g h aza de h et al, 2 0 1 9 ) whic h,  t o get h er wit h t he i ncrease d a m o u nts of 
calc ul us a n d pla q ue o bser ve d d uri n g  pre g na n c y,   c o ul d i m pact st u d y o utc o me (Sa ma nt et al., 
1 9 7 6 ).   
T o e ns ure st u d y s u bjects de m o nstrate t he re q uire d pr o pe nsit y f or pla q ue f or mati o n , o nl y 
s u bjects wit h a mea n T PI ≥ 1. 5 at Scree ni n g ( Visit 1) will e nter t he lea d -i n p eri o d. F urt her m ore, 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 4  of 5 8  
s u bjects wit h mil d-m o derate gi n gi vitis will be i n cl u de d  bas e d o n t h e  ne w classi ficati o n of 
s u bjects’ gi n gi val healt h (C ha p ple et al., 2 0 1 8 ) t heref ore, o nl y s u bjects wit h 1 0 % < B S  < 3 0 %  
( B S deri v e d fr o m BI ass ess me nt) will e nter t he lea d -i n peri o d. 
Eli gi ble s u bjects will c o m plete a l ea d -i n peri o d pri or t o Visit 2, d uri n g w hic h t he y will be 
pr o vi de d wit h a sta n dar d flat tri m t o ot h br us h a n d re g ular fl u ori de t o ot h paste ( b ot h mar kete d 
pr o d ucts) t o use i n place of t heir o w n oral h y gi e ne pr o d ucts. Use of t hese pr o d ucts will pr o vi de 
t he st u d y p o p ulati o n wit h a sta n dar dize d oral h y gie ne re gi me n pri or t o t h e Baseli ne visit a n d 
fa miliarize t he m wit h re q uire d usa ge re gi me n (1 -mi n ute  ti me d br us hi n g, t wice d ail y) a n d 
c o m pleti o n of a diar y aft er eac h br us hi n g.  
Eli gi ble s u bjects will be as ke d t o refrai n fr o m  oral h y gi e ne f or 1 2 -1 8 h o urs pri or t o V isits 2 a n d 
3  (i) t o sta n dar dize oral h y gie n e practice i n t he st u d y p o p ulati o n a n d (ii) e ns ure s uffi cie nt pla q ue 
gr o wt h t o all o w t he c oll ecti o n of s ufficie nt a m o u nts of sa m ples a n d re d uce i m pact o n st u d y 
o utc o mes.  
In m ost p u blis he d st u dies, t he effect of oral h y gie ne f or m ulati o ns  h as  bee n re p ort e d f or de ntal 
pla q ue or ga nis ms , h o we v er e val u ati n g micr o bi al p o p ulati o ns i n ot her areas of t he m o ut h c o ul d 
gi ve i nsi g hts i nt o t heir relati o n t o oral diseases (Haraszt h y VI, et al.  2 0 1 9 ). F or e x a m ple, t he 
mai n aeti ol o gical fact or of oral mal o d o ur is t he v olatile s ul p h ur c o m p o u n ds ( V S C) pr o d uce d 
b y oral bacteria  prese nt o n t o n g ue s urface (Ta k a has hi 2 0 1 5 ). Sali va has bee n use d wi del y i n  
micr o bi ol o gical st u dies  t o e x pl ore micr o bial di versit y, e x a mi ne pers o n-t o-p ers o n tra ns missi o n  
of or ga nis ms wit hi n t he m o ut h, a n d deter mi ne a nti micr o bial effects of f or m ulati o ns  (S va n ber g 
M & R olla G. 1 9 8 2 ). T heref ore, i n t his st u d y sa m ples will be c ollecte d fr o m  differe nt areas of 
t he m o ut h (t o n g ue, s u pra gi n gi val pla q ue, s u bgi n gi val s urface  a n d sali va) i n or der t o e x a mi ne 
t he effect of sta n n o us o n micr o or ga nis ms prese nt  i n differe nt oral nic hes w hic h c o ul d pr o vi de 
br oa der i nf or mati o n acr oss t he o verall oral ca vit y. 
M icr o bial a n d f u ncti o n al pr ofili n g  will be assesse d usi n g hi g h t hr o u g h p ut se q ue n ci n g 
tec h n ol o gi es: 
•  1 6s r R N A g e ne am plic o n se q ue nci n g is a met h o d ol o g y w hic h all o ws t he st u d y of t he 
bacterial c o m m u nit y (mi cr o bial  pr ofili n g)  i de ntif yi n g b acteria prese nt wit hi n a gi ve n 
sa m ple d o w n t o t he ge n us a n d/ or s pecies le v el.  
•  Meta ge n o mics a n d meta -tra nscri pt o mics are m et h o d ol o gies w hic h all o w t he st u d y of 
t he bacterial f u ncti o ns (f u ncti o nal pr ofili n g). M eta ge n o mics 
ge nerates data o n t h e 
ge n etic c o m p ositi o n,  all o wi n g t he u n dersta n di n g of t he f u ncti o nal p ote ntial of t he 
vari o us  bact erial gr o u p s. M eta-tr a nscri pt o mics ge n erat e s i nf or mati o n o n t he ge nes 
w hic h are tra nscri be d, gi vi n g dee per i nsi g ht i nt o t he acti vit y of t he vari o us bacterial 
gr o u ps . 
Data ge n erat e d  wit h t hes e tec h ni q ues  will  hel p t o ge n erat e h y p ot heses  o n t he p ote ntial effect of 
a sta n n o us c o ntai ni n g t o ot h paste o n t he o verall b acterial c o m m u nit y a n d acti vit y a n d t o i nf or m 
t he desi g n  of  f ut ure micr o bi o me st u dies. 
3. 3  
J u stifi c ati o n f or D o s e  
St u d y pr o d ucts are t o ot h pastes, i nte n de d f or t o pical oral use, a n d will be a p plie d b y 
t o ot h br us hi n g usi n g a ma n ual t o ot h br us h. 
T he usa ge re gi me n of t wice dail y br us hi n g ( m or ni n g a n d e ve ni n g) will be t he sa me f or all 
s u bjects, base d o n wi del y rec o m me n de d oral h y gie ne practice a n d t y pical c o ns u mer ha bit.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 5  of 5 8  
St u d y s u bjects will br us h f or 1 -ti me d mi n ute wit h t heir assi g ne d st u d y t o ot h paste o n eac h 
br us hi n g occasi o n i n li ne wit h t y pical br us hi n g ti mes s pecifie d f or si milar efficac y st u dies .  
After 6  wee ks ( 4 3  ± 4 d a ys) t wice dail y usa ge, eac h s u bject s h o ul d c o m plete bet wee n 7 8 -9 4  
br us hi n gs wit h t heir ra n d o mize d pr o d uct. S u bjects will c o m p lete a s u per vise d br us hi n g wit h 
t heir assi g ne d st u d y t o ot h paste at t he e n d of eac h st u d y visit ( w hile still at t he st u d y site) t o 
e na ble staff t o c o nfir m c orrect usa ge a n d t o e n c o ura ge c o m plia nce wit h t he re q uire d usa ge 
re gi me n f or t he d urati o n of t he st u dy.  
3. 4  
E n d of St u d y D efi niti o n  
A s u bject will be c o nsi dere d t o ha v e c o m plet e d t h e st u d y if t he y h a ve c o m plete d all p hases of 
t he st u d y i ncl u di n g t he last visit or t he last sc he d ule d pr oce d ure s h o w n i n t he Sc he d ule of 
Acti vities.  
T he e n d of t his st u d y is d efi ne d as t he dat e of t he l ast sc he d ule d pr oce d ure, as descri be d i n t he 
Sc he d ule of A cti vities ( Ta ble 7 -1 ), f or t he last s u bject.  
4  
S T U D Y P O P U L A TI O N  
4. 1  
T y p e a n d Pl a n n e d N u m b er of S u bj e ct s  
T he st u d y will be c o n d u cte d i n m ale a n d fe male s u bjects i n g o o d ge neral healt h, a ge d 1 8 -6 5 
years i ncl usi ve, t hat me et all st u d y criteria.  
S ufficie nt s u bjects will be scree n e d t o e ns ure a p pr o xi matel y a t otal of 5 5  s u bjects 1 5 a n d o mizat  
t o st u d y pr o d uct a n d a p pr o xi matel y 5 0 e val ua ble s u bjects c o m plet e t he e ntire st u d y 
(a p pr o xi matel y 2 5 s u bjects per pr o d uct ar m), all o wi n g 1 0 % dr o p o uts. N o f or mal sa m ple siz e 
has bee n perf or me d as per nat ure of t his st u d y ( met h o d ol o g y d e vel o p me nt), h o we ver  base d o n 
a pre vi o us i n sit u cli nical st u d y e v al ua ti n g t he m o de of acti o n of a sta n n o us fl u ori de t o ot h paste 
usi n g 1 6 S se q ue nci n g a n d meta -tra nscri pt o mics i n 1 3 s u bjects, t his was c o nsi dere d a s mall 
sa m ple siz e a n d o ne of t he reas o ns f or t he hi g h varia bilit y i n a m plic o n a n d ge ne e x pressi o n data 
(G u m ber et al. 2 0 2 2 ). Recr uiti n g m or e p artici p a nts w o ul d  p ote ntiall y re d uce t his ris k a n d 
t heref ore N = 5 0 is c o nsi dere d s ufficie nt t o pr o vi de relia ble esti mates of perf or ma n ce f or t h e 
p ur p oses of t his met h o d ol o g y de v el o p me nt st u d y a n d t o ai d i n t he desi g n of f ut ure cli nical 
st u dies.  
A n e nr olle d s u bject is o ne w h o has a gree d t o partici pate i n t he cli nical st u d y f oll o wi n g 
c o m pleti o n of t he i nf or me d c o nse nt pr ocess a n d s uccessf ull y met eli gi bilit y criteria t o pr ocee d 
be y o n d t h e scree ni n g visit as a p plica ble f or t he pr ot oc ol desi g n .  
T his st u d y ca n f ulfill its o bjecti ves o nl y if a p pr o priate s u bjects are e nr oll e d.  T he f oll o wi n g 
eli gi bilit y criteria are d esi g ne d t o sel ect s u bj ects f or w h o m partici pati o n i n t he st u d y is 
c o nsi dere d a p pr o priate.  All rele va nt me dical a n d n o n -me dical c o n diti o ns s h o ul d be ta ke n i nt o 
c o nsi derati o n w he n d eci di n g w het h er a s u bject is s uita ble f or t his pr ot oc ol.   
S u bject eli gi bilit y t o parti ci p ate i n t he cli nical st u d y s h o ul d be re vie we d a n d d oc u me nte d b y a n 
a p pr o priate m e m ber of t h e i n vesti gat or’s st u d y t ea m bef ore s u bjects are i n cl u de d i n t he st u d y.  
4. 2  
I n cl u si o n Crit eri a 
A n i n di vi d ual m ust meet all t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt i nt o 
t he st u d y:  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 6  of 5 8  
1.  S u bject pr o visi o n of a si g ne d a n d date d i nf or me d c o nse nt d oc u me nt i n di cati n g t hat t he 
s u bject has bee n i nf or me d of all perti ne nt as p ects of t he st u d y bef ore a n y ass ess me nt is 
perf or me d.  
2.  S u bject is male or fe male w h o, at t he  ti me of scree ni n g, is a ge d 1 8-6 5 years, i ncl usi ve.  
3.  S u bject w h o is willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits,  sa m pli n g sc h e d ule, 
treat me nt pla n a n d ot her st u d y pr oce d ures.  
4.  S u bject, i n t he o pi ni o n of t he i n vesti gat or or me di call y q u alifie d desi g n ee , i n g o o d ge neral 
a n d me ntal healt h.  
A T S C R E E NI N G ( Visit 1):  
5.  S u bject wit h at least 2 0 nat ural, per m a ne nt teet h ( e x cl u di n g 3 r d m olars).  
6.  S u bjects wit h at least 4 0 e val ua ble s urfaces.  
A n ev al u a ble s urf ace is d efi ne d as h avi n g 2/ 3r ds of t he n at ur al t o ot h s urf ace gr a d a ble f or 
t he selecte d cli nic al i n dices.  
T he f oll o wi n g s h o ul d n ot be i ncl u de d i n t he ev al u a ble s urf ace c o u nt: t hir d m ol ars; f ully 
cr o w ne d/exte nsively rest ore d teet h; gr ossly c ari o us teet h; ort h o d o ntic ally b a n de d/ b o n de d 
or a b ut me nt teet h; s urf aces wit h c alc ul us d e p osits w hic h, i n t he o pi ni o n of t he cli nic al 
ex a mi ner, w o ul d i nterfer e wit h t he b aseli ne assess me nts of t he selecte d cli nic al i n dices .  
7.  O verall mea n T PI s c ore ≥ 1. 5  
8.  S u bjects wit h 1 0 % < B S  < 3 0 %  
4. 3  
E x cl u si o n Crit eri a  
A n i n di vi d ual w h o  meets a n y of t he f oll o wi n g e x cl usi o n criteria will n ot be eli gi ble f or 
e nr oll me nt i nt o t he st u d y.  
1.  A s u bject  w h o is a n e m pl o yee of t he i n vesti gati o nal site, eit her directl y i n v ol ve d i n t he 
c o n d uct of t he st u d y or ot her wise s u per vise d b y t he i n vesti gat or , o r a me m ber of t heir 
i m me diate fa mil y; or a s p o ns or e m pl o yee dir ectl y i n v ol ve d i n t he c o n d uct of t he st u d y or a 
me m ber of t heir i m me diate fa mil y.  
2.  A s u bject w h o has partici pate d i n ot her st u dies (i ncl u di n g n o n -me dici nal st u dies) i n v ol vi n g  
i n vesti gati o nal pr od u ct(s) i n t he 3 0 d a ys pri or t o st u d y e ntr y a n d/ or w h o is partici pati n g i n 
ot her st u dies d uri n g st u d y partici pati o n.  
3.  A s u bject wit h , i n t he o pi ni o n of t he i n vesti gat or or me dicall y q ualifi e d  desi g nee,  a n ac ut e 
or c hr o nic me dical or ps yc hiatric c o n diti o n or la b orat or y a b n or m alit y t hat m a y i n crease t he 
ris k ass ociate d wit h st u d y p artici pati o n or i n vesti gati o nal pr o d uct a d mi nistrati o n or ma y 
i nterfere wit h t he i nter pretati o n of st u d y res ults a n d, i n t he ju d g me nt of t he i n vesti gat or or 
me dicall y q ualifie d d esi g nee, w o ul d ma ke t he s u bj ect i na p pr o priate f or e ntr y i nt o t his st u d y. 
4.  A s u bject wit h  a n y m e dical/ oral c o n diti o n w hic h, i n t he o pi ni o n of t he i n vesti gat or or 
me dicall y q ualifie d  desi g nee , c o ul d i m pact st u d y o utc o mes (f or e x a m ple, oral dr y ness or 
c o ul d directl y i nfl ue nce gi n gi val blee di n g ). 
5.  A s u bject ta ki n g  dail y d oses of me dicati o n/ ha vi n g dail y treat me nts w hic h, i n t he o pi ni o n of 
t he i n vesti gat or or me dicall y q ualifie d desi g nee, c o ul d i m pact st u d y o utc o mes (f or e x a m ple, 
is ca usi n g oral dr y ness). 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 7  of 5 8  
6.  A s u bject w h o is pre g n a nt (self -re p orte d; n o pre g na nc y t est re q uir e d) or i nte n di n g t o bec o me 
pre g na nt o ver t he c o urs e of t he st u d y.  
7.  A s u bject w h o is breastfee di n g.  
8.  A s u bject wit h k n o w n or s us pecte d i nt olera nce or h y perse nsiti vit y t o t he st u d y m aterials ( or 
cl osel y relate d c o m p o u n ds) or a n y of t heir state d i n gre di e nts.  
9.  A s u bject w h o is u n willi n g or u n a ble t o c o m pl y wit h t he Lif est yl e C o nsi derati o ns  descri be d 
i n t his pr otoc ol.  
1 0.  A s u bject w h o ha s diffic ult y c o m pl yi n g wit h st u d y pr oce d ures a n d e x a mi nati o ns, s uc h as 
e x cessi ve ga g gi n g d uri n g oral assess me nts . 
1 1.  A s u bject w h o has ha d r o uti ne de ntal pr o p h yl a xis wit hi n 1 2  wee ks of Scree ni n g.  
1 2.  A s u bject w h o has u n der g o ne a t o ot h bleac hi n g pr oce d ure (at-h o me or pr ofessi o nal) wit hi n 
8 wee ks of Scree ni n g.  
1 3.  A s u bject wit h  a n y of t he f oll o wi n g w hi c h , i n t he o pi ni o n of t he i n vesti gat or or me dicall y 
q ualifie d  desi g n ee , c o ul d i m pact st u d y o utc o m es or t he oral healt h of t he s u bjects if t he y 
were  t o partici pate i n t he st u d y: 
a. se vere gi n gi vitis.  
b.  si g ns of acti ve peri o d o ntal disease or w h o is recei vi n g or h as recei ve d tr eat me nt f or 
peri o d o ntal disease (i ncl u di n g s ur ger y) wit hi n 1 2 m o nt hs of Scree ni n g.  
c. acti ve caries . 
d.  e vi de nce of gr oss i ntra -oral ne glect or t he nee d f or e xte nsi ve de ntal t hera p y.  
e. rest orati o ns i n a p o or stat e of re p air or met al filli n gs . 
f. a n y d e ntal c o n diti o n (e. g. , malali g n me nt, o vercr o w di n g)  
g.  hi g h le vels of e xtri nsic de ntal stai n or calc ul us de p osits . 
1 4.  A s u bject wit h t he f oll o wi n g: 
a. a t o n g u e or li p pierci n g. 
b.  m ulti ple de ntal i m pla nts w hic h, i n t he o pi ni o n of t he i n vesti gat or or me dicall y q ualifie d  
desi g nee , c o ul d i m pact st u d y o utc o mes. 
c. fi x e d bri d ge(s) or re m o va ble partial de nt ures. 
d.  has or h as ha d fi x e d or re m o va ble ort h o d o ntic braces/ b a nds or a fi x e d ort h o d o ntic 
retai ner wit hi n 3 m o nt hs of Scree ni n g . 
1 5.  A s u bject w h o is u n willi n g t o f or g o use of a n ort h o d o ntic retai ner f or t he d urati o n of t he 
st u d y, pr o vi de d t here w o ul d be n o i m pact o n t he o utc o me of a n y pre vi o us, c o m plete d 
ort h o d o ntic treat me nt  or t he s u bject’s well-b ei n g . 
1 6.  S u bject w h o is a c urre nt s m o ker or a n e x -s m o ker w h o st o p pe d wit hi n 6 m o nt hs of Scree ni n g 
( Visit 1).  
1 7.  S u bject w h o is  a c urre nt l y us er of recreati o nal dr u gs (e. g., ca n na bis ) wit hi n 6 m o nt hs of 
Scree ni n g . 
1 8.  S u bject w h o c urre ntl y us es s m o keless f or ms of t o bacc o (e. g., c he wi n g t o bacc o, nic oti ne -
base d e -ci garettes)  wit hi n 6 m o nt h s of Scree ni n g .  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 8  of 5 8  
1 9.  VI SI T 1  ( Scree ni n g)  
•  A s u bject w h o has ta k e n a nti bi otics wit hi n 4  wee ks of Scree ni n g . 
•  S u bject w h o has use d a n a nti -bacterial m o ut h was h (e. g., c hl or h e xi di ne) or a n ot her 
oral care pr o d uct wit hi n 2 wee ks of Scree ni n g  t hat, i n t he o pi ni o n of t he i n v esti gat or 
or de ntall y q u alifie d desi g nee, c o ul d affect pla q ue f or mati o n or gi n gi v al healt h.  
2 0.  VI SI T 2 ( B aseli ne)   
•  A s u bject  w h o has ta ke n a nti bi otics d uri n g t he lea d -i n peri o d ( bet wee n Scree ni n g 
a n d Bas eli ne ). 
2 1.  S u bject wit h a rece nt hist or y ( wit hi n t he last year) of alc o h ol or ot her s u bsta nce a b use.  
2 2.  A s u bject w h o has pr e vi o usl y bee n e nr olle d i n t his st u d y.  
2 3.  S u bject w h o, i n t he o pi ni o n of t he i n vesti gat or or me dicall y q u alifie d d esi g nee, s h o ul d n ot 
partici pate i n t he st u d y.  
4. 4  
R a n d o mi z ati o n Crit eri a  
S u bjects will be ra n d o mize d i nt o t he st u d y pr o vi de d t he y h a ve satisfie d all s u bject selecti o n 
criteria.  
4. 5  
Lif e st yl e C o n si d er ati o n s  
If, i n t he o pi ni o n of t he i n vesti gat or or me di call y q ualifie d desi g n ee, a s u bject has n ot c o m plie d 
wit h a st u d y restricti o n (e. g., oral h y gie ne, dietar y or alc o h ol -relate d) pri or t o a st u d y visit or 
ca n n ot atte n d a st u d y visit, e ver y eff ort will be ma de t o rea p p oi nt t he m wit hi n t he per mitte d 
visit t olera nces (s ee Sc h e d ule of A cti vities, Ta ble 7 -1  a n d Secti o n 6. 2 , L ost T o F oll o w U p). T he 
reas o n f or re-a p p oi nt me nt will be d oc u me nte d i n t he electr o ni c cas e re p ort f or m  (e C R F). 
If re-a p p oi nt me nt is n ot p ossi ble  ( wit hi n t he visit t olera nce), t he f oll o wi n g visit s pecific acti o ns 
s h o ul d be ta ke n: 
•  Visit 2:  t he s u bject will be wit h dra w n fr o m t he st u d y. S u bjects ca n b e resc he d ule d i n 
o utsi de wi n d o w  visit  w here A E s will be rec or de d, a n d t he O S T e x a mi nati o n c o m plete d; 
n o sa m ples will be c ollecte d . T he s u bject ma y b e re place d. 
•  Visit 3:  t he s u bject will be wit h dra w n fr o m t he st u d y. S u bjects ca n b e resc he d ule d i n 
o utsi de wi n d o w visit w here  A E s will be rec or de d, a n d t he O S T e x a mi nati o n c o m plete d; 
n o sa m ples will be c ollecte d. T he s u bject will n ot be re place d. 
4. 5. 1  
D e nt al Pr o d u ct/ Tr e at m e nt a n d Or al H y gi e n e R e stri cti o n s   
Fr o m Scree ni n g ( Visit 1) t o t he S u bject’s L ast St u d y Visit : 
•  S u bjects s h o ul d n ot use a n y ot her oral care pr o d ucts (f or e x a m ple, t o ot h pastes, 
t o ot h br us hes, oral ri nses, t o n g ue clea ners, w hite ni n g/ bleac hi n g pr o d ucts) t ha n t h ose 
pr o vi de d d uri n g t he st u d y.  
•  S u bjects s h o ul d n ot carr y o ut a n y i nt er pr o xi mal de ntal clea ni n g. Us e of de ntal fl oss, 
t o ot h pic ks, water pic ks or i nter-de ntal br us hes is pr o hi bite d (e x ce pt f or t he re m o val of 
i m pacte d f o o d wit h n o n-a nti micr o bial pr o d ucts o nl y).  
•  S u bjects s h o ul d n ot c he w g u m or c o ns u me a n y c o nfecti o ner y c o ntai ni n g x ylit ol (e. g. 
s u gar-free mi nts, mi nt-fla v o ur ca n di es). 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 9  of 5 8  
•  S u bjects s h o ul d dela y a n y n o n -e mer ge nc y d e ntal treat me nt u ntil aft er st u d y c o m pleti o n 
(i ncl u di n g de nt al pr o p h yl a xis). 
•  S u bjects s h o ul d dela y a n y t o ot h w hite ni n g treat me nts ( pr ofessi o nal a n d/ or h o me use) 
u ntil after st u d y c o m pleti o n .  
Bef ore Visit s 2  & 3:  
•  S u bjects s h o ul d refrai n fr o m oral h y gie ne pr oce d ures f or 1 2 -1 8 h o urs bef ore t heir visit .  
4. 5. 2  
M e al s a n d Di et ar y R e stri cti o n s  
Bef ore Visits 2  & 3:  
•  S u bjects m ust n ot eat f or at least 4  h o urs a n d bef ore st u d y visit.  
•  S u bjects m ust n ot dri n k f or at least 2 h o urs bef ore st u d y visit.  
N ote:  S m all si ps of r o o m -te m per at ure w ater are per mitte d if re q uir e d t o t ake 
me dic ati o ns or t o relieve a dry m o ut h u p t o 1 h o ur bef ore t heir a p p oi nt me nt ti me  
•  S u bjects s h o ul d refrai n fr o m alc o h ol c o ns u m pti o n f or 2 4 h o urs b ef ore a cli nical 
assess me nt visit.  
4. 5. 3  
C o ntr a c e pti o n  
Gi ve n t he t o ot h pastes use d i n t his st u d y are c o m merciall y a vaila ble t o ot h pastes, a n d n o dr u gs 
will be utilise d i n t his cli nical st u d y, pre g na nc y testi n g a n d c o ntr ace pti ve re q uire me nts are n ot 
dee me d necessar y .  H o we ver, if s u bject re p orts pre g na n c y at scree ni n g,  s he  will n ot be i ncl u de d 
i n t he st u d y.  
4. 6  
S cr e e n F ail ur e s  
Scree n fail ures are defi n e d as s u bjects w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y ra n d o miz e d. T o e ns ure tra ns pare nt re p orti n g, a mi ni m u m set of i nf or mati o n 
will be rec or de d f or eac h scree n fail s u bject i ncl u di n g de m o gra p h y, reas o n f or scree n fail ure 
(e. g., wit h dra w al of c o ns e nt), eli gi bilit y criteri a, pr ot oc ol de viati o ns a n d AE s, as a p plica ble.  
I n di vi d uals w h o d o n ot meet t he criteria f or parti ci pati o n i n t his st u d y (scree n fail ure) ma y n ot 
be re -s cree ne d. 
4. 7  
S p o n s or’ s Q u alifi e d M e di c al P er s o n n el  
C o ntact i nf or mati o n f or t he s p o ns or ’s a p pr o priatel y q u alifie d m e dical/ de ntal pers o n nel f or t he 
st u d y is d oc u me nt e d i n t he St u d y C o ntact List l ocate d i n t he i n vesti gat or st u d y master file h el d 
at t he st u d y site.  
T he c o ntact n u m ber is o nl y t o be use d b y i n vesti gati o nal staff see ki n g a d vice o n me dical/ de ntal 
q uesti o ns or pr o ble ms i n t he e v e nt t hat t he esta blis he d c o m m u nicati o n pat h wa ys bet w ee n t h e 
i n vesti gati o nal site a n d t he st u d y te a m are n ot a vaila ble.   
T he c o ntact n u m b er is n ot i nte n de d f or direct us e b y st u d y s u bjects.  T o facilitate access t o 
a p pr o priatel y q ualifie d me dical/ de ntal pers o n nel o n st u d y -rel ate d me dical/ de ntal q uesti o ns or 
pr o ble ms, s u bjects will be pr o vi de d wit h a c o ntact car d.   T he c o ntac t car d will pr o vi de, as a 
mi ni m u m, pr ot oc ol i de ntifiers, t he s u bject’s st u d y i de ntificati o n n u m ber, c o ntact i nf or mati o n 
f or t he i n vesti gati o nal site, a n d c o ntact details i n t he e ve nt t hat t he i n vesti gati o nal site ca n n ot 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 0  of 5 8  
be reac h e d t o pr o vi de a d vice o n a m e dical q u esti o n or pr o ble m i d e ntifie d b y a healt hcare 
pr ofessi o nal ot her t ha n t h e i n vesti gat or.    
5  
S T U D Y P R O D U C T S  
F or t he p ur p oses of t his st u d y, per I nter nati o nal C o nfere n ce o n Har m o nizati o n (I C H) g ui d eli nes, 
a n d Hale o n  p olic y, st u d y i nter ve nti o n is defi ne d as an y i n vesti gati o nal i nter ve nti o n(s), mar kete d 
pr o d uct(s), pla ce b o, or me dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y partici pa nt 
acc or di n g t o t he st u d y pr ot oc ol.  
T his i ncl u des a pr o d uct wit h a mar keti n g a ut h ori zati o n w he n use d or a ss e m ble d (f or m ulate d or 
pac ka ge d) i n a wa y differe nt fr o m t he a p pr o ve d f or m, or w he n use d f or a n u na p pr o ve d 
i n dicati o n, or w he n use d t o gai n f urt her i nf or m ati o n a b o ut a n a p pr o ve d use.  
5. 1  
I n v e sti g ati o n al/ St u d y Pr o d u ct S u p pli e s 
T he f oll o wi n g st u d y pr o d ucts wil l be s u p plie d b y t he Cli nical S u p plies De part me nt, Hale o n : 
T a bl e 5 -1  
St u d y Pr o d u ct S u p pli e s  
P r o d uct Descri pti o n  
Test T o ot h p aste  
Ref ere nce T o ot h p aste ( C o ntr ol)  
P r o d uct N a me  
Se ns o d y ne Re pair a n d Pr otect ( U S 
mar ket)  
C ol gate Ca vit y Pr otecti o n  
( Re g ular fl u ori de t o ot h paste, U S 
mar ket)  
Fl u ori de c o nte nt  
1 1 0 0 p p m fl u ori de as S n F 2 
1 1 0 0  p p m fl u ori de as S M F P  
P ac k Desi g n  
O ne cart o n c o ntai ni n g 3 o ver wra p pe d t u bes of t o ot h paste  
Dis pe nsi n g Det ails  
Da y 1  ( Visit 2): O ne cart o n 
P r o d uct M aster 
F or m ul ati o n C o de  
 
C o m mercial pr o d uct ( N/ A)  
R o ute of 
A d mi nistr ati o n  
T o pical Oral Use  
D ose/ A p plic ati o n  
D ose t he t o ot h br us h wit h a stri p of t o ot h paste (ri b b o n of t o ot h paste 
acr oss t he f ull br us h hea d) o n eac h br us hi n g occasi o n 
Us a ge I nstr ucti o ns  
S u bj ects will br us h t heir teet h f or o ne ti me d mi n ute t wice a da y 
( m or ni n g a n d e ve ni n g) i n t heir us ual ma n ner. Mi ni mize s wall o wi n g a n d 
s pit o ut. 
Ret ur n Re q uire me nts  
Use d a n d u n use d sa m ples t o b e ret ur ne d t o s p o ns or 
 
 
 
 
 
 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 1  of 5 8  
T a bl e 5 -2  
L e a d -I n Pr o d u ct S u p pli e s  
P r o d uct  
Descri pti o n  
Le a d -I n T o ot h p aste  
P r o d uct N a me  
C ol gate Ca vit y Pr otecti o n  
( Re g ular fl u ori de t o ot h paste, U S mar ket)  
Fl u ori de C o nte nt  
1 1 0 0  p p m fl u ori de as S M F P  
M F C  
C o m mercial pr o d uct ( N/ A)  
P ac k Desi g n  
O ne o ver wra p pe d t u be of t o ot h paste  
Dis pe nsi n g Det ails  
Scree ni n g  ( Visit 1): O ne t u be 
P r o d uct 
A p plic ati o n  
D ose t he t o ot h br us h wit h a stri p of t o ot h paste (a ri b b o n of t o ot h paste acr oss 
t he f ull br us h hea d) o n eac h br us hi n g occasi o n 
R o ute of 
A d mi nistr ati o n  
T o pical Oral Use  
Us a ge I nstr ucti o ns  
S u bj ects will br us h t heir teet h f or o ne ti me d mi n ute t wice a da y ( m or ni n g 
a n d e ve ni n g) i n t heir us ual ma n ner. Mi ni mize s wall o wi n g a n d s pit o ut. 
Ret ur n 
Re q uire me nts  
All use d/ u n use d sa m ples t o be ret ur ne d  t o s p o ns or 
T a bl e 5 -3  
S u n dr y It e m s  
S u n dr y Ite ms t o be s u p plie d:  
Ite ms 
S u p plie d 
B y  
P ac k Desi g n  
Dis pe nsi n g Det ails  
Ret ur n/ Dis p os al Det ails  
Use d  
S a m ples  
U n use d 
S a m ples  
A q uafres h ®  Fle x 
t o ot h br us h ( U K 
mar ket)   
S p o ns or or desi g nate d ve n d or  
C o m mercial 
pac k  
Visit  1  
O ne t o ot h br us h  
D a y 1  ( Visit 2 )  
O ne t o ot h br us h  
Dis p ose at 
site 
 
Ret ur n t o s p o ns or 
 
C o u nt d o w n ti mer  
C o m mercial 
pac k ( 1 ti mer)   
Visit 1  
O ne ti mer  
S u bj ect t o 
kee p or 
dis p ose at 
site 
O pa q ue plastic ba gs  
N/ A  
Visit 1  
O ne ba g  
D a y 1  ( Visit 2)  
O ne ba g  
D osi n g c u ps f or o n -
site use ( pla q ue 
discl osi n g 
pr oce d ure)  
N/ A  
Pr o vi de t o site 
S ufficie nt f or cli nical st u d y 
nee ds  
Dis p ose at 
site 
Pla q ue Discl osi n g 
S ol uti o n  
C o m mercial 
pac k  
Pr o vi de t o site  
S ufficie nt f or cli nical st u d y 
nee ds . T o be use d as 
descri be d i n Secti o n 9. 1. 3. 1  
Pla q ue Discl os ure  
Dis p ose at 
site 
Detaile d i nstr ucti o ns f or t he ret ur n of st u d y pr o d uct/st u d y s u p plies f or t he acc o u nta bilit y c hec ks 
a n d s u bse q ue nt destr ucti o n w hic h will be pr o vi de d b y Hale o n  d uri n g  t he st u d y i n ti me f or st u d y 
cl ose o ut visit.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 2  of 5 8  
5. 1. 1  
D o s a g e F or m a n d P a c k a gi n g  
 All t o ot h pastes will be pr o vi de d t o t he cli nical st u d y site o v er wra p pe d i n w hite vi n yl (t o mas k 
t heir i de ntit y a n d o bs c ure a n y bra n di n g) wit h a st u d y la bel affi x e d. T he c o nte nt of t he pr o d uct 
la bels will be i n acc or da nce wit h all a p plica bl e re g ulat or y re q uire me nts a n d will be t he 
res p o nsi bilit y of t h e s p o ns or’s Gl o bal Cli nical S u p plies De part me nt. Eac h st u d y l a bel will 
c o ntai n, b ut n ot be li mite d t o, pr ot oc ol n u m ber, directi o ns f or us e a n d st ora ge re q uir e me nts.  
Care s h o ul d b e ta k e n wit h t he s u p p lie d pr o d ucts a n d t heir la bels t o e ns ure t he y are m ai ntai ne d 
i n g o o d c o n diti o n. It is i m p orta nt t hat all la bels re mai n i ntact a n d le gi ble f or t he d urati o n of t he 
st u d y. S u bjects s h o ul d b e i nstr ucte d t o n ot re m o ve or deface a n y p art of t h e o ver -wra p pi n g or 
st u d y la bel.  
All pr o d ucts s u p plie d are f or use o nl y i n t his cli nical st u d y a n d s h o ul d n ot be use d f or a n y ot her 
p ur p ose . 
5. 1. 2  
Pr e p ar ati o n a n d Di s p e n si n g   
S u bjects will be assi g ne d t o pr o d ucts i n acc or da n ce wit h t he ra n d o mizati o n sc he d ule ge nerate d 
b y a n a p pr o ve d Hale o n  v e n d or, pri or t o t he start of t he st u d y, usi n g vali dat e d s oft ware.  
T he pr o d uct dis pe nsi n g area will be se parate fr o m t he cli nical e x a mi nati o n area. St u d y 
t o ot h pastes will be dis pe nse d per pr ot oc ol i n bli n de d fas hi o n t o t he s u bject, b y tr ai ne d st u d y 
pers o n nel. T hese staff me m bers will n ot be i n v ol ve d i n a n y safet y or cli nical efficac y 
assess me nts or a n y ot her as pect of t he st u d y t hat c o ul d be i nfl ue nce d b y k n o wi n g w hic h pr o d uct 
a s u bject has b ee n assi g ne d t o. A n a d diti o nal me m ber of t he st u d y st aff will verif y t he 
dis pe nsi n g pr oce d ure has bee n c o m plete d acc uratel y f or eac h s u bject.   
A rec or d of pr o d uct dis pe nsi n g t o eac h s u bject will be mai ntai ne d i n t he dis pe nsi n g l o g; 
c o m pleti o n of t he dis pe nsi n g pr oce d ure will be rec or de d i n t he eC R F . 
5. 2  
A d mi ni str ati o n  
S u bjects will self -a d mi nister t he lea d-i n t o ot h paste (fr o m Visit 1 t o Visit 2) a n d t heir assi g n e d 
st u d y t o ot h paste (fr o m Visit 2 t o Visit 3) acc or di n g t o t he usa ge i nstr ucti o ns pr o vi de d b y st u d y 
pers o n nel at t he st u d y site a n d rec or d eac h br us hi n g i n t heir diar y.  
T o hel p e ns ur e s u bjects f ull y u n d ersta n d t h e a m o u nt of t o ot h paste t o use, t he br us hi n g 
i nstr ucti o ns a n d h o w t o c o m plete t he diar y:  
•  Scre e ni n g ( Visit 1):  Staff will de m o nstrate dis pe nsi n g a f ull ri b b o n of t o ot h paste al o n g 
t he le n gt h of t he t o ot h br us h hea d t o eac h q ualif yi n g s u bject a n d s u per vis e t heir first 
br us hi n g wit h t he lea d-i n t o ot h paste/ diar y c o m pl eti o n at t he e n d of t he visit, after all 
cli nical assess me nts ha ve bee n c o m plete d.  
•  B aseli ne ( Visit 2):  Staff will c hec k t he dis pe nsi n g of a f ull ri b b o n of t o ot h paste b y eac h 
ra n d o mize d s u bject a n d s u per vise t he first br us hi n g 
wit h t heir assi g ne d st u d y 
t o ot h paste/ diar y c o m pleti o n.   
O n -site a d mi nistrati o n of st u d y pr o d ucts will be rec or de d i n t he dis pe nsi n g l o g a n d t he e C R F .  
5. 2. 1  
Pr o d u ct D o si n g Err or s  
In t his st u d y , d osi n g err ors ma y res ult fr o m t he a d mi nistrati o n or c o ns u m pti o n of  t he wr o n g 
pr o d uct,  b y t h e wr o n g s u bject , i n t he wr o n g wa y. S uc h d osi n g err ors s h o ul d be ca pt ur e d i n t he 
eC R F.  D osi n g err ors are re p orta ble irres pecti ve of t he prese nce of a n ass oci ate d A E, i ncl u di n g:  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 3  of 5 8  
•  D osi n g err ors i n v ol vi n g s u bject e x p os ure t o a n y of t he st u d y pr o d u cts . 
•  P ote ntial d osi n g err ors or uses o utsi de of w hat was  f oresee n i n t he pr ot oc ol t hat d o or 
d o n ot i n v ol ve t he partici pati n g s u bject.  
If a d osi n g err or is acc o m pa nie d b y a n A E, as d eter mi ne d b y t h e i n vesti gat or or me dicall y 
q ualifie d desi g n ee , t he d osi n g err or a n d a n y ass ociate d A es are t o be ca pt ur e d i n t h e eC R F A E 
f or m.    
S uc h d osi n g err ors o cc urri n g t o a st u d y s u bj ect are t o be ca pt ure d i n t he eC R F.  I n t he e ve nt of 
me dicati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d 
i m me di atel y a n d u n der n o 
circ u mst a nce s h o ul d t his e xcee d 2 4 h o urs .  
5. 2. 2  
O v er d o s e  
A n o ver d ose is a deli berate or i na d verte nt a d mi nistrati o n of a pr o d uct at a n a m o u nt hi g her t ha n 
s pecifie d i n t he pr ot oc ol. O ver d ose is n ot li kel y t o occ ur i n t his st u d y . 
O ver d ose p er se is n ot a n A E. H o we v er, a n y cli nical se q uelae of a n o v er d ose s h o ul d be re p ort e d 
as a n A E (a n d seri o us a d verse e ve nt [S A E ], if a p pr o priate). F or re p orti n g, f oll o w t he A E a n d 
S A E re p orti n g i nstr ucti o ns . 
5. 3  
St u d y Pr o d u ct St or a g e   
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ur e c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y pr o d ucts  recei ve d a n d a n y discre p a ncies are re p orte d a n d 
res ol ve d bef ore us e acc or di n g t o t he s u p plie d s hi p pi n g d oc u me nt ati o n . 
T h e i n vesti gat or, or d esi g nee, will e ns ure t hat all st u d y pr o d ucts are st ore d i n a s ec ure d area 
wit h c o ntr olle d access u n der re q uire d st or a ge c o n diti o ns a n d i n acc or da n ce wit h a p plica ble 
re g ulat or y re q uire me nts a n d t he pr o d uct la b el.   
Site s yst e ms m ust be c a pa ble of meas uri n g a n d d oc u me nti n g (f or e x a m ple, via a l o g), at a 
mi ni m u m, dail y mi ni m u m a n d ma xi m u m te m perat ur es f or all site st ora ge l ocati o ns (as 
a p plica ble, i ncl u di n g fr o ze n, refri gerate d, a n d/ or r o o m -te m perat ure pr o d ucts).  T his s h o ul d be 
ca pt ure d fro m t he ti me of first pr o d uct recei pt t hr o u g h o ut t he st u d y.  E ve n f or c o nti n u o us 
m o nit ori n g s yste ms, a l o g or site pr oce d ure t hat e ns ures acti ve dail y e val u ati o n f or e x c ursi o ns 
s h o ul d be a v aila ble.  T he o perati o n of t h e te m perat ure-m o nit ori n g de vice a n d st o ra ge u nit (f or 
e x a m ple, refri gerat or), as a p plica ble, s h o ul d b e re g ularl y i ns pecte d t o e ns ure it is mai ntai ne d i n 
w or ki n g or der.  
A n y e x c ursi o ns fr o m t he pr o d uct -la bel st ora ge c o n diti o ns s h o ul d be re p orte d t o a p pr o priate sit e 
staff u p o n disc o ver y a n d c o m m unicate d t o s p o ns or as s o o n as p ossi ble.  T he site s h o ul d acti vel y 
p urs ue o pti o ns f or ret ur ni n g t he pr o d uct t o t he st ora ge c o n diti o ns as descri be d i n t he la beli n g, 
as s o o n as p ossi ble.  E x c ursi o ns fr o m t he st ora ge re q uir e me nts, i ncl u di n g a n y acti o ns ta ke n, 
m ust be d oc u me nte d as a pr ot oc ol de viati o n a n d re p orte d t o t he S p o ns or.   
O nce a n e x c ursi o n is i de ntifie d, t he affect e d pr o d uct ( or pr o d ucts) m ust be q uara nti ne d a n d n ot 
use d u ntil t he s p o ns or pr o vi des d oc u me ntati o n of per missi o n t o use. Use of a n y of t he affecte d 
pr o d uct(s) pri or t o s p o ns or a p pr o val will be c o nsi dere d a pr ot oc ol de viati o n.    
Site staff will i nstr uct s u bjects o n t he pr o per st ora ge re q uir e me nts f or all ta ke -h o me pr o d u cts.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 4  of 5 8  
5. 4  
St u d y Pr o d u ct A c c o u nt a bilit y  
All pr o d ucts s u p plie d are f or use o nl y i n t his cli nical st u d y a n d s h o ul d n ot be use d f or a n y ot her 
p ur p ose.  
All st u d y pr o d ucts m ust b e recei ve d b y a desi g n ate d pers o n at t he st u d y sites, ha n dle d a n d st or e d 
safel y a n d pr o perl y, a n d ke pt i n a sec ure d l ocati o n t o w hic h o nl y t he staff ha ve access. U p o n 
recei pt, all st u d y pr o d ucts s h o ul d be st or e d acc or di n g t o t he i nstr ucti o ns s p ecifie d o n t he pr o d uct 
la bels. St u d y pr o d ucts are t o be dis pe nse d o nl y t o s u bjects e nr olle d i n t he st u d y i n acc or da n ce 
wit h t he pr ot oc ol, b y a ut h orize d site staff.  
T he i n vest i gati ve site m ust mai ntai n a de q uate rec or ds d oc u me nti n g t he recei pt, use, l oss, or 
ot her dis p ositi o n of all t he pr o d uct s u p plies. All st u d y pr o d u cts will be acc o u nte d f or usi n g t he 
i n vesti gati o nal/st u d y pr o d uct acc o u nta bilit y f or m/rec or d. T he i n vesti gat or is res p o nsi ble f or 
st u d y pr o d uct acc o u nt a bilit y, rec o n ciliati o n, a n d rec or d mai nte n a nce.  
S u bjects will ret ur n use d a n d u n use d t u bes of t he lea d-i n t o ot h paste t o t he st u d y site at t heir 
Baseli ne  visit  ( Visit 2). S u bjects will bri n g t h e use d a n d u n us e d t u be s of t heir assi g ne d st u d y 
t o ot h paste t o eac h of t heir sc he d ule d visits t o t he st u d y site, per t he Sc he d ul e of Acti vities  (Ta ble 
7 -1 ); all st u d y pr o d ucts will be ret ur ne d at st u d y c o n cl usi o n. St u d y pr o d uct ret ur n will be 
d oc u me nte d usi n g t h e st u d y pr o d u ct acc o u nta bilit y f or m/rec or d . 
T he acc o u nt a bilit y rec or ds m ust be a vaila ble f or i ns pecti o n b y t h e st u d y m o nit or d uri n g t he 
st u d y. M o nit ori n g of pr o d uct acc o u nta bilit y will b e perf or me d b y t he m o nit or d uri n g site visits 
a nd at t he c o m pleti o n of t he st u d y.  
5. 4. 1  
D e str u cti o n of St u d y Pr o d u ct S u p pli e s  
At t he e n d of  t he st u d y, t he Pri nci p al I n vesti gat or or a n a p pr o priate desi g n ee, a n d a 
re pres e ntati ve of Hal e o n  (st u d y m o nit or) will i n ve nt or y all use d a n d u n use d st u d y pr o d ucts a n d 
su n dr y ite ms.  T he i n vesti gati o nal/st u d y pr o d uct acc o u nta bilit y rec or d f or ret ur ne d st u d y 
pr o d ucts will t he n b e c o m plete d. All st u d y pr o d uct ( use d a n d u n us e d) f or t his cli nical st u d y will 
be ret ur n e d f or destr ucti o n t o t he Hale o n  Cli nical S u p plies De part me n t or desi g nate d v e n d or 
usi n g t he ret ur n i nstr ucti o ns pr o vi de d.  
Detaile d i nstr ucti o ns f or t he ret ur n of st u d y pr o d uct/st u d y s u p plies f or t he acc o u nta bilit y c hec ks 
a n d s u bse q ue nt d estr ucti o n will be pr o vi de d b y Hale o n  d uri n g t he st u d y i n ti me f or st u d y cl ose 
o ut visit.  
5. 5  
Bli n di n g a n d All o c ati o n/ R a n d o mi z ati o n  
All s u bjects will be ce ntrall y ra n d o mi ze d t o o ne of t he tw o  st u d y t o ot h pastes usi n g a n 
I nteracti ve Res p o nse T ec h n ol o g y (I R T). Bef ore t he st u d y is i nitiate d, trai ni n g, l o gi n 
i nf or mati o n a n d directi o ns f or t he I R T will be pr o vi de d t o t he st u d y site. St u d y pr o d ucts will be 
dis pe nse d acc or di n g t o t he i nstr ucti o n recei ve d t hr o u g h t he I R T at t he a p pr o priate st u d y visits.  
Ret ur ne d st u d y pr o d ucts s h o ul d n ot be re -dis pe nse d t o  a n y s u bject.  
T his st u d y is des cri be d as a nal yst a n d e x a mi ner-bli n d ( a nal yst a n d cli nical e x a mi ners  will be 
bli n de d t o pr o d uct recei ve d). S u bjects, site staff, st u d y statisticia n(s), data ma na ge me nt staff, 
ot her e m pl o yees of t he S p o ns or (i ncl u di n g t he C R S ) a n d v e n d ors acti n g o n b e half of t he s p o ns or, 
w h o ma y i nfl ue n ce st u d y o utc o mes will als o be bli n de d t o pr o d uct all ocati o n.  T he m o nit ors a n d 
t he s p o ns or’s Cli nical St u d y Ma n a ger ma y n ot b e f ull y bli n de d as t he y will o bser ve s u bjects 
br us hi n g wit h t heir all o cate d st u d y pr o d uct w hile at t he st u d y site. As a matt er of st u d y c o n d uct, 
i ncl u di n g e mer ge n c y u n bli n di n g e v e nts, o nl y t he in vesti gat or ma y l ear n t he c o nte nts of o ne or 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 5  of 5 8  
m ore of t he pr o d u ct c o des use d t o all ocate st u d y pr o d uct , n ot t he cli nical e xa mi ners. Gi ve n t he 
a p plicati o n of I R T wit hi n t his st u d y, a n y s uc h k n o wle d ge will n ot affect t he decisi o n t o e nr oll 
a s u bject or i nfl ue n ce t he or der i n w hic h s u bjects are e nr olle d . 
T o e ns ure t he a nal yst a n d cli nical e x a mi ner s re mai n bli n de d t hr o u g h o ut t he st u d y: 
•  Site  staff i n v ol ve d i n t he dis pe nsi n g of st u d y pr o d ucts a n d s u per visi o n of o n -site 
br us hi n g will w or k i n a s e parat e area  a n d will n ot be i n v ol ve d i n a n y s afet y or pr o d uct 
effic ac y ass ess me nts.  
•  A nal yst a n d c li nical e x a mi ners will n ot be per mitte d i n a n y area w h ere st u d y pr o d uct  or 
diaries  are st ore d, dis pe nse d, or i n use.  
•  S u bjects will  be i nstr uct e d n ot t o  re m o ve t heir st u d y pr o d uct or diar y fr o m its o pa q ue 
carri er ba g o utsi de of t h e dis pe nsi n g r o o m, w hile at t he st u d y site.  
S u bjects will  be i nstr ucte d n ot t o  disc uss w hic h st u d y pr o d uct t he y ha v e bee n assi g n e d or usa ge 
i nstr ucti o ns wit h t he cli nical e x a mi ners . 
5. 6  
Br e a ki n g t h e Bli n d  
At t he i nitiati o n of t he st u d y, t he st u d y site will be i nstr ucte d o n t he met h o d f or brea ki n g t he 
bli n d i n case of e mer ge n c y. T h e met h o d will be a n electr o nic pr ocess.  
T he ele ctr o nic s yste m will be pr o gra m me d wit h bli n d -brea ki n g i nstr ucti o ns. I n case of a n 
e mer ge n c y, t he i n v esti gat or has t h e s ole res p o nsi bilit y f or det er mi ni n g if u n bli n di n g of a 
s u bject’s pr o d uct assi g n me nt is warra nte d. S u bject safet y m ust al wa ys b e t he first c o nsi derati o n 
i n ma ki n g s uc h a d eter mi nati o n. If t he i n v esti gat or deci des t hat u n bli n di n g is warra nte d, t h e 
i n vesti gat or s h o ul d ma k e e ver y eff ort t o c o ntact t he s p o ns or pri or t o u n bli n di n g a s u bject’s 
pr o d uct assi g n me nt u nless t his c o ul d dela y e mer ge nc y tr eat me nt of t h e s u bject.  
If a s u bject’s pr o d uct assi g n me nt is u n bli n de d, t he s p o ns or m ust be n otifie d wit hi n 2 4 h o urs 
after brea ki n g t he bli n d. T he date a n d reas o n t hat t he bli n d was br o ke n m ust be rec or de d i n t he 
s ource d oc u m e ntati o n a n d t he e C R F, as a p plica ble. 
A n y A E ass o ciate d wit h brea ki n g t he bli n d m ust be rec or de d a n d re p orte d as s pecifie d i n t his 
pr ot oc ol. T he st u d y site ma y als o be re q uir e d be re q uire d t o i nf or m t he I nstit uti o nal Re vie w 
B oar d (I R B)  if t he blin d is br o ke n .  
5. 7  
C o m pli a n c e  
T o facilitate c o m plia nce wit h pr o d uct usa ge, s u bjects will be pr o vi de d wit h a diar y at Scree ni n g 
( Visit 1) a n d at Baseli ne ( Visit 2) t o rec or d eac h br us hi n g wit h t he lea d-i n t o ot h paste a n d t heir 
assi g ne d st u d y pr o d u ct, r es pecti vel y.  
•  T he diaries will pr o vi de d etaile d usa ge i nstr ucti o ns f or t he s u bject t o refer t o t hr o u g h o ut 
t heir partici pati o n i n t he st u d y. 
•  S u bjects will be i nstr ucte d t o n ote a n y misse d/a d diti o nal br us hi n gs, t he reas o ns f or a n y 
misse d/a d diti o nal br us hi n gs, a n y iss u es wit h t he t o ot h paste use d, oral pr o ble ms, 
ill nesses a n d a n y ne w me dicati o ns/treat me nts i n t heir diaries.  
•  C o m plete d diaries will be re vie we d b y st u d y st aff at t he start of eac h st u d y visit. A n y 
m isse d or a d diti o nal br us hi n gs  will be ca pt ur e d i n t he e C R F as pr ot oc ol de viati o ns . 
S u bjects will be re -i nstr ucte d i n c orrect pr o d uct usa ge re q uire me nts/diar y c o m pleti o n , 
as nee de d .  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 6  of 5 8  
I nf or mati o n rec or de d i n t he diar y relati n g t o c ha n ges i n healt h a n d me dicati o ns/ treat me nts will  
be re vie we d b y t he i n vesti gat or , or me di call y  q ualifie d desi g nee , wit h t he s u bject a n d 
tra nscri be d i nt o t he eC R F , as a p pr o priate  (e. g., as a n A E). I nf or m ati o n relate d t o pr o d uct use 
s h o ul d als o tra nscri be d i nt o t he eC R F , as a p pr o priate , ta ki n g care t o mai ntai n t he bli n d. 
S u bjects will be i nstr ucte d t o bri n g all t u bes of t o ot h paste pr o vi de d ( use d a n d u n use d) t o eac h 
st u d y visit. St u d y staff will perf or m a vis u al c h ec k of pr o d uct usa ge. A n y s us p ecte d o ver or 
u n der use will be d o c u me nte d i n t he e C R F a n d t h e s u bject will be re -i nstr ucte d i n t he c orrect 
usa ge re q uir e me nts.  
S u per vise d br us hi n gs will be carrie d o ut at t he st u d y site at t h e e n d of Visit 1 a n d 2 t o faci litate 
c o m plia nce wit h usa ge i nstr ucti o ns. If an y d e viati o ns fr o m per pr ot o c ol pr o d uct usa ge are 
o bser ve d, t he s u bje ct will be re-i nstr ucte d of c orrect  pr o d uct us a ge.  
5. 8  
C o n c o mit a nt M e di c ati o n/ Tr e at m e nt( s)  
A n y me dicati o ns, treat me nts or vacci ne (i ncl u di n g o ver -t he-c o u nt er or prescri pti o n me dici nes, 
vita mi ns, a n d/ or her bal s u p ple me nts) ta ke n  or recei ve d  d uri n g t he st u d y,  fr o m si g ni n g t he 
i nf or me d c o nse nt, m ust be rec or de d i n t he eC R F wit h i n dicati o n, reas o n f or use, u nit d ose, dail y 
d ose, a n d start a n d st o p dates of a d mi nistrati o n. All s u bjects will be q uesti o ne d a b o ut 
me dicati o ns/treat me nts at eac h site visit.  
Me dicati o n /treat me nts ta ke n or recei ve d wit hi n 3 0 da ys of si g ni n g t he i nf or me d c o ns e nt f or m 
will be d oc u me nte d as a pri or me dicati o n/treat me nt. Me dicati o ns/treat me nts ta ke n or recei ve d 
after 
si g ni n g t he i nf or me d 
c o nse nt f or m 
will 
be 
d oc u me nte d 
as 
c o n c o mita nt 
me dicat i o n/treat me nts.  
F or t he D ur ati o n of t he St u d y: Scree ni n g ( Visit 1) t o S u bject’s L ast St u d y Visit  
•  S u bjects s h o ul d dela y a n y n o n -e m er ge n c y,  electi ve de ntal treat me nt s u ntil after st u d y 
c o m pleti o n (i ncl u di n g de ntal pr o p h yla xis).  
•  S h o ul d a ra n d o mi ze d s u bject  start a c o urse of treat me nt w hic h i ncl u des dail y, re g ul ar or 
i nter mitte nt use of a n y m e dicati o n , details of t h at me dicati o n/treat me nt will be rec or de d 
i n t he e C R F. T he i n vesti gat or, or t heir m e dicall y q ualifie d desi g nee , will deci de if t h e 
s u bject ca n c o nti n ue o n t he st u d y or s h o ul d b e wit h dra w n.  
•  S h o ul d a s u bject ta ke a me dicati o n w hic h, i n t he o pi ni o n of t he i n vesti gat or or t heir 
me dicall y q u alifie d desi g nee, c o ul d i m pact t he  st u d y o utc o me wit hi n 8 h o urs of a 
sc he d ule d st u d y visit, t he me dicati o n s h oul d be rec or de d i n t he e C R F a n d e ver y eff ort 
will be ma de t o rea p p oi nt t he m wit hi n per mitte d visit t olera nces  (see Sc he d ule of 
Acti vities , Ta ble 7 -1 ). T h e reas o n f or re-a p p oi nt m e nt will be d oc u me nte d i n t he e C R F.  
If re-a p p oi nt me nt is n ot p ossi ble, t he f oll o wi n g visit s pecific acti o ns s h o ul d be ta ke n : 
•  Scree ni n g ( Visit 1):  t he s u bject will be wit h dr a w n fr o m t he st u d y. N o ass ess me nts will 
be perf or me d . T he s u bject ma y be re place d. 
•  B aseli ne ( Visit 2):  t he s u bject will be wit h dra w n fr o m t he st u d y. S u bjects ca n be 
resc he d ul e d i n o utsi de wi n d o w visit w here A es will be rec or de d, a n d t he O S T 
e x a mi nati o n c o m plete d; n o sa m ples will be c ollecte d. T he s u bject ma y  b e re place d.  
•  Wee ks 
6  ( Visits 3): t he s u bject will b e wit h dr a w n fr o m t he st u d y. S u bjects ca n b e 
resc he d ul e d i n o utsi de wi n d o w visit w here A es will be rec or de d, a n d t he O S T 
e x a mi nati o n c o m plete d; n o sa m ples will be c ollecte d. T he s u bject will n ot  be re place d . 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 7  of 5 8  
6  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
S U B J E C T DI S C O N TI N U A TI O N/ WI T H D R A W A L  
6. 1  
S u bj e ct Di s c o nti n u ati o n/ Wit h dr a w al  
A s u bject ma y wit h dr a w fr o m t he st u d y at a n y ti me at his or her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or or s p o ns or f or safet y, b e ha vi oral 
reas o ns, or t he i na bilit y of t he s u bject t o c o m pl y wit h t he pr ot oc ol-re q uir e d sc he d ule of st u d y 
visits or pr oce d ures.   
T he f oll o wi n g circ u msta nces re q uire disc o nti n uati o n of st u d y pr o d uct a n d/ or pre m at ure s u bject 
wit h dra wal:  
•  Pr ot oc ol vi olati o n t hat  ma y i m pact t he s u bject’s s afet y  
•  In a bilit y of t he s u bject t o c o m pl y wit h t he pr ot oc ol -re q uir e d sc he d ule of st u d y visits, 
pr oce d ures  or lifest yle c o nsi derati o ns  
•  Wit h dra wal of i nf or me d c o nse nt  
•  S u bject l ost t o f oll o w -u p  
•  U n bli n di n g of t he s u bject  
•  Pre g n a nc y  
If a s u bj ect is disc o nti n ue d or pre mat urel y wit h dra ws fr o m t he st u d y, t he reas o n(s) f or 
disc o nti n uati o n or wit h dra wal a n d t h e ass ociate d date m ust be d oc u me nt e d i n t he rele va nt 
secti o n(s) of t he eC R F.  
6. 2  
L o st t o F oll o w u p  
If a s u bject fails t o ret ur n t o t he site f or a re q uire d st u d y visit t he site m ust atte m pt t o c o ntact 
t he s u bject a n d resc he d ul e t he misse d visit as s o o n as p ossi ble a n d c o u nsel t he s u bject o n t he 
i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule a n d ascertai n w het her  t he s u bject wis hes 
t o a n d/ or s h o ul d c o nti n ue i n t he st u d y. 
A s u bject will be c o nsi dere d l ost t o f oll o w u p if he or s he re p eate dl y fails t o ret ur n f or sc h e d ule d 
visits a n d is u na ble t o be c o ntacte d b y t he st u d y sit e. Bef ore a s u bject is dee me d l ost t o f oll o w 
u p, t he i n vesti gat or or desi g nee m ust ma ke e ver y eff ort t o re gai n c o nt act wit h t he s u bject ( w here 
p ossi ble, 3 tele p h o ne calls a n d, if necessar y, a certifie d letter t o t he s u bject’s last k n o w n maili n g 
a d dress or l ocal e q ui val e nt met h o ds). T hese c o ntact a tte m pts s h o ul d be d oc u me nte d. If c o ntact 
is ma de wit h t he s u bject, t he i n vesti gat or s h o ul d i n q uire a b o ut t he reas o n f or wit h dra wal, re q u est 
t hat t he s u bject ret ur n all pr o d ucts t h at t he y h a d b ee n dis pe ns e d a n d if a p pr o priate re q uest t h at 
t he s u bject ret ur n f or a fi nal visit a n d f oll o w-u p wit h t he s u bject re gar di n g a n y u nres ol ve d 
a d verse e ve nts ( A es). 
Fi nal safet y assess me nts ma y be carrie d o ut w he n t he s u bject ret ur ns t o t he st u d y site, at t h e 
i n vesti gat or’s discreti o n, w hic h c o ul d i ncl u de t he f oll o wi n g: 
S h o ul d t he s u bject c o nti n ue t o be u nreac h a ble, h e/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr o m t he st u d y a n d l ost t o f oll o w u p.  
Lac k of c o m pleti o n of all or a n y of t he earl y ter mi nati o n pr oce d ures will n ot be vie we d as 
pr ot oc ol de viati o ns s o l o n g as t he s u bj ect’s safet y was pres er ve d.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 8  of 5 8  
If t he s u bject wit h dra ws fr o m t he st u d y a n d wit h dra ws c o ns e nt f or discl os ure of f ut ure 
i nf or mati o n, n o f urt her e val uati o ns s h o ul d be p erf or me d, a n d n o a d diti o nal data s h o ul d be 
c ollecte d.  T he s p o ns or ma y retai n a n d c o nti n ue t o use a n y d ata c ollecte d bef ore s uc h 
wit h dra wal of c o nse nt.  
7  
S T U D Y P R O C E D U R E S  
T his secti o n lists t he pr oce d ures t o be c o m plete d at eac h pla n ne d st u d y visit.  T he ti mi n g of 
eac h pr oce d ure is liste d i n t he Sc he d ule of Acti vities (Ta ble 7 -1 ). 
A d here n ce t o t he st u d y d esi g n re q uire m e nts, i ncl u di n g all pr oce d ures are esse ntial a n d re q uire d 
f or st u d y c o n d uct.  
T a bl e 7 -1  
S c h e d ul e of A cti viti e s  
 
 
Pr o ce d ure/ Assess me nt  
Visit 1  
Scree ni n g  
 
Visit 2  
Visit 3  
D a y 1  
Baseli ne  
Wee k 6  
D a y 4 3 ( ± 4 
d a ys)  
I nf or me d C o nse nt 
X  
Le a d -I n (7  D a ys  ± 2 D a ys ) 
 
 
De m o gra p hics, Me dical Hist or y, Pri or/ C urre nt Me dicati o ns/ Treat me nts  
X  
 
 
I ncl usi o n/ E xcl usi o n Criteria 
X  
 
 
Oral E xa mi nati o ns t o  Deter mi ne Eli gi bilit y A gai nst I ncl usi o n/ E xcl usi o n 
Criteria  a n d t o I de ntif y Sc ora ble  s urfaces 
X  
 
 
M o difie d Gi n gi val I n de x ( M GI)  
X  
 
 
Blee di n g I n de x ( BI)  
X  
 
 
Discl ose de ntal pla q ue  
X  
 
 
T ures k y M o difie d Q ui gle y & Hei n Pla q ue I n de x ( T PI)  
X  
 
 
Oral S oft Tiss ue ( O S T) E xa mi nati o n  
X  
X  
X  
Oral Har d Tiss ue ( O H T) E xa mi nati o n  
X  
 
X  
Dis pe nse Lea d -I n T o ot h br us h, Re g ular Fl u ori de T o ot h paste, Diar y, 
Ti mer   
X  
 
 
O n -Site S u per vise d Br us hi n g wit h Lea d -I n T o ot h br us h a n d Re g ular 
Fl u ori de T o ot h paste; C o m plet e Diar y  
X  
 
 
S u bj ect Ret ur ns wit h Lea d -I n T o ot h br us h, Re g ular Fl u ori de T o ot h paste, 
C o m plete d Diar y   
 
X  
 
C o m plia nce C hec ks  
 
X  
X  
C o nc o mita nt Me dicati o ns/ Treat me nts  
 
X  
X  
S u bj ect C o nti n ua nce 1 
 
X  
 
Sa m ple c ollecti o n  
 
X  
X  
Ra n d o mizati o n 2 
 
X  
 
Dis pe nse T o ot h br us h, St u d y T o ot h paste , Diar y  
 
X  
 
O n -Site Br us hi n g wit h T o ot h br us h a n d assi g ne d st u d y T o ot h paste; 
C o m plete Diar y 2 
 
X  
 
S u bj ect Ret ur ns wit h T o ot h br us h , St u d y T o ot h paste , C o m pl ete d Diar y   
 
 
X  
A d verse E ve nts ( A E s)3 
X  
X  
X  
St u d y C o ncl usi o n  
 
 
X  
F o ot n otes:   
1.  S u bj ects will be re q uire d t o bri n g t heir st u d y s u p plies t o e ver y visit.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 9  of 5 8  
Staff will p erf or m a vis ual c hec k of t he ret ur ne d st u d y s u p plies/re vie w t he c o m plete d diar y.  
•  
Visits 2: c o m plia nce wit h lea d -i n t o ot h paste usa ge.  
•  
Visits 3: c o m plia nce wit h assi g ne d st u d y t o ot h paste usa ge.  
C hec k c o m plia nce wit h Lifest yle C o nsi derati o ns / Me dicati o n Re q uire me nts. 
2.  Ra n d o mi zati o n a n d o n -site br us hi n gs t o be carrie d o ut after sa m ple c ollecti o n . 
3.  A E s, a n d t heref ore all Seri o us A d verse E ve nts ( S A Es), will be c ollecte d fr o m i m me diatel y after 
eac h s u bject c o nse nts t o partici pate i n t he st u d y ( b y t he c o m pleti o n of t he I nf or me d C o nse nt 
F or m [I C F]) u ntil 5 da ys after last use of st u d y pr o d uct . 
7. 1  
Vi sit 1/ S cr e e ni n g  
T he f oll o wi n g pr oce d ures a n d assess me nts will be c o m plete d b y t he i n vesti gat or, or a s uita bl y 
q ualifie d/e x perie nce d desi g nee , a n d t h e cli nical e x a mi ners, pri or t o ra n d o mizati o n  t o st u d y 
pr o d uct. W here practicall y feasi ble, t h e y s h o ul d be c o m plete d i n t he or der liste d bel o w. Data 
c ollecte d wil l be rec or de d i n t he e C R F. 
7. 1. 1  
I nf or m e d C o n s e nt 
T he i n vesti gat or, or d esi g nee, m ust o btai n i nf or m e d c o nse nt fr o m eac h s u bject partici pati n g i n 
t his st u d y aft er a de q u ate e x pla nati o n of t he ai ms, met h o ds, o bjecti ves, a n d p ote ntial hazar ds of 
t he st u d y. T w o c o pies of t he i nf or me d c o nse nt f or m (I C F) will be si g n e d a n d date d b y t h e 
s u bject, t he s u bject will r etai n o ne c o p y a n d t he ot her will be ke pt at site.  
T he i n vesti gat or, or desi g nee, m ust als o e x plai n t o t he s u bjects t hat t h e y are c o m pletel y free t o 
ref use t o e nter t he st u d y or t o wit h dra w fr o m it at a n y ti me.  A p pr o priat e f or ms f or d oc u me nti n g 
a si g ne d a n d date d c o nse nt will be pr o vi de d b y eit her t he i n vesti gat or or b y Hale o n . 
T he i n vesti gat or, or desi g nee, s h o ul d si g n a n d date eac h c o p y of t he I C F t o c o nf ir m t hat t he 
c o nse nt pr ocess was c o m plete d c orrectl y aft er t he s u bject has si g n e d.   
T he ti me t he s u bject si g ne d t he i nf or me d c o nse nt f or m will be ca pt ure d as t his is t he p oi nt at 
w hic h all A d verse E ve nts will be ca pt ure d fr o m. T he date a n d ti me of c o nse nt  will be ca pt ure d  
i n t he eC R F.  
If, d uri n g a s u bject’s partici pati o n i n t he st u d y, a n y ne w i nf or mati o n bec o mes a vaila ble t hat 
ma y affect t he s u bject’s willi n g ness t o partici pate i n t he st u d y, eac h o n g oi n g s u bject s h o ul d 
recei v e a c o p y of t his ne w i nf or mati on a n d be re -c o nse nte d i nt o t he st u d y. Eac h s u bject s h o ul d 
be pr o vi de d wit h a c o p y of t he si g ne d a n d date d a me n de d c o nse nt f or m. T he date of re -c o ns e nt 
will be rec or de d o n t he e C R F.  
A list of In gre die nts i n t he t o ot h pastes t o b e us e d d uri n g t he st u d y will b e pr o vi de d t o eac h 
s u bject d uri n g t he c o ns e nt pr ocess t o e n a ble t he m t o c o nfir m w het her t he y h a ve a k n o w n aller g y 
or h y p erse nsiti vit y t o a n y of t he i n gre die nts liste d.  
After si g ni n g t he I C F, s u bjects will u n der g o t he scree ni n g assess me nts t o c o nfir m t hat t he y 
meet all t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria. If t he s u bject is c o nfir me d 
eli gi ble b y t he i n vesti gat or ( or desi g nee) t o partici pate i n t he st u d y t he s u bject is c o nsi d ere d 
e nr olle d i n t he st u d y.  
7. 1. 2  
D e m o gr a p hi c s  
T he f oll o wi n g d e m o gra p h ic i nf or mati o n will be rec or de d i n t he eC R F: year of birt h, s e x ( male 
or fe male) , race a n d et h nicit y. 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 0  of 5 8  
7. 1. 3  
M e di c al Hi st or y a n d Pri or M e di c ati o n/ Tr e at m e nt  
T he f oll o wi n g will be d oc u me nte d i n t he e C R F.  
•  Details of rele va nt me dical hist or y a n d rece nt s ur ger y ( wit hi n t he last year), i ncl u di n g 
aller gies a n d dr u g s e nsiti vities.  
•  Fe male s u bjects: pre g na n c y a n d breast -fee di n g stat us (self-re p orte d). 
•  Me dicati o ns/treat me nts, i ncl u di n g pres cri pti o n a n d n o n -prescri pti o n dr u gs, dietar y 
s u p ple me nts, ta ke n c urre ntl y a n d i n t he last 3 0 da ys . 
7. 1. 4  
Cli ni c al E x a mi n ati o n s a n d A s s e s s m e nt s  
T he f oll o wi n g cli nical e x a mi nati o ns will be c o m plete d as des cri be d i n St u d y Ass ess me nts  a n d 
t he fi n di n gs rec or de d i n t he e C R F. T o facilitate s u bject fl o w, s o urce d oc u me nts ma y be use d 
f or later tr a nscri pti o n i nt o t he e C R F (tra nscri pti o n fr o m s o urce d oc u me nts m ust be c o m plet e d 
wit hi n 5 da ys of rec or di n g t he d ata f or eac h s u bject).  
•  O S T e x a mi na ti o n 
•  O H T e x a mi nati o n  
•  M GI  assess me nt  
•  BI  ass ess me nt  
•  Pla q ue discl os ure  
•  T PI  ass ess me nt  
7. 1. 5  
I n cl u si o n/ E x cl u si o n Crit eri a 
I n cl usi o n a n d e x cl usi o n criteria i nf or mati o n will be d oc u me nte d i n t he eC R F.  
7. 1. 6  
S u bj e ct Eli gi bilit y  
T he i n vesti gat or a n d/ or me dicall y q u alifie d desi g nee will re vie w i ncl usi o n/e xcl usi o n criteria, 
me dical hist or y, pri or me dicati o ns t o c o nfir m s u bj ect eli gi bilit y t o partici p ate i n t he cli nical trial. 
T his will be d oc u me nte d i n t he eC R F.  
T o pre p are f or st u d y  partici pati o n, s u bjects will be i nstr ucte d i n t he Lif est yl e C o nsi derati o ns  
a n d a n y C o nc o mita nt Me dicati o n/ Treat me nt(s)  re q uire me nts of t he pr ot oc ol. 
7. 1. 7  
S u p er vi s e d Br u s hi n g wit h L e a d -i n T o ot h p a st e  
E nr olle d s u bjects will be pr o vi de d wit h t he lea d -i n t o ot h paste, a t o ot h br us h, a ti mer a n d  a diar y 
t o use d uri n g t he l ea d-i n peri o d.  
Staff will descri be t he t o ot h paste usa ge i nstr ucti o ns t o t he s u bject a n d de m o nstrate c o veri n g t h e 
f ull br ush hea d wit h a ri b b o n of t o ot h paste. Staff will t he n s u per vise t he s u bject carr yi n g o ut 
first t heir first br us hi n g wit h t he lea d-i n t o ot h paste a n d rec or di n g t he first use i n t heir diar y.  
A n y d e viati o n fr o m t he pr o d uct usa ge i nstr ucti o ns will be ca pt ure d as  a pr ot oc ol de viati o n  i n 
t he e C R F a n d t he s u bject will be re mi n de d of t he c orrect directi o ns f or use. Dis pe nsi n g of t he 
lea d-i n t o ot h paste a n d c o m pleti o n of t he s u per vis e d first br us hi n g will als o be d oc u me nt e d i n 
t he e C R F.  
S p o nta ne o usl y re p orte d A E s, a n d a n y A E s elicit e d b y as ki n g s u bjects t o res p o n d t o a n o n-
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 1  of 5 8  
lea di n g q u esti o n, s uc h as ‘ H o w d o y o u feel?’, o n c o m pleti o n of t he s u per vise d br us hi n g wit h 
t he lea d-i n t o ot h paste will be rec or de d i n t he e C R F. 
Staff will re mi n d s u bjects t o bri n g t heir lea d-i n pr o d ucts t o t heir ne xt st u d y visit a n d t o n ote a n y 
c ha n ges i n h ealt h , me dicati o ns or treat me nts i n t h eir diar y ( or re p ort s uc h c ha n ges t o st u d y staff 
bet wee n visits  usi n g t h e c o ntact n u m bers pr o vi d e d or  i nf or m t he st aff at t heir ne xt visit , if 
preferre d . 
7. 2  
St u d y P eri o d  
7. 2. 1  
Vi sit 2/ D a y 1    
T he f oll o wi n g pr oce d ures a n d assess me nts will be c o m plete d b y t he i n vesti gat or, or a s uita bl y 
q ualifie d/e x perie nce d d esi g nee, a n d t he cli nical e x a mi ners. T he y s h o ul d b e c o m plete d i n t he 
or der liste d bel o w . All data c ollecte d s ho ul d be rec or de d i n t he e C R F.  
7. 2. 1. 1  
C h a n g e s i n M e di c al Hi st or y a n d C o n c o mit a nt M e di c ati o n s/ Tr e at m e nt s  
Staff will as k s u bjects if t here ha v e bee n a n y c ha n ges i n t h eir healt h, c o nc o mita nt me dicati o ns 
a n d n o n-dr u g treat me nts/ pr oce d ures si nc e t heir l ast visit. All c ha n ges will be d oc u me nte d i n t he 
e C R F.  
S p o nta ne o us re p orti n g of A Es a n d t h ose elicite d b y as ki n g s u bj ects t o res p o n d t o a n o n -lea di n g 
q uesti o n, s uc h as ‘ H o w d o y o u feel?’, will be assesse d a n d A Es rec or de d i n t he e C R F.  
7. 2. 1. 2  
C o m pli a n c e c h e c k   
Staff will c o m plete vis u al c hec ks of ret ur ne d st u d y t o ot h past e a n d re vie w c o m plete d diar y. 
Rec or d a n y s us p ecte d o v er or u n d er use a n d t he n u m ber of a n y misse d or a d diti o nal br us hi n gs 
i n t he e C R F.  
A n y d e viati o ns fr o m t h e re q uir e d pr o d uct us a ge i nstr ucti o ns will be ca pt ure d as pr ot oc ol 
de viati o ns i n t he e C R F a n d s u bjects will be re -i nstr ucte d i n t he c orrect us a ge.  
N ot e: St aff  will r et ai n t he le a d-i n t o ot h p aste, c o m plete d le a d-i n di ary. St aff will d is pe nse St u dy 
peri o d di ary  a n d ne w t o ot h br us h  t o s u bjects. 
7. 2. 1. 3  
S u bj e ct A d h er e n c e a n d C o nti n u a n c e  
C o nfir m s u bject a d here n ce t o t he re q uire m e nts of t he pr ot oc ol a n d d o c u me nt c o nti n ua nce i n t he 
e C R F. Rec or d a n y de viati o ns fr o m st u d y re q uire m e nts i n t he e C R F.  
7. 2. 1. 4  
Cli ni c al E x a mi n ati o n s a n d S a m pl e c oll e cti o n  
T he f oll o wi n g cli nical safet y e x a mi nati o ns a n d sa m ple c ollecti o n will be carrie d o ut as 
descri be d i n St u d y Assess me nts . T he y m ust be c o m plete d i n t he or der s pecifie d bel o w  a n d t he 
fi n di n gs r ec or de d i n t he e C R F.  
T o facilitate s u bject fl o w, s o urce d oc u me nts ca n be use d f or l ater tr a nscri pti o n i nt o t he e C R F 
(tra nscri pti o n fr o m s o ur ce d oc u me nts m ust b e c o m plete d wit hi n 5 da ys of rec or di n g t he d ata 
f or eac h s u bject). 
•  O S T e x a mi nati o n  
•  Sa m ple c ollecti o n  i n 4  areas of t he m o ut h (s u pra gi n gi val pla q ue, t o n g ue, sali va  a n d 
s u bgi n gi val s urface)  usi n g s w a b a n d sali va c ollecti o n kits  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 2  of 5 8  
N ote:  Sa m ples will be c oll ecte d, fr oze n a n d pr ocesse d f or se q u e nci n g  as descri be i n Secti o n  
9. 2. 3 . 
7. 2. 1. 5  
R a n d o mi z ati o n  
Eli gi ble s u bjects will be assi g ne d a ra n d o misati o n n u m ber i n asce n di n g n u merical or der, as 
eac h s u bject is deter mi ne d t o be f ull y eli gi ble.  
7. 2. 1. 6  
S u p er vi s e d Br u s hi n g wit h St u d y T o ot h p a st e  
Ra n d o mise d s u bjects will be pr o vi de d wit h t heir all ocate d st u d y t o ot h past e, a ne w t o ot h br us h 
a n d a ne w  di ar y.  
St u d y st aff will descri be t he t o ot h paste usa ge i nstr ucti o ns t o t he s u bject, t he n s u per vise t heir 
first br us hi n g wit h st u d y t o ot h paste a n d rec or di n g of t he first use i n t heir di ar y. A n y de viati o n 
fr o m t he pr o d uct usa ge i nstr ucti o ns will be ca pt ure d as a pr ot o c ol de viati o n i n t he e C R F a n d 
t he s u bject will be re mi n de d of t he c orrect directi o ns f or use.  
Dis pe nsi n g of st u d y t o ot h paste a n d c o m pleti o n of t he s u per vise d first br us hi n g will be 
d oc u me nte d i n t he e C R F.  
S p o nta ne o usl y re p orte d A Es, a n d a n y A Es elicit e d b y as ki n g s u bjects t o res p o n d t o a n o n -
lea di n g q u esti o n, s uc h as ‘ H o w d o y o u feel?’, o n c o m pleti o n of t he s u per vis e d br us hi n g will be 
rec or de d i n t he e C R F. 
Ra n d o mize d s u bjects will be re -i nstr ucte d i n t he Lifest yle C o nsi derati o n s a n d C o nc o mita nt 
Me dicati o ns/ Treat me nts  re q uire me nts of t he st u d y. Staff will re mi n d t he m t o bri n g t heir st u d y 
pr o d ucts t o t heir ne xt st u d y visit a n d t o n ot e a n y c ha n ges i n healt h , me dicati o ns or tr eat me nts 
i n t heir diar y. Alter nati vel y, t he y ca n re p ort s uc h c ha n ges t o st u d y staff bet wee n visits  usi n g t h e 
c o ntact n u m bers pr o vi d e d i n t he I C F or  i nf or m t h e staff at t heir ne xt visit , if preferre d. 
7. 2. 2  
Vi sit 3/ D a y 4 3  ± 4   
T he f oll o wi n g pr oce d ures a n d assess me nts will be c o m plete d b y t he i n vesti gat or, or a s uita bl y 
q ualifie d/e x perie nce d d esi g nee, a n d t he cli nical e x a mi ners. T he y s h o ul d b e c o m plete d i n t he 
or der liste d bel o w . All data c ollecte d s h o ul d be rec or de d i n t he e C R F.  
7. 2. 2. 1  
C h a n g e s i n M e di c al Hi st or y a n d C o n c o mit a nt M e di c ati o n s/ Tr e at m e nt s  
Staff will as k s u bjects if t here ha v e bee n a n y c ha n ges i n t h eir healt h, c o nc o mita nt me dicati o ns 
a n d n o n-dr u g treat me nts/ pr oce d ures si nc e t heir l ast visit. All c ha n ges will be d oc u me n te d i n t he 
e C R F.  
S p o nta ne o us re p orti n g of A Es a n d t h ose elicite d b y as ki n g s u bj ects t o res p o n d t o a n o n -lea di n g 
q uesti o n, s uc h as ‘ H o w d o y o u feel?’, will be assesse d a n d A Es rec or de d i n t he e C R F.  
7. 2. 2. 2  
C o m pli a n c e c h e c k  
Staff will c o m plete vis u al c hec ks of ret ur ne d st u d y t o ot h past e a n d re vie w c o m plete d diar y. 
Rec or d a n y s us p ecte d o v er or u n d er use a n d t he n u m ber of a n y misse d or a d diti o nal br us hi n gs 
i n t he e C R F.  
A n y d e viati o ns fr o m t h e re q uir e d pr o d uct us a ge i nstr ucti o ns will be ca pt ure d as pr ot oc ol 
de viati o ns  i n t he e C R F a n d s u bjects will be re-i nstr ucte d i n t he c orrect us a ge.  
N ote:  St aff will r et ai n t he st u dy t o ot h p aste, t o ot h br us h a n d c o m plete d ‘ Week 6 ’ di ary. 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 3  of 5 8  
7. 2. 2. 3  
Cli ni c al E x a mi n ati o n s a n d S a m pl e c oll e cti o n  
T he f oll o wi n g cli nical safet y e x a mi nati o ns a n d sa m ple c ollecti o n will be carrie d o ut as 
descri be d i n St u d y Assess me nts . T he y m ust be c o m plete d i n t he or der s pecifie d bel o w  a n d t he 
fi n di n gs r ec or de d i n t he e C R F.  
T o facilitate s u bject fl o w, s o urce d oc u me nts ca n be use d f or l ater tr a nscri pti o n i nt o t he e C R F 
(tra nscri pti o n fr o m s o ur ce d oc u me nts m ust b e c o m plete d wit hi n 5 da ys of rec or di n g t he d ata 
f or eac h s u bject). 
•  O S T e x a mi nati o n  
•  O H T e x a mi nati o n  
•  Sa m ple c ollecti o n i n 4  areas of t he m o ut h (s u pra gi n gi val pla q ue, t o n g ue, sali va  a n d 
s u bgi n gi val s urface)  usi n g s w a b a n d sali va c ollecti o n kits  
N ote:  Sa m ples will be c ollecte d, fr oze n  a n d pr ocesse d f or se q u e nci n g  as descri be i n Secti o n  
9. 2. 3 . 
7. 3  
St u d y C o n cl u si o n  
T he St u d y C o n cl usi o n pa ge of t he eC R F will be c o m plete d f or all s u bjects w het her t he y 
c o m plete d all st u d y pr oce d ures or if t he y were disc o nti n ue d fr o m t he st u d y earl y.  If t he s u bject 
disc o nti n ue d earl y, at a n y p oi nt d uri n g t he st u d y, t he pri mar y reas o n f o r wit h dra wal s h o ul d be 
rec or de d o n t he St u d y C o ncl usi o n pa ge. 
If a s u bject has a n y cli nicall y si g nifica nt, st u d y-relate d a b n or malities or A Es at t h e e n d of  t he 
st u d y, t he H ale o n  me dical m o nit or ( or desi g nate d re pres e ntati ve) s h o ul d be n otifie d a n d, t h e 
s u bject ma y be as ke d t o re mai n at t he cli nical site or be as k e d t o ret ur n f or a f oll o w-u p visit t o 
e ns ure a n y iss ue is r es ol v e d or dee m e d n ot cli nicall y si g nifica nt.  
7. 4  
F oll o w -u p Vi sit  / P h o n e C all 
T he st u d y site ma y c o nta ct a s u bject t o f oll o w u p a n A E p ost -stu d y c o m pleti o n/ wit h dra wal 
a n d, i n s o me circ u msta nces, re q uest t he y ret ur n t o t he site f or a d diti o nal f oll o w -u p visits (fi nal 
safet y assess me nts). At t he discreti o n of t he i n vesti gat or, or m e dicall y q ualifie d desi g n ee , 
a d diti o nal oral e x a mi nati o ns ma y b e ca rrie d o ut at s uc h visits. 
8  
S T U D Y A S S E S S M E N T S  
E ver y eff ort s h o ul d be ma de t o e ns ure t hat pr ot oc ol -re q uire d tests a n d pr oce d ures are c o m plete d 
as descri be d.  H o we v er, it is a ntici pate d t hat fr o m ti me t o ti me t here ma y be cir c u msta nces, 
o utsi de t he c o ntr ol of t he i n vesti gat or t hat ma y m a ke it u nfeasi ble t o c o m plete a n assess me nt.  
I n t hes e cas es, t he i n vesti gat or m ust ta ke all ste ps necessar y t o e ns ure t h e safet y a n d well-bei n g 
of t he s u bject.  W he n a pr ot oc ol -re q uir e d assess me nt ca n n ot be p erf or me d, t he i n vesti gat or ( or 
desi g nee) will d oc u me nt t he reas o n f or t he misse d assess me nt as a pr ot oc ol de viati o n a n d a n y 
c orrecti ve a n d pre v e ntati ve acti o ns t hat he or s he has ta ke n t o e ns ure t hat re q uire d pr ocesses are 
a d here d t o as s o o n as p ossi ble.  T he S p o ns or m ust be i nf or me d of a n y misse d assess me nts i n a 
ti mel y ma n ner. 
8. 1  
S cr e e ni n g A s s e s s m e nt s  
Scree ni n g ass ess me nts will be perf or me d b y a p pr o priatel y trai ne d staff/cli nical e xa mi ners at 
t he ti mes, a n d i n t he or der, defi ne d i n t he St u d y  Pr oce d ures  s ecti o n of t his pr ot oc ol. 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 4  of 5 8  
8. 1. 1  
M o difi e d Gi n gi v al I n d e x ( M GI)  
T he M GI is a n o n -i n v asi ve vis ual assess me nt of gi n gi val i nfla m mati o n (L o be ne, 1 9 8 6 ). M GI 
will be  assesse d f or all e v al ua ble s urfaces of t he facial a n d li n g ual/ pal atal gi n gi va, f o ur sites per 
t o ot h (facial gi n gi va: p a pilla a n d mar gi n; li n g ual/ palatal gi n gi va: p a pilla a n d mar gi n) a n d s c ore d 
as f oll o ws.  
Sc ore  Descri pti o n  
0  
A bse nce of i nfla m mati o n 
1  
Mil d i nfla m mati o n; sli g ht c ha n ge i n c ol o ur, little c ha n ge i n c ol o ur; little c ha n ge i n 
te xt ure of a n y p orti o n of t he mar gi nal or pa pillar y gi n gi val u nit. 
2  
Mil d i nfla m mati o n; criteria as a b o ve b ut i n v ol vi n g t he e ntire mar gi n al or pa pillar 
gi n gi val u nit.  
3  
M o derate i nfla m mati o n; glazi n g, re d ness, o e de ma, a n d/ or h y pertr o p h y of t he 
mar gi n al or pa pillar y gi n gi val u nit.  
4  
Se vere i nfla m mati o n; mar ke d re d n ess, oe de m a a n d/ or h y pertr o p h y of t he mar gi n al 
or pa pillar y gi n gi val u nit, s p o nta ne o us blee di n g, c o n gesti o n, or ulcerati o n.  
8. 1. 2  
Bl e e di n g I n d e x ( BI)  
T he BI is a n i n vasi ve ass ess me nt of gi n gi val blee di n g ( Sa xt o n a n d va n der O u deraa, 1 9 8 9 ). BI 
will be assesse d f or all e val ua ble s urfaces of t he facial a n d li n g ual/ pal atal gi n gi va, si x sites per 
t o ot h ( mesi o b uccal, b uccal a n d dist o b uccal; 
mesi oli n g ual/ palatal, li n g ual/ palatal a n d 
dist oli n g ual/ palatal) a n d sc ore d as f oll o ws.  
Sc ore  
Descri pti o n  
0  
A bse nce of blee di n g o n pr o bi n g  
1  
Blee di n g o bser ve d wit hi n 3 0 sec o n ds of pr o bi n g 
2  
Blee di n g o bser ve d i m me diatel y o n pr o bi n g  
Sites wit h a sc ore of 1 or 2 will be classifie d as ‘ bl ee di n g’ sites.  
T o perf or m t he blee di n g assess me nt, a r o u n d -e n d pr o be (e. g., C PI T N * pr o be) is i nserte d 
a p pr o xi matel y 1 milli meter ( m m) i nt o  t he gi n gi v al s ulc us (at a p pr o xi matel y 6 0 d e grees) a n d 
m o ve d ar o u n d t he t o ot h fr o m t he distal i nter pr o xi mal area t o t he mesial i nter pr o xi mal area, 
ge ntl y stretc hi n g t he gi n gi val e pit heli u m. C o ntact wit h t he t o ot h s urface s h o ul d be a v oi de d. 
Prese nce/ a bse nce  of gi n gi val blee di n g is ass esse d f or 3 0 secs after pr o bi n g.  
Assess me nts s h o ul d be perf or me d o n e q ua dra nt at a ti me, wit h BI sc ores rec or de d f or t he m ost 
rece ntl y pr o be d q ua dra nt bef ore m o vi n g o n t o t he ne xt.  
* C PI T N = C o m m u nit y P eri o d o ntal I n de x of Treat me nt Nee ds  
8. 1. 3  
T ur e s k y M o difi c ati o n of t h e Q ui gl e y H ei n I n d e x ( T PI)  
T he T PI is a n o n -i n vasi ve assess me nt of s u pra-gi n gi val pla q ue acc u m ulati o n (L o be n e et al. 
1 9 8 2 , T ures k y et al. 1 9 7 0 ). TPI will be ass esse d f or all e v al ua ble s urfaces of  t h e facial a n d 
li n g ual s urfaces of t he te et h ( 7-7 i n eac h arc h ). Eac h t o ot h s urface is di vi de d i nt o 3 areas; t hree 
sc ores are rec or de d faciall y ( mesi ofacial, facial, dist ofacial) a n d t hree sc ores li n g u all y 
( mesi oli n g ual, li n g ual a n d dist oli n g ual), ge nerati n g si x sc ores per t o ot h.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 5  of 5 8  
T he pla q ue is first discl ose d, as descri b e d i n Secti o n 9. 1 . 3. 1, t he n eac h e v al ua ble site is sc ore d 
as f oll o ws : 
Sc ore  
Descri pti o n  
0  
N o pla q ue  
1  
Sli g ht flec ks of pla q u e at t he cer vical mar gi n of t h e t o ot h  
2  
T hi n, c o nti n u o us ba n d of pla q ue ( 1 milli metre ( m m) or s maller) at t he 
cer vical mar gi n of t he t o ot h  
3  
Ba n d of pl a q ue wi der t ha n 1 m m b ut c o veri n g less t ha n 1/ 3 of t he area  
4  
Pla q ue c o veri n g at least 1/ 3 b ut less t ha n 2/ 3 of t he area  
5  
Pla q ue c o veri n g 2/ 3 or m ore of t he cr o w n of t h e t o ot h  
8. 1. 3. 1  
Pl a q u e Di s cl o s ur e Pr o c e d ur e  
De ntal pla q ue f or ms as a c ol orless de p osit o n t he teet h a n d s o re q uires ‘stai ni n g’ wit h discl osi n g 
s ol uti o n pri or t o TPI assess me nt. T he discl osi n g s ol uti o n s u p plie d b y t he s p o ns or will be use d 
acc or di n g t o t he ma n ufact urer’s i nstr ucti o ns.  
•  At t he re q uest of t he s u bject, t o mi ni mize stai ni n g of t he li ps, t he cli nical assess or ma y 
a p pl y a t hi n la yer of petr ole u m jell y t o t he s u bject’s li ps as a barrier, pri or t o a p pl yi n g 
t he discl osi n g s ol uti o n.  
Care s h o ul d be ta ke n t o e ns ure n o petr ol e u m jell y c o m es i nt o c o ntact wit h t he la bial 
s urfaces of t he a nt eri or te et h as t his c o ul d i m pact T PI ass ess me nt f or t hes e s urfaces.  
•  S u bject ri nses wit h 1 0 m L ta p water f or 1 0 sec o n ds a n d e x pect orates t o re m o ve a n y f o o d 
de bris fr o m t he m o ut h.  
•  Discl osi n g s ol uti o n will be dis pe nse d i nt o a dis pe nsi n g c u p ( ~ 2. 5 ml) a n d s u bject ri nses 
f or 1 0 sec o n ds t o distri b ute t his s ol uti o n ar o u n d t heir m o ut h.  Ca re s h o ul d be ta ke n n ot 
t o disl o d ge t he pla q ue d uri n g t his pr ocess.  
S u bject ri nses wit h a n ot her 1 0 m L ta p wat er f or 1 0 sec o n ds a n d e x pect or ates t o re m o ve 
e x cess s ol uti o n fr o m t he m o ut h.  
8. 2  
S af et y a n d Ot h er A s s e s s m e nt s  
T he f oll o wi n g safet y assess me nts will be perf or me d b y a p pr o priatel y trai ne d staff/cli nical 
e x a mi ners, at t he ti mes a n d i n t he or der defi ne d i n t he St u d y Pr oce d ures  secti o n of t his pr ot oc ol. 
8. 2. 1  
Or al S oft Ti s s u e ( O S T) E x a mi n ati o n  
T he O S T e x a mi nati o n will be acc o m plis he d b y direct o bser vati o n a n d pal pati o n, usi n g 
retracti o n ai ds as a p pr o priate. It will i ncl u de e x a mi nati o n of t he la bial m uc osa (i ncl u di n g li ps), 
b uccal m uc os a, m uc o gi n gi val f ol ds, gi n gi val m u c osa, har d palate, s oft p alate, t o nsillar area, 
p har y n geal area, t o n g ue, s u bli n g ual area, s u b ma n di b ular area a n d s ali var y gla n ds. T h e res ults 
of t he e x a mi nati o n will be rec or de d i n t he e C R F as eit her ‘ n or m al’ or ‘a b n or mal’; t he details of 
a n y a b n or malities will be descri be d i n t he  e C R F.  
A n y O S T o bser vati o n t hat c ha n ges fr o m ‘ n or mal’ t o ‘a b n or mal’, or w ors e ns, fr o m Scree ni n g 
will be rec or de d as a n A E i n t he e C R F.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 6  of 5 8  
8. 2. 2  
Or al H ar d Ti s s u e ( O H T) E x a mi n ati o n  
T he O H T e x a mi nati o n will be acc o m plis he d b y direct o bser vati o n, usi n g retracti o n ai ds  as 
a p pr o priate. It will i de ntif y e n a mel irre g ularities, t o ot h fract ures, gr ossl y cari o us lesi o ns/ gr oss 
deca y, defecti ve/fa ult y rest orati o ns, direct & i n direct rest or ati o ns i ncl u di n g fi x e d/re m o val 
pr ost heses, n o n -cari o us t o ot h s urface l oss (a brasi o n, attri ti o n, a bfracti o n a n d er osi o n), a n y ot her 
har d tiss ue irre g ularities (e. g., h y p o/ h y per mi neralisati o n, decal cificati o n) a n d si g nifica nt t o ot h 
stai ni n g. C o n diti o ns will be liste d as ‘a bse nt’ or ‘ prese nt’; t h ose n ote d as ‘ prese nt’ will be 
descri be d i n t he e C R F . A n y O H T o bser vati o n t hat c ha n ges fr o m ‘a bse nt’ t o ‘ prese nt’, or 
w orse ns, fr o m Scree ni n g will be rec or de d as a n A E i n t he e C R F.  
T he prese n ce of i m pla nts, fi x e d or re m o va ble de nt ures, fi x e d or re m o va ble ort h o d o ntic 
braces/ b a n ds, fi x e d ort h o d o ntic retai ners , f ull cr o w ns or ve neers will be rec or de d, al o n g wit h 
e vi de nce of gr oss i ntra -oral ne glect or t he nee d f or e xte nsi ve de ntal t hera p y.    
8. 2. 3  
S a m pli n g a n d L a b or at or y Pr o c e d ur e s  
All sa m pli n g a n d la b orat or y pr oce d ures will be pr o vi de d i n se parat e w or k i nstr ucti o n 
d oc u me nt s. T he y  will be pre pare d b y PI or d esi g n ee a n d re vie we d b y Hale o n  a n d t he y will be 
a p pr o ve d b y PI or desi g n ee a n d C R S or desi g nee, a n d st ore d i n e D M S pri or t o Scree ni n g Visit.  
T he w or k i nstr ucti o n d oc u me nt s will c o ver , b ut n ot li mite d, t he f oll o wi n g ele me nts:  
•  Sa m ple c ollecti o n, preser vati o n pr ocess i n g a n d freez i n g at t he cli nical site  
•  D N A /R N A e xtracti o n, li brar y pre parati o n a n d se q ue nci n g  
•  Sa m ple destr ucti o n  
8. 2. 4  
Pr e g n a n c y T e sti n g  
F or H ale o n  st u dies i n w hic h n o dr u g is utilize d or st u dies of si n gle -us e mar kete d pr o d ucts t hat 
are classifie d as a n o n -m e dici nal pr o d uct i n t he mar ket w here t he testi n g is occ urri n g a n d t here 
is n o pre g n a nc y w ar ni n g o n la belli n g, a pre g na n c y test will n ot be re q uire d. 
Fe male s u bjects will pr o vi de ver bal c o nfir mati o n of pre g na n c y stat us at Scree ni n g ( Visit 1) a n d 
will be as ke d t o i nf or m st u d y staff i m me diatel y s h o ul d t his c ha n ge at a n y p oi nt d uri n g t he st u d y.  
Fe male s u bjects w h o are pre g na nt or i nte n di n g t o bec o me pre g n a nt d uri n g t he st u d y (self -
re p orte d) will be e x cl u de d. 
9  
A D V E R S E E V E N T A N D S E RI O U S A D V E R S E E V E N T S  
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
re p orti n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g 
u p A Es t hat are s eri o us, c o nsi dere d relate d t o t he st u d y pr o d uct  or t he st u d y, or t hat ca use d t he 
s u bject t o disc o nti n ue t he st u d y pr o d uct or st u d y. 
9. 1  
D efi niti o n of a n A d v er s e E v e nt ( A E)  
A n A E is a n y u nt o war d me dical occ urre nce i n a cli nical st u d y s u bject, te m p orall y ass oci ate d 
wit h t he use of a st u d y pr o d uct i ncl u di n g a n y w as h o ut or lea d -i n pr o d uct ( or me dical de vice), 
w het her or n ot c o nsi dere d relate d t o t he st u d y pr o d uct, i ncl u di n g a n y was h o ut or lea d -i n pr o d uct 
( or me dical d e vice). 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 7  of 5 8  
N O T E: A n A E ca n t heref ore b e a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la borat or y fi n di n g), s y m pt o m, or disease ( ne w or e x acer bate d) te m p orall y ass ociate d wit h t he 
use of a st u d y pr o d uct i n cl u di n g a n y was h o ut or l ea d -i n pr o d u ct ( or me dical de vice). 
E ve nts Meeti n g  t he A E Defi niti o n:   
•  A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts (e. g. , E C G, ra di ol o gical sca ns, vital si g n meas ure me nts), 
i ncl u di n g t h ose t hat w ors e n fr o m baseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he 
me dical a n d scie ntific j u d g me nt of t he i n v esti gat or (i.e., n ot relat e d t o pr o gressi o n of 
u n derl yi n g dise ase).  
•  E x acer bati o n of a c hr o ni c or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
•  Ne w c o n diti o ns detect e d or dia g n os e d after st u d y p r o d uct a d mi nistrati o n e ve n t h o u g h 
it ma y ha v e bee n prese nt bef ore t h e start of t he st u d y. 
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y 
pr o d uct or a c o nc o mita nt me dicati o n. O ver d ose per se will n ot be re p ort e d as a n 
A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self -har mi n g 
i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of se q uelae. 
•  " Lac k of effic ac y" or "fail ure of e x pecte d p har mac ol o gical acti o n" p er se will n ot be 
re p orte d as a n A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y ass ess me nts. 
H o we ver, t he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of 
effic ac y will be re p orte d as A E if t he y f ulfill t he d efi niti o n of a n A E.  
E ve nts N O T  meeti n g t he A E defi niti o n:  
•  A n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs (if a p plica ble) or ot her a b n or mal 
safet y assess me nts w hic h are ass ociat e d wit h t he u n derl yi n g diseas e, u nless j u d ge d b y 
t he i n vesti gat or t o b e m ore se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n.  
•  T he diseas e/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease/ dis or der b ei n g st u die d, u nless m ore se v ere t ha n e x pecte d f or t he s u bject’s 
c o n diti o n.  
•  Me d ical or s ur gic al pr oce d ure (e. g., e n d os c o p y, a p pe n d ect o m y) is n ot t he A E. T he 
c o n diti o n t hat lea ds t o t he pr oce d ure is a n A E (e. g. , a p pe n dicitis).  
•  Sit uati o ns w here a n u nt o war d 
me dical occ urre nce di d n ot o cc ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pi tal). 
•  A ntici pate d da y -t o-da y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) pres e nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w ors e n.  
9. 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)  
A Seri o us A d v erse E ve nt ( S A E) is a p artic ular cat e g or y of a n  a d verse e ve nt w here t he a d verse 
o utc o me is seri o us. If a n e ve nt is n ot a n A E p er defi niti o n a b o ve, t he n it ca n n ot be a n S A E e v e n 
if seri o us c o n diti o ns are met (e. g., h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n d er st u d y, 
deat h d ue t o pr o gressi o n o f disease). 
A seri o us a d verse e v e nt is a n y u nt o w ar d me dical occ urre nce at a n y d ose t h at:  
•  Res ults i n de at h  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 8  of 5 8  
•  Is lif e-t hre ate ni n g  
▪ T he ter m 'life -t hreate ni n g' i n t he defi niti o n of 's eri o us' refers t o a n e ve nt i n w hic h 
t he s u bject was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, 
w hic h h y p ot h eticall y mi g ht ha ve ca us e d deat h, if it were m or e se vere;  
•  Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n   
▪ I n ge neral, h os pitaliz ati o n si g nifies t hat t he s u bject has bee n detai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge n c y war d f or 
o bser vati o n a n d/ or treat me nt t hat 
w o ul d n ot ha ve bee n a p pr o priat e i n t he 
p h ysicia n’s office or o ut patie nt setti n g. 
C o m plicati o ns t hat occ ur d uri n g 
h os pita lizati o n are A Es. If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y 
ot her seri o us criteria, t he e ve nt is s eri o us. 
W he n i n d o u bt as t o 
w het her 
“ h os pitaliz ati o n” occ urre d, or was necessar y, t he A E s h o ul d be c o nsi dere d seri o us.  
▪ H os pitalizati o n f or el ecti ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m baseli ne is n ot c o nsi dere d a n A E. 
•  Res ults i n persiste nt or si g nific a nt dis a bilit y/i nc a p acit y  
▪ T he ter m disa bilit y me a ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal li fe f u ncti o ns. 
▪ T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica n ce s uc h as u nc o m plicate d hea dac he, na us ea, v o miti n g, diarr hea, i nfl ue nza, 
a n d acci de ntal tra u ma (e. g. , s prai ne d a n kle) w hic h ma y i nterfere wit h or pre ve nt 
e ver y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial disr u pti o n  
•  Res ults i n c o n ge nit al a n o m al y/ birt h defect  
•  Ot her sit u ati o ns:  
▪ Me dical or s cie ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het h er S A E 
re p orti n g is a p pr o priate i n ot her sit uati o ns s uc h as i m p orta nt me dical e v e nts t hat 
ma y n ot b e i m me diatel y life -t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut 
ma y j e o par dize t he s u bj ect or ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o n e of t he ot her o utc o mes liste d i n t he  a b o ve d efi niti o n. T hese e ve nts 
s h o ul d us uall y be c o nsi d ere d seri o us. 
▪ E x a m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve tr eat me nt 
i n a n e mer ge nc y r o o m or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias or 
c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of dr u g 
de pe n de n c y or dr u g a b us e.  
N ote:  Classificati o n of a n A E as ‘seri o us’ is base d o n t he o utc o me of t he e ve nt a n d is a fact or 
i n deter mi ni n g re p orti n g re q uire me nts. 
9. 3  
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n 
All A Es, a n d t heref ore all S A Es will be c ollecte d i m me diatel y after a s u bject pr o vi des c o nse nt  
t o partici pate i n t h e st u d y b y t h e c o m pleti o n (si g nat ure) of t he I C F a n d u ntil 5  da ys f oll o wi n g 
last a d mi nistrati o n of t he st u d y pr o d uct ( or last pr o ce d ure).  
Me dical occ urre nces t hat be ga n bef ore o btai ni n g i nf or me d c o nse nt will be rec or de d i n t he 
Me dical Hist or y/ C urre nt Me dical C o n diti o ns  secti o n of t he eC R F n ot t he A E secti o n.  
Details rec or de d b y t he s u bject o n a diar y or si milar d oc u me nt t hat  meet t he defi niti o n of a n A E 
m ust als o be disc usse d wit h t he s u bjects a n d tra ns cri be d i n t he A E secti o n of t he eC R F.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 9  of 5 8  
All S A Es will be rec or de d a n d re p ort e d t o t he s p o ns or or desi g nee i m me diatel y a n d u n der n o 
circ u msta nce s h o ul d t his e x cee d 2 4 h o urs. T he i n v esti gat or will s u b mit a n y u p date d S A E data 
t o t he s p o ns or wit hi n 2 4 h o urs of it bei n g a vaila bl e . 
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k A Es or S A Es after t he c o ncl usi o n of t he st u d y 
partici pati o n . H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at an y ti me 
after a s u bject has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be 
reas o na bl y relate d t o t he st u d y pr o d uct  or st u d y partici pati o n, t he i n vesti gat or m ust pr o m ptl y 
n otif y t he s p o ns or.  
9. 4  
R e p orti n g Pr o c e d ur e s  
T he i n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u m e nti n g a n d re p orti n g 
e ve nts t hat meet t he defi niti o n of a n A E a n d re mai n res p o nsi ble f or f oll o wi n g u p o n A Es t hat 
are seri o us, c o nsi dere d relate d t o t he st u d y pr o d uct(s), par tici p ati o n i n t he st u d y, or a st u d y 
pr oce d ure, or t hat c a use d t he s u bject t o disc o nti n ue t he st u d y pr o d uct or st u d y.  
S p o nta ne o us re p orti n g of a d verse e ve nts a n d t h ose elicite d b y as ki n g s u bjects t o res p o n d t o 
n o n -lea di n g s uc h as “ H o w d o y o u feel” will be assesse d a n d a n y A E’s rec or de d i n t he eC R F  
a n d re p ort e d a p pr o priatel y. 
T he i n vesti gat or ( or m e dicall y q ualifie d desi g nee) is t o re p ort all directl y o bser ve d A Es a n d all 
A Es s p o nta ne o usl y re p orte d b y t h e st u d y s u bjec t. I n a d diti o n, eac h st u d y s u bj ect will b e 
q uesti o ne d a b o ut A Es.  
Eac h A E is t o be assesse d t o deter mi ne if it meets t he criteria f or a S A E.  If a n S A E occ urs, 
e x pe dite d re p orti n g will f oll o w l ocal a n d i nter nati o nal re g ulati o ns, as a p pr o priate.  
W he n a n A E o cc urs, it is t he res p o nsi bilit y of t he i n vesti gat or ( or me dicall y q ualifie d desi g n ee) 
t o re vie w all d oc u me ntati o n (e. g., h os pital pr o gress n otes, la b orat or y, a n d dia g n ostics re p orts) 
relate d t o t he e v e nt. 
T he i n vesti gat or or site staff will t he n rec or d all  rele va nt i nf or m ati o n re gar di n g a n A E i n t he 
eC R F a n d all details r elati n g t o a n S A E i n t he pa p er S A E F or m pr o vi de d.  
It is n ot  acce pta ble f or t he i n vesti gat or ( or m e dicall y q ualifi e d desi g nee) t o se n d p h ot oc o pies 
of t he s u bject’s me dical rec or ds t o Hal e o n  i n lie u of c o m pleti o n of t he A E eC R F pa ge/ S A E 
f or m. 
T here ma y be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d b y 
Hale o n .  I n t his i nsta nce, all s u bject i de ntifiers, e x ce pt f or t he s u bject n u m ber, will be re d acte d 
o n t he c o pies o f t he me di cal rec or ds pri or t o s u b missi o n t o Hale o n . 
T he i n vesti gat or ( or me dicall y q ualifie d desi g nee) will atte m pt t o esta blis h a dia g n osis of t he 
e ve nt base d o n si g ns, s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n.  T he dia g n osis will be t he 
d oc u me nte d as  t he A E/ S A E were  k n o w n a n d n ot t he i n di vi d ual si g ns/s y m pt o ms. (e. g. u p per 
res pirat or y tr act i nfecti o n, seas o nal aller g y, etc. i nstea d of r u n n y n ose). 
A Es elicite d b y t h e i n vesti gat or ( or me dicall y q ualifie d desi g nee) i n a sta n dar d ma n ner at t he 
st u d y visits s h o ul d als o be rec or de d i n t he A E secti o n of t he eC R F a n d/ or usi n g t he S A E f or m 
(s u bject t o t h e cl assificati o n of t he A E). Care will be t a ke n n ot t o i ntr o d uce bi as w he n 
q uesti o ni n g a s u bject a b o ut a n y c ha n ges i n t heir healt h. O pe n -e n d e d a n d n o n -lea di n g ver bal 
q uesti o ni n g s h o ul d be us e d.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 0  of 5 8  
9. 4. 1  
R e p orti n g of a n A d v er s e E v e nt  
All A Es will be re p orte d o n t he A E pa ge of t he eC R F b y t h e i n vesti gat or or site staff.  It s h o ul d 
be n ote d t hat t he f or m f or c ollecti o n of S A E i nf or mati o n is n ot t he sa me as t he A E eC R F.  
W her e t he sa me data are c ollecte d, t he A E eC R F p a ge a n d t he S A E f or m m ust be c o m plete d i n 
a c o nsiste nt ma n ner.  F or e x a m ple, t he sa me A E t er m s h o ul d be use d o n b ot h.  A Es s h o ul d be 
re p orte d usi n g c o ncise m e dical ter mi n ol o g y o n t h e eC R F as well as o n t he f or m f or c ollecti o n 
of S A E i nf or mati o n.  
9. 4. 2  
R e p orti n g of a S eri o u s A d v er s e E v e nt  
I n a d diti o n t o rec or di n g t he details of eac h A E o n t he A E eC R F p a ge, a n S A E f or m s h o ul d b e 
c o m plete d, as f ull y as p ossi ble. Har d c o pies of t he ‘ pa p er’ S A E f or m will be pr o vi de d i n t h e 
in vesti gat or st u d y master file. Ori gi nal S A E f or ms will be retai ne d i n t he i n vesti gat or st u d y 
master file.  
It is esse ntial t o e nt er t he f oll o wi n g i nf or mati o n:  
•  Pr ot oc ol a n d s u bject i de ntifiers  
•  S u bject de m o gra p h y  
•  Descri pti o n of e v e nts, wit h dia g n osis if a vai la bl e 
•  I n v esti gat or o pi ni o n of relati o ns hi p t o st u d y pr o d uct ( or st u d y pr oce d ure, if a p pr o priate) 
•  Criteri o n f or seri o us ness.  
T he f oll o wi n g are desir a ble a n d are of partic ular rele va n ce f or i n vesti gat or a n d Hale o n  
assess me nt of t he S A E re p ort:  
•  Date of o nset of A E  
•  Date A E st o p pe d, if rele v a nt  
•  St u d y pr o d uct start dat e  
•  St u d y pr o d uct e n d d ate if rele va nt  
•  Acti o n ta ke n i n relati o n t o t he st u d y pr o d u ct  
•  O utc o me if k n o w n  
T he S A E f or m, c o m plete d as f ull y as p ossi ble, m ust be sca n ne d a n d e -maile d t o t he Case 
Ma na ge me nt  Gr o u p  mail b o x 
, wit h c o p y t o t he a p pr o pri ate 
St u d y M a na ger , wit h t he st u d y n u m ber a n d s u bject n u m ber i n t he s u bject li ne of t he e mail 
i m me di atel y a n d u n der n o circ u mst a nce s h o ul d t his e xcee d 2 4 h o urs after st u d y site 
pers o n nel lear n of t he e v e nt. T he i n vesti gat or will s u b mit a n y u p d ate d S A E data t o t he s p o ns or, 
i m me di atel y a n d u n der n o circ u mst a nce s h o ul d t his e xcee d 2 4 h o urs of it bei n g a v aila ble.  
T he i nitial re p ort will be f oll o we d u p wit h m ore i nf or mati o n as rele va nt, or as re q ueste d b y t h e 
st u d y ma na ger.  
T he St u d y  Ma n a ger will be res p o nsi ble f or f or war di n g t he S A E f or m t o ot h er Hale o n  p ers o n nel 
as a p pr o priat e.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
P P D

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 1  of 5 8  
9. 5  
E v al u ati n g A d v er s e E v e nt s  
9. 5. 1  
A s s e s s m e n t of I nt e n sit y 
T he i n vesti gat or or me dicall y q u alifie d desi g nee will ma ke a n assess me nt of i nte nsit y f or eac h 
A E re p orte d d uri n g t he st u d y a n d will assi g n it t o o ne of t he f oll o wi n g cate g ories:  
•  Mil d:  A n e ve nt t hat is easil y t olerat e d b y t he s u bject, ca usi n g mi ni mal disc o mf ort a n d 
n ot i nterferi n g wit h e ver y d a y acti vities.  
•  M o derate:  A n e ve nt t hat is s ufficie ntl y disc o mf orti n g t o i nterfere wit h n or m al e ver y da y 
acti vities  
•  Se vere:  A n e ve nt t hat pr e ve nts n or mal e ver y da y acti vities.  
N O T E: A n A E t hat is assesse d as se vere s h o ul d n ot be c o nf use d wit h a n S A E. Se vere is a 
cate g or y utilize d f or rati n g t he i nte nsit y of a n e v e nt; a n d b ot h n o n -seri o us A Es a n d S A Es ca n 
be assesse d as se vere. F or e x a m ple, a hea d ac he m a y b e se v ere (i nterferes si g nifica ntl y wit h t he 
s u bject's us u al f u ncti o n) b ut w o ul d n ot be classifi e d as seri o us u nless it met o ne of t he criteria 
f or S A Es, liste d a b o ve. A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least 1 of t he pre defi ne d 
o utc o mes as descri be d i n t he defi niti o n of a n S A E, N O T w he n it is rate d as se vere. 
9. 5. 2  
A s s e s s m e nt of C a u s alit y  
T he ca us alit y ass ess me nt is o ne of t he criteria use d w he n d eter mi ni n g re g ul at or y re p orti n g 
re q uire me nts.  
F or eac h A E (seri o us a n d n o n -seri o us), t he i n vesti gat or ( or me di call y q ualifie d desi g n ee) m ust  
pr o vi de a n assess me nt of ca usalit y o n t he A E eC R F pa ge a n d t he S A E f or m (s u bject t o t he 
classificati o n of t he A E). T he i n vesti gat or will als o d oc u me nt i n t he me dical n otes t hat he/s he 
has re vie we d t he A E a n d assesse d ca usalit y, w here a p plica ble.  
A “reas o na ble p ossi b ilit y” of a rel ati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal rel ati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be r ule d o ut. 
Ge nerall y, t he facts (e vi d e nce) or ar g u m e nts t o s u g gest a ca us al relati o ns hi p s h o ul d be pr o v i de d. 
T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p a n d will als o c o ns ult 
t he Pr o d uct I nf or mati o n (mar kete d pr o d ucts ), i n t he deter mi nati o n of his/ her assess me nt.  
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, ot her ris k fact ors, a n d 
t he te m p oral relati o ns hi p of t he e ve nt t o t he st u d y pr o d uct will be c o nsi dere d a n d i n vesti gat e d. 
F or eac h A E/ S A E, t h e i n vesti gat or m ust d oc u me nt i n t he me di cal n otes t hat he/s he has re vie we d 
t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y. 
T he i n vesti gat or’s assess me nt of ca usalit y m ust be pr o vi d e d f or all A Es (seri o us a n d n o n -
seri o us); t he i n vesti gat or m ust rec or d t he ca usal relati o ns hi p i n t he eC R F, as a p pr o priate, a n d 
re p ort s uc h a n assess me nt i n acc or da n ce wit h t he S A E re p orti n g re q uir e me nts if a p plica ble.  
T here ma y b e sit uati o ns w he n a n S A E has o cc urre d, a n d t he i n vesti gat or h as mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o Hale o n .  H o w e ver, it is ver y i m p ort a nt t h at t he 
i n vesti g at or al w a ys m a ke a n assessme nt of c a us alit y f or e ver y e ve nt pri or t o t he i niti al 
tr a ns missi o n of t he S A E d at a t o Hale o n . T h e i n vesti gat or ma y c ha n ge his/ her o pi ni o n of 
ca usalit y i n li g ht of f oll o w -u p i nf or mati o n a n d se n d a n S A E f oll o w -u p re p ort wit h t he u p date d 
ca usalit y assess me nt .   
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 2  of 5 8  
9. 6  
F oll o w -u p of A E s a n d S A E s   
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr oacti vel y f oll o w u p wit h eac h 
s u bject a n d pr o vi de f urt h er i nf or mati o n o n t he s u bject’s c o n diti o n. 
All A Es (seri o us a n d n o n -seri o us) will be f oll o we d u ntil res ol uti o n, u ntil t he c o n diti o n sta bilizes, 
u ntil t he e ve nt is ot her wise e x plai ne d, or u ntil t he s u bject is l ost t o f oll o w -u p.   
T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of  s u p ple me ntal 
meas ure me nts a n d/ or e v al uati o ns as ma y be i n dicate d or as re q uest e d b y Hale o n  t o el uci date as 
f ull y as p ossi ble t he nat ure a n d/ or ca usalit y of t h e A E. T his ma y i n cl u de a d diti o nal la b orat or y 
tests or i n vesti gati o ns, hist o pat h ol o gical e x a mi natio ns, or c o ns ultati o n wit h ot her healt h care 
pr ofessi o nals.  
Ne w or u p date d i nf or mati o n will be rec or de d o n t he A E eC R F pa ge a n d o n t he S A E f or m 
(s u bject t o t he classificati o n of t he A E). 
T he i n vesti gat or will s u b mit a n y u p date d S A E d ata t o Hale o n  wit hi n 2 4 h o urs of recei pt of t he 
i nf or mati o n. 
I n v esti gat ors are n ot o bli ge d t o acti vel y see k A Es i n f or mer s u bjects.  H o we v er, if t he 
i n vesti gat or le ar ns of a S A E, i ncl u di n g d eat h, at a n y ti me after a s u bject h as bee n dis c har ge d 
fr o m t he st u d y, a n d c o nsi ders t he e ve nt reas o n a bl y rel ate d t o t he st u d y pr o d uct or st u d y 
partici pati o n, t he i n vesti gat or will pr o m ptl y n otif y Hale o n  b y e maili n g t h e i nf or mati o n t o t he 
Case Ma na ge me nt Gr o u p  mail b o x at Hale o n  
, wit h c o p y t o 
t he a p pr o priat e St u d y Mana ger . 
T he i n vesti gat or will s u b mit a n y u p d ate d S A E dat a t o Hale o n  wit hi n t he desi g nat e d re p orti n g 
ti me fra mes. 
9. 7  
Wit h dr a w al D u e t o a n A d v er s e E v e nt  
Wit h dra wal d ue t o A Es s h o ul d be disti n g uis he d fr o m wit h dra wal d ue t o ot her ca us es, acc or di n g 
t o t he defi niti o n of a n A E n ote d earlier, a n d rec or de d o n t he a p pr o priate A E eC R F  pa ge.  
W he n a s u bject wit h dra ws beca use of a n S A E, t he S A E m ust be re p orte d i n ac c or da n ce wit h 
t he re p orti n g re q uire me nts defi ne d. 
9. 8  
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s 
Hale o n  has a le gal res p o nsi bilit y t o n otif y, as a p pr o priate, t he l ocal re g ul at or y a ut h orit y a n d 
ot her re g ulat or y a ut h orities a b o ut t he safet y of a pr o d uct u n der cl i nical i n vesti gati o n.  Pr o m pt 
n otificati o n of S A Es b y t he i n vesti gat or t o Hale o n  is esse ntial s o t hat le gal o bli gati o ns a n d 
et hical res p o nsi bilities t o war ds t he safet y of s u bjects are met.  
Hale o n  will c o m pl y wit h c o u ntr y s pecific re g ulat or y re q uire me nts re lati n g t o safet y re p orti n g 
t o t he re g ulat or y a ut h orit y, I R B/ E C a n d i n vesti gat ors.  
B ot h t he i n vesti gat or a n d t he s p o ns or will c o m pl y wit h all l ocal me dical de vice re p orti n g 
re q uire me nts  
I n v esti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse reacti o ns 
( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire m e nts a n d s p o ns or p olic y a n d f or war de d t o 
i n vesti gat ors as n ecessar y. 
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her s pecific 
safet y i nf or mati o n e. g., s u m mar y or listi n g of S A E fr o m t he s p o ns or will re vie w a n d t h e n file 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
P P D

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 3  of 5 8  
it al o n g wit h t he I n vesti gat or’s Br oc h ure i n t he i n vesti gat or st u d y master file, a n d will n otif y 
t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts. 
9. 9  
Pr e g n a n c y  
9. 9. 1  
Ti m e P eri o d f o r C oll e cti n g Pr e g n a n c y I nf or m ati o n 
Pre g n a nc y i nf or mati o n will be c ollecte d o n all pre g na nci es re p orte d w hile a fe male s u bject is 
partici pati n g i n t he st u d y fr o m t he si g ni n g of i nf or me d c o ns e nt u ntil 5 da ys aft er last 
a d mi nistrati o n of st u d y pr o d uct.  
9. 9. 2  
A cti o n  t o b e T a k e n if Pr e g n a n c y O c c ur s 
T he i n vesti gat or will rec or d pre g n a nc y i nf or m ati o n o n t he a p pr o priate f or m sca n a n d e -mail it 
t o t he Case Ma na ge m e nt Gr o u p mail b o x 
, wit h c o p y t o t h e 
a p pr o priate St u d y Ma na ger . Ori gi n al pre g n a nc y i nf or mati o n f or ms will be retai ne d i n t h e 
i n vesti gat or st u d y master file.  
T he s u bject will be f oll o we d t o deter mi ne t he o ut c o me of t he pre g n a nc y. I nf or mati o n o n t he 
stat us of t he m ot her a n d i nfa nt / ne o n ate (i ncl u di n g c o nc o mita nt me dicati o ns ta ke n b y t h e 
m ot her d uri n g t he pre g n a nc y) will be f or war de d b y t he i n vesti gat or t o t he Case Ma na ge me nt 
Gr o u p mail b o x at Hale o n  
, wit h c o p y t o t he a p pr o priat e   
St u d y M a na ger . Ge nerall y, f oll o w-u p will be n o l o n ger t ha n 6 t o 8 wee ks f oll o w i n g t h e 
esti mate d deli ver y date. A n y ter mi nati o n of t he pre g n a nc y will be re p orte d.  
W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E, a b n or mal pre g na n c y o utc o m es (e. g. , 
s p o nta ne o us a b orti o n, fet al deat h, still birt h, c o n ge nital a n o malies, ect o pic pre g na nc y) are, a n d 
s h o ul d be rec or de d as a n S A E. 
A n y fe male s u bject w h o bec o mes pre g na nt w hile partici pati n g will  be wit h dra w n.  
9. 1 0  
M e di c al D e vi c e I n ci d e nt s  
T he me dical de vice i n t his st u d y is t he t o ot h br us h ( Class 1 Me dical De vice) s u p plie d t o all 
s u bjects f or use at site a n d t hr o u g h o ut t he treat me nt peri o d.  Me dical de vices are b ei n g pr o vi de d 
b y H ale o n  f or us e i n t his st u d y. 
9. 1 0. 1  
D efi niti o n of a n I n ci d e nt  
A me dical de vic e i nci de nt is a n y malf u n cti o n or deteri or ati o n i n t he c haracteristics a n d/ or 
perf or ma n ce of a d e vice  as well as a n y i na de q uac y i n t he la beli n g or t he i nstr ucti o ns f or use 
w hic h, directl y or i n directl y, mi g ht lea d t o or mi g ht ha ve le d t o t he deat h of a s u bject/ user/ ot her 
pers o n or t o a seri o us det eri orati o n i n his/ her state of healt h.  
N ot all i nci de nts le a d t o deat h or seri o us deteri orati o n i n healt h. T he n o n occ urre nce of s uc h a 
res ult mi g ht h a ve bee n d u e t o ot her f ort u n ate circ u msta nces or t o t he i nter ve nti o n of healt h care 
pers o n nel.  
It is s ufficie nt t h at: 
A n i nci de nt ass ociate d wit h a de vice h a p pe ne d a n d  
•  T he i nci de nt was s uc h t hat, if it occ urre d a gai n, mi g ht lea d t o deat h or a seri o us 
deteri orati o n i n he alt h.  
•  A seri o us deteri orati o n i n state of healt h ca n i ncl u de a n y of t he f oll o wi n g:  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
P P D
P P D

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 4  of 5 8  
•  Lif e -t hreate ni n g ill ness 
•  Per ma ne nt i m pair me nt of b o d y f u ncti o n or per ma n e nt da ma ge t o b o d y str uct ure  
•  C o n diti o n necessitati n g me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he a b o ve  
•  Fetal distress, f etal deat h, or a n y c o n ge nital a b n or malit y or birt h defects  
E x a m ples of i nci de nts:  
•  A s u bject, user, care gi ver, or healt hcare pr ofessi o nal is i nj ure d as a res ult of a me dical 
de vice fail ure or its mis use.  
•  A s u bject’s st u d y treat me nt is i nterr u pte d or c o m pr o mise d b y a me di cal de vi ce fail ure.  
•  A mis dia g n osis d ue t o m e dical de vice fail ur e lea ds t o i na p pr o priate treat me nt.  
•  A s u bject’s healt h deteri orates d ue t o me dical de vice fail ure.  
9. 1 1  
R e p orti n g of I n ci d e nt s a n d M alf u n cti o n s  
All i nci de nts m ust be re p orte d t o  Hale o n  i m me di atel y a n d u n der n o circ u mst a nce s h o ul d 
t his e xcee d 2 4 h o urs of t he i n v esti gat or or desi g n ee bec o mi n g a ware of t h e sit uati o n.  
A n y me dical de vice i nci de nt occ urri n g d uri n g t he st u d y will be d oc u me nte d i n t he s u bject's 
me dical rec or ds, if i n acc or da nce wit h t he i n vesti gat or's n or mal cli nical practice, a n d o n t he 
a p pr o priate I nc i d e nt Re p ort F or m.  I n a d diti o n, f or i nci de nts f ulfilli n g t he defi niti o n of a n A E 
(seri o us a n d n o n-seri o us), t he a p pr o priate A E eC R F pa ge a n d S A E f or m will be c o m plete d a n d 
re p orte d as per t he A E a n d S A E re p orti n g secti o ns. 
T he I nci de nt Re p ort F or m will be  c o m plete d as t h or o u g hl y as p ossi ble a n d si g ne d b y t he 
i n vesti gat or bef ore tr a ns mittal t o Hale o n .  It is ver y i m p orta nt t hat t he i n vesti gat or d escri bes 
a n y c orrecti ve or re me di al acti o ns ta ke n t o pr e ve nt rec urre nce of t he i nci de nt.  
T he c o m plete d I nci d e nt R e p ort F or m s h o ul d be sca n ne d a n d e maile d t o  t he Case Ma na ge me nt 
Gr o u p  mail b o x 
, wit h c o p y t o t he a p pr o priate   St u d y 
Ma na ger , wit h t he st u d y n u m b er a n d s u bject n u m ber i n t he s u bject li ne of t he e mail 
i m me di atel y a n d u n der n o circ u mst a nce s h o ul d t his e xcee d 2 4 h o urs after st u d y site 
pers o n nel lear n of t he e ve nt. If t here is a n S A E, t he c o m plete d S A E f or m s h o ul d be se nt t o get her 
wit h t his re p ort f or m.  H o we ver, if a c o p y of t he S A E re p ort is se nt wit h t his f or m, t his d oes n ot 
re place t he pr oce d ure t o re p ort a n S A E.  T h e ori gi nal I nci de nt Re p ort F or m will be retai ne d i n 
t he i n vesti gat or st u d y master file.  
T he i nitial re p ort will be f oll o we d u p wit h m ore i nf or mati o n as rele va nt, or as re q ueste d b y t h e   
st u d y ma na ger. 
T he i n vesti gat or will f oll o w t he f oll o wi n g directi o ns re gar di n g t h e re p orti n g of a de vi ce fail ure 
( malf u ncti o n): 
•  N otif y H ale o n  i m me diatel y ( b y f oll o wi n g t he pr o cess descri be d a b o ve). 
•  Sc he d ule t he s u bject t o ret ur n t o t he site pr o m ptl y t o ret ur n t he faile d d e vice.  
•  Rec or d  a n y i nci d e nts o n t he eC R F a n d I n ci de nt Re p ort F or m f oll o wi n g i nstr ucti o ns 
gi ve n i n t he secti o n a b o v e.  
•  F or a n y i nci d e nt/ malf u ncti o n occ urri n g wit h a me dical de vice (i ncl u di n g t h ose t hat are 
part of c o m bi nati o n pr o d ucts) s u p plie d b y Hale o n , ret ur n t he faile d de vice t o t he s p o ns or 
as s o o n as p ossi ble, i ncl u di n g d oc u me nt ati o n of t he details of t he fail ure . 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
P P D

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 5  of 5 8  
•  F or a n y i nci d e nt /malf u ncti o n  occ urri n g wit h a me dical de vice  (i ncl u di n g t h ose t hat are 
part of c o m bi nati o n pr o d ucts)  s u p plie d b y t he I n vesti gat or site, re p ort t he i n ci de nt t o t he 
de vice ma n ufact ur er  a n d f oll o w t he ma n ufact urer i nstr ucti o ns f or t he ret ur n of t he faile d 
de vice  ( w hilst ke e pi n g H ale o n  i nf or me d). 
9. 1 2  
F oll o w -u p of M e di c al D e vi c e I n ci d e nt s  
Me dical d e vice i nci de nts i n v ol vi n g a n A E will be f oll o we d a n d re p orte d i n t he sa me ma n ner as 
ot her A Es. T his a p plies t o all s u bjects, i ncl u di n g t h ose w h o disc o nti n ue st u d y pr o d uct or are 
wit h dra w n fr o m t he st u d y.  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat f oll o w -u p i ncl u des a n y s u p ple me nt al 
i n vesti gati o ns as in dicate d t o el uci date t he nat ur e a n d/ or ca us alit y of t he i n ci de nt.  
Ne w or u p date d i nf or mati o n will be rec or de d o n t h e ori gi nall y c o m plete d I n ci de nt Re p ort f or m 
wit h all c ha n ges si g ne d a n d date d b y t he i n vesti gat or.  
9. 1 3  
R e g ul at or y R e p orti n g R e q uir e m e nt s f or M e d i c al D e vi c e I n ci d e nt s 
T o f ulfill re g ulat or y re p orti n g o bli gati o ns w orl d wi de, t he i n vesti gat or is res p o nsi ble f or t he 
detecti o n a n d d oc u me ntati o n of e ve nts meeti n g t h e defi niti o ns of i nci de nt or malf u ncti o n t hat 
occ ur d uri n g all peri o ds of t he st u d y i n w hic h t h e me dical de vice is us e d.  
T he i n vesti gat or will pr o m ptl y re p ort all i nci de nts occ urri n g wit h a n y me di cal de vice pr o vi de d 
f or use i n t he st u d y i n or der f or t h e s p o ns or t o f ulfill t he le gal res p o nsi bilit y t o n otif y a p pr o priate 
re g ulat or y a ut h orities a n d ot her e ntities a b o ut certai n safet y i nf or mati o n relati n g t o me dical 
de vices bei n g use d i n cli nical st u dies.  
T he i n vesti gat or, or res p o nsi ble pers o n acc or di n g t o l ocal re q uire me nts (e. g. , t he hea d of t h e 
me dical i nstit uti o n), will c o m pl y wit h t he a p plica bl e l ocal re g ulat or y re q uire me nts relati n g t o 
t he re p orti n g of i nci de nts t o t he I R B/I E C. 
1 0  
D A T A M A N A G E M E N T  
As use d i n t his pr ot oc ol, t he ter m C R F is u n derst o o d t o refer t o eit her a pa per f or m or a n 
electr o nic d ata rec or d or b ot h, de pe n di n g o n t h e d ata c ollecti o n met h o d.  
F or t his st u d y, s u bject data will be e ntere d i nt o a n electr o nic C R F (e C R F), usi n g a v ali date d 
s yste m. Dat a relati n g t o S A Es, pre g na nc y a n d i nci de nts will als o be c ollecte d o n pa per f or ms . 
T he i n vesti gat or is res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y 
p h ysicall y or electr o ni call y si g ni n g t he C R F.  
T he s o urce d oc u me nts w hic h c o ntai n t he s o urce of data rec or de d i n t he C R F s h o ul d  be s pecifi e d .  
T he C R F  a n d/or diar y  ca n be use d as a s o urce d o c u me nt at t he discreti o n of dat a ma na ge me nt.  
Eac h s u bject will be assi g ne d a n d i d e ntifie d b y a u ni q ue Scree ni n g S u bject N u m ber. A n y 
refere nce ma de t o a n i n di vi d ual s u bject wit hi n t he st u d y m ust be d o ne usi n g t heir u ni q ue 
Scree ni n g S u bject N u m b er.  
1 0. 1  
C a s e R e p ort F or m  
A C R F is a pri nte d, o pt ical, or electr o ni c d oc u me nt desi g ne d t o rec or d t he pr ot oc ol re q uire d 
i nf or mati o n t o be re p ort e d t o t he s p o ns or o n eac h trial s u bject. 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 6  of 5 8  
F or eac h s u bject w h o h as gi ve n i nf or me d c o nse nt/asse nt t he C R F m ust b e c o m plete d a n d si g ne d 
b y t he Pri nci pal I n v esti gat or  ( or a ut h orize d desi g nee) t o certif y t hat t he data are c o m plete a n d 
c orrect.  T he i n v esti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce dat a) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e C R F. 
Ma na ge me nt of cli nical data will be perf or me d i n acc or da nce wit h T hir d Part y B D M Ve n d or 
a p plica ble sta n d ar ds a n d data cle a ni n g pr oce d ures wit h o versi g ht b y Hal e o n  t o e ns ure i nte grit y 
of t he data, f or e x a m ple, t o re m o ve err ors a n d i nc o nsiste ncies i n t he data.  
T o pr otect t he pri vac y of s u bjects, n o Pers o nal I nf or mat i o n ( PI) (i ncl u di n g t he s u bject's n a me 
or i nitials or f ull birt h date) is t o be rec or de d i n t he C R F or as part of t h e q u er y te xt.  
All C R F pa ges s h o ul d be c o m plete d d uri n g a s u bject assess me nt w he n t he C R F h as b ee n 
desi g nat e d as t he s o urce.  Data t hat is s o urce d else w here s h o ul d be e ntere d i nt o t he C R F i n a n 
a gree d u p o n ti mefra me b et wee n t he I n vesti gat or a n d S p o ns or.   
Hale o n  will o btai n a n d retai n all C R Fs a n d ass ociate d st u d y data as a p plica bl e at t he c o m pleti o n 
of t he st u d y.  
1 0. 2  
D at a H a n dli n g  
D oc u me ntati o n o f all d ata ma na ge me nt acti vities s h o ul d all o w ste p-b y -ste p retr os p ecti ve 
assess me nt of data q u alit y a n d st u d y p erf or m a nce.  
A n y c h a n ges or c orrecti o ns t o data will be perf or me d i n t he Electr o nic Data Ca pt ure ( E D C) 
S yste m, a n d it will i ncl u d e rati o nale f or c ha n ges. T he E D C s yste m has a n a u dit trail, w hic h will 
pr o vi de a c o m plete rec or d of t he c ha n ges a n d c orrecti o ns e n d orse d b y t he I n vesti gat or.  
A d verse e v e nts will be c o de d usi n g Me di cal Di cti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
a n d a n y c o n c o mita nt me dic ati o ns ter ms (if a p plica ble) usi n g a n i nter nal v ali date d me dicati o n 
dicti o nar y.   
1 0. 2. 1  
D at a Q u eri e s  
Pr o gra m me d e dit c hec ks will be ge n erat e d a ut o maticall y, as t he d ata are bei n g e nt ere d i nt o t he 
s yste m. Re p orts a n d listi n gs o n t he eC R F data will als o be r u n, i n  a d diti o n t o t he q ueries alr ea d y 
pr o gra m me d a n d ge n erate d b y t he s yste m, t o raise ma n ual q ueries as nee d e d f or site 
clarificati o n or c orrecti o n. T he Cli nical Dicti o nar y De vel o p me nt a n d Ma n a ge me nt Gr o u p will 
raise q u eries as n ee d e d o n safet y data t o c o de t he ter ms ( A Es a n d Dr u gs or c o nc o mita nt 
me dicati o n) a p pr o priatel y.  
T he st u d y m o nit or will perf or m o n g oi n g re vie w t he of t he C R Fs i n acc or da n ce wit h t he 
m o nit ori n g pla n, t o c o nfir m t hat data e ntere d i nt o t he C R F b y a ut h orize d site pers o n nel are 
acc urate, c o m plet e, a n d verifia ble fr o m s o urce d oc u me nts; t hat t he safet y a n d ri g hts of 
partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d uct e d i n acc or da n ce wit h t he 
c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y a gree m e nts, I C H G C P, a n d all a p plic a bl e 
re g ulat or y re q uire me nts. 
A n y q u eries will be ge nerate d i n t he E D C S yste m t o t he I n vesti gat or or desi g nee, e na bli n g t he 
err ors t o be a d dress e d i n parallel wit h Data Ma n a ge m e nt re vie w. T h e st u d y m o nit or ca n als o 
r u n re p orts a n d listi n gs o n t he C R Fs, t o raise ma n ual q ueries as nee d e d f or site clarificati o n or 
c orrecti o n.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 7  of 5 8  
1 0. 2. 2  
E xt er n al d at a  
E xter nal d ata are s u bj ect data o btai n e d e xter nall y t o t he C R F. T hese data are ge nerate d fr o m  
la b orat or y i nstr u me nts, c o m p uters or ot her s o urces a n d t he n tra nscri be d i nt o a file a n d f or mat 
a gree d u p o n b y Hal e o n t o i de ntif y t he s u bject a n d ti me p oi nt refere nce d i n t he C R F a n d/ or 
pr ot oc ol. Rec o nciliati o n will be perf or me d bet wee n t he sa m ples c ollecte d a n d t he e xter nal data  
t o e ns ure s u bject a n d ti m e p oi nt refere nce d i n t he C R F a n d/ or pr ot oc ol.   
1 1  
S T A TI S TI C A L C O N SI D E R A TI O N S A N D D A T A A N A L Y S E S  
1 1. 1  
S a m pl e Si z e D et er mi n ati o n  
S ufficie nt s u bjects will be scree ne d t o e ns ure a p pr o xi matel y a t otal of 5 5  s u bjects are 
ra n d o miz e d t o st u d y pr o d uct a n d 5 0  e val u a ble s u bjects c o m plete t he e ntire st u d y  
(a p pr o xi matel y 2 5 s u bjects per pr o d uct ar m). N o f or mal sa m ple siz e h as bee n perf or me d as p er 
nat ure of t his st u d y ( met h o d ol o g y de v el o p me nt), h o we ver  b ase d o n a pre vi o us i n sit u cli nical 
st u d y e val u ati n g t he m o d e of acti o n of a sta n n o us fl u ori de t o ot h paste usi n g 1 6 S se q ue nci n g a n d 
meta -tra nscri pt o mics i n 1 3 s u bjects, t his was c o nsi dere d a s mall sa m ple siz e a n d o ne of t he 
reas o ns f or l o w er precisi o n i n ma ki n g i nf ere n ce re gar di n g a m plic o n a n d ge ne e x pressi o n data 
(G u m ber et al. 2 0 2 2 ). Recr uiti n g m or e p artici p a nts w o ul d p ote ntiall y re d uce t his ris k a n d 
t heref ore N = 5 0 is c o nsi dere d s ufficie nt t o pr o vi de relia ble esti mates of perf or ma n ce f or t h e 
p ur p oses of t his st u d y a n d t o ai d i n t he desi g n of f ut ure cli nical st u dies.  
1 1. 2  
P o p ul ati o n s  for A n al y si s  
1 1. 2. 1  
D efi niti o n s of A n al y si s P o p ul ati o n s  
T he Safet y p o p ulati o n will i ncl u de all ra n d o mize d s u bjects w h o c o m plete at least o ne use of 
st u d y pr o d uct. T his p o p ulati o n will be base d o n t he st u d y pr o d uct t he s u bject recei v e d. All 
safet y assess me nts will b e base d o n t his a nal ysis p o p ulati o n.  
A n e val u a ble micr o bi o me res ult will be 1) s uffici e nt D N A/ R N A e xtracte d fr o m t he sa m ples, 
a n d 2) after se q u e nci n g, at least 5 0 0 0 1 6 S r R N A a m plic o n rea ds per sa m ple f or 1 6 S a nal ysis, 
a n d 3 0 milli o n s h ot g u n rea ds p er s a m ple f or t he meta ge n o mic/ meta -tr a ns cri pt o mics a nal yses 
(Secti o n 9. 2. 3 ). 
T he  Micr o bi o me  p o p ulati o n will i ncl u de all ra n d o mize d s u bjects w h o c o m plete at least o ne us e 
of st u d y pr o d uct a n d wit h a n e val ua bl e micr o bi o me res ult  (at least o ne area at b ot h baseli ne a n d 
Wee k 6) . T his p o p ulati o n  will be base d o n t he st u d y pr o d uct t o w hi c h t he s u bject was 
ra n d o mize d.  
T he Per Pr ot o c ol ( P P) p o p ulati o n is defi ne d as all s u bjects i n t he micr o b i o me p o p ulati o n w h o 
are c o nsi d ere d u n affecte d b y pr ot o c ol de viati o ns.  
Ot her  e x cl usi o n of a n y d ata fr o m t he a nal yses will be deter mi ne d d uri n g a Bli n d Data Re vie w 
( B D R) M eeti n g pri or t o data base l oc k.  
A n y reas o ns f or e x cl usi o n fr o m a n a n al ysis p o p ul ati o n will be liste d, if a p plica b le.  
1 1. 3  
St ati sti c al  A n al y s e s  
A d diti o nal details of t he pr o p ose d statistical a nal ys es will be d oc u me nte d i n t he statistical 
a nal ysis pla n ( S A P) a n d t he  micr o bi o me  a nal ysis pla n, w hic h will be writte n f oll o wi n g 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 8  of 5 8  
fi nalizati o n of t he pr ot oc ol a n d pri or t o st u d y u n bli n di n g/a nal ysis (as a p pr o priate).  T his secti o n 
is a s u m mar y of t he pla n n e d bi oi nf or matics data a n al yses f or micr o bial a n d f u ncti o nal pr ofili n g . 
I n b ot h micr o bi o me a n d f u ncti o nal pr o fili n g a nal yses t he baseli ne sa m ples will be e val uate d t o 
c o nfir m h o m o g e neit y of t he p o p ulati o n . 
1 1. 3. 1  
Mi cr o bi o m e  Pr ofili n g (1 6 S r R N A g e n e a m pli c o n a n al y si s)  
Eac h e n d p oi nt c o m paris o ns s h o w n as p ri mar y a n d ex pl orat or y e n d p oi nt s ( o verall a n d b y 
differe nt areas of t h e m o ut h)  f or micr o bio me  pr ofili n g  i n Secti o n  3  will i ncl u de t he f oll o wi n g 4 
t y pes of a nal yses: 
1.  Ta x o n o m y assi g n me nt  
a. Se q ue nce q u alit y filteri n g, pair m er gi n g a n d d e n oisi n g  
b.  Assi g n rea ds t o s pecies le vel ta x o n o m y base d o n se q ue nce ali g n me nt a gai nst H O M D 
Refse q data b ase  
c. I nteracti ve bar c hart dis pla yi n g ta x o n o m y pr ofiles f or eac h sa m ple 
2.  Al p ha di versit y c o m paris o n  ( di versit y wit hi n sa m ples) 
a. Rarefacti o n pl ots f or i n di vi d ual sa m ples or sa m ple gr o u ps  
i. O bser ve d s p ecies  
ii. S ha n n o n i n de x  
iii. Si m ps o n i n de x  
b.  B o x pl ot re prese n tati o n of al p ha-di versit y f or eac h e n d p oi nt c o m paris o n  
i. O bser ve d s p ecies  
ii. S ha n n o n i n de x  
iii. Si m ps o n i n de x  
c. Gr o u p si g nifi ca nce of Al p ha -di versit y i n dices  
N o n -para metric Kr us kal Wallis H test will be p erf or me d t o deter mi ne w het her a n y of 
t he 3 al p ha-di versit y i n di c es meas ure d has si g nifi ca nt differe n ce b et wee n t h e gr o u ps or 
ti me p oi nts ( wit hi n treat me nt) bei n g c o m pare d. 
3.  Beta di versit y c o m paris o n  ( di versit y b et wee n s a m ples) 
a. Beta di versit y will be me as ure d f or eac h e n d p oi nt gr o u ps wit h t w o differe n ce i n dices:  
i. Bra y -C ur tis dissi milarit y  
ii. Aitc his o n dista nce ( E u cli dea n dista nce calc ulate d b y ce nter -l o g rati o tr a nsf or me d 
c o u nt data)  
b.  B ot h Bra y -C urtis a n d Aitc his o n i n dices will be dis pla ye d wit h t w o t y pes of or di nati o n 
pl ots:  
i. N M D S: N o n -metric m ulti -di me nsi o nal scali n g  
ii. P C o A: P ri nci pal C o or di nate A nal ysis 
c. Gr o u p si g nifi ca nce of bet a -di versit y i n dices  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 9  of 5 8  
P E R M A N O V A ( per m utati o nal m ulti variate a nal ysis of varia nce) will be perf or me d t o 
deter mi ne w h et her t h e beta di versit y bet w ee n t he gr o u ps or ti me p oi nts ( wit hi n 
treat me nt) is si g nifi ca ntl y differe nt. 
4.  Differe ntial a b u n da n ce a nal ysis  
a. A N C O M -B C 2 ( A n al ysis of C o m p ositi o ns of 
Micr o bi o mes wit h Bias C orrecti o n, 
versi o n 2) will be use d t o i de ntif y s pecies t hat are differe ntiall y a b u n da nt bet wee n 
c o m pare d gr o u ps. S peci es t hat are differe ntiall y a b u n da nt bet wee n gr o u ps will ha ve p -
val ues < 0. 0 5 after a dj ust e d false disc o ver y rate ( F D R)  
b.  Differe nt a b u n da nt s p eci es will als o be i de ntifie d b y a ra n k -base d a p pr oac h: L Ef Se 
( Li n ear Discri mi na nt A nal ysis Effect Size), w hic h uses ra n k-bas e d Kr us kal -Wallis 
( K W) s u m-ra n k test t o detect feat ur es wit h si g nifica nt differe ntial (relati ve) a b u n da nce 
wit h res pect t o t he cl ass of i nterest . 
1 1. 3. 2  
F u n cti o n al Pr ofili n g  
T he meta ge n o mic/ meta -tra nscri pt o mics a n al yses as s h o w n i n e x pl orat or y e n d p oi nts  ( o verall 
a n d b y differe nt areas of t he m o ut h)  i n Secti o n 3  will be p erf or m e d wit h t he  
H u b 
pi peli ne, t hat i ncl u des:  
1.  C haracterizati o n of f u ncti o nal p ote ntial of t he micr o bi o me c o m m u nit y usi n g
Pat h wa ys, E nz y me C o m miss i o n ( E C), Pfa m, C A Z y a n d G o Ter ms. 
2.  Strai n -le vel ta x o n o mic classificati o n wit h p h yl o ge netic i nfere nce of n o v el or ga nis ms 
mea ni n g  t hat if a n o vel strai n is i de ntifie d, t he pi peli ne will call its nearest nei g h b or a n d 
i nf or m users h o w t o i nter pret t he strai n-le v el statistics.  
3.  M ulti -ki n g d o m I D & c haract erizati o n wit h o ne si n gle pi p eli ne: Bacteria, Vir uses, 
P ha ges, F u n gi, Pr otists, Bact erial M A G’s, A M R ge n es & Vir ule nce Fact ors.  
4.  Precisi o n Filters f or c o nfi de nce –  a d va nce d mac hi ne lear ni n g filters f or differe ntiat i n g 
si g nal fr o m n oise, m ea ni n g t hat t he res ults are l ess i m pacte d b y false p ositi ves.  
5.  Sa m ple -t y pe a g n ostic a n al ysis.  
1 1. 3. 3  
S af et y A n al y s e s  
A Es will be re gar de d as ‘treat me nt e mer ge nt’ if t he y occ ur o n or after t he first st u d y pr o d uct 
use at Visit 2 ; eac h A E will be cate g orize d as oral or n o n-oral b y t he i n vesti gat or, or me dicall y 
q ualifie d desi g nee. A Es will be re vie we d b y t he s p o ns or’s C R S pri or t o data bas e l oc k a n d 
u n bli n di n g a n d c o d e d usi n g t he M e d D R A.  
A listi n g of all A Es will be prese nte d f or all s u bjects  i n t he Safet y p o p ulati o n, wit h t he f oll o wi n g 
A Es s u m maries ( n u m ber of disti nct A Es a n d fre q ue n c y/ pr o p orti o n of s u bjects affecte d) 
prese nte d b y  tr eat me nt gr o u p a n d o verall:  
•  Treat me nt e mer ge nt A Es  ( o verall oral/ n o n oral, seri o us, treat me nt rel ate d )  
•  Treat m e nt e mer ge nt A Es b y S yste m Or ga n Class ( S O C) a n d Preferre d T er m ( P T)  
1 1. 3. 4  
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s  
De m o gra p hic a n d Baseli ne c haracteristics will be s u m marize d b y tr eat me nt gr o u p f or t he Safet y 
a n d micr o bi o me  p o p ulati o ns, a n d f or t he P P p o p ulati o n if a P P a nal ysis is p erf or me d.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
C CI
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 0  of 5 8  
Cate g orical varia bl es (s uc h as se x, race  a n d et h nicit y) will be s u m marize d b y t he n u m ber a n d 
perce nt a ge of s u bjects wit h eac h rele va nt c haract eristic i n eac h treat me nt gr o u p. C o nti n u o us 
varia bles s u c h as (a ge) will be s u m m arize d b y mea n, S D, me di a n, mi ni m u m a n d ma xi m u m 
val ues i n eac h treat me nt gr o u p.  
1 1. 3. 5  
St u d y Pr o d u ct C o m pli a n c e a n d U s e of Ot h er T h er a pi e s.  
1 1. 3. 5. 1  St u d y Pr o d u ct C o m pli a n c e  
C o m plia nce wit h pr o d uct use ( n u m b er of br us hi n gs) will be liste d f or t he micr o bi o m e  
p o p ulati o n at eac h visit, a n d c u m ulati vel y f or t h e o verall treat me nt peri o d (f or m ost s u bjects 
t his will be 6  wee ks) b y treat me nt gr o u p.  
N u m ber of e x pecte d br us hi n gs at Visit 3  = 2 × N u m ber of da ys b et wee n Visit 3  a n d V 2  
N u m ber of act ual br us hi n gs at Vis it 3  =  
( N u m ber of e x pecte d br us hi n gs) –  ( N u m ber of 
misse d br us hi n gs) + ( N u m ber of a d diti o nal 
br us hi n gs) bet wee n Visit 3  a n d V 2  
% C o m pli a nce at ‘ Visit 3 ’ =       ( N u m ber of act u al br us hi n gs bet w ee n Visit 3  & V 2)      x 1 0 0  
       ( N u m ber of e x pecte d br us hin gs bet w ee n V 3  & V 2)  
 
1 1. 3. 5. 2  Pri or a n d C o n c o mit a nt M e di c ati o n s  
Pri or me dicati o ns, c o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies ta ke n d uri n g t he 
st u d y will be liste d f or t h e Safet y p o p ulati o n. 
1 1. 3. 6  
H a n dli n g of Dr o p o ut s a n d Mi s si n g D at a  
S u bjects w h o wit h dra w fr o m t he st u d y earl y will be i ncl u de d i n t he st u d y a nal ysis u p t o t h e 
p oi nt of wit h dra wal. S u bjects w h o wit h dra w after ra n d o mi z ati o n will n ot be re pl ace d. N o dat a 
will be i m p ute d i n t he case of dr o p o uts or missi n g data.   
1 1. 3. 7  
I nt eri m A n al y si s  
N o i nteri m a nal ysis is pla n ne d f or t his st u d y .  
1 2  
S T U D Y G O V E R N A N C E C O N SI D E R A TI O N S  
1 2. 1  
Q u alit y C o ntr ol  
I n acc or da n ce wit h a p pli ca ble re g ulati o ns i ncl u di n g G C P, a n d Hale o n  pr oce d ures, Hale o n  or 
desi g nee (i. e. , t hir d-part y ve n d or) m o nit ors will c o ntact t he site pri or t o t he start of t he st u d y t o 
re vie w wit h t he site staff t he pr ot oc ol, st u d y re q uire me nts, a n d t h eir res p o nsi bilities t o satisf y 
re g ulat or y, et hical, a n d H ale o n  re q uir e me nts. 
W he n re vie wi n g data c ollecti o n pr oce d ures, t he disc ussi o n 
will i ncl u de i de ntificati o n, 
a gree m e nt a n d d oc u me ntati o n of data ite ms f or w hic h t he eC R F will ser ve as t he s o urce 
d oc u me nt.  
Hale o n  or desi g n ee will m o nit or t he st u d y a n d site acti vit y t o v erif y t hat t h e:  
•  Data are a ut he ntic, acc urate, a n d c o m plete.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 1  of 5 8  
•  Safet y a n d ri g hts of s u bjects are b ei n g pr otecte d.  
•  St u d y is c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her 
st u d y a gree me nts, G C P, a n d all a p plica ble re g ulat or y re q uire m e nts.  
T he e xte nt a n d n at ure of m o nit ori n g will b e des cri be d i n a writte n m o nit ori n g pl a n o n fi le at 
Hale o n . T he i n vesti gat or ( or desi g nee) a grees t o all o w t he m o nit or direct access t o all rele va nt 
d oc u me nts a n d a grees t o c o -o perate wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n 
t he c o urse of t h ese m o nit ori n g visits are res ol ve d. 
1 2. 2  
Q u alit y A s s ur a n c e  
T o e ns ure c o m plia nce wit h G C P a n d all a p plica ble re g ulat or y re q uire me nts, Hale o n  ma y 
c o n d uct a q ualit y ass ur a nce assess me nt a n d/ or a u dit of t he site rec or ds, a n d t he re g ulat or y 
a ge ncies ma y c o n d u ct a re g ulat or y i ns pe cti o n at a n y ti me d uri n g or aft er c o m pleti o n of t he 
st u d y.  
I n t he e v e nt of a n assess me nt, a u dit or i ns pecti o n, t he i n vesti gat or (a n d i nstit uti o n) m ust a gree 
t o gra nt t he a d vis or(s), a u dit or(s) a n d i ns pect or(s) direct access t o all rele va nt d oc u me nts a n d 
t o all ocate t heir ti me a n d t he ti me of t heir staff t o disc uss t he c o n d uct of t he st u d y, a n y 
fi n di n gs/rele v a nt iss ues a n d t o i m ple me nt a n y c orrecti ve a n d/ or pre ve ntati v e acti o ns t o a d dress 
a n y fi n di n gs/iss ues i de ntifie d.  
T he i n vesti gat or(s) will n otif y H ale o n  or its a ge nts i m me diatel y of a n y re g ulat or y i ns p ecti o n 
n otificati o n i n relati o n t o t he st u d y. F urt her m ore, t he i n vesti gat or will c o o perate wit h Hale o n  
or its a ge nts t o pre pare t he st u d y site f or t he i ns pecti o n a n d will all o w Hale o n  or its a ge nt, 
w he ne ver f easi ble, t o be prese nt d uri n g t he i ns pe cti o n. T he i n vesti gat or will pr o m ptl y a p pl y 
c o pies of t he i ns pe cti o n fi n di n g t o Hale o n  or its a ge nt. Bef ore res p o nse s u b missi o n t o t h e 
re g ulat or y a ut h orit y, t he i n vesti gat or will pr o vi de Hale o n  or its a ge nts wit h a n o p p ort u nit y t o 
re vie w a n d c o m me nt o n r es p o nses t o a n y s uc h fi n di n gs.  
T he s p o ns or will be a vail a ble t o hel p i n vesti gat ors pre pare f or a n i ns pecti o n.  
1 2. 3  
R e g ul at or y a n d Et hi c al C o n si d er ati o n s  
1 2. 3. 1  
I n stit uti o n al R e vi e w B o ar d/ Et hi c s C o m mitt e e  
It is t he res p o nsi bilit y of t he i n vesti gat or t o ha v e pr os pecti ve a p pr o val of t he st u d y pr ot o c ol, 
pr ot oc ol a me n d me nts,  i nf or me d c o nse nt, i n vesti gat or br oc h ure/safet y state m e nt (i ncl u di n g a n y 
u p dates) a n d ot her rele v a nt d oc u me nts, e. g. , recr uit me nt a d vertise me nts, if a p plica ble, fro m t he 
I R B/ E C.  All c orres p o n de nce wit h t he I R B/ E C s h o ul d be retai ne d i n t he i n vesti gat or file.  
C o pies of I R B/ E C a p pr o vals s h o ul d be f or war de d t o Hale o n  pri or t o t he i nitiati o n of t he st u d y, 
a n d als o w he n s u bse q u e nt a me n d me nts t o t he pr ot oc ol are ma de.  
T h e o nl y circ u msta n ce i n w hic h a n a me n d me nt ma y b e i nitiate d pri or t o I R B/ E C a p pr o val is 
w here t h e c h a n ge is ne cessar y t o eli mi nate a p p are nt i m me diate hazar ds t o t he s u bjects.  I n t hat 
e ve nt, t he i n vesti gat or m ust n otif y t he I R B/ E C a n d Hale o n  i n writi n g i m mediatel y after t h e 
i m ple me ntati o n. 
1 2. 3. 2  
Et hi c al C o n d u ct of t h e St u d y  
T he st u d y will be c o n d ucte d i n acc or da n ce wit h t he pr ot oc ol a n d le gal a n d re g ulat or y 
re q uire me nts, as w ell as t he ge n eral pri nci ples set f ort h i n t he I nter n ati o nal Et hical G ui deli nes 
f or Bi o me di cal Researc h I n v ol vi n g H u m a n S u bjects ( C o u ncil f or I nt er nati o nal Or ga nizati o ns 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 2  of 5 8  
of 
Me dical Scie n ces 2 0 0 2), I nter nati o nal Et hical G ui deli nes f or Healt h -Relate d Researc h 
I n v ol vi n g H u m a ns ( C o u ncil f or I nter nati o nal Or ga nizati o ns of 
Me dical Scie nces, 2 0 1 6), 
g u i deli nes f or G C P (I C H 1 9 9 6 a n d re visi o n 2), a n d t he Declarati o n of Helsi n ki ( W orl d Me dical 
Ass ociati o n 2 0 1 3).  
I n a d diti o n, t he st u d y will be c o n d u cte d i n acc or da nce wit h t he pr ot oc ol, t he I C H g ui deli ne o n 
G C P, a n d a p plica ble l ocal re g ul at or y re q uire me nts a n d la ws.  
1 2. 3. 3  
S u bj e ct I nf or m ati o n a n d C o n s e nt  
All parties will e ns ure pr otecti o n of s u bj ect p ers o nal data a n d will n ot i ncl u de s u bject na mes or 
ot her i de ntifia ble data i n a n y re p orts, p u blicati o ns, or ot her discl os ures, e x ce pt w here re q uire d 
b y la ws.  
W he n st u d y d ata are c o m pile d f or tra nsfer t o Hale o n a n d ot her a ut h orize d parties, s u bject na mes, 
a d dresses, a n d ot her i de ntifia ble data will be re place d b y n u meri cal c o d es base d o n a n u m b eri n g 
s yste m pr o vi de d b y Hale o n  i n or der t o de-i de ntif y st u d y s u bjects.   
T he  st u d y site will mai nt ai n a c o nfi de ntial list of s u bjects w h o partici pate d i n t he st u d y, li n ki n g 
eac h s u bject’s n u merical c o de t o his or her act ual i de ntit y.  I n case of data tr a nsfer, Hale o n  will 
mai ntai n hi g h sta n dar ds of c o nfi de ntialit y a n d pr otecti o n o f s u bjects’ pers o nal data c o nsiste nt 
wit h a p plica ble pri va c y la ws.  
T he  i nf or m e d c o ns e nt d oc u me nts m ust be i n c o m plia nce wit h I C H G C P, l ocal re g ulat or y 
re q uire me nts, a n d l e gal r e q uire me nts, i ncl u di n g a p plica ble pri vac y l a ws. 
T he  i nf or me d c o nse nt d oc u me nts u se d d uri n g t he i nf or me d c o nse nt pr ocess m ust be re vie we d 
a n d a p pr o ve d b y t h e s p o ns or, a p pr o ve d b y t he I R B/ E C bef ore use, a n d a vail a ble f or i ns pe cti o n.  
T he i n vesti gat or m ust e ns ure t hat eac h st u d y s u bj ect,  is f ull y i nf or me d a b o ut t he nat ur e a n d 
o bjecti ves o f t he st u d y a n d p ossi ble ris ks ass ociate d wit h partici pati o n.  
1 2. 3. 4  
S u bj e ct R e cr uit m e nt  
A d vertise me nts a p pr o ve d b y I R Bs/ E Cs a n d i n v esti gat or data bas es ma y be use d as recr uit me nt 
pr oce d ures.   Use of et hics c o m mittee a p pr o ve d, ge neric, prescree ni n g q uesti o n naire  t o assess 
basic s u bject c haracteristics t o deter mi ne ge neral eli gi bilit y f or t his st u d y is all o we d.   T his 
ge n eric q uesti o n naire ma y b e use d b y sites as a p h o ne scri pt a n d/ or t o re vie w i nter nal d ata bas es 
t o i de ntif y s u bjects.   
Hale o n  will ha v e a n o p p ort u n it y t o re vie w a n d a p pr o ve t he c o nte nt of a n y st u d y recr uit me nt 
materials direct e d t o p ote ntial st u d y s u bj ects bef ore s uc h materi als are us e d.  
1 2. 3. 5  
R e p orti n g of S af et y I s s u e s a n d S eri o u s Br e a c h e s of t h e Pr ot o c ol or 
I C H G C P  
Wit hi n Hale o n  a seri o us breac h is defi ne d as a breac h li kel y t o affect t o a si g nifica nt de gree t he 
safet y a n d ri g hts of a s u bject or t he relia bilit y a n d r o b ust ness of t he data ge nerate d i n Hale o n  -
s p o ns ore d h u ma n s u bject researc h st u dies.  
I n t he e ve nt of a n y pr o hi biti on or restricti o n i m p ose d (i.e., cli nical h ol d) b y a n a p plica bl e 
c o m pete nt a ut h orit y i n a n y area of t he w orl d, or if t he i n vesti gat or is a ware of a n y n e w 
i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be n efits a n d ris ks of t he i n vesti gati o nal 
pr o d uc t, Hale o n  s h o ul d b e i nf or me d i m me diatel y.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 3  of 5 8  
I n a d diti o n, t he i n vesti gat or will i nf or m Hale o n  i m me diatel y of a n y ur ge nt safet y meas ures 
ta ke n b y t h e i n vesti gat or t o pr otect t he st u d y s u bjects a gai nst a n y i m me diate hazar d, a n d of a n y 
seri o us breac hes of t his pr ot oc ol or of I C H G C P t hat t he i n vesti gat or bec o m es a ware of.  
1 2. 4  
P o sti n g of I nf or m ati o n o n P u bli cl y A v ail a bl e Cli ni c al Tri al 
R e gi st er s  
St u d y i nf or mati o n fr o m t his pr ot oc ol will be p oste d o n p u blicl y a v aila ble cli nical trial re gisters 
bef ore e nr oll me nt of s u bj ects be gi ns i n acc or da n ce wit h a p plica ble Hal e o n  pr ocesses.  
Hale o n  i nte n ds t o ma k e a n o n y mize d s u bject -le vel data fr o m t his trial a vaila ble t o e xter nal 
researc hers f or s cie ntific a nal ys es or t o c o n d u ct f urt her researc h t hat ca n hel p a d va nce m e dical 
scie nce or i m pr o ve patie nt care. T his hel ps e ns ure t he d ata pr o vi d e d b y trial partici pa nts are 
use d t o ma xi m u m effect i n t he creati o n of k n o wle d ge a n d u n derst a n di n g . 
1 2. 5  
Pr o vi si o n of St u d y R e s ult s t o I n v e sti g at or s  
W here re q uire d b y a p plica ble re g ulat or y re q uir e me nts, a n i n vesti gat or si g nat or y will be 
i de ntifie d f or t he a p pr o val of t he cli nical st u d y re p ort.  T he i n vesti gat or will be pr o vi de d 
reas o na bl e access t o statistical ta bles, fi g ures, a n d rele va nt re p orts a n d will ha ve t he o p p ort u nit y 
t o re vie w t he c o m plet e st u d y res ults at a Hale o n  site or ot her m ut uall y-a greea ble l ocati o n.  
Hale o n  will als o pr o vi d e t he i n vesti gat or wit h t he f ull s u m mar y of t he st u d y res ults.  T he 
i n vesti gat or is e n c o ura ge d t o s hare t he s u m mar y res ults wit h t he st u d y s u bj ects, as a p pr o priate. 
T he pr oce d ures a n d ti mi n g f or p u blic discl os ure of t he res ults s u m mar y a n d f or de vel o p me nt of 
a ma n uscri pt f or p u blicati o n will be i n acc or da n ce wit h Hale o n  P olic y.  
A ma n uscri pt will be pr o gresse d f or p u blicati o n i n t he scie ntific literat ur e if t he res ults pr o vi d e 
i m p orta nt scie ntific or me dical k n o wle d ge. 
1 2. 6  
R e c or d s R et e nti o n  
F oll o wi n g cl os ure of t he  st u d y, t he i n vesti gat or m ust mai ntai n all site st u d y rec or ds (e x ce pt f or 
t h ose re q uire d b y l oc al re g ulati o ns t o be mai ntai ne d else w here), i n a s afe a n d sec ure l o cati o n.   
T he rec or ds (st u d y/ site master file) m ust be mai ntai ne d t o all o w eas y a n d ti mel y re trie val, w he n 
nee de d (e. g. , f or a Hal e o n  a u dit or re g ulat or y i ns pecti o n) a n d m ust be a v aila ble f or re vi e w i n 
c o nj u ncti o n wit h assess me nt of t he facilit y, s u p p orti n g s yst e ms, a n d rel e va nt site staff.  
W here per mitte d b y l ocal la ws/re g ulati o ns or i nstit uti o na l p olic y, s o me or all of t hese rec or ds 
ca n be mai ntai ne d i n a f or mat ot her t ha n har d c o p y (e. g. , micr ofic he, sca n ne d, electr o nic); 
h o we ver, ca uti o n nee ds t o be e x ercise d bef ore s u c h acti o n is ta ke n.  
T he i n vesti gat or m ust e ns ure t hat all re pr o d ucti o ns are le gi ble a n d are a tr u e a n d acc urate c o p y 
of t he ori gi nal a n d meet accessi bilit y a n d retrie v al sta n dar ds, i ncl u di n g re -ge nerati n g a h ar d 
c o p y, if re q uire d.  F urt her m ore, t he i n vesti gat or m ust e ns ure t h ere is a n acce pta ble b ac k -u p of 
t hese re pr o d ucti o ns a n d t hat a n acce pta ble q ualit y c o ntr ol pr ocess e xists f or ma ki n g t hese 
re pr o d ucti o ns. 
T he i n vesti gat or m ust ass ure t hat t he s u bject’s a n o n y mit y will be mai ntai ne d.  O n C R Fs or ot her 
d oc u me nts s u b mitte d t o Hale o n , s u bjects s h o ul d n ot be i de ntifie d b y t heir n a mes or i nitials, b ut 
b y a n i de ntificati o n c o d e. T he i n vesti gat or s h o ul d kee p a se p arat e l o g of s u bjects’ c o d es, na m es 
a n d a d dresses.  D oc u me nts n ot f or s u b missi o n t o Hale o n , e. g., s u bjects’ writte n c o nse nt f or ms, 
s h o ul d be mai ntai ne d b y t he i n vesti gat or i n strict c o nfi de nce. 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 4  of 5 8  
Rec or ds a n d d o c u me nts, i ncl u di n g si g ne d I C F, pertai ni n g t o t he c o n d uct of t his st u d y m ust be 
retai ne d b y t he i n vesti gat or as per t he si g ne d c o ntr act ual a gree me nt, fr o m t he iss ue of t he fi nal 
Cli nical St u d y Re p ort ( C S R) or e q ui vale nt s u m ma r y, u nless l ocal re g ulati o ns or i nstit uti o nal 
p olicies re q uir e a l o n ger rete nti o n peri o d. T he mi ni m u m rete nti o n ti me will meet t he strictest 
sta n dar d a p plica bl e t o t hat site f or t he st u d y, as dictate d b y a n y i nstit uti o nal re q uire me nts or 
l ocal la ws or re g ulati o ns, Hale o n  sta n dar ds/ pr oce d ures, a n d/ or i nstit uti o nal re q uire me nts.   
N o st u d y d oc u me nt s h o ul d be d estr o ye d wit h o ut a pri or writte n a gree me nt b et wee n Hale o n  a n d  
t he i n vesti gat or. T h e i n vesti gat or 
m ust n otif y Hale o n  of a n y c ha n ges i n t he arc hi v al 
arra n ge me nts, i ncl u di n g, b ut n ot li mite d t o, arc hi val at a n off -site facilit y or tra nsfer of 
o w ners hi p of t he rec or ds i n t he e ve nt t he i n vesti gat or is n o l o n ger ass ociate d wit h t he site.  
1 2. 7  
Mi cr o bi al a n d F u n cti o n al Pr ofili n g D at a  R et e nti o n  
Ra w 1 6 S r R N A se q ue nce re a ds a n d data will be st ore d a n d ma de accessi ble t o Hale o n t hr o u g h 
t he 
 st ora ge ser vice.  
 has m ulti ple bac k-u p 
st ora ge a n d re d u n da nc y strate gies a n d data will be ke pt u p t o 6 m o nt hs after t he c o m pleti o n of 
t he st u d y. D ata a nal ys es are als o pr o vi d e d i n a bi oi nf or matic re p ort t hat is d o w nl oa da ble.  
F or t he data u pl oa de d t o a n d st ore d i n 
 t he data is st ore d o n t he h ub sec urel y 
f or 6 m o nt hs after c o m pleti o n of st u d y wit h o ut c ost. Ra w se q ue n ces d ata will als o be st ore d o n 
t he 
 ser ver sec urel y u p t o 6 m o nt hs after t he c o m pleti o n 
of st u d y .  
Ra w se q ue nce rea ds a n d f u ncti o nal pr ofili n g res ults of t he meta -tra nscri pt o mic a nal yses, if 
a p plica ble, will be st ore d a n d ma de accessi ble t o Hale o n t hr o u g h t he
 u p t o 6 
m o nt hs after t he c o m pleti o n of t he st u d y.  
1 2. 8  
C o n diti o n s f or T er mi n ati n g t h e St u d y  
Pre mat ure ter mi nati o n of t his st u d y ma y  o cc ur beca use of a re g ulat or y a ut h orit y decisi o n, 
c ha n ge i n o pi ni o n of t he I R B/ E C, or st u d y pr o d uct safet y pr o ble ms, or at t he discreti o n of 
Hale o n .    
If a st u d y is pre mat urel y ter mi nate d, Hale o n  will pr o m ptl y n otif y t h e i n vesti gat or.  After 
n otificati o n, t he i n vesti gat or m ust pr o m ptl y c o ntact all partici pati n g s u bjects a n d s h o ul d ass ur e 
a p pr o priate t hera p y/ f oll o w -u p f or t he s u bjects.  As directe d b y Hale o n , all st u d y mat erials m ust 
be c ollecte d a n d all C R F’s  c o m plete d t o t he greatest e xte nt p ossi ble. W here re q uire d b y t h e 
a p plica ble re g ulat or y re q uire me nts, Hale o n  s h o ul d i nf or m t he re g ulat or y a ut h orit y(ies) a n d t he 
i n vesti gat or s h o ul d pr o m ptl y i nf or m t h e I R B/ E C a n d pr o vi de t he I R B/ E C a det aile d writte n 
e x pla nati o n of t he ter mi nati o n or s us pe n si o n.  
If t h e I R B/ E C ter mi nates or s us pe n ds its a p pr o val/fa v ora ble o pi ni o n of a trial, t he i n vesti gat or 
s h o ul d pr o m ptl y n otif y t he Hale o n  a n d pr o vi de Hale o n  wit h a d etaile d writte n e x pla nati o n of 
t he ter mi nati o n or s us pe nsi o n. 
U p o n c o m pleti o n or pre mat ure disc o nti n uati o n of t he st u d y, t he Hale o n  m o nit or will c o n d uct 
site cl os ure acti vities wit h t he i n vesti gat or or site staff, as a p pr o priate, i n acc or da nce wit h 
a p plica ble re g ulati o ns i ncl u di n g G C P, a n d Hale o n  Sta n dar d O perati n g Pr oce d ures.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
C CI
C CI
C CI
C CI
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 5  of 5 8  
1 3  
R E F E R E N C E S  
A da ms S E , Ar n ol d D , M ur p h y B , C arr oll P , Gree n A K , S mit h A M , Mars h P D , C he n T , Marri ott 
R E , Bra di n g M G. A ra n d o mise d cli nical st u d y t o d eter mi ne t he effect of a t o ot h paste c o ntai ni n g 
e nz y mes a n d pr otei ns o n pla q ue oral micr o bi o me ec ol o g y . Sci Re p . 2 0 1 7; 2 7; 7: 4 3 3 4 4 . 
A g h aza de h Z, Be hr o ozia n A, N ajafi H, Fara marzi M. C o m paris o n of gi n gi v al a n d d e ntal i n dices 
i n lactati n g a n d n o n-la ctati n g m ot hers d uri n g first 6 m o nt h after deli ver y. Pes q ui Bras 
O d o nt o pe diatria Clí n I nt e gr 2 0 1 9; 1 9:e 4 5 8 6 . 
Ac her k o u k A, Patel N , B utler A, A mi ni P.  A ra n d o mise d cli nical st u d y i n v esti gati n g efficac y 
of a sta n n o us fl u ori de t o ot h paste i n i m pr o vi n g gi n gi val healt h after 3 wee ks' us e. B M C oral 
healt h. 2 0 2 1; 2 1( 1): 4 4 1.  
Arc hila L, Bartize k R D, Wi nst o n J L, et al. T he c o m parati ve effica c y of sta bilize d sta n n o us 
fl u ori de/s o di u m he x a meta p h os p hate d e ntifrice a n d s o di u m fl u ori de/tricl osa n/c o p ol y m er 
de ntifrice f or t he c o ntr ol of gi n gi vitis: A 6 m o nt h ra n d o mize d cli nical st u d y. J o ur nal of 
peri o d o nt ol o g y. 2 0 0 4; 7 5( 1 2): 1 5 9 2 -9.  
Bacca L, Le usc h M, La nzalac o A, et al. A c o m paris o n of i ntra oral a nti micr o bial effects of 
sta bilize d sta n n o us fl u ori de de ntifrice, ba ki n g s o da/ per o xi de de ntifrice, c o n ve nti o nal Na F 
de ntifrice a n d esse ntial oil m o ut hri nse. 1 9 9 7; 8( 2 S pec N o): 5 4 -6 1.  
Bella m y P, B o ul di n g A, Far me r S, et al. Ra n d o mize d di gital pla q ue i ma gi n g trial e val uati n g 
pla q ue i n hi biti o n efficac y of a n o v el sta bilize d sta n n o us fl u ori de de ntifrice c o m pare d wit h a n 
a mi ne fl u ori de/sta n n o us fl u ori de de ntifrice. J o ur nal of Cli nical De ntistr y. 2 0 1 2; 2 3( 3): 7 1.  
C ha p ple  I L C, Meale y B L, V a n D y k e T E, et al. Peri o d o ntal healt h a n d gi n gi val diseas es a n d 
c o n diti o ns o n a n i ntact a n d a re d u ce d p eri o d o nti u m: C o nse ns us re p ort of w or k gr o u p 1 of t h e 
2 0 1 7 w orl d w or ks h o p o n t he classificati o n of peri o d o ntal a n d peri -i m pla nt diseases a n d 
c o n diti o ns. T he J o ur nal of peri o d o nt ol o g y. 2 0 1 8; 8 9.  
Ere na A M, B oris y b G G, H usec S M, 
Welc h  J L M. Oli g ot y pi n g a nal ysis o f t he h u ma n oral 
micr o bi o me . P N A S. 2 0 1 4; 1 1 1 ( 2 8) : E 2 8 7 5 – E 2 8 8 4 . 
G u m ber H K, L o u ya kis A S, Sar ma T, Fa bija nic KI,  Pa ul R,  Melle n br uc h 
K, Kil patric k -
Li ver ma n  L. Effect of a Sta n n o us Fl u ori de De ntifrice o n Bi ofil m  C o m p ositi o n, Ge ne 
E x pressi o n a n d Bi o mec h a nical Pr o perties . 2 0 2 2; 1 0 ( 9): 1 6 9 1.  
Hale o n cli nical st u d y 2 0 5 0 5 1 ( 2 0 1 7). A St u d y t o I n v esti gate t he A nti micr o bial Acti vit y of t w o 
Test T o o t h pastes i n a Pla q ue Gl yc ol ysis a n d Re gr o wt h M o del ( data o n file). 
Hale o n cli nical st u d y 2 0 7 0 1 4 ( 2 0 1 8). A Cli nical St u d y I n v esti gati n g t h e Gi n gi vitis Efficac y of 
a Sta n n o us Fl u ori de D e ntifrice i n a C hi nese P o p ul ati o n ( data o n file).  
Haraszt h y  VI, Ra yla e  C C , Sree ni vasa n  P K. A nti micr o bial effects of a sta n n o us fl u ori de  
t o ot h paste i n disti nct oral micr oe n vir o n me nts. J A D A. 2 0 1 9 ;1 5 0( 4):  S 1 4 -S 2 4 . 
He T, Bar ker M L, G o yal C R, et al. A nti -gi n gi vitis effects of a n o v el 0. 4 5 4 % sta bilize d sta n n o us 
fl u ori de de ntifri ce relati v e t o a p ositi ve c o ntr ol. A merica n j o ur n al of d e ntistr y. 2 0 1 2; 2 5( 3): 1 3 6. 
Kast uri R, W hite D, La n zalac o A, et al. Effects of ni ne wee ks' use of a ne w sta bilize d sta n n o us 
fl u ori de de ntifric e o n i ntri nsic pla q ue vir ule n ce e x presse d as aci d o ge ni cit y a n d re gr o wt h: A 
m o difie d p gr m st u d y. 1 9 9 5; 6: 7 1 -9.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 6  of 5 8  
Kilia n M, C ha p ple I L C, Ha n ni g M, Mars h P D, Me uric V, Pe derse n A M L, T o netti M S, Wa de 
W G, Za ura  E. T he oral micr o bi o me –  a n u p date f or oral healt hcare pr ofessi o nals. 2 0 1 6; 
2 2 1( 1 0): 6 5 7 -6 6 6.  
L o be n e, R., S o par kar, P . & Ne w ma n, M. ( 1 9 8 2)] Use of d e ntal fl oss. Effect o n pl a q ue a n d 
gi n gi vitis. Cli nical pre ve nti ve de ntistr y. 1 9 8 2, 4( 1), 5 -8  
L o be n e R R. A 
M o difie d Gi n gi val I n d e x f or Use i n Cli nical Trials. Cli nical Pre ve ntati ve 
De ntistr y. 1 9 8 6; 8( 1): 3.  
Ma ki n S A. Sta n n o us fl u ori de de ntifrices. A merica n j o ur nal of de ntistr y. 2 0 1 3; 2 6: 3 A -9 A.  
Miller S, Tr u o n g T, He u R, et al. Rece nt a d va nces i n sta n n o us fl u ori de tec h n ol o g y: A nti bacteri al 
effic ac y a n d mec ha nis m of acti o n t o war ds h y p erse nsiti vit y. I nter n ati o nal de ntal j o ur nal. 
1 9 9 4; 4 4( 1 S u p pl 1): 8 3 -9 8.  
Par ki ns o n C R, Tar gett D, G ui bert R, et al. ( 2 0 1 4) Cli nical St u d y I n vesti gati n g t he Gi n gi vitis 
Efficac y of a n E x peri me ntal T o ot h paste ( A bstract # 1 3 6 3). A A D R/ C A D R A n n ual Meeti n g. 
C harl otte, N ort h Car oli na.  
Par ki ns o n  C, A mi ni P, W u J, et al. A 2 4 -wee k ra n d o mize d cli nical st u d y i n v esti gati n g t he a nti -
gi n gi vitis efficac y. A merica n j o ur nal of d e ntistr y. 2 0 1 8a; 3 1( 1): 1 7 -2 3.  
Par ki ns o n C R, A mi ni P, J ose A, et al. A 1 2 -wee k ra n d o mize d cli nical st u d y i n v esti gati n g t he 
a nti-gi n gi vitis efficac y of a 0. 4 5 4 % w/ w sta n n o us fl u ori de de ntifrice. A merica n j o ur nal of 
de ntistr y. 2 0 1 8 b; 3 1( 2): 8 1 -5.  
Par ki ns o n C R, Mille ma n K R, Mille ma n J L. Gi n gi vitis efficac y of a 0. 4 5 4 % w/ w sta n n o us 
fl u ori de de ntifric e: a 2 4-wee k ra n d o mize d c o ntr ol le d trial. B M C oral healt h 2 0 2 0; 8 9: 1 -8.  
Sa ma nt A, Mali k C, C ha bra S, et al. Gi n gi vitis a n d peri o d o ntal disease i n pre g na nc y. J o ur nal 
of Peri o d o nt ol o g y. 1 9 7 6 ; 4 7( 7): 4 1 5 -8.  
Sa xt o n C, Va n der O u d erra F G J. T he Effect of a De ntifrice C o ntai ni n g Zi nc Citrate  & 
Tricl osa n o n De v el o pi n g Gi n gi vitis. J o ur nal of Peri o d o ntal Researc h. 1 9 8 9; 2 4: 7 5.  
S va n ger g M & R olla G. Stre pt oc occ us m uta ns i n pla q ue a n d s ali va after m o ut hri nsi n g wit h 
S n F 2 . E ur o pea n J o ur nal of Oral Scie nces. 1 9 8 2; 9 0( 4) : 2 9 2 -2 9 8 . 
Ta ka has hi  N. Oral Mi cr o bi o me Meta b olis m: Fr o m “ W h o Are T he y? ” t o “ W hat Are T h e y 
D oi n g? ”. J o ur nal of De ntal Researc h. 2 0 1 5 ;9 4( 1 2) : 1 6 2 8 – 1 6 3 7 . 
Ti na n off N. Pr o gress re gar di n g t he use of sta n n o us fl u ori de i n cli nical d e ntistr y. T h e J o ur nal of 
cli nical de ntistr y. 1 9 9 5; 6: 3 7 -4 0.  
Ti na n off N. Re vie w of t he a nti micr o bial acti o n of sta n n o us fl u ori d e. T h e J o ur nal of cli nical 
de ntistr y. 1 9 9 0; 2( 1): 2 2.  
T ures k y, S., Gil m ore, N. & Glic k ma n, I. ( 1 9 7 0)] Re d uce d pl a q ue f or mati o n b y t he c hl or o met h yl 
a nal o g ue of Vi cta mi ne C. J o ur nal of peri o d o nt ol o g y, 4 1( 1), 4 1 -4 3.  
Va n L o vere n C. A nti micr o bial acti vit y of fl u ori de a n d its i n vi v o i m p orta nce: I de ntificati o n of 
researc h q uesti o ns. Caries researc h. 2 0 0 1; 3 5( S u p pl. 1): 6 5-7 0.  
Va n L o v ere n CJJ o dr. T he a nti micr o bial acti o n of fl u ori de a n d its r ole i n caries  i n hi biti o n. 
1 9 9 0 b; 6 9( 2 _s u p pl): 6 7 6 -8 1.  
Wa de W G. T he oral micr o bi o me i n healt h a n d disease . P har m ac ol Res . 2 0 1 3; 6 9( 1): 1 3 7-1 4 3.  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 7  of 5 8  
W hite D, C o x E, Lia n g N, et al. A ne w pla q ue gl yc ol ysis a n d re gr o wt h m et h o d ( p gr m) f or t h e 
i n vi v o deter mi nati o n of a nti micr o bial de ntifrice/ri nse efficac y t o war ds t he i n hi biti o n of pla q ue 
gr o wt h a n d meta b olis m --met h o d de vel o p me nt, vali dati o n a n d i nitial acti vit y s cree ns. 1 9 9 5;  
6: 5 9 -7 0.  
Wils o n 
M, Pratte n J, e dit ors. La b orat or y ass ess me nt of a nti micr o bials f or pla q ue -relat e d 
diseases 1 9 9 9: Bi oli ne.  
1 4  
A P P E N DI CI E S  
1 4. 1  
A B B R E VI A TI O N S  
T he f oll o wi n g is a list of a b bre viati o ns t hat ma y b e use d i n t he pr ot oc ol.  
T a bl e 1 4 -1  
A b br e vi ati o n s  
A E  
a d v er s e e v e nt  
B D R  
bli n d e d d at a r e vi e w  
BI  
Bl e e di n g i n d e x  
B S  
Bl e e di n g sit e s  
C PI T N  
C o m m u nit y P eri o d o nt al I n d e x of Tr e at m e nt N e e d s  
C R F  
c a s e r e p ort f or m  
E C  
et hi c s c o m mitt e e  
E C G  
el e ctr o c ar di o gr a m  
e C R F  
El e ctr o ni c C a s e R e p ort F or m  
E D C  
El e ctr o ni c D at a C a pt ur e  
 
 
G C P  
G o o d Cli ni c al Pr a cti c e  
G G T  
g a m m a -gl ut a m yl tr a n s p e pti d a s e  
I B 
i n v e sti g at or’ s br o c h ur e 
I C H 
I nt er n ati o n al C o nf er e n c e o n H ar m o ni s ati o n 
I C F 
I nf or m e d c o n s e nt f or m 
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
I R B 
i n stit uti o n al r e vi e w b o ar d 
I R T 
I nt er a cti v e R e s p o n s e T e c h n ol o g y 
M e d D R A  
m e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
M F C  
M a st er F or m ul ati o n C o d e  
M GI  
M o difi e d gi n gi v al i n d e x  
O S T  
Or al s oft ti s s u e  
O H T  
Or al h e alt h ti s s u e  
P E R M A N O V A  
P er m ut ati o n al m ulti v ari at e a n al y si s of v ari a n c e  
PI  
pri n ci p al i n v e sti g at or  
P P  
P er pr ot o c ol  
PI  
P er s o n al i nf or m ati o n  
P p m  
P art p er milli o n  
P T  
Pr ef err e d T er m  
Q C  
q u alit y c o ntr ol  
r R N A 
Ri b o s o m al ri b o n u cl ei c a ci d  
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI
C CI
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 1   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 8  of 5 8  
S A E  
S eri o u s a d v er s e e v e nt s  
S A P  
St ati sti c al a n d a n al y si s pl a n  
S D  
St a n d ar d d e vi ati o n  
S M F P  
s o di u m m o n ofl u or o p h o s p h at e  
S n F 2  
St a n n o u s fl u ori d e  
S O C  
S y st e m Or g a n Cl a s s  
S O P  
st a n d ar d o p er ati n g pr o c e d ur e  
T PI  
T ur e s k y M o difi e d Q ui gl e y & H ei n Pl a q u e I n d e x  
U K  
U nit e d Ki n g d o m  
U S  
U nit e d St at e s  
V S C  
V ol atil e s ul p h ur c o m p o u n d s  
Z n Cl 2  
Zi n c c hl ori d e  
 
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
C CI

Si g nat ure Pa ge f or  3 0 0 1 0 1 T M F- 2 4 6 9 3 6 v 2. 0
Si g nat ure Pa ge f or T M F- 2 4 6 9 3 6 v 2. 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure: 
G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure: 
G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure: 
G M T + 0 0 0 0
3 0 0 1 0 1 Pr ot oc ol Pr oject Fr o d o 1 3 Se p 2 0 2 3 | T M F- 2 4 6 9 3 6 | 2. 0
P P D
P P D
P P D
P P D
P P D
P P D