A Randomized, Examiner Blind, Crossover, in Situ Erosion Study To Investigate The Efficacy Of An Experimental Dentifrice In Remineralization Of Softened Enamel Compared To Placebo and Reference Dentifrices
Phase: NA
Conditions: Tooth Erosion
Sponsor: HALEON

Hale o n  
Cli nical Pr ot oc ol  
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
C LI NI C A L P R O T O C O L  
A R a n d o mi z e d, E x a mi n er Bli n d, Cr o s s o v er, in s it u Er o si o n St u d y T o 
I n v e sti g at e T h e Effi c a c y Of A n E x p eri m e nt al D e ntifri c e I n 
R e mi n er ali z ati o n Of S oft e n e d E n a m el C o m p ar e d T o Pl a c e b o a n d 
R ef er e n c e D e ntifri c e s  
Pr ot o c ol N u m b er:  
3 0 0 0 5 7  
C o m p o u n d/ Pr o d u ct N a m e:  
S o di u m Fl u ori d e  a n d P ot a s si u m Nitr at 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 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
 
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  
1 8 4 Li b ert y C or n er R o a d, W arr e n, N J, U S A   
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
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)  
A m e n d m e nt 1  
2. 0  
C h a n g e t o d e s cri pti o n of n u m b er of s u bj e ct s r e q uir e d 
fr o m “a p pr o xi m at el y  3 3 s u bj e ct s” t o “ u p t o  3 3 s u bj e ct s” 
r a n d o mi z e d a n d a c h a n g e fr o m “t o e n s ur e 
a p pr o xi m at el y  3 0 s u bj e ct s c o m pl et e” t o “t o e n s ur e at 
l e ast  3 0 s u bj e ct s c o m pl et e”.  
A m e n d m e nt 2  
3. 0  
Cl arifi c ati o n t h at a ± 1 0 mi n s wi n d o w f or a p pli a n c e r e -
i n s erti o n f oll o wi n g l u n c h/ di n n er i s a c c e pt a bl e. 
 
 
 
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 me nts ma de at t he re q u est of 
c o u ntr y healt 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 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
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Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
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 on 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 g e t hat I a m res p o nsi ble f or o verall st u d y c o n d uct. 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 he 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 cte 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 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
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 g e  ................................................................ 4  
Ta ble of C o nte nts  ................................................................................................................ 5  
List of fi g ures  ...................................................................................................................... 9  
1  
P R O T O C O L S U M M A R Y  ................................................................................................ 1 0  
1. 1  
S y n o psis  ................................................................................................................. 1 0  
1. 2  
Sc he d ule of A cti vities  ............................................................................................ 1 4  
2  
I N T R O D U C TI O N ............................................................................................................. 1 6  
2. 1  
St u d y Rati o nale  ...................................................................................................... 1 6  
2. 2  
Bac k gr o u n d  ............................................................................................................ 1 7  
2. 3  
Be nefit/ Ris k Assess me nt  ....................................................................................... 1 8  
2. 4  
Mec ha nis m of Acti o n/I n dicati o n  ........................................................................... 1 8  
3  
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 8  
4  
S T U D Y D E SI G N  .............................................................................................................. 1 9  
4. 1  
O verall Desi g n  ....................................................................................................... 1 9  
4. 2  
Scie ntific Rati o nale f or St u d y Desi g n  ................................................................... 2 2  
4. 3  
J ustificati o n f or D ose ............................................................................................. 2 3  
4. 4  
E n d of St u d y Defi niti o n  ......................................................................................... 2 3  
5  
S T U D Y P O P U L A TI O N  .................................................................................................... 2 4  
5. 1  
T y pe a n d Pla n ne d N u m b er of S u bjects  ................................................................. 2 4  
5. 2  
I n cl usi o n Criteria ................................................................................................... 2 4  
5. 3  
E xcl usi o n Criteria  .................................................................................................. 2 4  
5. 4  
Ra n d o mizati o n Criteria  .......................................................................................... 2 5  
5. 5  
Lifest yle C o nsi derati o ns  ........................................................................................ 2 5  
5. 5. 1  
Oral H y gie ne R estricti o ns  ..................................................................... 2 5  
5. 5. 2  
Meals a n d Dietar y Restri cti o ns  ............................................................. 2 6  
5. 5. 3  
Alc o h ol a n d T o bacc o  ............................................................................ 2 6  
5. 5. 4  
Me dicati o n a n d Treat me nt Restricti o ns  ................................................ 2 6  
5. 5. 5  
C o ntrace pti o n  ........................................................................................ 2 7  
5. 6  
Scree n Fail ures ....................................................................................................... 2 7  
5. 7  
S p o ns or’s Q ualifie d Me dical Pers o n nel  ................................................................ 2 7  
5. 8  
Cli nical Assess or Rater/ Cli nical Assess or Q ualificati o ns  ..................................... 2 7  
6  
I N V E S TI G A TI O N A L/ S T U D Y P R O D U C T S................................................................... 2 7  
6. 1  
I n v esti gati o nal/ St u d y Pr o d uct S u p plies ................................................................. 2 8  
6. 1. 1  
Me dical De vices  .................................................................................... 2 9  
6. 1. 2  
D osa ge F or m a n d Pac k a gi n g  ................................................................. 2 9  
6. 1. 3  
Pre parati o n a n d D is pe nsi n g................................................................... 3 0  
6. 2  
A d mi nistrati o n  ....................................................................................................... 3 0  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
6. 2. 1  
Pr o d uct Usa ge Err ors  ............................................................................ 3 0  
6. 2. 2  
O ver d ose  ............................................................................................... 3 1  
6. 3  
I n v esti gati o nal/ St u d y Pr o d uct St ora ge .................................................................. 3 1  
6. 4  
I n v esti gati o nal/ St u d y Pr o d uct Acc o u nta bilit y ....................................................... 3 1  
6. 4. 1  
Destr uc ti o n of I n v esti gati o nal/ St u d y Pr o d uct S u p plies ........................ 3 2  
6. 5  
Bli n di n g a n d All ocati o n/ Ra n d o mizati o n  ............................................................... 3 2  
6. 6  
Brea ki n g t he Bli n d  ................................................................................................. 3 3  
6. 7  
C o m plia nce  ............................................................................................................ 3 3  
6. 8  
C o nc o mita nt Me dicati o n/ Treat me nt(s)  .................................................................. 3 3  
7  
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  ......................................................................... 3 4  
7. 1  
S u bject Disc o nti n uati o n/ Wit h dra wal  ..................................................................... 3 4  
7. 2  
L ost t o F oll o w u p  ................................................................................................... 3 4  
8  
S T U D Y P R O C E D U R E S  ................................................................................................... 3 5  
8. 1  
Visit 1/ Scree ni n g  ................................................................................................... 3 5  
8. 1. 1  
I nf or me d C o nse nt .................................................................................. 3 5  
8. 1. 2  
De m o gra p hics  ....................................................................................... 3 6  
8. 1. 3  
Me dical Hist or y a n d Pri or Me dicati o n/ Treat me nt  ................................ 3 6  
8. 1. 4  
Oral E xa mi nati o ns  ................................................................................. 3 6  
8. 1. 5  
Sali var y Fl o w Rate Meas ure me nts  ....................................................... 3 6  
8. 1. 6  
I n cl usi o n/ E xcl usi o n Criteria ................................................................. 3 6  
8. 1. 7  
Tr y -i n of Palatal A p plia n ce ................................................................... 3 6  
8. 1. 8  
S u bject Eli gi bilit y  ................................................................................. 3 6  
8. 1. 9  
Dis pe nse Was h -o ut Pr o d ucts a n d Diar y Car ds  ..................................... 3 7  
8. 1. 1 0  
A d verse E v e nts a n d I n ci de nts  ............................................................... 3 7  
8. 2  
St u d y Peri o d  .......................................................................................................... 3 7  
8. 2. 1  
Visit 2/ St u d y Peri o d 1  ........................................................................... 3 7  
8. 2. 2  
Visit 3 / St u d y Peri o d 1 –  F oll o w u p  ..................................................... 3 8  
8. 2. 3  
Visits 4 & 5 –  St u d y Peri o d 2  ............................................................... 3 8  
8. 2. 4  
Visits 6 & 7 –  St u d y Peri o d 3  ............................................................... 3 8  
8. 3  
St u d y P r oce d ures ................................................................................................... 3 9  
8. 3. 1  
Diar y Re vie w  ........................................................................................ 3 9  
8. 3. 2  
Pre -Treat me nt Oral S oft Tiss ue assess me nt  .......................................... 3 9  
8. 3. 3  
Place palatal a p plia nce i n s u bject’s m o ut h. ........................................... 3 9  
8. 3. 4  
S u per vise d treat me nt  ............................................................................. 3 9  
8. 3. 5  
Palatal a p plia nces i ntra oral p hase –  4 h o urs  ........................................ 3 9  
8. 3. 6  
Palatal a p plia nces i ntra oral p hase –  1 2 h o urs  ...................................... 4 0  
8. 3. 7  
St u d y C o ncl usi o n  .................................................................................. 4 0  
8. 3. 8  
F oll o w -u p Visit / P h o ne Call  ................................................................ 4 0  
9  
S T U D Y A S S E S S M E N T S  ................................................................................................. 4 0  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
9. 1  
Scree ni n g Assess me nts  .......................................................................................... 4 0  
9. 1. 1  
Sali var y fl o w  ......................................................................................... 4 0  
9. 2  
Efficac y Assess me nts  ............................................................................................ 4 1  
9. 3  
Safet y a n d Ot her Assess me nts  ............................................................................... 4 1  
9. 3. 1  
Oral S oft Tiss ue ( O S T) E xa mi nati o n  .................................................... 4 1  
9. 3. 2  
Oral Har d Tiss ue ( O H T) E xa mi nati o n  .................................................. 4 1  
9. 3. 3  
Pre g na nc y T esti n g  ................................................................................. 4 2  
9. 4  
La b orat or y T ests  .................................................................................................... 4 2  
1 0  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  ........................................... 4 2  
1 0. 1  
Defi niti o n of a n A d verse E ve nt ( A E)  .................................................................... 4 2  
1 0. 2  
Defi niti o n of a Seri o us A d verse E ve nt ( S A E)  ....................................................... 4 3  
1 0. 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  .................. 4 4  
1 0. 4  
Re p orti n g Pr oce d ures ............................................................................................. 4 5  
1 0. 4. 1  
Re p orti n g of a n A d verse E ve nt  ............................................................. 4 5  
1 0. 4. 2  
Re p orti n g of a Seri o us A d verse E ve nt  .................................................. 4 6  
1 0. 5  
E val uati n g A d verse E ve nts  .................................................................................... 4 6  
1 0. 5. 1  
Assess me nt of I nte nsit y  ........................................................................ 4 6  
1 0. 5. 2  
Assess me nt of Ca usalit y  ....................................................................... 4 7  
1 0. 6  
F oll o w -u p of A Es a n d S A Es .................................................................................. 4 7  
1 0. 7  
Wit h dra wal D u e t o a n A d verse E ve nt  ................................................................... 4 8  
1 0. 8  
Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ...................................................... 4 8  
1 0. 9  
Pre g na nc y  .............................................................................................................. 4 8  
1 0. 9. 1  
Ti me Peri o d f or C ollecti n g Pre g na nc y I nf or mati o n.............................. 4 8  
1 0. 9. 2  
Acti o n t o be Ta ke n if Pre g na nc y Occ urs  .............................................. 4 8  
1 0. 1 0  Me dical De vic e I n ci de nts  ...................................................................................... 4 9  
1 0. 1 0. 1  
Defi niti o n of a n I nci d e nt  ....................................................................... 4 9  
1 0. 1 1  Re p orti n g of I nci de nts a n d Malf u ncti o ns  .............................................................. 5 0  
1 0. 1 2  F oll o w -u p of Me di cal De vice I nci de nts  ................................................................ 5 0  
1 0. 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 ...................... 5 1  
1 1  D A T A M A N A G E M E N T  .................................................................................................. 5 1  
1 1. 1  
Case Re p ort F or m  .................................................................................................. 5 1  
1 1. 2  
Data Ha n dli n g  ........................................................................................................ 5 2  
1 1. 2. 1  
Data Q ueries  .......................................................................................... 5 2  
1 1. 3  
Pr ocessi n g Patie nt Re p orte d O utc o mes  ................................................................. 5 2  
1 1. 4  
E xter nal Dat a  ......................................................................................................... 5 2  
1 2  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  .................................. 5 3  
1 2. 1  
Sa m ple Size Deter mi nati o n  ................................................................................... 5 3  
1 2. 2  
P o p ulati o ns f or A nal ysis  ........................................................................................ 5 3  
1 2. 2. 1  
Defi niti o ns of A nal ysis P o p ulati o ns  ..................................................... 5 3  
1 2. 2. 2  
E xcl usi o ns of Data fr o m A nal ysis ......................................................... 5 3  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
1 2. 3  
Statistical A nal yses  ................................................................................................ 5 4  
1 2. 3. 1  
Pri mar y A nal ysis  ................................................................................... 5 4  
1 2. 3. 2  
Sec o n dar y A n al yses  .............................................................................. 5 5  
1 2. 3. 3  
E x pl orat or y A nal ysis  ............................................................................. 5 5  
1 2. 3. 4  
Safet y A nal yses  ..................................................................................... 5 6  
1 2. 3. 5  
E xcl usi o n of Data fr o m A nal ysis  .......................................................... 5 6  
1 2. 3. 6  
De m o gra p hic a n d Baseli ne C haracteristics  ........................................... 5 6  
1 2. 3. 7  
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 6  
1 2. 3. 8  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  .............................................. 5 6  
1 2. 3. 9  
I nteri m A nal ysis .................................................................................... 5 7  
1 3  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 7  
1 3. 1  
Q ualit y C o ntr ol  ...................................................................................................... 5 7  
1 3. 2  
Q ualit y Ass ura nce  .................................................................................................. 5 7  
1 3. 3  
Re g ulat or y a n d Et hical C o nsi derati o ns  ................................................................. 5 8  
1 3. 3. 1  
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee ..................................... 5 8  
1 3. 3. 2  
Et hical C o n d uct of t he St u d y  ................................................................ 5 8  
1 3. 3. 3  
S u bject I n f or mati o n a n d C o nse nt .......................................................... 5 8  
1 3. 3. 4  
S u bject Recr uit me nt  .............................................................................. 5 9  
1 3. 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 9  
1 3. 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 9  
1 3. 5  
Pr o visi o n of St u d y Res ults t o I n vesti gat ors  ........................................................... 5 9  
1 3. 6  
Rec or ds Rete nti o n  .................................................................................................. 6 0  
1 3. 7  
C o n diti o ns f or Ter mi nati n g t he St u d y  ................................................................... 6 0  
1 4  R E F E R E N C E S  .................................................................................................................. 6 1  
1 5  A P P E N DI CI E S .................................................................................................................. 6 3  
1 5. 1  
A b bre viati o ns  ......................................................................................................... 6 3  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
Li st of i n t e xt t a bl e s  
Ta ble 3 -1  
St u d y O bje cti ves a n d E n d p oi nts  ........................................................... 1 8  
Ta ble 6 -1  
I n v esti gati o nal/ St u d y Pr o d uct S u p plies ................................................ 2 8  
Ta ble 6 -2  
Was h o ut Pr o d uct S u p plies  .................................................................... 2 8  
Ta ble 6 -3  
S u n dr y Ite ms  ......................................................................................... 2 9  
Ta ble 1 5 -1  
A b bre viati o ns  ........................................................................................ 6 3  
 
 
Li st of fi g ur e s  
Fi g ure 4 -1  
Sc he matic dia gra m of a) i ntra oral a p plia nce, b) e n a mel s peci me ns’ 
h ol der, c) e na mel s peci me ns place d i n t he h ol der a n d d) palatal 
a p plia nce wit h e na mel s p eci me ns i n t he m o ut h.  ................................... 2 0  
Fi g ure 4 -2  
Sc he matic dia gra m s h o wi n g fl o w of pr oce d ures.  ................................. 2 1  
Fi g ure 4 -3  
Sc he matic dia gra m s h o wi n g i nserti o n a n d re m o val of palatal 
de vice o ver t he 1 3 h o ur st u d y da y. ........................................................ 2 2  
 
 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
1  
P R O T O C O L S U M M A R Y  
1. 1  
S y n o p si s  
S h ort Titl e:  
A n  I n Sit u Er osi o n St u d y to I n v esti gate the Efficac y o f an E x p eri me ntal De ntifrice t o 
Re mi neraliz e E n a mel . 
B a c k gr o u n d a n d R ati o n al e : 
T his st u d y will i n vesti gate t he a bilit y of a n e x peri me ntal de ntifri ce c o ntai ni n g 1 1 5 0 p p m 
fl u ori de t o re mi neralize aci d-s ofte ne d d e ntal e na m el a n d hel p pre ve nt f urt her de mi neralizati o n 
c o m pare d t o a 0 p p m fl u ori de place b o de ntifrice a n d a mar k ete d, fl u ori de -c o ntai ni n g de ntifrice 
( Refere nce De ntifric e).  T he st u d y will utilize a n esta blis he d i n sit u m o del w here partiall y 
de mi neralize d e na mel s p eci me ns will be place d i n a de ntal palatal a p plia nce, treate d i ntra orall y 
t he n all o we d t o re mi neralize i n sit u f or 4 a n d 1 2 h o urs.  Efficac y will be e val uate d t hr o u g h 
la b orat or y m eas ur e me nt of t he s urface micr o har d ness rec o ver y ( S M H R), rel ati ve er osi o n 
resista nce ( R E R), aci d r esista nce rati o ( A R R) a n d t he e na mel fl u ori d e u pta ke ( E F U). 
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 i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o e n h a n c e r e mi n er ali z ati o n of 
e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) aft er 4 
h o ur s of i ntr a -or al e x p o s ur e . 
% S M H R at  4  hr s.  
S e c o n d ar y  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o i n hi bit d e mi n er ali z ati o n of 
e n a m el c o m p ar e d t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) aft er 4 
h o ur s of i ntr a -or al e x p o s ur e.  
% R E R at 4 hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o e n h a n c e r e mi n er ali z ati o n of 
e n a m el c o m p ar e d t o a m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 
1 1 0 0 p p m fl u ori d e aft er 4 h o ur s of i ntr a -or al e x p o s ur e . 
% S M H R at  4  hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o e n h a n c e r e mi n er ali z ati o n of 
e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) a n d a 
m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 1 1 0 0 p p m fl u ori d e aft er 1 2 
h o ur s of i ntr a -or al e x p o s ur e . 
% S M H R at  1 2  hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt a l d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o i n hi bit d e mi n er ali z ati o n of 
e n a m el c o m p ar e d t o a r ef er e n c e d e ntifri c e c o nt ai ni n g 1 1 0 0 p p m 
fl u ori d e aft er 4 h o ur s of i ntr a-or al e x p o s ur e.  
% R E R at 4 hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o i n hi bit d e mi n er ali z ati o n of 
e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) a n d a 
m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 1 1 0 0 p p m fl u ori d e aft er 1 2 
h o ur s of i ntr a -or al e x p o s ur e . 
% R E R 1 2  hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o pr o m ot e fl u ori d e u pt a k e i n 
e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) a n d a 
m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 1 1 0 0 p p m fl u ori d e aft er 4 
a n d 1 2 h o ur s of i ntr a -or al e x p o s ur e . 
E F U at  4  a n d 1 2  hr s.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e  c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o r e d u c e f ut ur e a ci d-i n d u c e d 
d e mi n er ali z ati o n  i n e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m 
fl u ori d e) a n d a m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 1 1 0 0 p p m 
fl u ori d e aft er 4 a n d 1 2 h o ur s of i ntr a-or al e x p o s ur e . 
A R R at 4 a n d 1 2 hr s.  
T o i n v e sti g at e t h e effi c a c y of a m ar k et e d, r ef er e n c e d e ntifri c e  
c o nt ai ni n g 1 1 0 0 p p m fl u ori d e . t o e n h a n c e r e mi n er ali z ati o n, i n hi bit 
d e mi n er ali z ati o n, t o r e d u c e f ut ur e a ci d -i n d u c e d d e mi n er ali z ati o n a n d 
t o pr o m ot e fl u ori d e u pt a k e i n e n a m el c o m p ar e d  t o a pl a c e b o 
d e ntifri c e  ( 0 p p m fl u ori d e) aft er 4 a n d 1 2 h o ur s of i ntr a -or al  e x p o s ur e . 
% S M H R, % R E R, E F U, A R R 
at 4 a n d 1 2 hr s.  
E x pl or at or y  
T o c al c ul at e t h e pr o p orti o n of s u bj e ct s w h o e vi d e n c e a R E R r ati o 
( % R E R 0 p p m fl u ori d e pl a c e b o a n d 5 % K N O 3  : % R E R e x p eri m e nt al 
d e ntifri c e c o nt ai ni n g 1 1 5 0 p p m fl u ori d e) > = 3 a n d > = 2. 5  
% R E R a t 4  a n d 1 2  hr s.  
S af et y  
T o a s s e s s t h e or al  t ol er a bilit y of a n  e x p eri m e nt al d e ntifri c e  
c o nt ai ni n g 1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3 . 
Tr e at m e nt e m er g e nt 
a d v er s e e v e nt s  
A b bre vi ati o ns: S M H R: S urface micr o har d ness rec o ver y, R E R: Relati ve er osi o n resista nce, E F U: E na mel 
fl u ori de u pta ke, A R R: Aci d resista nce rati o, K N O3: p otassi u m nitrate. 
St u d y D e si g n : 
T his will be a ra n d o mize d, c o ntr olle d, si n gle ce nt er, si n gle - bli n d (t o t he de ntal e xa mi ner a n d 
s peci me n a nal ysts), 3 peri o d, 3 treat me nt, cr oss-o v er, i n sit u desi g n .  Pre vi o usl y de mi neralize d 
b o vi ne e na mel s peci me ns will be place i ntra orall y usi n g a palatal a p plia nce a n d t h e 
re mi neralizi n g perf or m a nce of t he e x p eri me ntal, refere nce a n d place b o de ntifrices e val u ate d at 
4 a n d 1 2 h o urs p ost t o ot h br us hi n g, base d o n s urf ace micr o h ar d ness meas ure me nts  of t he b o vi ne 
e na mel s peci me ns .  T his st u d y will be carrie d o ut i n healt h y a d ults wit h a ma xillar y de ntal arc h 
s uita ble f or t he ret e nti o n of t he palatal a p plia n ce.  S u bjects will  be recr uit e d fr o m a n e xisti n g 
pa nel of s u bjects pre -fitte d wit h a palatal a p plia nce. 
I n t his st u d y t here will be 7 visits, 1 scree ni n g v isit t o assess s u bject eli gi bilit y, 3  treat me nt 
v isits, w here t he st u d y de ntifrices will be dis pe nse d a n d use d u n der t he s u per visi o n of a s uita bl y 
trai ne d st u d y site pers o n nel, a n d 3 f oll o w u p visits t o perf or m a n O S T e x a mi nati o n, assess f or 
A d verse E ve nts a n d all o w t he s u bject t o ret ur n t heir palatal a p plia nce .  S ufficie nt s u bjects will  
be scree n e d t o ra n d o mize u p t o 3 3 s u bjects t o st u d y treat me nt t o e ns ure at least 3 0 s u bjects 
c o m plete t he st u d y.  At scree ni n g ( Visit 1), s u bjects will gi ve t heir writte n i nf or me d c o nse nt  t o 
partici pate i n t he 
st u d y.  
De m o gra p h y , rele va nt 
me dical 
hist or y 
a n d 
c urre nt 
me dicati o ns /treat me nts will be rec or de d, f oll o we d b y oral s oft tiss ue ( O S T) a n d oral har d tiss ue 
( O H T) e xa mi nati o ns.  S u bjects will t he n ha ve t heir sti m ulate d a n d u nsti m ulate d sali var y fl o w 
rates meas ure d a n d s u bjects meeti n g t he rele va nt st u d y i ncl usi o n/e xcl usi o n criteria will tr y -i n 
t heir palatal a p plia n ce a n d be c o nsi dere d eli gi ble t o e nr oll i n t he st u d y.  E nr olle d s u bjects will 
t he n be dis pe nse d t he was h-o ut de ntifrice, t o ot h br us h a n d diar y.   
Pri or t o eac h tr eat me nt visit, t here will be a w as h o ut peri o d of a mi ni m u m of 3 da ys.  D uri n g 
t his peri o d s u bjects will use t heir o w n d e ntifrice  a n d t o ot h br us h f or at l east o ne da y, a n d a 0 p p m 
fl u ori de was h o ut de ntifrice  a n d st u d y t o ot h br us h ( pr o vi de d) f or t w o da ys i m me diatel y pri or t o 
t he ne xt sc he d uled visit (i ncl u di n g o n t he m or ni n g of t he sc he d ule d visit).   
At treat me nt visits ( Visits 2, 4 & 6), s u bjects will pr o vi de details of t heir c o nc o mita nt 
me dicati o ns a n d u n d er g o a n O S T e xa mi nati o n.   S u bject’s diaries will be re vie we d t o e ns ure 
c o m plia nce wit h  t he use of t he was h-o ut de ntifrice.  S u bjects dee me d s uita ble t o c o nti n ue i n t he 
st u d y will be ra n d o mize d t o t he or der of tr eat m e nts ( Visit 2 o nl y) a n d wear a n oral pal atal 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
a p plia nce h ol di n g 8 b o vi ne e n a mel s peci me ns.  Details of e na mel s peci me n pre p arati o n will be 
s pecifie d i n t he La b orat or y Pr oce d ures D oc u me nt.  T he p alatal a p plia n ces will be s pecificall y 
ma de f or eac h eli gi ble s u bject, a n d eac h will carr y t w o plastic h ol ders c o nt ai ni n g a t otal of ei g ht 
b o vi ne e na mel s peci me ns (f o ur i n eac h h ol der).  O nc e t he a p plia nce is fitte d i n t he m o ut h, a 
fi ve mi n ute e q uili brati o n peri o d will e ns ue f oll o wi n g w hic h eac h s u bject will br us h t heir teet h 
wit h  t heir assi g ne d pr o d u ct, o ne pr o d uct per treat me nt visit as descri be d b el o w.   
U n der s u per visi o n w hile t he i ntra oral a p plia nce is i n place, t he s u bjects will br us h t he b uccal 
s urfaces of t heir n at ural t eet h usi n g 1. 5 ± 0. 1 g of de ntifrice a n d a s oft t o ot h br us h f or 2 5 sec o n ds 
t o creat e a sl urr y.  S u bjects will be i nstr ucte d n ot t o e x pectorate t he sl urr y a n d will t he n s wis h 
t he sl urr y ar o u n d t heir m o ut h f or 9 5 sec o n ds t o per mit dir ect c o ntact of t he d e ntifrice sl urr y 
wit h t he e na mel s peci me ns.  After e x p ect orati n g t he sl urr y, t he s u bjects will ge ntl y ri nse t heir 
m o ut hs wit h 1 5 m L of ta p wa ter f or 1 0 s ec o n ds b ef ore e x pect orati n g a gai n.  T he t o ot h br us h, 
h o we ver, will n ot c o me i nt o c o ntact wit h t he e na mel s peci me ns or t h e a p plia nce as t his c o ul d 
ca use a brasi o n of t he e na mel s peci me ns.   
S u bjects will t he n re mai n at t he st u d y site f or 4 h o urs p ost t o ot h br us hi n g w he n t heir a p plia nce 
will be re m o ve d (at 4 hrs ± 1 0 mi ns p ost t o ot h br us hi n g) a n d 4 desi g nate d e na mel s peci me ns will 
be wit h dra w n fr o m t he a p plia nce.  S u bjects will t he n be ser ve d a n o pti o nal l u nc h  w hic h will be 
c o ns u me d wit hi n a 3 0 ± 1 0 mi n u te ti me peri o d.  T he s u bjects will t he n br us h a n d ri nse t heir 
m o ut h wit h water, after w hic h t he y will ha ve t heir a p plia nce rei nserte d a n d be all o we d t o lea ve 
t he site.  S u bjects will be re mi n de d t o n ot eat or dri n k (e xce pt f or water) w hile weari n g t heir 
a pplia nce.  
S u bjects will be gi v e n v er bal a n d writte n h o me i nstr ucti o ns / diar y w hic h will i nstr uct t he m t o 
re m o ve t heir a p plia n ce at 8. 5  h o urs f oll o wi n g t he t o ot h br us hi n g.  T he ti me f or re m o v al will be 
detaile d o n t he i nstr ucti o n / diar y s heet.  T h e y will be allo we d t o eat a m eal of t heir c h oice o ver 
a 3 0 ± 1 0 mi n ute ti me d p eri o d, br us h t heir teet h a n d ri nse t heir m o ut h wit h water a n d refit t heir 
a p plia nce after t he 3 0 ± 1 0 mi n ute ti me d peri o d is u p.  After 1 3 ± 0. 5 h o urs f oll o wi n g t he i nitial 
br us hi n g ti me, t he s u b ject will be i nstr ucte d t o re m o ve t heir a p plia n ce, ri nse it u n der r u n ni n g 
water a n d st ore m oist i n t he s u p plie d c o ntai n er i n t heir refri gerat or o v er ni g ht.  T he ti me f or t his 
re m o val will als o be gi v e n o n t heir i nstr ucti o n/ diar y s heet.  I n a d diti o n, a m e m ber of t he st u d y 
tea m will gi ve a re mi n der call t o t he s u bject pri or t o t he c o m pleti o n of t he 1 2  h o ur i ntra oral 
e x p os ure.  S u bjects will t he n atte n d a f oll o w-u p visit ( Visits 3, 5  a n d 7) t he f oll o wi n g da y t o 
ret ur n t heir a p plia nce t o t he site a n d t o recei ve a n O S T e xa mi nati o n t o e val uate a n y p ote ntial 
oral A Es.  At Visit 6 o nl y, t he s u bjects will ret ur n t heir was h o ut de ntifri ce a n d a t t h e fi n al p ost 
treat me nt visit ( Visit 7) t he s u bject will als o recei v e a n O H T e xa m a n d e n d of st u d y 
d oc u me ntati o n  will be c o m p lete d. 
T he e na m el s peci me ns will be e val uate d b ot h pri or t o a n d aft er i ntra -oral e x p os ure.  S urface 
micr o har d ness ( S M H) will be use d t o e val uate c ha n ges i n t he mi neral c o nte nt of e na mel a n d is 
use d t o calc ulate s urface micr o har d ness rec o v er y  ( % S M H R), relati ve er osi o n resista nce 
( % R E R) a n d aci d resist a nce rati o  ( A R R).  T he i nc or p orati o n of fl u ori de i nt o t he e na mel 
s peci me ns will be assesse d b y e na mel fl u ori de u pta ke ( E F U) meas ure m e nts.  F or eac h treat me nt 
a n d s u bject, t hes e meas ure me nts will be perf or me d o n  t he sa me e na mel s p eci me n as d escri b e d 
i n t he La b orat or y Pr oce d ure D oc u me nt, i n t he f o ur e na mel s peci me ns re m o ve d at eac h ti me 
p oi nt.  T he er osi ve aci d c halle n g e s, wit h a c o m merciall y a v aila ble gra p efr uit j uice, will b e 
carri e d o ut ex viv o a n d t h eref ore d oes n ot p os e a ris k t o t he s u bject’s teet h .   
A Es a n d me dical de vic e i nci de nts will be m o nit ore d t hr o u g h o ut t he st u d y a n d rec or de d at e ver y 
site visit f oll o wi n g si g ni n g of i nf or me d c o ns e nt. 
 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
St u d y Pr o d u ct s : 
T e st  D e ntifri c e  
Pl a c e b o  C o ntr ol  
R ef er e n c e D e ntifri c e  
E x p eri m e nt al D e ntifri c e  c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3 * 
0 p p m fl u ori d e  d e ntifri c e 
c o nt ai ni n g 5 % K N O 3  
Cr e st Pr o -H e alt h D e n sif y 
D ail y Pr ot e cti o n  
* K N O 3 is c o m m o nl y use d i n ot her mar kete d a nti se nsiti ve t o ot h paste. 
All de ntifrices will be a p plie d i n t he sa me ma n ner b y br us hi n g 1. 5 ± 0. 1 g of de ntifrice o n t o t he 
b uccal s urfaces of t heir nat ural te et h f or 2 5 ti m e d sec o n ds a n d t he n s wis hi n g t he res ulti n g 
de ntifrice sl urr y ar o u n d t he m o ut h, wit h o ut f urt her br us hi n g, f or a ti me d peri o d of 9 5 sec o n ds . 
S u bjects will use a 0 p p m fl u ori de was h o ut de ntifrice t wice d ail y f or 2 da ys pri or t o eac h 
treat me nt visit i n place of t heir us ual oral h y gie ne practice. 
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 : 
St u d y s u bjects of eit her se x a n d a n y ge n d er, a g e d 1 8 -6 5 years, w h o are i n  g o o d ge neral healt h 
a n d a ma xillar y de nt al arc h s uita ble f or t he rete nti o n of t he palatal a p plia nce . 
S ufficie nt  s u bjects will be scree ne d to ra n d o mize u p t o 3 3 s u bjects t o st u d y treat me nt t o  e ns ure 
at least  3 0  e val ua bl e s u bjects c o m plete all peri o ds of t he st u d y. 
St ati sti c al A n al y si s:  
T he % S M H R , % R E R a n d A R R at t he s u bject visit le vel (t o be use d i n t he a nal ysis) will be 
deri ve d as t he mea n of t he s peci me n mea ns (acr oss re plicat es wit hi n a s peci me n) wit hi n t hat 
visit.  
T he mea n E F U acr oss s p eci me ns relati n g t o a s pecific ti me p oi nt ( 4 or 1 2 h o urs) will be deri ve d 
t o re prese nt t he visit le vel E F U at t he ti me p oi nt t o be use d i n t he a nal ysis.  
A se parat e mi xe d m o del (i ncl u di n g res ults acr oss all 3 st u d y pr o d ucts) will be use d t o a nal yze 
eac h p ara m eter at eac h ti me p oi nt ( 4 or 1 2 h o urs) wit h fi xe d effects f or tr eat me nt a n d st u d y visit, 
as well as ra n d o m effect f or s u bject. Ke n war d R o gers  de grees of free d o m a p pr oac h will be 
a p plie d. T he least s q uare mea ns f or eac h st u d y pr o d uct will be prese nte d al o n g wit h t he 3 
pair wise differe n ces  of i nterest  bet wee n least s q u are mea ns (i ncl u di n g t w o-si de d p-val ue a n d 
9 5 % c o nfi de n ce i nter val) t o test f or  a differe n ce b et wee n pr o d u cts.  
Statistical testi n g of all e n d p oi nts i n t his st u d y will be c o n d ucte d at a t w o-si de d si g nifica nce 
le vel of 0. 0 5. A se q u e ntial testi n g strate g y will be a p plie d t o preser ve t he o verall t y pe-1 err or 
c o ntr ol f or t he res p ecti ve se q u e ntial c o m paris o ns bet wee n t he  E x peri me ntal de ntifrice a n d 
Place b o  C o ntr ol at 1 2 h o urs  f or t he % S M H R ( pri mar y e n d p oi nt) a n d % R E R (sec o n d ar y 
e n d p oi nt). T here will be n o f urt her a dj ust me nts f or m ulti plicit y.
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
1. 2  
S c h e d ul e of A cti viti e s  
T he sc he d ule of acti vities ta ble pr o vi des a n o ver vie w of t he s u bject visits a n d st u d y pr oce d ures.   
T he i n vesti gat or ma y sc he d ule v isits ( u n pla n ne d visits) i n a d diti o n t o t h ose liste d o n t he sc he d ule of acti vities, t o c o n d uct e val uati o ns or assess me nts 
re q uire d t o pr otect t he w ell-bei n g of t he s u bject.  
Pr o c e d ur e/ A s s e s s m e nt  
S cr e e ni n g  
St u d y P eri o d  1  
St u d y P eri o d 2  
St u d y P eri o d 3  
Vi sit 1  
 
Vi sit 2  
( Tr e at m e nt) 
Vi sit 3  
( V 2 + 1 d a y) 
 
Vi sit 4  
( Tr e at m e nt) 
Vi sit 5  
( V 4 + 1 d a y) 
 
Vi sit 6  
( Tr e at m e nt) 
Vi sit 7  
( V 6 + 1 d a y) 
I nf or m e d c o n s e nt 
X  
Mi ni m u m 3 d a y s i n cl u di n g a 2 d a y s w a s h o ut u si n g s u p pli e d  n o n -fl u ori d e d e ntifri c e  
 
 
Mi ni m u m 3 d a y s i n cl u di n g a 2 d a y s w a s h o ut u si n g s u p pli e d  n o n -fl u ori d e d e ntifri c e  
 
 
Mi ni m u m 3 d a y s i n cl u di n g a 2 d a y s w a s h o ut u si n g s u p pli e d  n o n -fl u ori d e d e ntifri c e  
 
 
D e m o gr a p hi c s  
X  
 
 
 
 
 
 
M e di c al hi st or y  
X  
 
 
 
 
 
 
C urr e nt/ pri or/ c o n c o mit a nt m e di c ati o n r e vi e w  
X  
X  
X  
X  
X  
X  
X  
O S T E x a mi n ati o n 1  
X  
X  
X  
X  
X  
X  
X  
O H T E x a mi n ati o n  
X  
 
 
 
 
 
X  
A s s e s s m e nt of sti m ul at e d a n d u n sti m ul at e d s ali v a fl o w r at e 2  
X  
 
 
 
 
 
 
R e vi e w of in cl u si o n/ e x cl u si o n c rit eri a 
X  
 
 
 
 
 
 
Tr y -i n of p al at al a p pli a n c e  
X  
 
 
 
 
 
 
S u bj e ct eli gi bilit y  
X  
 
 
 
 
 
 
Di s p e n s e w a s h -o ut pr o d u ct s a n d di ar y  
X  
 
 
 
 
 
 
Di ar y r e vi e w  
 
X  
X  
X  
X  
X  
X  
S u bj e ct c o nti n u a n c e  
 
X  
X  
X  
X  
X  
 
R a n d o mi z ati o n  t o tr e at m e nt s e q u e n c e  
 
X  
 
 
 
 
 
Pl a c e p al at al a p pli a n c e  fitt e d wit h e n a m el s p e ci m e n s i nt o s u bj e ct’ s 
m o ut h
3  
 
X  
 
X  
 
X  
 
S u p er vi s e d t o ot h br u s hi n g 
 
X  
 
X  
 
X  
 
I ntr a or al p h a s e 4 h o ur s 3, 4  
 
X  
 
X  
 
X  
 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
Pr o c e d ur e/ A s s e s s m e nt  
S cr e e ni n g  
St u d y P eri o d  1  
St u d y P eri o d 2  
St u d y P eri o d 3  
Vi sit 1  
 
Vi sit 2  
( Tr e at m e nt) 
Vi sit 3  
( V 2 + 1 d a y) 
 
Vi sit 4  
( Tr e at m e nt) 
Vi sit 5  
( V 4 + 1 d a y) 
 
Vi sit 6  
( Tr e at m e nt) 
Vi sit 7  
( V 6 + 1 d a y) 
I ntr a or al p h a s e 1 2 h o ur s 3, 5  
 
X  
 
X  
 
X  
 
A d v er s e e v e nt s r e vi e w 6  
X  
X  
X  
X  
X  
X  
X  
M e di c al d e vi c e i n ci d e nt s r e vi e w 1  
 
X  
X  
X  
X  
X  
X  
R et ur n w a s h -o ut pr o d u ct s  
 
 
 
 
 
X  
 
R et ur n p al at al a p pli a n c e  
 
 
X  
 
X  
 
X  
St u d y c o n cl u si o n  
 
 
 
 
 
 
X  
A b bre viati o ns: O S T: Oral S oft Tiss ue, O H T: Oral Har d Tiss ue . 
F o ot n otes:  
1.  
At V isits 2 , 4  & 6  O S T e xa mi nati o n will be perf or me d pri or t o i nserti o n of t he a p plia nce  a n d at Visits 3, 5 & 7 w he n t he s u bject ret ur ns t heir palatal a p plia nce . 
2.  
Re -e val uati o n of sali va fl o w ma y be re q uire d wit hi n t he st u d y s h o ul d t he s u bject be gi n a treat me nt of me dicati o n s li kel y t o i n d uce xer ost o mia. 
3.  
La b orat or y a nal ysis of e na mel s peci me ns perf or me d pri or t o placi n g a n d after re m o vi n g t he s peci me ns fr o m t he palatal a p plia nce as descri be d i n t he  se parate la b orat or y pr oce d ures d oc u me nt . 
4.  
F o ur e na mel s peci me ns will be re m o ve d fr o m t he palatal a p plia nce after weari n g t he a p plia nce f or 4 h o urs ± 1 0 mi n after t o ot h br us hi n g.  S u bject will be offere d l u nc h t o be eate n o ver a 3 0 ± 1 0 mi n ute peri o d a n d t he n be 
all o we d t o lea ve t he site wit h i nstr uc ti o ns o n h o w a n d w he n t o eat di n ner ( 3 0 ± 1 0 mi n ute peri o d bet wee n h o urs 8. 5 a n d 9), a n d re m o ve ( h o ur 1 3), st ore a n d ret ur n t heir a p plia nce. 
5.  
S u bjects will re m o ve t heir a p plia nce after 1 2 h o urs ± 3 0 mi ns of weari n g p ost t o ot h br us hi n g ( 1 3 ± 0. 5 h o urs si nce br us hi n g wit h pr o d uct) .  S u bjects will t he n ri nse a n d st ore t he a p plia nce as i nstr ucte d b y t he site staff.  
S u bjects will ret ur n t he a p plia nce t o t he st u d y site t he f oll o wi n g da y .  T he st u d y site staff will rec o ver t he 4 re mai ni n g e na mel secti o ns, t he n the a p plia nce will be clea ne d, disi nfecte d a n d st ore d at site u ntil t he ne xt treat me nt 
visit.  
6.  
A d verse E ve nts ( A Es), Seri o us A d verse E ve nts ( S A Es) a n d me dical de vice i nci de nts c ollecte d fr o m i m me diatel y after s u bject pr o vi des c o nse nt 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).  Me dical de vice i n t his st u d y is t he s u p plie d t o ot h br us h. 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
2  
I NT R O D U C TI O N  
De ntal er osi o n is t he irre versi ble l oss of t o ot h s u bsta nce b y c h e mical pr ocesses n ot i n v ol vi n g 
bacteria. It is a c yclical pr ocess, i nfl ue nce d b y de mi neralizati o n a n d re mi neralizati o n. 
De mi neralizati o n of t he e na mel s urface ca n o cc ur b y t he e x p os ure t o aci ds eit her fr o m i nter nal 
ori gi n, s uc h as gastric aci ds fr o m refl u xes, a n d or e xter nal fr o m dietar y s o urces; if of s ufficie nt 
fre q ue n c y a n d se v erit y. T he er osi ve c halle n ges i n viv o are brief a n d it’s u nli kel y t he y are a 
maj or ca use of s urface l oss w he n o cc urri n g o n t heir o w n (S hellis et al., 2 0 1 1 ), b ut t his s ofte ni n g 
of t he har d tiss ues s ur face ma kes it m ore s usce pti ble t o f urt her p h ysical wear fr o m a brasi o n 
(t o ot h br us hi n g) a n d attriti o n ( gri n di n g) res ulti n g i n tiss ue l oss.  T he pr ocess of de mi neralizati o n 
c ycles wit h re mi neralizati o n, w hic h is t he pr ocess of placi n g mi nerals bac k i nt o t he pre vi o usl y 
de mi neralize d har d tiss u e b y t he i o nic c o nstit ue nts of sali va, i deall y t o ac hie ve mi neral t hat is 
m ore resista nt t o s u bse q u e nt de mi neralizati o n (C oc hra ne et al., 2 0 1 2 ).  
It is w ell  acce pte d t h at fl u ori de c o ntai ni n g de ntifrices s h o ul d be p art of a n a p pr o priate cli nical 
ma na ge me nt strate g y f or t he pre ve nti o n of caries (Br u nelle a n d Carl os, 1 9 9 0 ) (Ste p he n, 1 9 9 3 ) 
(Bartize k et al., 2 0 0 1 ) a n d t o pr o m ote t o ot h re mi neralizati o n a n d re d u ce de mi neralizati o n 
(Feat herst o ne et al., 1 9 9 0 ) (C h o w, 1 9 9 0 ). Fl u ori de ca n b e a d mi nistere d i n m a n y differe nt f or ms, 
m ost c o m m o nl y s o di u m fl u ori de ( Na F), s o di u m m o n ofl u or o p h os p hate ( Na M F P) a n d sta n n o us 
fl u ori de (S n F 2). H o we v er, besi des t he fl u ori de f or m a n d c o nce ntrati o n, t here are ot her as pects 
of a d e ntifrice t hat ha v e a n i nfl ue nce i n t he u pta ke of fl u ori de t o e na mel as has bee n s h o w n i n 
i n vitr o a n d i n sit u i n vesti gati o ns (Barl o w et al., 2 0 0 9 , F o wler et al., 2 0 0 6 , F o wler et al., 2 0 0 9 ).  
I n vitr o a n d in sit u  er osi o n m o dels are t he m ost c o m m o nl y use d met h o d s t o i n vesti gate t he 
s h ort-ter m perf or ma nce  of ne w  de n tifrice f or m ulati o ns i n dicate d f or de nt al er osi o n (S hellis et 
al., 2 0 1 1).  C urre ntl y, t here is n o vali date d cli nical met h o d ol o g y or cli nical i n de x t o m o nit or t he 
pr o gressi o n of er osi ve t o ot h wear  a n d e na m el tiss ue l oss (S hellis et al., 2 0 1 1 ), a n d most of t he 
de vices us e d f or dete cti o n of c h a n ges i n mi neral c o nte nt ca n  o nl y be perf or me d o n s peciall y 
pre pare d s peci me ns  (Atti n, 2 0 0 6 ).  I n sit u de ntal er osi o n m o dels i n v ol ve t he use of a p plia nces 
or ot her de vic es i n t he h u ma n m o ut h t hat si m ulate t he pr ocess (Zer o, 1 9 9 5 ) a n d t he y all o w t he 
effect of a n er osi ve c halle n ge t o be e val uate d u n der i ntra oral c o n diti o ns b ut wit h s o me 
c ontr olle d e x peri me ntal varia bles. I n sit u m o dels are place d i n bet wee n t he c o nti n u u m of in 
vitr o m o dels a n d cli nical st u dies a n d ca n pr o vi de e vi de nce of t he p ote ntial effect of n e w 
t hera pies i n i n hi biti n g de mi neralizati o n a n d pr o m oti n g re mi neralizati o n (Z er o, 1 9 9 5 ). H o we v er, 
t he e xtra p olati o n of t heir res ult t o cli nicall y rele va nt e vi de nce m ust be caref ull y c o nsi dere d. 
I n t his st u d y, an  i n sit u de ntal er osi o n m o del will be use d t o i n vesti gate t he efficac y of a n 
e x peri me ntal d e ntifric e i n pr o m oti n g t he e na mel re mi neralizati o n of pre vi o usl y de mi neralize d 
(er o de d) b o vi ne e na m el.  T he e x p eri me ntal d e ntifri ce will c o nt ai n 1 1 5 0 p p m fl u ori de (as s o di u m 
fl u ori de [ Na F]) a n d 5 % w/ w p otassi u m nitrate [ K N O3], a n i n gre die nt wit h well -esta blis he d 
effic ac y at pr o vi di n g reli ef fr o m de nti nal h y perse nsiti vit y (Sc hiff et al., 1 9 9 4 , Gilla m, 1 9 9 6 ).  
T his st u d y will e m pl o y as a refere n ce c o ntr ol a mar kete d, d e nti frice i n dicate d f or er osi o n a n d 
c o ntai ni n g 1 1 0 0 p p m fl u ori de as sta n n o us fl u ori de, a n d a place b o  de ntifrice  w hic h will be 
si milar t o t he e x peri me nt al de ntifrice b ut will c o nt ai n 0 p p m fl u ori de. 
2. 1  
St u d y R ati o n al e  
T his i n sit u st u d y has bee n desi g ne d t o e val uate t he efficac y of a n e x peri me ntal de ntifrice t o 
re mi neralize pre vi o usl y de mi neralize d (er o de d) e n a mel o ver a 1 2 h o ur p eri o d.  E xisti n g cli nical 
data s u p p orts t h e a bilit y of s o di u m fl u ori de t o r e mi neralize e na mel o ver a 4 h o ur peri o d i n t his 
i n sit u m o del ( see Secti o n 2. 2 ), h o we ver t he s p ecific c o m bi nati o n of i n gre die nts (acti ves a n d 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
e xci pie nts) i n t he e x peri me ntal de ntifrice ha ve n ot bee n teste d pre vi o usl y.  A d diti o nall y, t he 
i nte n de d clai ms ass ociate d wit h t he e x peri me ntal de ntifrice re q uire a test peri o d of 1 2 h o urs 
w hic h is l o n ger t ha n pre vi o usl y e val uate d.  
W hilst t he e x peri me ntal de ntifrice will ma ke clai ms o n t he s uita bilit y of t he f or m ulati o n t o hel p 
miti gate a gai nst de nti nal h y perse nsiti vit y ( D H), t he a nti -D H perf or ma nce of 5 % K N O 3 is 
alrea d y w ell esta blis he d ( see Secti o n 2. 2 ).  D H ass ess me nts are t heref ore n ot re q uire d.  
2. 2  
B a c k gr o u n d  
T his is a ra n d o mize d, c o ntr olle d, si n gle-bli n d (t o t he de ntal e x a mi ner a n d s peci me n a n al ysts), 
si n gle-ce nter, 3 treat me nt, 3 treat me nt p eri o d cr oss -o ver, i n sit u st u d y i n ge nerall y healt h y 
s u bjects. 
T he e x peri me ntal f or m ul ati o n  teste d i n t his st u d y is base d o n t he c urre ntl y mar kete d Se ns o d y ne 
Pr o na mel de ntifric e a n d teste d i n vitr o f or s u peri or perf or ma nce.  I n or der t o s u p p ort t h e 
mar keti n g of t he de ntifri ce , a n i n sit u i n vesti gati o n c o m pari n g t he e x p eri me ntal de ntifrice wit h 
a 0 p p m fl u ori de  place b o  de ntifrice  ( pri mar y o bjecti ve) a n d wit h a rele va nt mar kete d de ntifri ce  
(sec o n dar y o bjecti ves) is nee de d t o i n vesti gate t he efficac y i n e n ha nci n g re mi neralizati o n a n d 
pre ve nti n g f urt her de mi neralizati o n.  T heref ore, t he ai m of t his st u d y is t o i n vesti gate t h e 
perf or ma n ce of a n e x peri me ntal de ntifrice f or m ul ati o n i n pr o m oti n g e na mel re mi neralizati o n 
a n d i n hi biti n g p ost -treat me nt e na mel de mi neralizati o n i n a n i n sit u er osi o n m o del, i n 
c o m paris o n wit h a 0 p p m fl u ori de  place b o  a n d wit h a mar kete d c o m petit or de ntifrice pr o d u ct. 
W he n d e ntal e na mel c o nt acts a n aci dic me di u m it ca n de mi neralize, res ulti n g i n diss ol uti o n of 
calci u m a n d p h os p hate i o ns fr o m t he h y dr o x ya p atite t hat c o nstit utes t he maj orit y of t he mi neral 
p hase of t he e na m el.  I n de ntal e na mel er osi o n, t h e diss ol uti o n occ urs p re d o mi na ntl y fr o m t he 
s urface of t he e na mel, res ulti n g i n a re d ucti o n i n t he har d ness of t he s urface.  T his ca n be 
meas ure d usi n g t he t ec h ni q ue of s urface micr o har d ness ( S M H) w here a s mall dia m o n d ( K n o o p) 
is use d t o pr o d uce a n i n de nt o n t he s urface u n der a c o ntr olle d l oa d/ d urati o n.  T he le n gt h of t h e 
i n de nt o n t he e na mel s urface ca n t he n b e meas ure d u n der a micr osc o pe a n d is directl y relate d 
t o t he har d ness of t he e na mel (t he l o n ger t he i n de nt, t he s ofter t he e na mel).  T h us, t he e xt e nt of 
re/ de mi neralizati on ca n b e e val uat e d b y meas ure m e nt of t he S M H.  
I n sit u m o dels e m pl o yi n g S M H t o meas ure t he s oft ness of de ntal e n a mel s peci me ns ca n 
t heref ore b e use d t o e val u ate t he effect of d e ntifrices o n t he re- a n d de-mi neralizati o n pr ocesses 
i n v ol ve d i n de ntal er osi o n.  T he  i n sit u m o del t o be use d i n t his st u d y has bee n e xte nsi vel y use d 
t o i n vesti gate t he perf or ma nce of t he c urre ntl y mar kete d Se ns o d y ne Pr o na mel  i n pre vi o usl y 
p u blis he d st u dies (Barl o w et al., 2 0 0 9 , Creet h et al., 2 0 2 0 , Creet h et al., 2 0 1 8 , Ma g gi o et al., 
2 0 1 0 , Ne h me et al., 2 0 1 6 , Ne h me et al., 2 0 1 9 ) a n d ot her st u dies perf or me d b y G S K C H 
.  T h e m o del c o nsists of placi n g pre vi o usl y de mi neralize d,  st erilize d 
b o vi ne e na mel s peci me ns  i ntra orall y usin g a p alatal a p plia nce.  T he e na mel s peci me ns are 
e x p ose d t o t he test treat me nts i n t he m o ut h d uri n g t he treat me nt a p plicati o n, t he n t he s peci me ns 
are all o we d t o re mi nerali ze i ntra orall y u n der t he acti o n of t he s u bject’s sali va.  T h e s p eci me ns 
are t he n re m o ve d fr o m t he palat al a p plia n ce at ti me i nter vals p ost treat me nt a n d t he e xte nt of 
re mi neralizati o n e val uate d b y c o m paris o n of t he S M H pre a n d p ost oral e x p os ure t o yiel d t he 
s urface micr o har d ness rec o ver y [ S M H R] (e x press e d as a perce nta ge).  T he e na mel s peci me ns 
ca n t he n be f urt her treat e d wit h aci d ex sit u a n d f oll o we d b y a d diti o nal S M H e val uati o ns t o 
calc ulate t he resista nce of t he re mi neralize d e n a mel t o f urt her aci d s ofte ni n g (t he aci d resista nce 
rati o [ A R R]) a n d t he c o m bi ne d i m pact of t he treat me nt on re mi neralizati o n a n d 
de mi neralizati o n (t h e rel ati ve er osi o n resista nce [ R E R]).  A d diti o nall y, t he e na mel s p eci me ns 
ca n be c he micall y a nal yz e d t o meas ure t he a m o u nt of fl u ori de i nc or p orat e d i nt o t he e na mel b y 
t he treat me nt (t he e na mel fl u ori de u pta ke [ E F U].  Ta ke n as a w h ole, t hese e n d p oi nts ca n be 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
utilize d t o e val u ate t he p erf or ma n ce of a d e ntifrice t o r e mi neralize e xisti n g er osi ve lesi o ns a n d 
hel p pr otect a g ai nst f ut ure er osi ve c halle n ges.  
I n t his st u d y, m ost of t he desi g n will be retai ne d fr o m pre vi o us st u dies (Creet h et al., 2 0 2 0 ), b ut 
t he ti me p oi nts will be m o difie d a n d perf or ma n ce will be e val uate d 4 a n d 1 2 h o urs p ost br us hi n g 
rat her t ha n after 2 a n d 4 h o urs as use d pre vi o usl y.   
2. 3  
B e n efit/ Ri s k A s s e s s m e nt  
C o m plete i nf or mati o n f or t his e x peri me nt al de ntifrice  m a y be f o u n d i n t he si n gle refere nce 
safet y d oc u me nt ( S R S D), w hic h f or t his st u d y is t he Safet y State me nt.  
W hilst t he e xact f or m ulati o n of t he e x peri me ntal de ntifrice u n d er i n vesti g ati o n ha s n ot bee n 
pre vi o usl y cli nicall y teste d, si milar pr o d ucts c o ntai ni n g s o di u m fl u ori de ha ve bee n e v al uate d 
i n cli nical st u dies (see Bac k gr o u n d Secti o n 2. 2 ).  T hese st u dies de m o nstrat e d t he a nti-er osi o n 
effic ac y a n d safet y of si milar f or m ulati o ns  c o ntai ni n g s o di u m fl u ori de .  T he acti ve i n gre di e nts 
a n d f or m ulati o n e xci pie nts c o ntai ne d i n t he st u d y de ntifrices ha ve a hist or y of safe use i n oral 
care pr o d ucts a n d are c urre ntl y use d i n mar kete d dail y use de ntifrices . 
2. 4  
M e c h a ni s m of A cti o n/I n di c ati o n  
T he test de ntifrice f or m ulati o n bei n g i n vesti gate d  c o ntai ns 0 . 2 5 4 % w/ w Na F, e q ui val e nt t o 
1 1 5 0  p p m fl u ori de  a n d 5 % w/ w K N O 3. T he efficac y of t he e x peri me ntal de ntifrice i n e n ha nci n g 
e na mel re mi neralizati o n is bei n g i n vesti gate d i n a n i n sit u i ntra oral m o del wit h b o vi ne e na mel 
s peci me ns i n healt h y s u bjects. 
3  
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 3 -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 i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o e n h a n c e r e mi n er ali z ati o n of 
e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) aft er 4 
h o ur s of i ntr a -or al e x p o s ur e . 
% S M H R at  4  hr s.  
S e c o n d ar y  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o i n hi bit d e mi n er ali z ati o n of 
e n a m el c o m p ar e d t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) aft er 4 
h o ur s of i ntr a -or al e x p o s ur e.  
% R E R at 4 hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o e n h a n c e r e mi n er ali z ati o n of 
e n a m el c o m p ar e d t o a m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 
1 1 0 0 p p m fl u ori d e aft er 4 h o ur s of i ntr a -or al e x p o s ur e . 
% S M H R at  4  hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p e ri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o e n h a n c e r e mi n er ali z ati o n of 
e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) a n d a 
m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 1 1 0 0 p p m fl u ori d e aft er 1 2 
h o ur s of i ntr a -or al e x p o s ur e . 
% S M H R at  1 2  hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o i n hi bit d e mi n er ali z ati o n of 
e n a m el c o m p ar e d t o a r ef er e n c e d e ntifri c e c o nt ai ni n g 1 1 0 0 p p m 
fl u ori d e aft er 4 h o ur s of i ntr a-or al e x p o s ur e.  
% R E R at 4 hr s.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o i n hi bit d e mi n er ali z ati o n of 
e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) a n d a 
m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 1 1 0 0 p p m fl u ori d e aft er 1 2 
h o ur s of i ntr a -or al e x p o s ur e . 
% R E R 1 2  hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o pr o m ot e fl u ori d e u pt a k e i n 
e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m fl u ori d e) a n d a 
m ar k et e d, r ef er e n c e d e ntifri c e  c o nt ai ni n g 1 1 0 0 p p m fl u ori d e aft er 4 
a n d 1 2 h o ur s of i ntr a -or al e x p o s ur e . 
E F U at  4  a n d 1 2  hr s.  
T o i n v e sti g at e t h e effi c a c y of a n e x p eri m e nt al d e ntifri c e  c o nt ai ni n g 
1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3  t o r e d u c e f ut ur e a ci d-i n d u c e d 
d e mi n er ali z ati o n  i n e n a m el c o m p ar e d  t o a pl a c e b o d e ntifri c e ( 0 p p m 
fl u ori d e) a n d a m ar k et e d, r ef er e n c e d e ntifri c e c o nt ai ni n g 1 1 0 0 p p m 
fl u ori d e aft er 4 a n d 1 2 h o ur s of i ntr a-or al e x p o s ur e . 
A R R at 4 a n d 1 2 hr s.  
T o i n v e sti g at e t h e effi c a c y of a m ar k et e d, r ef er e n c e d e ntifri c e  
c o nt ai ni n g 1 1 0 0 p p m fl u ori d e . t o e n h a n c e r e mi n er ali z ati o n, i n hi bit 
d e mi n er al i z ati o n, t o r e d u c e f ut ur e a ci d-i n d u c e d d e mi n er ali z ati o n a n d 
t o pr o m ot e fl u ori d e u pt a k e i n e n a m el c o m p ar e d  t o a pl a c e b o 
d e ntifri c e  ( 0 p p m fl u ori d e) aft er 4 a n d 1 2 h o ur s of i ntr a -or al e x p o s ur e . 
% S M H R, % R E R, E F U, A R R 
at 4 a n d 1 2 hr s.  
E x pl or at or y  
T o c al c ul at e t h e pr o p orti o n of s u bj e ct s w h o e vi d e n c e a R E R r ati o 
( % R E R 0 p p m fl u ori d e pl a c e b o a n d 5 % K N O 3  : % R E R e x p eri m e nt al 
d e ntifri c e c o nt ai ni n g 1 1 5 0 p p m fl u ori d e) > = 3 a n d > = 2. 5  
% R E R a t 4  a n d 1 2  hr s.  
S af et y  
T o a s s e s s t h e or al  t ol er a bilit y of a n  e x p eri m e nt al d e ntifri c e  
c o nt ai ni n g 1 1 5 0 p p m fl u ori d e a n d 5 % K N O 3 . 
Tr e at m e nt e m er g e nt 
a d v er s e e v e nt s  
A b bre vi ati o ns: S M H R: S urface micr o har d ness rec o ver y, R E R: Relati ve er osi o n resista nce, E F U: E na mel 
fl u ori de u pta ke, A R R: Aci d resista nce rati o , K N O3: p otassi u m nitrate. 
 
T his st u d y will be c o nsi dere d s uccessf ul if t h e e x peri me ntal de ntifrice c o ntai ni n g 1 1 5 0 p p m 
fl u ori de a n d 5 % K N O3 de m o nstrates a statisticall y si g nifica nt e n ha nce me nt of re mi neralizati o n, 
as meas ur e d b y % S M H R i n c o m paris o n wit h t he place b o d e ntifrice after 4  h o urs i ntra oral p has e.  
4  
S T U D Y D E SI G N  
4. 1  
O v er all D e si g n  
T his will be a ra n d o mize d, c o ntr olle d, si n gle ce nt er, si n gle - bli n d (t o t he de ntal e xa mi ner a n d 
s peci me n a n al ysts), 3 peri o d, 3 treat me nt, cr oss-o ver, i n sit u desi g n w h ic h c o nsists of placi n g 
pre vi o usl y de mi neralize d b o vi ne e na mel s peci me ns i ntra orall y usi n g a palatal a p plia nce a n d 
e val uati n g t he re mi neralizi n g perf or ma n ce of t he e x peri me nt al, refere nce a n d place b o 
de ntifrices 4 a n d 1 2 h o urs p ost t o ot h br us hi n g, base d o n  s urface micr o h ar d ness meas ure me nts  
of t he b o vi ne e n a mel s peci me ns .  T his st u d y will be carrie d o ut i n h ealt h y a d ults wit h a 
ma xillar y de ntal arc h s uita ble f or t he rete nti o n of t he palatal a p plia nce.  S u bjects will  be 
recr uite d fr o m a n e xisti n g pa nel (I R B #:
) of s u bjects pre -fitte d wit h a palatal 
a p plia nce. 
I n t his st u d y t here will be 7 visits, 1 scree ni n g v isit t o assess s u bject eli gi bilit y, 3  treat me nt 
v isits t o assess pr o d uct efficac y , w here t he st u d y de ntifrices  will be dis p e nse d a n d use d u n d er 
t he s u per visi o n of a s uita bl y trai ne d st u d y site pers o n nel, a n d 3 f oll o w u p visits t o perf or m a n 
O S T e xa mi nati o n, assess f or A d verse E ve nts a n d all o w t he s u bject t o ret ur n t heir pal atal 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
a p plia nce.  S ufficie nt s u b jects will be scree n e d t o ra n d o mize u p t o 3 3 s u bj ects t o st u d y treat me nt 
t o e ns ure at least 3 0 s u bjects c o m plete t he st u d y.  At scree ni n g ( Visit 1), s u bjects will gi ve t heir 
writte n i nf or me d c o nse nt  t o partici pate i n t he st u d y.  De m o gra p h y, rele va nt me dical hist or y a n d 
c urre nt me dicati o ns /treat me nts will be rec or de d, f oll o we d b y oral s oft tiss ue ( O S T) a n d oral 
har d tiss ue ( O H T) e x a mi nati o ns .  S u bjects will t he n ha ve t heir sti m ulate d a n d u nsti m ulate d 
sali var y fl o w rates m eas ure d a n d s u bjects meeti n g t he rel eva nt  st u d y criteria will tr y -i n t heir 
palatal a p plia nce a n d  be c o nsi dere d eli gi ble t o e nr oll i n t he st u d y.  E nr olle d s u bjects will t he n 
be dis pe nse d t he was h -o ut de ntifrice, t o ot h br us h a n d diar y.   
Pri or t o eac h tr eat me nt visit, t here will be a was h o ut per i o d of a mi ni m u m of 3 da ys.  D uri n g 
t his peri o d s u bjects will use t heir o w n d e ntifrice  a n d t o ot h br us h f or at l east o ne da y, a n d a 0 p p m 
fl u ori de was h o ut de ntifrice  a n d st u d y t o ot h br us h ( pr o vi de d) f or t w o da ys i m me diatel y pri or t o 
t he ne xt sc he d ule d visit (i ncl u di n g o n t he m or ni n g of t he sc he d ule d visit).   
At treat me nt visits ( Visits 2, 4 & 6), s u bjects will pr o vi de details of t heir c o nc o mita nt 
me dicati o ns a n d u n d er g o a n O S T e xa mi nati o n.   S u bject’s diaries will be re vie we d t o e ns ure 
c o m plia nce wit h t he use of t he was h -o ut de ntifrice.  S u bjects dee me d s uita ble t o c o nti n ue i n t he 
st u d y will be ra n d o mize d t o t he or der of tr eat m e nts ( Visit 2 o nl y) a n d wear a n oral pal atal 
a p plia nce h ol di n g 8 b o vi ne e n a mel s peci me ns.  Details of e na mel s peci me n pre p arati o n will be 
s pecifie d i n t he La b orat or y Pr oce d ures D oc u me nt.  T he palatal a p plia nces ( Fi g 4 -1 ) will be 
s pecificall y ma d e f or eac h eli gi ble s u bject, a n d eac h will carr y t w o plastic h ol ders c o ntai ni n g a 
t otal of ei g ht b o vi ne e n a mel s peci me ns (f o ur i n eac h h ol der).  O nce t he a p plia nce is fitte d i n t he 
m o ut h, a fi ve mi n ute e q uili brati o n peri o d will e ns ue f oll o wi n g w hic h e ac h s u bject will br us h 
t heir teet h wit h  t heir assi g ne d pr o d uct, o ne pr o d uct per treat me nt visit as descri be d bel o w.   
 
Fi g ur e 4 -1  
S c h e m ati c di a gr a m of a) i ntr a or al a p pli a n c e, b) e n a m el s p e ci m e n s’ 
h ol d er, c) e n a m el s p e ci m e n s  pl a c e d i n t h e h ol d er a n d d) p al at al 
a p pli a n c e wit h e n a m el s p e ci m e n s i n t h e m o ut h.  
 
U n der s u per visi o n w hile t he i ntra oral a p plia nce is i n place, t he s u bjects will br us h t he b uccal 
s urfaces of t heir n at ural t eet h usi n g 1. 5 ± 0. 1 g of de ntifrice a n d a s oft t o ot h br us h f or 2 5 sec o n ds 
t o creat e a sl urr y.  S u bjects will be i nstr ucte d n ot t o e x pect or ate t he sl urr y a n d will t he n s wis h 
t he sl urr y ar o u n d t heir m o ut h f or 9 5 sec o n ds t o per mit dir ect c o ntact of t he d e ntifrice sl urr y 
wit h t he e na mel s peci me ns.  After e x p ect orati n g t he sl urr y, t he s u bjects will ge ntl y ri nse t heir 
m o ut hs wit h 1 5 m L of ta p water f or 1 0 s ec o n ds b ef ore e x pect orati n g a gai n .  T he t o ot h br us h, 
h o we ver, will n ot c o me i nt o c o ntact wit h t he e na mel s peci me ns or t h e a p plia nce as t his c o ul d 
ca use a brasi o n of t he e na mel s peci me ns.   
S u bjects will t he n re mai n at t he st u d y site f or 4 h o urs p ost t o ot h br us hi n g w he n t heir a p plia nce 
will be re m o ve d (at 4 hrs ± 1 0 mi ns p ost t o ot h br us hi n g) a n d 4 desi g nate d e na mel s peci me ns will 
be wit h dra w n fr o m t he a p plia nce.  S u bjects will t he n be ser ve d a n o pti o nal l u nc h w hic h will be 
c o ns u me d wit hi n a 3 0 ± 1 0 mi n ute ti me peri o d.  T he s u bjects will t he n br us h a n d ri nse t heir 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
m o ut h wit h water, after w hic h t he y will ha ve t heir a p plia nce rei nserte d a n d be all o we d t o lea ve 
t he site.  
S u bjects will be gi v e n v er bal a n d writte n h o me i nstr ucti o ns / diar y w hic h will i nstr uct t he m t o 
re m o ve t heir a p plia n ce at 8. 5  h o urs f oll o wi n g t he t o ot h br us hi n g.  T he ti me f or re m o v al will be 
detaile d o n t he i nstr ucti o n / diar y s heet.  T he y will be a d vise d t o eat a meal of t heir c h oice o ver 
a 3 0 ± 1 0 mi n ute ti me d p eri o d, br us h t heir teet h a n d ri nse t heir m o ut h wit h water a n d refit t heir 
a p plia nce after t he 3 0 ± 1 0 mi n ute ti me d peri o d is u p.  After 1 3 ± 0. 5 h o urs f oll o wi n g t he i nitial 
br us hi n g ti m e, t he s u bject will be i nstr ucte d t o re m o ve t heir a p plia n ce, ri nse it u n der r u n ni n g 
water a n d st ore m oist i n t he s u p plie d c o ntai n er i n t heir refri gerat or o v er ni g ht.  T he ti me f or t his 
re m o val will als o be gi v e n o n t heir i nstr ucti o n/ diar y s heet.  I n a d diti on, a m e m ber  of t he st u d y 
tea m will gi ve a re mi n der call t o t he s u bject pri or t o t he c o m pleti o n of t he 1 2  h o ur i ntra oral 
e x p os ure.  S u bjects will t he n atte n d a f oll o w-u p visit ( Visits 3, 5  a n d 7) t he f oll o wi n g da y t o 
ret ur n t heir a p plia nce t o t he site a n d t o recei ve a n O S T e xa mi nati o n t o e val uate a n y p ote ntial 
oral A Es ca use d b y t h e pre vi o us da y’s pr oce d ures.  At Visit 6 o nl y t he s u bjects will ret ur n t heir 
was h o ut de ntifrice a n d a t t he fi nal p ost treat me nt visit ( Visit 7) t he s u bject will als o recei ve a n 
O H T  e xa m a n d e n d of st u d y d oc u me ntati o n  will be c o m plete d . 
T he e na m el s peci me ns will be e val uate d b ot h pri or t o a n d aft er i ntra -oral e x p os ure.  S urface 
micr o har d ness ( S M H) will be use d t o e val uate c ha n ges i n t he mi neral c o nte nt of e na mel a n d is 
use d t o calc ul ate s urface micr o har d ness rec o v er y  ( % S M H R), relati ve er osi o n resista nce  
( % R E R) a n d aci d resist a nce rati o  ( A R R).  T he i nc or p orati o n of fl u ori de i nt o t he e na mel 
s peci me ns will be assesse d b y e na mel fl u ori de u pta ke ( E F U) meas ure m e nts.  F or eac h treat me nt 
a n d s u bject, t hes e meas ure me nts will be perf or me d o n t he sa me e na mel s p eci me n as d escri b e d 
i n t he La b orat or y Pr oce d ure D oc u me nt, i n t he f o ur e na mel s peci me ns re m o ve d at eac h ti me 
p oi nt.  T he er osi ve aci d c halle n g e s, wit h a c o m merciall y a v aila ble gra p efr uit j uice, will b e 
carri e d o ut ex viv o a n d t h eref ore d o es n ot p ose a ris k t o t he s u bject’s teet h .  T he o verall st u d y 
desi g n se q ue nce of e ve nts is detaile d  i n Fi g 4 -2 , wit h a pict orial of w he n t he a p plia nce is 
w or n/re m o ve d  s h o w n i n Fi g 4 -3 . 
 
Fi g ur e 4 -2  
S c h e m ati c di a gr a m s h o wi n g fl o w of pr o c e d ur e s.  
B as eli n e S M H  
( B) 
Er osiv e c h all e n g e 1  
P ost er osi o n S M H  
( E 1) 
E n a m el s p eci m e ns 
pl ac e d in a p pli a nc e  
Intr a or al a p pli a nc e pl ac e d 
i n s u bj ect’s m o ut h 
5 mi n e q uili br ati o n  
2 5 s ec t o ot h br us hi n g  
9 5 s ec s wirli n g  
S u bj ect r e m o v es 
a p pli a nc e f or 3 0 mi n ut es 
t o e at l u nc h ( 4 h o urs p ost 
br us hi n g) a n d di n n er ( 8. 5 
h o urs p ost br us hi n g).  
S u bj ect r e m o v es a n d 
st or es a p pli a nc e 1 3 h o urs 
p ost br us hi n g ( 1 2 h o urs 
i ntr a or al ex p os ur e) 
P ost er osi o n S M H  
( E 2) 
Er osiv e c h all e n g e 2  
P ost  r e mi n S M H  
( R) 
M e as ur e m e nt  
Ex viv o  a ci d ex p os ur e 
I n sit u 
4 E n a m el s p eci m e ns 
r e m o v e d fr o m 
a p pli a nc e aft er  4 hrs 
a n d 1 2  hrs  i ntr a or al 
ex p os ur e  
L e g e n
s p eci m e ns pr oc ess e d 
t hr o u g h st eriliz er 
E F U  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
Fi g ur e 4 -3  
S c h e m ati c di a gr a m s h o wi n g i n s erti o n a n d r e m o v al of p al at al d e vi c e 
o v er t h e 1 3 h o ur st u d y d a y.  
 
A Es a n d me dical de vic e i nci de nts will be m o nit ore d f or a n d rec or de d at e ver y site visit 
f oll o wi n g si g ni n g of i nf or me d c o nse nt. 
4. 2  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  
T he pr ocesses of re mi neralizati o n a n d de mi neralizati o n ass ociate d wit h d e ntal e na mel er osi o n 
ca n n ot c urre ntl y be e val uate d i n viv o si nce t he tec h ni q ues re q uire d t o assess t hese are 
destr ucti ve t o e na m el.  A n i n sit u desi g n utilizi n g e na mel s peci me ns is t heref ore a p pr o pri ate.  
T he a p plia nces a n d t h e p ositi o ni n g of t he e na mel s peci me ns will be u ni q ue f or eac h i n di vi d ual 
s u bject, a n d s o t he m ost a p pr o priate met h o d t o e val uate t he perf or ma nce of t he t hree de ntifri ces 
i n t his st u d y is a wit hi n s u bject c o m paris o n, a n d t heref ore a cr oss o v er desi g n will be use d f or 
t his st u d y. 
T h e a bilit y f or fl u ori de t o re har de n/r e mi neralize aci d-s ofte n ed e na mel has bee n o bser ve d  as 
earl y as 1 h after de ntifrice  use i n i n sit u e x peri me ntal  c o n diti o ns si milar t o t h ose use d h ere a n d 
see n t o pr o gressi vel y i ncrease after 2 a n d 4 h (Ne h me et al., 2 0 1 9 ).  E val uati o n of t he effect of 
t he e x peri me ntal de ntifri ce after 4 a n d 1 2 h o urs i ntra oral re mi neralizati o n is t heref ore e x p ecte d 
t o be s ufficie nt ti me f or meas ura ble b e nefits t o be o bser ve d.  Ti me i nter vals of l o n ger t ha n 1 2 
h o urs ma y n ot be i nf or mati ve gi ve n t he rec o m me n dati o ns pr o vi de d b y t he A merica n De ntal 
Ass ociati o n f or effecti ve t o ot h br us hi n g (A D A, 2 0 2 2 ) i ncl u de br us hi n g teet h t wice dail y. 
T he S M H tec h ni q ue us e d here t o e val uate t he mi nera lisati o n state has b ee n wi del y use d i n ma n y 
pre vi o us st u dies w here it has pr o ve n t o be s ufficie ntl y se nsiti ve t o detect c ha n ges i n t he mi neral 
c o nte nt of de nt al e na m el (Barl o w et al., 2 0 0 9 , Creet h et al., 2 0 1 5 , Z er o et al., 2 0 0 6 , Li p pert a n d 
L y n c h, 2 0 1 4, Ne h m e et al., 2 0 1 9 ).  T h e tec h ni q u e ca n t heref ore be c o nsi dere d a p pr o priat e f or 
t he e val uati o n of t he e n d p oi nts i n t his st u d y. 
B o vi ne e na mel is use d i n t his st u d y as a m o del f or H u ma n e n a mel.  B o vi ne e na mel has 
pre vi o usl y bee n de m o nstrate d t o be a s uita ble s u bstit ute f or er osi o n st u dies (W hite et al., 2 0 1 0 ).  
T he a d va nt a ges of B o vi ne o ver H u ma n e na mel are t hat lar ger s peci me ns of B o vi ne e na mel ma y 
be o btai ne d ( o wi n g t o lar ger t o ot h size), great er a vaila bilit y of B o vi ne e na mel a n d m ost 
i m p orta ntl y t hat B o vi ne e na mel is s u bsta ntiall y fl u ori de-free c o m pare d t o H u ma n e na mel t hat 
has  bee n s u bjecte d t o fl u ori date d water s u p pl y / de ntal pr o d ucts.  
A 2 -da y w as h o ut peri o d w here t h e s u bjects d o n ot use a n y oral h ealt h pr o d uct c o ntai ni n g 
fl u ori de, is re q uire d pri or t o eac h treat me nt visit t o e ns ure n o resi d ual fl u ori de resi des i n t he 
m o ut h t hat c o ul d c o m pr o mise t he a bilit y t o acc uratel y assess t he efficac y of t he test pr o d ucts.  
Base d o n e x p erie n ce fr o m pre vi o us st u dies, t w o d a ys are s ufficie nt t o mi ni mize a n y carr y -o v er 
effect.   S u bjects will use t heir o w n d e ntifrice f or at least 1 da y b et we e n st u d y peri o ds t o e ns ure 
s ufficie nt e x p os ure t o fl u ori de t o pr o vi de a n a nti-caries be n efit.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
Acc or di n g t o t he I nter nati o nal C o nfere nce o n Har m o nisati o n  (I C H) g ui deli nes  (I C H, N o v 
2 0 1 6 ), f or a st u d y t o be classifie d as tr ul y d o u ble-bli n d, n ot o nl y d oes t he e xa mi ner (a n d a n y 
a p pr o priate me m ber of staff w h o ma y be i n v ol ve d i n t he  dis pe nsi n g of pr o d ucts, a nal ysis of 
data  etc.) nee d t o be bli n d  t o t he treat me nt a s u bject recei ves, b ut t h e pr o d ucts u n der t est m ust 
be i de ntical i n e v er y wa y (c ol or, fla v or,  r he ol o g y, a p peara nce, pac ka gi n g).  Gi ve n t h e 
e x peri me ntal de ntifrices a n d t he r efere nce d e ntifrice will differ i n a p p eara nce a n d fl a v or , t he 
le vel of bli n d ness f or t his st u d y is descri be d as ‘e xa mi ner bli n d’ o nl y.  T he st u d y will be bli n de d 
wit h res pect t o t he de ntal e xa mi ner a n d e na mel s p eci me n a nal ysts t o e ns ure t here is n o bias i n 
t he assess me nts. 
F or t he pri mar y o bje cti ve of t his st u d y, a 0 p p m fl u ori de  place b o de ntifri ce will be use d as 
c o m parat or t o est a blis h if t he fl u ori de pres e nt i n t he e x peri me ntal de ntifrice ca n pr o vi de 
e n ha nce me nt of re mi neralizati o n a n d pre v e nti o n of de mi n eralizati o n i n t his i n sit u m o del. 
A d diti o nall y, a rele va nt c o m merciall y a vaila ble fl u ori de -c o ntai ni n g  de ntifrice will be use d as a 
Refere n ce (s ec o n d ar y o bjecti ves) t o i n vesti gate t he s u peri or perf or ma nce of t he e x peri me ntal 
de ntifrice i n e n h a nci n g r e mi ner alizati o n a n d pre v e nti n g de mi neralizati o n.  
W hilst t he i n di vi d ual pr o d ucts bei n g teste d i n t his st u d y are n ot c o ntra -i n dicate d f or pre g na n c y 
a n d use of t he m w o ul d n ot be e x pecte d t o ca us e h ar m eit her t o t he m ot her or f oet us, pre g na nt 
fe males will be e xcl u de d fr o m t his st u d y d u e t o t he i ncreas e d pre vale nce a n d se v erit y of 
gi n gi vitis a n d peri o d o ntal disease al o n g wit h i ncreas e d a m o u nts of calc ul us a n d pla q ue 
o bser ve d wit h pre g n a nc y.  T he se verit y of t hese c o n diti o ns is k n o w n t o var y d uri n g t he c o urse 
of pre g n a nc y (Sa ma nt et al., 1 9 7 6 ), a n d t h us pre g na nc y w o ul d b e a c o nf o u n di n g fact or of t h e 
o bjecti ves i n t his st u d y.  Pre g na nt fe males a n d t h ose i nte n di n g t o bec o me pre g na nt are t h us 
e xcl u de d i n t his st u d y.  Pre g na nc y wil l be e val u ate d t hr o u g h self-re p orte d pre g na nc y stat us b y 
s u bjects. 
4. 3  
J u stifi c ati o n f or D o s e  
S u bjects will use t heir assi g ne d de ntifrices f or 2 mi n utes, i n a gree me nt wit h rec o m me n d ati o ns 
pr o vi de d b y t he A merica n De ntal Ass ociati o n f or effecti ve t o ot h br us hi n g (A D A, 2 0 2 2 ) a n d t o 
ali g n wit h pre vi o us si milar cli nical st u dies perf or me d b y t he s p o ns or (Barl o w et al., 2 0 0 9 , 
Creet h et al., 2 0 2 0 ). 
O n eac h br us hi n g occasi o n, t he t o ot h br us h will b e d ose d wit h 1. 5 ± 0. 1 g of d e ntifrice.  T his d ose 
is i n li ne wit h t he pr o p ose d pr o d uct la belli n g f or t he e x peri me ntal de ntifrice a n d t he c urre nt 
pr o d uct la b elli n g f or t h e mar kete d refere nce de ntifrice.  W hilst t he pr o d uct l a bel will n ot c o ntai n 
details of a mass of d e ntifrice t o be use d, f or t his st u d y desi g n it is i m perati ve t hat a sta n dar dize d 
d ose is utilize d t o a v oi d bet wee n s u bject/ peri o d differe n ces.  1. 5 g is c o nsi dere d t o be c o nsiste nt 
wit h t he pr o d uct la bel w hic h details a f ull -br us h hea d of de ntifrice t o be use d.  
N o d ose m o dificati o n is per mitte d i n t his st u d y.  A n y v ariati o n fr o m t he pr o d uct usa g e 
i nstr ucti o ns s h o ul d be c o m m u nicate d t o st u d y site pers o n nel a n d rec or de d as a de viati o n. 
4. 4  
E n d of St u d y D efi n iti o n 
A s u bject is c o nsi dere d t o ha ve c o m plete d t h e st u d y if t he y ha ve c o m plete d all p hases of t h e 
st u d y, i ncl u di n g t he last visit or t he last s c 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 St u d y is defi ne d as t he dat e of t he l ast la b o rat or y testi n g rel ate d t o pri mar y a n d 
sec o n dar y e n d p oi nts, t o be ac hie v e d n o later t ha n 2  m o nt hs after t he date of t he last s u bject last 
visit . 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
5  
S T U D Y P O P U L A TI O N  
5. 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  
V ol u nteers of eit her s e x a n d a n y g e n der, a ge d 1 8 –  6 5 years  will be recr uit e d w h o c o m pl y wit h 
t he i ncl usi o n a n d e xcl usi o n criteria.  S u bjects will be i nitiall y recr uite d fr o m t he st u d y site’s 
data base, alt h o u g h a d diti o nal s u bjects fr o m o utsi de of t he data base ma y be recr uite d if re q uir e d.  
S ufficie nt s u bjects will be scree ne d t o ra n d o mize u p t o 3 3  s u bjects t o e ns ure at least 3 0 
e val ua ble s u bjects c o m plete t he e ntire st u d y.  
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 directl y or v ia t heir le gall y a ut h orize d 
re pres e ntati ve 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 select 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 dit i 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 her 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 partici pate 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 tea m be f ore s u bjects are i n cl u de d i n t he st u d y. 
5. 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, 
a n d c o nti n ua nce i n t he st u d y:  
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 d icati n g t hat t he 
s u bject has bee n i nf or me d of all perti ne nt as pects of t he st u d y bef ore a n y assess me nt is 
perf or me d.  
2.  S u bject is of eit her se x a n d a n y ge n der w h o, at t h e ti me of scree ni n g, is bet wee n t he a g es 
of 1 8 -6 5 years, i ncl usi ve.  
3.  S u bject is willi n g a n d a ble t o c o m pl y wit h sc he d ule d visits, a n d ot her st u d y pr oce d ures 
a n d restricti o ns.  
4.  S u bject is i n g o o d ge neral a n d me ntal healt h wit 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, n o cli nicall y si g nifica nt or rele va nt a b n or malities i n me dical 
hist or y or u p o n oral e xa mi nati o n , or c o n diti o n, t hat w o ul d i m pact t he s u bject’s safet y, 
well bei n g or t he o utc o me of t he st u d y, if t he y were t o partici pate i n t he st u d y, or affect t he 
i n di vi d ual’s a bilit y t o u n dersta n d a n d f oll o w st u d y pr oce d ures a n d re q uire me nts . 
5.  S u bject wit h ge nerall y g o o d oral healt h t hat f ulfil all of t he f oll o wi n g:  
a. Ha vi n g  a n unsti m ulate d sali var y fl o w rate of at least 0. 2 m L/ mi n ute a n d a 
sti m ulate d sali var y fl o w rate of at least 0. 8 m L/ mi n ute. 
b.  Ha vi n g a m a xillar y de nt al arc h s uita ble f or t he ret e nti o n of t he palatal a p pli a nce . 
c. Ha vi n g n o lesi o ns of t he oral ca vit y t hat c o ul d i nterfere wit h t he st u d y e val u ati o ns.  
5. 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 xcl 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.  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 a me m ber of t heir i m me diate fa mil y; or a n e m pl o yee of t he 
i n vesti gati o nal site ot her wise s u per vise d b y t he i n vesti gat or; or, a Hal e o n  e m pl o yee 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
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 a me m ber of t heir i m me diate fa mil y  
(em pl o yees of t he st u d y site a n d ass ociate d aca d e mic i nstit utes w h o are n ot directl y 
i n v ol ve d i n t he c o n d uct of t he st u d y are eli gi ble t o be c o nsi dered as s u bjects .) 
2.  S u bject w h o has partici p ate 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 o d uct(s) wit hi n 3 0 da ys pri or t o st u d y e ntr y a n d/ or d uri n g st u d y 
partici pati o n.  
3.  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 ualifie d  desi g nee,  a n ac ute 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 malit y t hat ma y i ncreas e t he 
ris k ass ociate d wit h st u d y partici 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 j u d g me nt of t he i n vesti gat or or 
me dicall y q ualifie d desi g nee, w o ul d ma ke t h e s u bject i na p pr o pri ate f or e ntr y i nt o t his 
st u d y. 
4.  S u bject w h o is pre g na nt (self -re p orte d) or i nte n di n g t o bec o me pre g n a nt o v er t he d urati o n 
of t he st u d y  or w h o is breastfee di n g.  
5.  S u bject wit h k n o w n or s us pecte d i nt olera n ce or h y perse nsiti vit y t o t he st u d y materials ( 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 die nts.  
6.  A 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 ualifie d de si g nee, ca n’t 
c o m pl y wit h st u d y re q uire me nts or w h o s h o ul d n ot partici pate i n t he st u d y f or ot her 
reas o ns. 
7.  S u bject u n willi n g or u na ble t o c o m pl y wit h t he Lifest yle C o nsi derati o ns  descri be d i n t his 
pr ot oc ol.  
8.  S u bject ta ki n g m e dicati o n t hat ma y i nterfere si g nifica ntl y wit h t he sali va fl o w  i n t he 
j u d g me nt of t he i n vesti gat or. S h o ul d ne w me dicati o ns t hat ma y i nterfere wit h t he sali va 
fl o w be a d de d, a sec o n d sali var y fl o w test will be perf or me d.  
9.  S u bject wit h  a n y c o n diti o n t hat w o ul d i m pact o n t he ir safet y or well bei n g or affect t heir  
a bilit y t o u n dersta n d a n d f oll o w st u d y pr oce d ures a n d re q uir e me nts.   
1 0.  S u bject wit h a n y si g n of gr ossl y cari o us lesi o ns (acti ve), m o derate or se v ere p eri o d o n tal 
c o n diti o ns, or se v ere t o ot h wear . S u bject prese nti n g at scree ni n g wit h mi n or caries ma y 
c o nti n ue i n t he st u d y if t heir cari o us lesi o ns are re paire d pri or t o t he first treat me nt visit of 
t he st u d y. 
1 1.  S u bject w h o w ears a n oral pierci n g or oral a p plia nce or  ort h o d o ntia ( besi d es s u bjects 
weari n g per ma ne nt l o w er retai ners, w hi c h are eli gi ble).  
1 2.  S u bject w h o has pre vi o usl y bee n e nr olle d i n t his st u d y.  
5. 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 ha ve satisfie d all s u bject select i o n 
criteria.  
5. 5  
Lif e st yl e C o n si d er ati o n s  
T he cli nical site ma y c o ntact s u bjects t o re mi n d t he m of lifest yle restricti o ns a n d a p pr oac hi n g 
sc he d ule d visits. 
5. 5. 1  
Or al H y gi e n e R e stri cti o n s  
D uri n g t he e ntire st u d y:  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
•  S u bjects will be as ke d t o st o p usi n g t he ir o w n de ntifrice t w o da ys b ef ore Visit 2, 4 a n d 6, 
w he n t he y will use t he pr o vi de d 0 p p m fl u ori de  was h o ut de ntifrice a n d t o ot h br us h t o br us h 
t heir teet h (i ncl u di n g i n t he m or ni n g of t he sc he d ule d Visit).  
•  S u bjects will n ot be per mitte d t o use a n y fl u ori de -c o ntaini n g pr o d ucts (i ncl u di n g 
de ntifrices a n d m o ut h w as hes) f or 2 da ys pri or t o Visit 2, 4 a n d 6.  
•  S u bjects will be re q ueste d n ot t o ha ve a n y electi ve de ntal pr oce d ures i ncl u di n g teet h 
pr ofessi o nall y cle a ne d ot her t ha n t h ose perf or me d wit hi n t he st u d y (e xcl u di n g  e mer ge n c y 
de ntal treat me nt).  
Visit 2, 4  a n d 6 : 
•  S u bjects s h o ul d refrai n fr o m tal ki n g f or t he first h o ur after br us hi n g o n eac h treat me nt 
visit.  
•  S u bjects s h o ul d n ot lea ve t he st u d y site d uri n g t he first 4. 5 h o urs of eac h treat me nt visit 
u ntil after t he e na m el s pe ci me ns ha ve bee n re m o ve d a n d t he a p plia n ce h as bee n re -
i nserte d p ost l u nc h. 
•  S u bjects s h o ul d refrai n fr o m slee pi n g w hile weari n g t heir palatal a p plia nce.  
5. 5. 2  
M e al s a n d Di et ar y R e stri cti o n s  
Visit 2, 4  a n d 6 : 
•  S u bjects m ust a bstai n fr o m all f o o d a n d dri n k ( e x ce pt water) at least 3 0 mi n utes  pri or t o  
Visits 2, 4 a n d 6.  
•  S u bjects will n ot be per mitte d t o dri n k f or t he first t w o h o urs of t he i ntra oral test peri o d 
(after treat me nt a d mi nistr ati o n) b ut ma y dri n k wat er aft er t his u n der t he s u p er visi o n of t he 
st u d y pers o n nel.  T he y m a y dri n k water at h o me, as desire d.  T he p alatal a p plia nce m ust 
be re m o ve d b ef ore dri n ki n g water a n d re -i ns erte d i m me diatel y after. 
•  S u bjects will n ot be per mitte d t o eat w hile weari n g t heir i ntra oral a p plia nce.  T he y ca n 
o nl y eat i n t he 3 0 ± 1 0 mi n ute peri o ds desi g nate d f or l u nc h a n d di n ner w he n t he a p plia nce 
is re m o ve d fr o m t he m o ut h. 
•  S u bjects will be all o we d a 3 0 ± 1 0 mi n ute l u nc h ti me t o c o ns u me a meal after t he 
c o m pleti o n of t he 4 h o ur i ntra oral p hase ( wit h t heir a p plia nce re m o ve d).  Pri or  t o lea vi n g 
t he site s u bjects will br us h t heir teet h a n d ri nse t h eir m o ut h wit h water a n d ha ve t heir 
a p plia nce refitte d a n d t he site staff will pr o vi de oral a n d writte n i nstr ucti o ns / diar y f or t he 
re mai n der of t he da y.   
•  At h o me t he s u bjects will be a d vise d t o eat a meal of t heir c h oice o ver a 3 0 ± 1 0  mi n ute 
peri o d wit h t heir palatal a p plia nce re m o ve d bet w ee n h o urs 8. 5 a n d 9 f oll o wi n g treat me nt 
br us hi n g.  S u bjects will t he n br us h t heir teet h a n d ri nse t heir m o ut h wit h water  a n d refit 
t heir a p plia nce at t he e n d of t he all otte d 3 0 ± 1 0  mi n ute peri o d.  
5. 5. 3  
Al c o h ol a n d T o b a c c o  
D uri n g Visit 2, 4  a n d 6 : 
•  S u bjects will n ot be per mitte d t o s m o ke, use c he wi n g t o bacc o  or va pe, dri n k alc o h ol or 
c he w g u m d uri n g t he tr eat me nt da ys fr o m i nserti o n of t heir a p plia nce u ntil it is re m o ve d 
after 1 2 h o urs of i ntra oral e x p os ure . 
5. 5. 4  
M e di c ati o n a n d Tr e at m e nt R e stri cti o n s  
•  T he details of c urre nt a n d c o nc o mita nt me dicati o ns will be c ollecte d, a n d s u bjects will be 
all o we d t o partici pate if t hese me dicati o ns are j u d ge d t o be n o n -i nterferi n g b y t he 
i n vesti gat or as per i ncl usi o n a n d e xcl usi o n criteri a. 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
•  S u bjects m ust use o nl y t he de ntifrice a n d t o ot h br us h pr o vi de d bet wee n st u d y visits.  
S u bjects s h o ul d n ot use a n y ot her oral h y gie n e pr o d uct ot her t ha n  t h ose s u p plie d. 
•  S h o ul d a s u bject be gi n a c o urse of me di cati o n t hat c o ul d i n d uce xer ost o mia, sali var y fl o w 
f or t hat s u bject will be re-assesse d t o e ns ure c o m plia nce t o i ncl usi o n criteri a 5a.  
5. 5. 5  
C o ntr a c e pti o n  
T here are n o c o ntrace pti o n re q uire me nts f or s u bj ect s partici pati n g i n t his st u d y.  At eac h visit, 
fe male s u bjects of c hil d-beari n g p ot e ntial s h o ul d ver ball y c o nfir m t he y are n ot c urre ntl y 
pre g na nt or pla n ni n g t o b ec o me pre g na nt.  
5. 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 mize d.  T o e ns ure tra ns pare nt re p orti n g of scree n fail ure s u bjects, a 
mi ni mal set of scree n fail ure i nf or mati o n will  be c ollecte d,  i ncl u di n g d e m o gra p h y, reas o n f or 
scree n fail ure (e. g. wit h dra wal of c o nse nt), eli gi bilit y criteria, a n y pr ot oc ol de viati o ns a n d a n y 
a d verse e ve nts or i nci d e nts 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. 
5. 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 pri atel y q ualifie d me dical/ de nt al pers o n nel f or t he 
st u d y is d oc u me nte 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 nta ct n u m ber is o nl y t o be use d b y site 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 ve nt t hat t he esta blis he d c o m m u nicati o n pat h wa ys bet wee n t he st u d y site 
a n d t he s p o ns or’s st u d y tea 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 -relate 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 ntact 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 st u d y site, a n d c o ntact details i n t he e ve nt t hat t he st u d y site ca n n ot be reac h e d t o pr o vi de 
a d vice o n a me dical q uesti o n or pr o ble m i de ntifie d b y a healt hcare pr ofessi o nal ot her t ha n t he 
i n vesti gat or. 
5. 8  
Cli ni c al A s s e s s or R at er/ Cli ni c al A s s e s s or Q u alifi c ati o n s  
Cli nical e xa mi ner (s) i n v ol ve d i n t he scree ni n g, a n d safet y assess me nts will be a p pr o priatel y 
q ualifie d de ntal pr ofessi o nals, re gistere d t o practice i n t he U S.  La b orat or y pers o n nel i n v ol ve d 
i n a nal ysis a n d pre p arati o n of t he e na m el bl oc ks will be a p pr o pri atel y e x p erie nce d a n d tr ai ne d. 
Oral e x a mi nati o ns t o deter mi ne s u bject eli gi bilit y a n d t o m o nit or t he safet y/ perf or ma nce of 
st u d y pr o d ucts will be perf or me d b y a p pr o priat el y trai ne d cli nical e xa mi ner(s), wit h pri or 
rele va nt cli nical e x peri e n ce.   
6  
I N V E S TI G A TI O N A L/ 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 u i deli 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 a n y i n vesti gati o nal 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
i nter ve nti o n(s), mar ket e d pr o d uct(s), place 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 uc t wit h a mar keti n g a ut h ori zati o n w he n us e d or ass e m ble d (f or m ulate d or 
pac ka g e 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.  
6. 1  
I n v e sti g ati o n al/ St u d y Pro 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 will 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 6 -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 
 
Test  De ntifri ce  
Pl ace b o  C o ntr ol  
De ntifrice  
Refere nce De ntifri ce  
Pr o d uct Descri pti o n  
E x peri me ntal 
De ntifrice  c o ntai ni n g 
1 1 5 0 p p m fl u ori de 
a n d 5 % K N O 3 
0 p p m fl u ori de  
place b o de ntifrice 
c o ntai ni n g 5 % K N O 3 
Crest Pr o -Healt h 
De nsif y Dail y 
Pr otecti o n [ 1 1 0 0 p p m 
fl u ori de as S n F 2] 
Pr o d uct M aster 
F or m ul ati o n C o de 
( M F C) 
 
 
C o m mercial pr o d uct 
–  U S Mar ket place  
P ac k Desi g n  
S u p plie d i n plai n w hite t o ot h paste t u bes  
S u p plie d i n 
o ver wra p pe d 
c o m mercial t u bes  
Dis pe nsi n g Det ails  
St u d y staff t o wei g h 1. 5 ± 0. 1 g of de ntifrice o nt o t h e s u p plie d br us h.  
D ose/  Pr o d uct 
A p plic ati o n  
S u bjects will use  1. 5 ± 0. 1 g of t he all ocate d pr o d uct a n d b r us h t he 
b uccal s urfaces of t heir n at ural teet h f or 2 5 ti me d sec o n ds a n d t he n 
s wis h t he res ulti n g de ntifrice sl urr y ar o u n d t he m o ut h, wit h o ut f urt her 
br us hi n g, f or a ti me d peri o d of 9 5 sec o n ds.  Aft er e x pect orati n g t he 
sl urr y, t he s u bjects will ge ntl y ri nse t heir m o ut hs wit h 1 5 m L of ta p 
water f or 1 0 sec o n ds b ef ore e x pect orati n g a g ai n.  A p plicati o n will be 
u n der s u per visi o n of t he st u d y sta ff. 
R o ute of 
A d mi nistr ati o n  
Oral t o pical  
Ret ur n 
Re q uire me nts  
Use d a n d u n use d st u d y pr o d uct t o be ret ur n e d t o t he s p o ns or  
 
T a bl e 6 -2  
W a s h o ut Pr o d u ct S u p pli e s  
 
W a s h o ut D e ntifri c e  
Pr o d u ct N a m e  
0 p p m fl u ori d e , 5 % p ot a s si u m nitr at e W a s h o ut D e ntifri c e 
P a c k D e si g n  
S u p pli e d i n st a n d ar d w hit e t o ot h p a st e t u b e s.  
Di s p e n si n g D et ail s  
O n e t u b e at s cr e e ni n g  
Pr o d u ct M a st er 
F or m ul ati o n C o d e ( M F C)  
 
D o s e/ A p pli c ati o n  
F ull ri b b o n of d e ntifri c e  o n h e a d of t o ot h br u s h pr o vi d e d  
R o ut e of A d mi ni str ati o n  
Or al t o pi c al  
U s a g e I n str u cti o n s  
S u bj e ct s will br u s h t h eir t e et h a c c or di n g t o t h eir n or m al br u s hi n g h a bit s 
t wi c e a d a y ( m or ni n g a n d e v e ni n g) 
R et ur n R e q uir e m e nt s  
U s e d a n d u n u s e d w a s h o ut d e ntifri c e t o b e r et ur n e d t o t h e s p o n s or 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
T a bl e 6 -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:  
It e m 
S u p pli e d 
B y  
P a c k D e si g n  
Di s p e n si n g 
D et ail s  
R et ur n/ Di s p o s al D et ail s  
U s e d S a m pl e s  
U n u s e d 
S a m pl e s  
Or al -B S e n si S oft 
M a n u al T o ot h br u s h  
( e xtr a s oft) [ U S A 
M ar k et pl a c e]  
H al e o n  
I n di vi d u al 
t o ot h br u s h 
2  at e a c h 
tr e at m e nt vi sit.  1 
pr o vi d e d at 
s cr e e ni n g  
D e str o y at sit e 
u si n g sit e 
di s p o s al 
pr o c e d ur e s  
R et ur n  
C o u nt d o w n Ti m er s  
H al e o n  
I n di vi d u al 
s u p pli e d i n 
c o m m er ci al 
p a c k  
Ti m er s r e m ai n at 
t h e st u d y sit e, 
t h e y ar e n ot 
di s p e n s e d  
D e str o y at sit e 
u si n g sit e 
di s p o s al 
pr o c e d ur e s  
R et ur n  
D o si n g c u p s  
H al e o n  
C o m m er ci al 
p a c k  
1 at e a c h 
tr e at m e nt vi sit  
D e str o y at sit e 
u si n g sit e 
di s p o s al 
pr o c e d ur e s  
R et ur n  
All ot her s u n dr y ite ms s uc h as s ali va sa m pli n g c ollecti o n e q ui p me nt a n d u nfla v ore d g u m  will 
be s u p plie d b y t he st u d y site.   Gra pefr uit j uice (c o m merciall y a v aila ble) f or t he ex viv o aci d 
c halle n ge will als o be s o urce d b y t he st u d y 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 b e pr o vi d e d b y t he s p o ns or 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. 
Ot her materials re q uir e d f or t he st u d y e g B o vi ne e na mel bl oc ks a n d m a n ufact ure of t he p alatal 
a p plia nces are d etaile d i n t he la b orat or y pr o ce d ures d oc u me nt or  
 S O Ps.  
6. 1. 1  
M e di c al D e vi c e s  
T he t o ot h br us hes t o be use d i n t his st u d y are me dical de vices . 
All de vice deficie nci es, (i ncl u di n g malf u ncti o n, use err or a n d i na de q u ate la belli n g) s hall be 
d oc u me nte d, a n d re p orte d b y t he i n vesti gat or t hr o u g h o ut t he cli nical i n vesti gati o n (see Secti o n 
1 0. 1 0 ) a n d a p pr o priatel y ma na ge d b y t he s p o ns or. 
6. 1. 2  
D o s a g e F or m a n d P a c k a gi n g  
T he st u d y pr o d ucts are de ntifric es, 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 b r us h. 
T he  e x peri me ntal , was h o ut a n d place b o c o ntr ol de ntifrice s will be ma n ufact ure d a n d fille d i nt o 
plai n w hite t u bes b y t h e s p o ns or; t he refere nce d e ntifrice will be s u p plie d i n its c o m mercial 
pac k.  All st u d y de ntifric es will be eit her o ver wra p p e d i n w h ite vi n yl [t he c o m mercial Refere n ce 
Pr o d uct] or pr o vi de d i n a plai n w hite t u be [ pl ace b o  c o ntr ol a n d T est De ntifrice] (t o mas k t heir 
i de ntit y a n d o bsc ure t he bra n di n g of t he mar ket e d pr o d uct) wit h a st u d y la bel affi x e d. T h e 
c o nte nt of t he pr o d uct la bels wil l be i n acc or da nce wit h all a p plica ble 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 he s p o ns or’s Cli nical  S u p plies G r o u p. Eac h st u d y la 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.  
Eac h s u bject will be pr o vi de d wit h a sta n dar di ze d d ose of t heir assi g ne d st u d y de ntifrice 
wei g he d b y t he st u d y site.  
S u n dr y ite ms will be s u p plie d i n t heir  c o m mercial pac ka gi n g f or dis pe nsi n g b y st u d y staff as 
s pecifie d i n Ta ble 6. 2  a n d Ta ble 6. 3  res p ecti vel y.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
Care s h o ul d be t a ke n wit h t he s u p plie d pr o d ucts a n d t heir la bels s o t hat t h e 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 be i nstr ucte d t o n ot re m o ve or deface a n y part of t h e 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.  
6. 1. 3  
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 st u d y treat me nt i n acc or da n ce wit h t he ra n d o mizati o n sc he d ul e 
ge nerat e d b y t he st u d y s p o ns or, pri or t o t he start of t he st u d y, usi n g vali date d s oft ware.  
T he pr o d uct dis pe nsi n g a rea will be se parate fr o m t he cli nical e xa mi nati o n area. St u d y 
de ntifrices will be dis pe nse d t o t he s u bject, b y trai ne d site 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 s afet y/ pr o d uct perf or ma n ce 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 t he k n o wle d ge of pr o d uct a s u bject has bee n assi g ne d t o. A n 
a d diti o nal me m ber of t he site staff 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.  
6. 2  
A d mi ni str ati o n  
O nl y s u bjects e nr olle d i n t he s t u d y ma y recei ve st u d y pr o d ucts  a n d o nl y a ut h orize d site staff 
ma y s u p pl y or a d mi nister st u d y pr o d ucts . All st u d y i nter ve nti o ns m ust be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr oll e d, a n d m o nit ore d ( ma n u al or a ut o mat e d) area i n acc or da nce wit h t he 
la bele d st ora g e c o n diti o ns wit h access  li mite d t o t he a ut h orize d site staff o nl y . 
S u bjects will be i nstr ucte d t o a d mi nister  t heir assi g ne d pr o d uct per t he usa ge i nstr ucti o ns 
pr o vi de d t o t he s u bject  u n der s u per visi o n b y a m e m ber of t he st u d y site w h o will n ot be i n v ol ve d 
i n a n y safet y/ pr o d uct perf or ma nce 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 t he k n o wl e d ge of pr o d uct a s u bject has bee n assi g n e d t o.  
O n -site a d mi nistrati o n  of st u d y pr o d ucts will als o be rec or de d i n t he C R F.  
I nstr u cti o ns o n usa ge of t he st u d y pr o d ucts are det aile d i n T able 6 -1 . 
S u bjects s h o ul d e ns ure t he y c o m pl y wit h t he oral h y gie ne restricti o ns ( Secti o n 5. 5. 1 ), 
partic ularl y t o e ns ur e t hat t he 0 p p m fl u ori de  was h o ut de ntifrice is use d f or 2 d a ys pri or t o a 
treat me nt visit, a n d t hat n o ot her de ntifrice/ m o ut hri nse is use d i n t his peri o d.  Details of t he 
s u bject’s oral h y gi e ne will be d oc u me nte d i n t he pr o vi de d s u bject diar y w hi c h will be c h ec ke d 
b y site staff at e ac h visit t o m o nit or c o m plia nce.  
6. 2. 1  
Pr o d u ct U s a g e  Err or s  
I n t his st u d y, pr o d uct usa ge err ors ma y res ult, i n t his st u d y, 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 he wr o n g s u bject,  
•  at t he wr o n g ti me,  
•  or at t he wr o n g d os a ge.  
S uc h err ors occ urri n g t o a st u d y s u bject are t o be ca pt ure d i n t he C R F.  I n t h e e ve nt of a pr o d uct 
usa ge  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. 
Pr o d uct usa ge  err ors are re p orta ble irres pecti ve of t he prese n ce of a n ass ociate d A E, i ncl u di n g:  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
•  Usa ge 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 ucts;  
•  P ote ntial pr o d uct  err ors or uses o utsi de of w hat is 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 st u d y pr o d uct usa ge err or is acc o m pa ni e d b y a n A E, as deter mi ne d b y t he i n vesti gat or, t he 
usa ge  err or a n d, a n y ass o ciate d a d v erse e ve nt(s) are t o be ca pt ur e d i n t he C R F A E f or m.  
6. 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.  
6. 3  
I n v e sti g ati o n al/ 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 ntati o n . 
T he i n vesti gat or, or desi g nee, will e ns ure t hat all st u d y pr o d ucts are st ore d i n a sec ure d, 
e n vir o n me ntall y m o nit ore d ( ma n ual or a ut o mate d) area wit h c o ntr olle d access (a ut h orize d sit e 
staff o nl y) i n acc or da n ce wit h t he la bele d st ora ge c o n diti o ns a n d Cli ni cal St u d y S u p plies 
C hec klist , a n d i n acc or da nce wit h a p plica bl e re g ul at or y re q uir e me nts.  
Site s yste ms m ust be ca 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 n s (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 fr o 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 xc 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 ora ge u nit (f or 
e xa 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 xc 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 u nicate 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 g e 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 u st 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.  
6. 4  
I n v e sti g ati o n al/ 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 a t 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 s ec ure d l ocati o n t o w hic h o nl y a ut h orize d site staff ha v e 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
access. U p o n recei pt, all st u d y pr o d ucts s h o ul d be st ore d acc or di n g t o t he i nstr ucti o ns s pecifie 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 nce wit h t he pr ot oc ol, b y a ut h orize d site staff. 
T he st u d y site m ust mai ntai n a de q uat e 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 pl ies. All st u d y pr o d ucts 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 nciliati o n, a n d rec or d mai nte n a nce.  
S u bjects will c o m plete diaries t o detail t heir us a ge of t he was h o ut d e ntifrice w hic h will be use d 
t o m o nit or usa ge c o m plia nce. 
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 he 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 be perf or med b y t he m o nit or d uri n g site visits 
a n d at t he c o m pleti o n of t he st u d y.  
6. 4. 1  
D e str u cti o n of 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  
At t he e n d of t he st u d y, t he Pri nci pal I n vesti gat or or a n a p pr o priate desi g nee, a n d a 
re pres e ntati ve of t he s p o ns or (st u d y m o nitor) 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 s u n dr y ite ms.  T he 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 
be 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 ne d f or 
destr ucti o n t o t he s p o ns or’s Cli nical S u p plies Gr o u p  or desi g nate d ve 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 destr ucti o n will be pr o vi de d b y t he s po ns or  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. 
6. 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 mize d usi n g a n I nteracti ve Res p o nse Tec h n ol o g y (I R T). 
Bef ore t he st u d y is i niti ate d, trai ni n g, l o gi n i nf or mati o n a n d dir ectio ns f or t he I R T will be 
pr o vi de d. 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 descri be d as si n gle -bli n d ( t he de ntal e xa mi ner(s) a n d la b orat or y s peci me n a nal ysts  
perf or mi n g t he st u d y ass ess me nts will be bli n de d t o t he pr o d uct recei ve d).  
E m pl o yees of t he S p o ns or w h o ma y i nfl ue nce st u d y o utc o mes a n d t he de ntal e xa mi ner(s) a n d 
la b orat or y-b ase d s p eci m e n a n al yst(s) will be bli n de d t o t he pr o d uct all ocati o n of s u bjects.  T o 
e ns ure t h e e x a mi ner a n d s peci me n a n al yst(s) re mai n bli n de d t hr o u g h o ut t he st u d y, t he y are n ot 
per mitte d i n t he r o o m w hile  pr o d uct is dis pe ns e d.  All c o m merci al st u d y pr o d ucts will b e 
o ver w ra p pe d t o c o nceal a n y la belli n g.  I n a d diti o n, s u bjects will recei ve treat me nt i n a se parate 
area fr o m w here cli nical assess me nts are p erf or me d.   T he dis pe nsi n g staff will n ot be i n v ol ve d 
i n a n y cli nic al assess me nts or la b orat or y a nal ysis d uri n g t he st u d y.  St u d y site staff t hat p erf or m 
st u d y c o nse nt ca n als o dis pe nse t he st u d y pr o d uct b ut ca nn ot perf or m a n y cli nical assess me nts .  
La b orat or y pers o n n el t h at carr y o ut t he s p eci m e n a n al ysis will als o b e bli n de d t o pr o d uct 
all ocati o n a n d n ot be i n v ol ve d i n a n y cli nical assess me nt.   A d diti o nall y, s u bjects s h o ul d be ke pt 
se parat e fr o m t he area w h ere t he st u d y de ntifrices are dis pe nse d o nt o t he t o ot h br us hes t o pre ve nt 
t he m o bser vi n g t he de ntifrice t u bes. 
All st u d y site staff will be bli n de d e xce pt f or t h ose staff m e m bers dir ectl y deali n g wit h 
dis pe nsi n g st u d y pr o d ucts.   S ite staff, st u d y statisticia n(s), data ma na ge m e nt staff a n d ot h er  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
e m pl o yees of t he sp o ns or a n d ve n d ors acti n g o n be half of t he s p o ns or, w h o ma y i nfl ue nce  st u d y 
o utc o mes will be bli n de d t o t he pr o d uct all ocati o n . 
6. 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.  T he met h o d will be a n ele ctr 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 deter 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 deter mi nati o n. If t he i n v esti gator 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 ke 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 treat 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 nbli 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 o urce d oc u m e ntati o n a n d case re p ort f or m, as a p plica ble. 
A n y A E ass ociate d wit h brea ki n g t he bli n d m ust b e 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 bli n d is br o ke n.  
6. 7  
C o m pli a n c e  
St u d y pr o d ucts will be a d mi nistere d u n der t he s u per visi o n of i n vesti ga t or site pers o n nel.  T h e 
date a n d ti me of eac h d os e/a p plicati o n/a d mi nistrati o n will be rec or de d i n t he s o urce d oc u me nts 
or directl y i n t he C R F.    
A diar y will be s u p plie d t o pr o m ote c o m plia nce a n d t o ca pt ur e details of use  of t he was h o ut 
de ntifrice d uri n g t he 2 da ys pri or t o treat me nt visits.  S u bjects ma y als o rec or d a d diti o nal 
i nf or mati o n s uc h as A Es or me di cati o ns use d. A n y a d diti o nal details rele va nt t o efficac y or 
safet y s h o ul d b e re vie we d b y t he i n v esti gat or ( or s uita bl y q ualifie d desi g n ee) wit h t he s u bjects 
a n d tra nscri b e d t o t he C R F as a p pr o priate.  
T he n u m ber of a n y misse d or a d diti o nal a p plicati o ns of t he was h o ut de ntifri ce  will be ca pt ure d 
as pr ot oc ol de viati o ns a n d tra nscri be d fr o m t he diar y i nt o t he C R F. S u bjects will be re -
i nstr ucte d i n t he c orrect usa ge re q uir e me nts a n d di ar y c o m pleti o n as nee de d.  
6. 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 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 C 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 2 8 da ys  pri or t o  si g ni n g t he i nf or me d c o nse nt f or m a n d u ntil first 
st u d y 
pr o d uct 
a p plicati o n 
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 after first st u d y pr o d uct a p plicati o n will be d oc u me nte d as 
c o nc o mita nt me dicati o n/treat me nts.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
7  
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  
7. 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 dra w fr o m t he st u d y at a n y ti me at t heir o w n re q u est or ma y be wit h dra w n 
at a n y ti me at t he discreti o n o f t he i n vesti gat or or s p o ns or f or safet y, be 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 uire d sc he d ul e 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 u re 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  
•  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 na 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 C R F.  
7. 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 site. 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 o r 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 atte 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 pr o vi d e d  a n d, if a p pr o priate, re q uest t hat 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 h e s u bject re g ar di n g a n y u nres ol ve d a d verse e v e 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 he 
i n vesti gat or’s discreti o n, w hic h c o ul d i ncl u de a n oral e xa mi nati o n.  
S h o ul d t he s u bject c o nti n ue t o be u n reac 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 bject’s safet y was pres er ve d.  
If the 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 data c ollecte d bef ore s u c h 
wit h dra wal of c o nse nt.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
8  
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 secti o n.  
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 a ll 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. 
8. 1  
Vi sit 1/ S cr e e ni n g  
Scree ni n g pr o ce d ures will be c o n d ucte d b y t he I n vesti gat or, or s uita bl y q ualifie d desi g nee.  
S u bjects will be scree n e d a mi ni m u m of 3 da ys  pri or t o ra n d o mizati o n t o c o nfir m t hat t he y meet 
t he s u bject selecti o n criteria f or t he st u d y a n d t o e ns ure 2 da ys of fl u ori de -free de ntifrice us e.   
T he f oll o wi n g pr oce d ures will be c o m plete d  i n t he f oll o wi n g or der ( w h ere v er p ossi ble), a n d t he 
fi n di n gs rec or de d i n t he C R F: 
 
1.  I nf or me d C o nse nt. 
2.  De m o gra p hics . 
3.  Re vie w of me dic al hist or y (i ncl u di n g s m o ki n g/t o bacc o use st at us) a n d pri or/c o nc o mita nt 
me dicati o n/treat me nt . 
4.  O S T a n d O H T e x a mi nati o ns . 
5.  Meas ure me nt of sti m ulate d a n d u nsti m ulate d sali var y fl o w rate.  
6.  Re vie w of t he i ncl usi o n/e xcl usi o n criteria. 
7.  Tr y -i n palatal a p plia n ce. 
8.  S u bject eli gi bilit y . 
9.  Dis pe nse was h o ut pr o d u ct t o ot h br us h  a n d was h o ut diar y. I nstr uct s u bjects i n diar y 
c o m pleti o n.  
1 0.  A Es rec or de d . 
8. 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 after a de q uate 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.  A n i n gre die nts listi n g f or t he st u d y de ntifrices will be pr o vi de d t o eac h s u bject d uri n g 
t he c o nse nt pr ocess t o e na ble t he m t o c o nfir m t he y are n ot a ware of a n y aller g y or 
h y perse nsiti vit y t o a n y of t he i n gre die nts liste d.   T he i nf or me d c o nse nt (I C F) will be si g ne d a n d 
date d b y t he s u bject.  A c o p y of t he si g ne d c o nse nt will be ma de a n d distri b ute d t o t he s u bj ect 
pri or t o t heir lea vi n g t heir st u d y visit . 
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 da te 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 nfir 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 ne 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 fr o m 
w hic h all A d verse E v e nts will be ca pt ure d. T he dat e a n d ti me of c o nse nt will be ca pt ure d i n  t h e 
C 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 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
recei v e a c o p y of t his ne w i nf or mati o n 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 C R F.  
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 ne e) 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.  
8. 1. 2  
D e m o gr a p hi c s  
T he f oll o wi n g de m o gra p hic i nf or mati o n will be rec or de d i n t he C R F: year of birt h, ge n der a n d 
race.  Et h nicit y a n d race of  s u bjects will be rec or de d i n acc or da nce wit h F D A G ui da n ce (U S 
F D A, 2 0 0 5 ). 
8. 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  
Details of rele va nt me dical a n d s ur gical hist or y (i n t he last year), i ncl u di n g aller gies or dr u g 
se nsiti vit y, will be d oc u me nte d i n t he C R F. 
Pri or 
me dicati o ns/treat me nts, i ncl u di n g prescri pti o n a n d n o n -prescri pti o n dr u gs, dietar y 
s u p ple me nts a n d her bal re me dies, ta ke n i n t he l ast 2 8 da ys a n d pri or t o 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 i n t he C R F.  
8. 1. 4  
Or al E x a mi n ati o n s  
T he cli nical e x a mi ner(s) will perf or m t he f oll o wi n g e xa mi nati o ns/assess me nts.  
•  O S T e xa mi nati o n.  
•  O H T e xa mi n ati o n.  
Oral e xa mi nati o ns/assess me nts s h o ul d o nl y be perf or me d b y s uita bl y q ualifie d e xa mi ner(s) as 
descri be d i n Secti o n 5. 8 . 
T o facilitate s u bject fl o w, cli nical assess me nts ma y be rec or de d o n a pa per s o urce d oc u me nt 
a n d a n y a b n or m alities later tra nscri be d i nt o t he C R F.  
8. 1. 5  
S ali v ar y Fl o w R at e M e a s ur e m e nt s  
Meas ure me nt of t he s u bject’s sti m ulate d a n d u nsti m ulate d sali var y fl o w will b e ma de per 
Secti o n 9. 1. 1  a n d t he fi n di n gs d oc u me nte d i n t he C R F.  
8. 1. 6  
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 xcl usi o n criteria i nf or mati o n will be d oc u me nte d i n t he C R F. 
8. 1. 7  
Tr y -i n of P al at al A p pli a n c e 
Palatal a p pli a nces will be fitte d a n d c hec k e d f or c o mf ort at t he Scree ni n g visit. S u bjects will be 
as ke d t o wear t heir a p pli a nces f or u p t o 1 5 mi n utes t o det er mi ne c o mf ort, fit a n d weara bilit y. 
A p plia nces will be a dj ust e d as nee de d.  T he s u bj ect ma y re peat t he a p plia n c e tr y-i n p orti o n of 
t he scree ni n g visit after a dj ust me nt . 
8. 1. 8  
S u bj e ct Eli gi bilit y  
T he i n vesti gat or a n d/ or me dicall y q ualifie d desi g nee will re vie w  t he i ncl usi o n/e xcl usi o n 
criteria, me dical hist or y, pri or a n d c urre nt me dicati o ns /treat me nts a n d t he fi n di n gs of the oral 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
e xa mi nati o ns  t o c o nfir m s u bject eli gi bilit y t o partici pate i n t he cli nical trial. T his will b e 
d oc u me nte d i n t he C R F.  
Eli gi ble s u bjects will be a p p oi nte d t o atte n d t he st u d y site f or baseli ne assess me nts ( Visit 2) a 
mi ni m u m of 3 da ys after t heir sc ree ni n g visit a n d will be i nstr ucte d t o use o nl y t heir s u p plie d 
0 p p m fl u ori de  d e ntifrice [ was h o ut pr o d uct] a n d s u p plie d t o ot h br us h (acc or di n g t o t heir n or mal 
ha bit) f or t he 2 da ys pri or t o t heir ne xt a p p oi nt me nt.  
T o pre pare f or st u d y partici pati o n, s u bjec ts will be i nstr ucte d i n t he Lifest yle G ui deli nes  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. 
8. 1. 9  
Di s p e n s e W a s h -o ut P r o d u ct s a n d D i ar y C ar d s  
S u bjects will be dis pe nse d wit h t he was h o ut t o ot h br us h a n d t he 0 p p m fl u ori de  was h o ut  
de ntifrice  t o use d uri n g t he was h o ut peri o d. S u bjects will be i nstr ucte d t o br us h t heir teet h wit h 
t he 0 p p m fl u ori de was h o ut  de ntifrice  t wice a da y d uri n g t he 2 da ys pri or  t o Visit 2, 4  a n d 6  
(i ncl u di n g t he m or ni n g of t he treat me nt visit) a n d rec or d it i n t he diar y pr o vi de d .  
8. 1. 1 0  
A d v er s e E v e nt s a n d I n ci d e nt s  
A d verse E ve nts a n d I nci d e nts will be rec or de d i n t he C R F as descri be d i n  Secti o n 1 0 .  A n y A Es 
will be rec or de d i n t he C R F.  
8. 2  
St u d y P eri o d  
T here will be a n i nter val of at least 3 da ys bet wee n st u d y peri o ds (i.e., a d mi nistrati o n of 
s u bse q ue nt d oses of i n vesti gati o nal pr o d uct will n ot occ ur u ntil at least 3 da ys after t he pre v i o us 
d ose of i n vesti gati o nal pr o d uct).   Pri or t o eac h treat me nt visit  ( Visits 2, 4 & 6), there will be a 
was h o ut peri o d of a mi ni m u m of 3 da ys.  D uri n g t his peri o d  s u bjects will use t heir o w n 
de ntifrice  a n d t o ot h br us h f or at le ast o ne d a y, a n d a 0 p p m fl u or i de was h o ut de ntifrice  a n d st u d y 
t o ot h br us h ( pr o vi de d) f or tw o da ys i m me diatel y pri or t o t he treat me nt visit (i ncl u di n g i n t he 
m or ni n g of t he sc he d ule d visit).   
All p r oce d ures will be c o n d ucte d b y t he I n vesti gat or, or s uita bl y q ualifie d desi g ne e.  T o 
facilitate s u bject fl o w, cli nical a n d i nstr u me nt al assess me nts ma y be rec or de d o n a pa p er s o urce 
d oc u me nt a n d later tra ns cri be d i nt o t he C R F.   
8. 2. 1  
Vi sit 2/ St u d y P eri o d 1  
S u bjects will u n der g o, i n t he f oll o wi n g or der ( w h ere ver p ossi ble)  a n d t he fi n di n gs rec o r de d i n 
t he C R F. 
 
1.  C ha n ges i n c o nc o mita nt me dicati o n or n o n -dr u g treat me nts/ pr oce d ures will be 
d oc u me nte d.  
2.  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 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 ass esse d a n d a n y A Es 
rec or de d i n t he C R F. 
3.  S u bject u n der g oes a n O S T e xa mi nati o n.  
4.  Re vie w of  s u bject diar y t o assess f or c o m plia nce. 
5.  S u bject c o nti n ua nce  assesse d. 
6.  S u bjects ra n d o mize d t o treat me nt peri o ds.  
7.  S u bject has a p plia nce c o ntai ni n g e na mel bl oc ks fitte d. 
8.  S u bject u n der g oes s u per vise d pr o d uct a p plicati o n.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
9.  4 h o urs after de ntifric e a p plicati o n s u bject has 4 e na mel bl oc ks re m o ve d a n d a 3 0 ± 1 0 
mi n ute l u nc h peri o d will be gi ve n w here t he s u bject d oes n ot wear t he palat al a p plia nce.  
After t he 3 0 mi n ute l u nc h peri o d, s u bject will br us h t heir teet h a n d ri nse t h eir m o ut h wit h 
water a n d re pla ce t heir a p plia nce.  
1 0.  A Es a n d i nci de nts rec or de d.  
1 1.  S u bject is all o we d t o lea ve site after t h e 4. 5 h o ur ti me p oi nt.  S u bject will recei ve oral a n d 
writte n i nstr ucti o ns f or di n ner (at 8. 5 h o ur ti me p oi nt t o 9 h o ur ± 1 0 mi ns ti me p oi nt) a n d 
will t he n br us h t heir teet h a n d ri nse t heir m o ut h wit h water pri or t o r efitti n g t heir 
a p plia nce a n d i nstr ucti o ns/ diar y f or t he e n d of t he treat me nt da y ( 1 3 h o ur).  
1 2.  S u bject re m o ves, ri nses a n d st ores a p plia nce i n t he c o ntai ner pr o vi d e d 1 3 ± 0. 5 h o urs after 
de ntifrice a p plicati o n a n d bri n gs it t o t he site o n t he f oll o wi n g da y.  
 
Ra n d o mize d s u bjects will be a p p oi nte d t o atte n d t he st u d y site t he n e xt da y a n d re mi n de d of 
t he Lifest yle G ui deli nes a n d t o bri n g t heir c o m plete d diar y wit h t he m t o t he ne xt visit.  
8. 2. 2  
Vi sit 3 / St u d y P eri o d 1 –  F oll o w u p  
S u bjects will u n der g o, i n t he f oll o wi n g or der ( w h ere ver p ossi ble)  a n d t he fi n di n gs rec or de d i n 
t he C R F. 
 
1.  S u bject ret ur ns palatal a p plia nce.  
2.  C ha n ges i n c o nc o mita nt me dicati o n or n o n -dr u g treat me nts/ pr oce d ures will be 
d oc u me nte d.  
3.  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 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 ass esse d a n d a n y A Es 
rec or de d i n t he CR F.  
4.  S u bject u n der g oes a n O S T e xa mi nati o n.  
5.  Re vie w of  s u bject diar y t o assess f or c o m plia nce. 
6.  S u bject c o nti n ua nce  assesse d. 
7.  A Es a n d i nci de nts rec or de d.  
 
Ra n d o mize d s u bjects will be a p p oi nte d t o atte n d t he st u d y site f or t heir n e xt visit a n d re mi n de d 
of t he L ifest yle G ui deli nes, t he was h o ut re q uire m e nts a n d t o bri n g t heir c o m plete d diar y wit h 
t he m t o t he ne xt visit.  
8. 2. 3  
Vi sit s 4 & 5 –  St u d y P eri o d 2  
Pr oce d ures will be t he sa me as f or Visits 2 & 3 wit h t he e xce pti o n t hat ra n d o mizati o n will n ot 
be perf or me d.  
8. 2. 4  
Vi sit s 6 & 7 –  St u d y P eri o d 3  
Pr oce d ures will be t he sa me as f or Visits 4 & 5 wit h t he e xce pti o n t hat at Visit 6 s u bjects will 
ret ur n t heir was h o ut paste a n d br us h a n d at Visit 7 a n O H T e xa mi nati o n will a d diti o nall y be 
perf or me d at t he sa me ti me as t he O S T e xa mi nati o n.  T he s u bject c o ncl u des t he st u d y at t he 
e n d of Visit 7 pr oce d ures.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
8. 3  
St u d y Pr o c e d ur e s  
8. 3. 1  
Di ar y R e vi e w  
T he diar y s h o ul d be c o m plete d b y t he s u bjects d etaili n g t heir oral h y gie ne fr o m scree ni n g till 
t he e n d of t he st u d y.  A d diti o nall y, t he re m o val a n d st ora ge of t he a p plia n ce b y t he s u bjects o n 
test da ys s h o ul d be detaile d t o get her wit h a n y c h a n ges i n c o nc o mita nt me dicati o n use d b y t he 
s u bjects. 
T he diar y s h o ul d b e re vi e we d at e ver y visit b y t he i n vesti gat or, or s uita bl y q ualifie d desi g ne e, 
a n d t he s u b ject. A n y s u bject c o m me nt ca pt ur e d i n t he diar y w hic h is c o nsi dere d a n a d v erse 
e ve nt will be ass esse d a n d re p orte d as defi ne d i n t h e  A d verse E ve nt a n d Seri o us A d verse E ve nts  
secti o n of t his pr ot oc ol.  
A n y a d diti o nal c o m me nts  relati n g t o me dicati o ns/treat me nts pr o vi de d i n t he diar y will be 
re vie we d b y t h e i n vesti gat or or me dicall y q ualifie d desi g nee wit h t he s u bject a n d e ntere d i nt o 
t he C R F as a p pr o priate.  
A d diti o nal a n d misse d was h o ut pr o d uct a p plicati o ns will be c o nsi dere d de viati o ns fr o m t he 
pr ot oc ol a n d will be rec or de d o n t he De viati o ns L o g  a n d as a de viati o n i n t he C R F . 
8. 3. 2  
Pr e -Tr e at m e nt Or al S oft Ti s s u e a s s e s s m e nt  
T he cli nical e x a mi ner(s) will perf or m t he f oll o wi n g e xa mi nat i o ns/assess me nts. 
•  O S T e xa mi nati o n  [ Pre-tr eat me nt at Visits 2, 4 & 6 a n d p ost-treat me nt at Visits 3, 5 & 
& 7] . 
•  O H T e xa mi nati o n  [at Visits 1 ( pre-treat me nt) a n d 7 ( p ost treat me nt)]. 
Oral e xa mi nati o ns/assess me nts s h o ul d o nl y be perf or me d b y s uita bl y q ualifie d e xa mi ner(s) as 
descri be d i n Secti o n 5. 8 . 
8. 3. 3  
Pl a c e p al at al a p pli a n c e i n s u bj e ct’ s m o ut h.  
A s uita bl y trai ne d st u d y  site desi g nee will place t he palatal a p plia nce (c o ntai ni n g 8 e na mel 
s peci me ns) i n t he s u bjects’ m o ut h f oll o we d b y a n e q uili brati o n peri o d of at least 5 mi n utes 
bef ore tr eat me nt.  Details of s peci me n pre parati o n is pr o vi de d i n t he La b orat or y Pr oce d ures 
d oc u me nt.  Asse m bl y of t he a p plia nce is pr o vi d e d i n t he  
 Cli nical S O P.  
8. 3. 4  
S u p er vi s e d tr e at m e nt  
S t u d y pr o d ucts will be us e d f oll o wi n g t he i nstr ucti o ns (see Ta ble 6 -1 ) a n d u n der t he s u per visi o n 
of st u d y site pers o n nel.  
8. 3. 5  
P al at al a p pli a n c e s i ntr a or al p h a s e –  4  h o ur s  
After c o m pleti n g t he br us hi n g pr oce d ures, s u bjects will wear t heir palatal a p plia nce f or 4 h o urs 
±  1 0 mi n .  After t his peri o d, t he st u d y site desi g nee will re m o ve t he a p plia nce a n d f o ur pre-
desi g nate d e n a mel s peci me ns will be re m o ve d f or a nal ysis ( Secti o n 9. 4 ).  T he s u bject will be 
offere d a l u nc h t o be c o ns u me d o ver a 3 0 ± 1 0 mi n ute peri o d.  F oll o wi n g t his t he s u bject will 
br us h t heir teet h wit h wat er a n d t he a p plia n ce will be rei nsert e d.  T he s u bject will be i nstr ucte d 
o n w he n a n d h o w t o re m o ve t heir a p plia n ce f or di n ner a n d after 1 2 h o urs of i ntra -oral e x p os ure 
( 1 3 h o ur ti me p oi nt f oll o wi n g br us hi n g wit h i n vesti gati o nal de ntifrice) a n d h o w t o was h / st or e 
it at h o me a n d sc he d ule d t o ret ur n t o t he site t he f oll owi n g da y.  T he s u bject will be all o we d t o 
lea ve t he site f or t he rest of t he da y. 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
8. 3. 6  
P al at al a p pli a n c e s i ntr a or al p h a s e –  1 2 h o ur s  
After 1 2 h o urs ± 3 0 mi ns i ntr a-oral e x p os ure, s u bjects will re m o ve t heir a p p lia nce a n d g e ntl y 
ri nse it u n der r u n ni n g t a p water.  T h e a p plia n ce will t he n be st ore d m oist i n t he s u p plie d 
c o ntai ner i n t heir refri gerat or o ver ni g ht .  T he a p pli a nce will t he n b e ret ur n e d t o t he cli nical site 
t he f oll o wi n g da y. 
8. 3. 7  
St u d y C o n cl u si o n  
T he St u d y C o ncl usi o n pa ge of t he C R F will be c o m plete d f or a ll 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 or 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 Hale 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.  
8. 3. 8  
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 ntact a s u bject t o f oll o w u p a n A E p ost -st u 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). If nee de d, a d diti o nal cli nical e xa mi nati o ns ma y  be carrie d o ut at s uc h visits.  
9  
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 circ u msta nces, 
o utsi de t he c o ntr ol of t he i n vesti gat or t hat ma y ma 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 u st be i nf or me d of a n y misse d assess me nts i n a 
ti mel y ma n ner.  T he o ut c o me of all e xa mi nati o ns a n d assess me nts s h o ul d be rec or de d i n t he 
C R F.  
9. 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. 
9. 1. 1  
S ali v ar y fl o w  
At t he scree ni n g visit, b ot h u nsti m ulate d a n d sti m ulate d sali va will be c ollecte d f or e val uati o n 
of fl o w rates as part of t he i ncl usi o n criteria. Sali va sa m ples c ollecte d will be destr o ye d 
i m me diatel y after t he y are wei g he d. 
U nsti m ul ate d s aliv ary fl o w  
F or t he u nsti m ulate d sali va c ollecti o n, s u bjects will sit q uietl y f or fi ve mi n utes bef ore be gi n ni n g 
t he treat me nt perio d. D uri n g t he fi ve -mi n ute test peri o d, t he y will be i nstr ucte d t o all o w t heir 
sali va t o p o ol, e m pt yi n g i nt o a c ollecti o n t u be w he ne ver t h e y feel t he y nee d t o s wall o w.  T he 
c ollecti o n t u be will be wei g he d, pre/ p ost c ollecti o n a n d u nsti m ulate d sali va fl o w r ate calc ul ate d 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
( 1 g = 1 ml).  U nsti m ulate d sali va fl o w rate m ust b e ≥ 0. 2 ml/ mi n f or t he s u bject t o be eli gi ble 
f or e nr oll me nt i n t he st u d y. 
S ti m ul ate d s aliv ary fl o w 
F or t he sti m ulate d sali va c ollecti o n, s u bjects will c he w o n a piece of u nfla v ore d g u m base f or 
o ne ti me d mi n ute. After o ne mi n ute, s u bjects will be i nstr ucte d t o s wall o w a n y p o ole d sali va. 
T he y will t he n c he w t he g u m base f or t w o ti me d mi n utes d uri n g w hic h ti me t he y will e m pt y 
a n y p o ole d s ali va i nt o a c ollecti o n t u be w he ne ver t he y feel t he y nee d t o s w all o w.  T he c ollecti o n 
t u be will be wei g he d, pre/ p ost c ollecti o n a n d u nsti m ulate d sali va fl o w rat e calc ulate d ( 1 g = 
1 ml).   Sti m ulate d sali va fl o w rate m ust be ≥ 0. 8 ml/ mi n f or t he s u bject t o be eli gi ble f or 
e nr oll me nt i n t he st u d y.  
9. 2  
Effi c a c y A s s e s s m e nt s  
I n t his st u d y t here are n o cli nical efficac y assess m e nts perf or me d. All efficac y ass ess me nts will 
be perf or m e d ex vi v o  o n t he e na mel s peci me ns re m o ve d at t he  ti mes 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. E na mel s peci me n pre parati o n a n d a nal ysis are descri be d i n 
t he La b orat or y Pr oce d ures D oc u me nt.  
9. 3  
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 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  secti o n of t his pr ot oc ol. 
9. 3. 1  
Or al S oft Ti s s u e  ( O S T) E x a mi n ati o n  
T his pr oce d ure will be c o n d ucte d b y a q ualifie d, e x perie nce d cli nical  e xa mi ner.  T he O S T 
e xa mi nati o n will be acc o m plis he d b y dire ct o bser vati o n a n d pal pati o n wit h retracti o n ai ds , as 
a p pr o priate. T he e xa mi nati o n will c o ver  t he oral la bial m uc osa (i ncl u di n g li ps), b uccal m uc osa, 
m uc o gi n gi val f ol ds, gi n gi val m uc osa, har d p alate, s oft palate, t o nsillar area, p har y n geal area, 
t o n g ue, s ubli n g ual area, s u b ma n di b ular area a n d sali var y gla n ds.   A b n or mal fi n di n gs fr o m  t he 
e xa mi nati o n will be rec or de d i n t he C R F, wit h det ails of a n y a b n or malities.  T he res ults of t he 
O S T e xa mi nati o n perf or me d at scree ni n g will be use d t o deter mi ne s u bject eli g i bilit y. A n y ne w 
O S T a b n or malit y or w orse ni n g of a pre -e xisti n g c o n diti o n o bser ve d b y t he cli nical e xa mi ner or 
re p orte d b y t he s u bject after t he scree ni n g e xa mi nati o n  will be rec or de d as a n A E.  
W here p ossi ble, t his pr oce d ure s h o ul d be c o n d ucte d b y a si n gle  cli nical e xa mi ner.   
9. 3. 2  
Or al H ar d Ti s s u e ( O H T) E x a mi n ati o n  
T his pr oce d ure s h o ul d b e c o n d ucte d b y a q u alifie d, e x perie n ce d cli nical  e xa mi ner.  T he O H T 
e xa 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 
a n d will i de ntif y a n y gr ossl y cari o us lesi o ns , si g ns of er osi ve wear, e na mel irre g ularities, t o ot h 
fract ur e, gr oss ge neralize d de ntal cari es de ca y, decalcifi cati o n a n d fa ult y rest orati o ns. T he 
prese nce of a n y i m pla nts, fi xe d or re m o va ble de nt ures, fi xe d or re m o va ble ort h o d o ntic 
braces/ b a n ds, fi xe d ort h o d o ntic retai ners, f ull cr o w ns or ve neers will be rec or de d. O bser vati o ns 
will be liste d as eit he r a bse nt or prese nt, a n d c o n diti o ns n ote d as prese nt will be descri be d i n 
t he C R F. A n y c h a n ge o bser ve d b y t he cli nical e xa mi ner or re p orte d b y t he s u bject after t he 
scree ni n g e xa mi nati o n will be rec or de d as a n A E . 
T he res ults of t h e  O H T e xa mi nati o n perf or m e d at Scree ni n g will be us e d t o deter mi ne s u bject 
eli gi bilit y.  
W here p ossi ble, t his pr oce d ure s h o ul d be c o n d ucte d b y a si n gle cli nical e xa mi ner.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
9. 3. 3  
Pr e g n a n c y T e sti n g  
P re g na nc y testi n g of s u bjects of c hil d-beari n g p ote ntial is n ot re q uire d f or t his st u d y ( see 
Secti o n 4. 2  f or d etails).  S u bjects of c hil d -b eari n g p ote ntial will be as k e d  t o pr o vi de ver bal 
c o nfir mati o n of pre g n a nc y stat us at scree ni n g ( Visit 1) a n d t o i nf or m site staff if t he y fi n d t he y 
are pre g na nt w hile partici pati n g i n t he st u d y.  I n case of a p ositi ve c o nfir me d pre g n a nc y, t h e 
s u bject will be wit h dra w n fr o m t he st u d y. 
9. 4  
L a b or at or y T e st s  
All la b orat or y pr oce d ures will be detaile d i n a s e parate La b orat or y Pr oce d ures D oc u me nt w hic h 
will c o ver: - 
P re p ar ati o n  
•  Pre parati o n of e na mel s p eci me ns.  
•  I n vitr o er osi ve c h alle n ge.  
Effic acy me as ure me nts  
•  S urface micr o har d ness ( S M H).  
•  E na mel fl u ori de u pta k e ( E F U).  
E n a mel S peci me n St or a ge  
•  All e na mel s peci me n s a m ples will be sec urel y st ore d i n a refri gerat or at t he cli nical 
site t o pre ve nt t he s peci m e ns fr o m de gra dati o n a n d micr o bial c ol o nizati o n.   
S peci me n Rete nti o n  
•  La b orat or y s p eci me ns will be retai ne d b y t he st u d y site f or at least si x m o nt hs 
f oll o wi n g data base l oc k. Bef ore destr u cti o n, a cli nical st u d y site desi g nee will c o ntact 
t he s p o ns or i n writi n g re q uesti n g per missi o n t o destr o y t he s peci me ns.  T h e s p o ns or 
will pr o vi de a p pr o val i n writi n g f or sa m ple destr u cti o n.  If destr ucti o n is n ot 
a p pr o ve d, t he n S p o ns or will pr o vi de a n alter nate  ti me peri o d f or destr u cti o n of 
s peci me ns or pr o vi de i nstr ucti o ns f or tra nsfer of t he s peci me ns t o a n alter nati ve 
l ocati o n f or f urt h er la b orat or y a nal ysis.  S peci me ns will be ulti matel y destr o ye d vi a 
a ut ocla vi n g.  
1 0  
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 h e 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 h e 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. 
1 0. 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 ociate 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 was 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). 
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 b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer 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:   
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
•  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 orse 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 vesti gat or (i.e., n ot relat e d t o pr o gressi o n of 
u n derl yi n g disease).  
•  E xacer 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 ose d after st u d y pr o d uct a d mi nistrati o n e ve n t h o u g h 
it ma y ha ve 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 "f ail ure of e x p ecte d p har mac ol o gical acti o n" per 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 i f 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 m e nts w hic h are ass ociat e d wit h t he u n derl yi n g disease, u nless 
j u d ge d b y t he i n vesti gat or t o be m ore se v ere t h a n e x pecte d f or t he s u bject’s c o n diti o n.  
•  T he disease/ dis or der bei n g st u die d or e x pect e d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease/ dis or der bei n g st u die d, u nless 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.  
•  Me dical or s ur gic al pr oce d ure (e. g. e n d osc o p y, a p pe n dect 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 n ce di d n ot occ ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
•  A ntici pate d da y -t o-d a y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) prese nt 
or detecte d at t he start of t he st u d y t hat d o n ot w orse n.  
1 0. 2  
D efi niti o n of a S eri o u s A d v er s e E v e nt ( S A E)  
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 der st u d y, 
deat h d ue t o pr o gressi o n of disease).  
A seri o us a d verse e v e nt is a n y u nt o war d me dical occ urre nce at a n y d ose t h at:  
•  Res ults i n de at h  
•  Is life- t hre ate ni n g  
▪ T he ter m 'life -t hr eate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e v e nt i n w hic h 
t he s u bject was at ris k of deat h at the ti me of t he e ve nt. It d o es n ot refer t o a n 
e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca use 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   
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
▪ I n g e neral, h os pitalizati o n si g nifies t hat t he s u bject has bee n detai n e 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 g e nc y war d f or 
o bser vati o n a n d/ or tr eat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he 
p h ysicia n’s offic e or o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g 
h os p italizati 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 seri o us. W he n i n d o u bt as t o w het her 
“ h os pitalizati 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  ele cti 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 b aseli 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 mea 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 life 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 n ces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, n a usea, 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 v er 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 scie ntifi c j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E 
re p orti n g is a p pr o priat e i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat 
ma y n ot be 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 je o par dize t he s u bject or ma y re q uir e me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e v e nts 
s h o ul d us uall y be c o nsi dere d seri o us. 
▪ E xa m ples of s uc h e v e nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve 
treat 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 r es ult i n h os pitalizati o n, or de vel o p me nt of 
dr u g de pe n de nc y or dr u g a b use.  
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. 
1 0. 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 he 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 C 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 C R F.  
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 d iatel y a n d u n der n o 
circ u msta nce s h o ul d t his e xcee 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 gate 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 s t 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 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
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.  
1 0. 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 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 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), partici 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 C R F a n d 
re p orte d a p pr o priat el 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 bject. I n a d diti o n, eac h st u d y s u bject 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 pria te. 
W he n a n A E occ 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 nee) 
t o re vie w all d oc u me nt ati 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 g ar di n g a n A E i n t he 
C R F a n d all details relati n g t o a n S A E i n t he pa per 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 ualifie 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 o r ds t o Hale o n i n lie u of c o m pleti o n of t he A E C 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 of 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 w here 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 he 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 s ecti o n of t he C 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 g es i n t heir healt h. O pe n -e n d e d a n d n o n -lea di n g v er bal 
q uesti o ni n g s h o ul d be use d.   A Es will be cat e g ori ze d as oral or n o n -oral b y t he e xa mi ner pri or 
t o data base l oc k. 
1 0. 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 C R F b y t he i n vesti gat or or site staf f.  It s h o ul d 
be n ote d t hat t h e 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 C R F.  W h ere 
t he sa me data are c ollecte d, t he A E C R F pa 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 xa m ple, t he sa me A E ter m s h o ul d be us e d o n b ot h.  A Es s h o ul d b e 
re p orte d usi n g c o n cise m e dical ter mi n ol o g y o n t he C 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.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
1 0. 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 C R F pa ge, a n S A E f or m s h o ul d be 
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 
i n 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 vaila ble  
•  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 date  
•  St u d y pr o d uct e n d date 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 uct  
•  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 Ma 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 date 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 vaila 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 he   
st u d y ma na ger. 
T he St u d y Ma na 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 her Hale o n  p ers o n nel 
as a p pr o priat e.  
1 0. 5  
E v al u ati n g A d v er s e E v e nt s  
1 0. 5. 1  
A s s e s s m e nt of I nt e n sit y  
T he i n vesti gat or or me dicall y q ualifie 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 olerate 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 da 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 ve nt; a n d b ot h n o n -seri o us A Es a n d S A Es ca n 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
be assesse d as se vere. F or e xa m ple, a h ea d ac he m a y be se v ere (i nterferes si g nifica ntl y wit h t he 
s u bject's us ual 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.  
1 0. 5. 2  
A s s e s s m e nt of C a u s alit y  
T he ca us alit y assess me nt is o ne of t he criteria use d w he n d eter mi ni n g re g ulat 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 nee) m ust  
pr o vi de a n assess me nt of ca usalit y o n t he A E C 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 ot es t hat t he y 
ha ve  re vi e we d t he A E a n d assesse d ca usalit y, w here a p plica bl e.  
A “reas o na ble p ossi bilit 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 vi 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 Safet y Stat eme nt , 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 gate 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 h e 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 C R F, as a p pr o pri ate, 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 has 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 we 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 assess me nt of c a us alit y f or e v er 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.  
1 0. 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 g e f or t h e 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 ncl 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 xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care 
pr ofessi o nals.  
Ne w or u p d ate d i nf or m ati o n will be rec or de d o n t he A E C 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 h e 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. 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
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 lear ns of a S A E, i ncl u di n g deat 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 nsiders t he e ve nt reas o n a 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 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 g e 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 Ma na ger. 
T he i n vesti gat or will s u b mit a n y u p date d S A E data t o Hale o n wit hi n t he desi g nate d re p orti n g 
ti me fra mes. 
1 0. 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 C 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 acc or da n ce wit h 
t he re p orti n g re q uire me nts defi ne d. 
1 0. 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 g al 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 cli nical i n vesti gati o n.  Pr o m pt 
n ot ificati 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 relati 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 p ecte 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 necessar 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 he n file 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 r e q uire me nts. 
1 0. 9  
Pr e g n a n c y  
1 0. 9. 1  
Ti m e P eri o d f or C oll e cti n g Pr e g n a n c y I nf or m ati o n  
Pre g na 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.  
1 0. 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 he 
a p pr o priate  St u d y Ma na ger . Ori gi nal 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.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
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 onc 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 na 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 priate   
St u d y Ma 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 wi n g t he 
esti mate d deli ver y date. A n y ter mi nati o n of t he pre g na 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 nc y o utc o mes (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 fr o m t he 
st u d y. 
1 0. 1 0  
M e di c al D e vi c e I n ci d e nt s  
T he defi niti o ns a n d pr oce d ures det aile d are i n acc or da nce wit h I S O 1 4 1 5 5 . 
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. 
Me dical de vic es are b ei n g pr o vi de d b y Hale o n f or use i n t his st u d y; t he me dical de vice i n t his 
st u d y is t he s u p plie d t o ot h br us h. 
1 0. 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 lea 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 ha 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 h at, if it occ urre d a gai n, mi g ht lea d t o deat h or a s eri 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:  
•  Life -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 n al 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 dical de vi ce 
fail ure. 
•  A mis dia g n osis d ue t o me dical de vice fail ure 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.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
1 0. 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 vesti 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 nci 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 C 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 descri 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 Re 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 g e 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 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 no 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 he   
st u d y ma na ger. 
T he i n vest i 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 Hale o n i m me diatel y ( b y f oll o wi n g t he pr ocess 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.  
•  Re c or d a n y i nci d e nts o n t he C R F a n d I n ci de nt Re p ort F or m f oll o wi n g i nstr u cti o ns 
gi ve n i n t he secti o n a b o v e.  
•  F or a n y i n ci de 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 Hal e o n, r et 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 ntati o n of t he details of t he fail ure  
•  F or a n y i n ci de 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, r e p ort t h e i nci de nt 
t o t he de vice ma n ufact ur er a n d f oll o w t he m a n ufact urer i nstr ucti o ns f or t h e ret ur n of 
t he faile d de vic e ( w hilst kee pi n g Hale o n i nf or me d). 
1 0. 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 ntal 
i n vesti gati o ns as i n dicate d t o el uci date t he nat ur e a n d/ or ca us alit y of t he i nci 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.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 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 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
1 0. 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 di 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 he 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 hi c h t he 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 dical 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 nd 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 uir e me nts (e. g. t he hea d of t he 
me dical i nstit uti o n), will c o m pl y wit h t he a p plica ble 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 1  
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 he 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 vali date d 
s yste m. Data 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 o c u me nts (e. g. h os pital rec or ds, cli nical a n d office c harts, la b orat or y n otes, 
me m ora n da, s u bject diaries, q uesti o n naires, e val uati o n c hec klists, p har mac y dis pe nsi n g 
rec or ds, rec or de d data fr o m a ut o mate d i nstr u me nts, micr ofic hes, p h ot o gra p hic n e gati ves, 
micr ofil m or ma g netic me dia, x -ra ys, s u bject files a n d rec or ds ke pt at t he p har mac y, at t h e 
la b orat or y a n d at t he m e dic o-tec h ni cal de p art m e nts i n v ol ve d i n t he cli nical st u d y) w hic h 
c o ntai n t he s o urce of d ata rec or de d i n t he C R F s h o ul d  be s pecifie d .  T he C R F a n d t he 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 data ma na g e 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 1. 1  
C a s e R e p ort F or m  
A C R F is a pri nte d, o ptical, 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 
inf 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.  
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 d ata will be p erf or me d i n acc or da n ce wit h t he T hir d Part y Bi ostatistics 
a n d Dat a 
Ma n a ge me nt  Ve n d or a p plica bl e sta n dar ds a n d dat a cl ea ni n g pr oce d ures wit h 
o versi g ht b y Hale 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 dat a.  
T o pr otect t he pri vac y of s u bjects, n o Pers o nal I nf or mati o n ( PI) (i ncl u di n g t he s u bject's na m e 
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.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
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 nate 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 1. 2  
D at a H a n dli n g  
D oc u me ntati o n of all d ata ma na g e me nt acti vities s h o u l 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 perf or m a nce.  
A n y c ha 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 de rati o nale f or c ha n g es. 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 g es a n d c orrecti o ns e n d orse d b y t he I n vesti gat or.  
1 1. 2. 1  
D at a Q u eri e s  
Pr o gra m me d e dit c hec ks will be ge nerat e d a ut o maticall y, as t he data are bei n g e ntere d i nt o t he 
s yste m. Re p orts a n d listi n gs o n t he C R F data will als o be r u n, i n a d diti o n t o t he q ueries alrea 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 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 n it 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 ucte d i n acc o r 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 plica bl e 
re g ulat or y re q uire me nts. 
A n y q ueries 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 paralle l wit h Data Ma n a ge me 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.  
1 1. 3  
Pr o c e s si n g P ati e nt R e p ort e d O ut c o m e s  
Pa per bas e d patie nt re p orte d o utc o me ( P R O) dat a ma y  b e rec or de d t o t h e st u d y diaries a n d 
e ntere d i nt o t he dat a ma n a ge me nt s yste m ( D M S).    
All P R O s o urce data s h o ul d be re vie we d b y t he st u d y staff a n d t he st u d y m o nit or t o e ns ure 
acc urate tra nscri pti o n of data a n d t hat a n y p ote nti al A Es or c o n c o mita nt m e dica ti o ns re p orte d 
o n t hese d o c u me nts are disc usse d wit h t he s u bj ect a n d tra ns cri be d acc uratel y t o t he C R F a n d/ or 
D M S.   P R Os t hat are classe d as s o urce data will be retai ne d b y t he i n v esti gat or a n d tr ue/certifie d 
c o pies ma y be se nt t o a d esi g nate d ve n d or or Ha le o n as re q uire d.   
T o pr otect t he pri vac y of s u bjects, n o Pers o nal I nf or mati o n ( PI) (i ncl u di n g t he s u bject's na me 
or i nitials or birt h date) is t o be rec or de d o n a n y P R O t hat will be f or war de d t o Hale o n  or T hir d -
Part y Ve n d or.  
1 1. 4  
E xt er n al D at a  
E xter nal Data a re s u bject data o btai ne d e xter nall y t o t he C R F. T hese data are ge n erate 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.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
A n a gree d q ualit y c o ntr ol pr ocess will be perf or m e d a gai nst t he tra ns cri be d data t o t he s o urce 
t o e ns ure t he acc urac y of t he tra nscri pti o n. T he tra nscri be d data is tra ns mitte d i n a n a gree d u p o n 
f or mat t o Hale o n .  
Rec o nciliati o n will be perf or me d bet w ee n t h e tra nscri be d data a n d t he cli nical data base t o 
e ns ure s u bject a n d ti me p oi nt refere n ce d i n t h e Cli nical Data base m atc h bef ore Cli nical 
Data base Freeze (l oc ki n g of t he data bas e) ca n occ ur.  
1 2  
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 2. 1  
S a m pl e Si z e D et er mi n at i o n 
A s ufficie nt n u m ber of h ealt h y s u bjects will be scree ne d t o e ns ure t hat u p t o 3 3 s u bjects will be 
ra n d o mize d t o p artici pat e i n t he st u d y t o e ns ure at least 3 0 e val ua ble s u bjects c o m plete t h e 
st u d y. Wit h a sa m ple size of 3 0 s u bjects c o m pleti n g t he st u d y, t here will be 9 7 % p o wer t o d etect 
a differe nce i n me a ns of 7. 5 % i n % S M H R at 1 2 h o urs, ass u mi n g a sta n d ar d de viati o n ( S D) of 
differe n ces of 9. 9 4 % usi n g a paire d t -t est wit h a 0. 0 5 t w o-si de d si g nifica nce le vel.  
T hese differe nces a n d v aria bilit y were o bser v e d w he n c o m pari n g a si milar test pr o d uct t o a 
si milar Place b o C o ntr ol a n d Refere nce De ntifrice at 4 h o urs i n G S K C H st u d y 2 0 8 1 6 6. I n t he 
a bse nce of a n y hist orical st u dies wit h res ults at 1 2 h o urs, t he res ult at 1 2 h o urs will be ass u me d 
t o be si milar t o 4 ho urs f or t he p ur p ose of sa m ple size calc ul ati o n.  
A rece nt net w or k meta -a nal ysis ( Hale o n st u d y 3 0 0 0 3 3) acr oss 1 4 st u dies usi n g t he sa me desi g n 
i n v ol vi n g 2 2 differe nt gr o u pe d t y pe of st u d y pr o d ucts s u g gests a S D of differe n ces as hi g h as 
1 2. 1 6 % at 4 h o urs.  E ve n wit h s uc h a hi g her S D, t here w o ul d still be 9 0 % ( 8 0 %) p o wer t o detect 
a differe nce i n mea ns of 7. 5 % ( 6. 5 %) i n % S M H R at 1 2 h o urs.  
Pre vi o us Hale o n st u d y 2 0 8 1 6 6 a n d net w or k meta -a nal ysis 3 0 0 0 3 3 s u g gest res pecti ve S D of 
differe n ces f or % R E R bet wee n 1 7. 5 % a n d 2 0. 3 %. S uc h esti mates of varia bilit y w o ul d gi ve 9 0 % 
( 8 0 %) p o wer t o dete ct res pecti ve differe n ce i n mea ns of 1 0. 7 % a n d 1 2. 4 % ( 9. 3 % a n d 1 0. 7 %). 
1 2. 2  
P o p ul ati o n s  f or A n al y si s 
1 2. 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 f oll o wi n g a nal ysis p o p ulati o ns will be defi ne d:  
•  T he Scree ne d  p o p ulati o n will i ncl u de all s u bjects w h o are s cree ne d. 
•  T he I nte nt-t o-Treat (I T T)  p o p ulati o n will i ncl u de all s u bjects w h o are ra n d o mize d. 
St u d y pr o d uct gr o u p will be assi g ne d t o eac h visit f or a nal yses b ase d o n t he st u d y 
pr o d uct  se q ue n ce t he s u bject was ra n d o mize d t o. 
•  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 recei ve at l east 1 d ose 
of  st u d y pr o d uct . St u d y pr o d uct gr o u p will be assi g ne d f or a n al yses bas e d o n t he last 
k n o w n st u d y pr o d uct  t he s u bject act uall y recei ved pri or t o t he safet y e ve nt . 
•  T he Per -Pr ot oc ol ( P P)  p o p ulati o n will i ncl u de all s u bjects fr o m t he I T T p o p ulati o n 
w h o ha ve at least o ne visit wit h n o n -missi n g er o si o n para meters u naffect e d b y 
pr ot oc ol de viati o ns . St u d y pr o d uct gr o u p will be assi g ne d t o eac h visit f or a nal yses 
base d o n t he st u d y pr o d u ct t he s u bject recei ve d. 
1 2. 2. 2  
E x cl u si o n s of D at a fr o m A n al y si s  
E xcl usi o ns of a n y d ata fr o m t he a n al yses will be deter mi ne d  d uri n g a Bli n de d Data Re vie w 
( B D R) meeti n g pri or t o d ata base l oc k a n d u n bli n di n g. 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
If it is n ot p ossi ble t o deri ve t he er osi o n p ara m eter at t he visit le vel d ue t o missi n g data fr o m 
s peci me ns n ot c ollecte d a n d/ or data dee me d t o be n o n-e val ua ble b y t he la b or at or y, t he data will 
be treate d as missi n g i n t he I nte nt -T o -Treat (I T T) a nal yses.  
If t here are a s ufficie nt n u m ber of pr ot oc ol de vi ati o ns ( P D) i de ntifie d w hic h ma y i m pact t h e 
relia bilit y of a visit le vel er osi o n para meters i n t he I T T a nal ysis, a Per-Pr ot o c ol ( P P) a nal ysis 
will be perf or me d e xcl u di n g t he res ult i n q u esti o n. T he P P a nal ysis will be perf or me d if t he 
n u m ber of s u bjects i n t he I T T p o p ulati o n e xcl u de d fr o m t he P P p o p ulati o n is greater t ha n 1 0 %. 
Eac h P D will be assesse d as part of t he B D R, b ut p o ssi ble P Ds (list n ot e x ha usti ve) w hic h ma y 
i m pact t he relia bilit y of er osi o n para meters are n o n-c o m plia nce wit h t he use of st u d y pr o d uct 
at t he visit, lifest yle c o nsi derati o ns or i nstr ucti o ns f or re m o val a n d ret ur n of palatal a p plia nce.  
T he P Ds will be as si g ne d t o st u d y pr o d ucts base d o n t he visit(s) affecte d. T he n u m ber a n d 
perce nt a ge of I T T p o p ulati o n s u bjects wit h t he f oll o wi n g P D e ve nts will be prese nte d b y st u d y 
pr o d uct (a n d o v erall):  
•  P D  
•  I m p ort a nt P D 
•  I m p ort a nt P D lea di n g t o e xcl usi o n of data fr o m t he P P a nal ysis  
1 2. 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 ysis will be d oc u me nte d i n t he statistical 
a nal ysis pla n ( S A P), w hic h will be writte n f oll o wi n g fi nalizati o n of t h e pr ot oc ol a n d pri or t o 
st u d y u n bli n di n g. T his secti o n is a s u m mar y of t he pla n ne d statistical a nal yses of t he m ost 
i m p orta nt e n d p oi nts i ncl u di n g pri mar y a n d sec o n dar y e n d p oi nts. 
Statistical testi n g of all e n d p oi nts i n t his st u d y will be c o n d ucte d at a t w o -si de d si g nifica nce 
le vel of 0. 0 5. A se q u e ntial testi n g strate g y will be a p plie d t o preser ve t he o verall t y pe-1 err or 
c o ntr ol f or t he res p ecti ve se q u e ntial c o m paris o ns bet wee n t he  E x peri me ntal de ntifrice a n d 
Place b o  C o ntr ol at 4  h o urs  f or t he % S M H R ( pri mar y e n d p oi nt) a n d 
% R E R (sec o n dar y 
e n d p oi nt). T her e will be n o f urt her a dj ust me nts f or m ulti plicit y.  
All a nal yses of er osi o n para meters will be pri maril y base d o n t he I T T p o p ulati o n. If t here is 
m ore t ha n a 1 0 % differe nce i n t he o v erall n u m ber of s u bjects i n cl u de d i n t he P P a n d I T T 
a nal ys es, t he P P a nal ys es will als o be perf or m e d as s u p p orti ve a nal ys es. 
1 2. 3. 1  
Pri m ar y A n al y si s  
T he pri mar y e n d p oi nt will be t he % S M H R at 4  h o urs a n d t he c o m p aris o n bet w ee n t he 
E x peri me ntal de ntifric e a n d Place b o  C o ntr ol.  
T he n ull a n d alter nati ve h y p ot heses are:  
•  • H 0: t here is no differe nce bet wee n t he pr o d ucts . 
•  • H 1: t here is a differe n ce bet wee n t he pr o d ucts .  
F or eac h re plicate wit hi n eac h s peci me n (c ollecte d after 4  h o urs i n sit u re mi n eralizati o n) wit hi n 
a partic ular st u d y visit, t he % S M H R (at t he re plicate le vel) will be deri ve d as [( E 1 -R)/( E 1 -B)] 
* 1 0 0  
w here:  
B = i n de ntati o n le n gt h ( μ m) of s o u n d e na mel at b aseli ne  
E 1 = i n de ntati o n le n gt h ( μ m) after first er osi ve c h alle n ge  
R = i n de ntati o n le n gt h ( μ m) after 4  h o urs i n sit u re mi neralizati o n 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
T he % S M H R at t he s u bject visit le vel ( t o be use d i n t he a nal ysis) will be deri ve d as t he mea n 
of t he s peci me n mea ns (acr oss e val ua ble re plicate % S M H R wit hi n a s peci me n) wit hi n t hat visit. 
Missi n g data or data dee me d as n o n -e val ua ble b y t he la b orat or y will n ot be use d i n t hese 
deri vati o ns.  
A mi xe d m o del (i ncl u di n g res ults acr oss all 3 st u d y pr o d ucts) will b e use d t o a n al yze 
t he % S M H R at 4  h o urs wit h fi xe d effects f or treat me nt a n d st u d y visit, as well as ra n d o m effect 
f or s u bject. Ke n w ar d R o gers de grees of free d o m a p pr oac h will be a p plie d. T he least s q uare 
mea ns f or eac h st u d y pr o d uct will be prese nte d al o n g wit h t he differe nces b et wee n least s q uare 
mea ns ( E x peri me ntal de ntifrice - Place b o  C o ntr ol; i ncl u di n g t w o -si de d p-val ue a n d 9 5 % 
c o nfi de nce i nter val) t o test f or a differe n ce bet w ee n pr o d ucts.   
T he ass u m pti o n of resi d ual n or malit y a n d varia nce h o m o ge neit y will be i n vesti gate d fr o m t he 
mi xe d m o del t hr o u g h resi d ual pl ots. If vi olate d, a n o n -para metric met h o d ( Wilc o x o n Si g ne d 
Ra n k Test) will be perf or me d f or eac h pair wise c o m paris o n of i nterest as  s u p p orti ve a nal yses.  
1 2. 3. 2  
S e c o n d ar y A n al y s e s  
T he res ults fr o m t he mi xe d m o del a p plie d fr o m t he pri mar y a nal ysis f or % S M H R at 4 h o urs 
will als o be use d t o test a n d prese nt t he p air wise differe n ces i n % S M H R at 1 2 h o urs bet wee n 
t he E x peri me ntal de ntifrice  vers us t h e Refere nce d e ntifrice a n d t he Refere n ce de ntifri ce vers us 
t he Place b o C o ntr ol. 
T he R i n t he deri vati o n of eac h sec o n dar y e n d p oi nt re prese nts t he i n d e ntati o n le n gt h ( μ m) after 
t he 4 or 1 2 h o urs i n sit u re mi neralizati o n as a p pr o priate.  
T he % R E R a n d A R R at t he s u bject visit le vel (t o be use d i n t he a n al ysis)  will be deri ve d fr o m 
wit hi n s peci me n re plicat e res ults i n si milar fas hi o n t o t he % S M H R.  
T he % R E R (at t he re plicate le vel) will be deri ve d as  [( E 1 −E 2)/( E 1 −B)] *  1 0 0  
w here E 2 = I n d e ntati o n le n gt h ( μ m) after sec o n d er osi ve c h alle n ge. 
T he A R R will be deri ve d as 1 − [( E 2−R)/( E 1 −B)].  
T he E F U res ult will be recei v e d fr o m t he la b orat or y per s peci me n, p o ole d acr oss m ulti ple 
micr o drill e na mel bi o ps i es wit hi n eac h s p eci me n. T he mea n acr oss s peci me ns relati n g t o a 
s pecific ti me p oi nt ( 4 or 1 2 h o urs) will be deri ve d.  T he nat ur al l o g of t his mea n will be use d t o 
re pres e nt t he s u bject visit le vel  E F U  at t he ti me p oi nt t o be use d i n t he a nal ysis. 
T he sa me mi xe d m o del as a p plie d f or t he pri mar y a nal ysis f or % S M H R at 4  h o urs  will be 
a p plie d f or t he % S M H R at 1 2  h o urs  a n d t he % R E R, A R R a n d E F U at 4 a n d 1 2 h o urs. T he s a me 
3 pair wise c o m paris o ns of i nterest will be prese nte d.  F or E F U t he bac k -tr a nsf or me d val ues will 
be prese nt e d t o re prese nt t he least s q uare g e o metri c mea ns a n d g e o metric m ea n rati o (a n d 9 5 % 
CIs).  T h e r esi d uals fr o m eac h m o del will be e xa mi ne d a n d si milar t o t he pri mar y a n al ysis, 
s u p p orti n g n o n-para metri c res ults be prese nte d if re q uire d.  
S u m mar y statistics i ncl u di n g t he c o u nts ( missi n g a n d n o n -missi n g), mea n, S D, sta n dar d err or 
( S E), me dia n, mi ni m u m, an d ma xi m u m will be prese nte d b y st u d y pr o d uct f or eac h para meter 
(i ncl u di n g B, E 1, R, E 2) f or eac h ti me-p oi nt ( 4 a n d 1 2 h o urs).  
1 2. 3. 3  
E x pl or at or y A n al y si s  
T he pr o p orti o n of s u bj ects w h o e vi de nce a R E R rati o ( Place b o C o ntr ol : E x peri me ntal 
de ntifrice) > = 3 a n d > = 2 . 5 will be prese nte d al o n g wit h as y m pt otic 9 5 % c o nfi de nce i nter vals 
f or b ot h 4 a n d 1 2 h o ur ti me p oi nts. Assi g n me nts will be ma de i n cert ai n sce nari os of R E R 
val ues at t he ti me p oi nt as f oll o ws:  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
•  E x peri me ntal d e ntifrice R E R ≥ 0 a n d Place b o C o ntr ol < 0 = S u bj ect e vi de nce d R E R 
rati o 
•  Place b o C o ntr ol ≥ 0 = S u bject di d n ot e vi de nce R E R rati o  
1 2. 3. 4  
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 aft er t he first use of st u d y 
pr o d uct  i n t he st u d y. I n t his cr oss o ver trial, e ve nts will be assi g ne d t o t he st u d y pr o d uct bei n g 
recei v e d at t he o nset of t he e ve nt. Treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) wit h a n  o nset 
date/ti me bet wee n visits  w ill be assi g ne d t o t he st u d y pr o d uct recei v e d i n t he pre vi o us peri o d. 
T E A Es wit h a n o ns et aft er last use of  a n y st u d y pr o d uct  will be assi g ne d t o t he last st u d y pr o d uct 
use d .  
T he n u m ber of disti nct e ve nts a n d t he n u m ber a n d perce nt a ge of s u bjects ha vi n g at least o ne 
e ve nt will be pres e nte d b y st u d y pr o d uct a n d o verall  f or t he f oll o wi n g: 
•  A Es ( o verall o nl y)  
•  S A Es  ( o verall o nl y) 
•  T E A Es  
•  Seri o us T E A Es  
•  Oral T E A Es  
•  Pr o d uct Relate d T E A Es  
•  De vice relate d A Es  
•  De vice I n ci de nts  
All A Es a n d de vice i n ci de nts will be liste d pr o vi di n g all rele va nt det ails c ollecte d i n t he C R F.  
1 2. 3. 5  
E x cl u si o n of D at a fr o m A n al y si s  
E xcl usi o n  of a n y data 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) 
Meeti n g pri or t o data bas e l oc k. A n y reas o ns f or e xcl usi o n fr o m a n a nal ysis p o p ulati o n will be 
liste d, if a p plica ble.  
1 2. 3. 6  
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 d a ta (a ge, s e x, race, et h nicit y) will b e s u m marize d d escri pti vel y. 
Me dical hist or y will be liste d pr o vi di n g all rele va nt details c ollecte d i n t he C R F.  
1 2. 3. 7  
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 2. 3. 7. 1  St u d y Dr u g/ Pr o d u ct C o m pli a n c e  
N o n -c o m plia nce wit h st u d y pr o d uct will be ca pt ur e d as a P D a n d s u m marize d.  
1 2. 3. 7. 2  Pri or a n d C o n c o mit a nt M e di c ati o n s  
All pri or a n d c o nc o mita nt me dicati o ns  will be liste d pr o vi di n g all rele va nt details c ollecte d i n 
t he C R F. 
1 2. 3. 8  
H a n dli n g of Dr o p o ut s a n d Mi s si n g D at a  
If it is n ot p ossi ble t o deri ve t he er osi o n p ara m eter at t he visit le vel d ue t o missi n g data fr o m 
s peci me ns n ot c ollecte d a n d/ or data dee me d t o be n o n-e val ua ble b y t he la b orat or y, t he data will 
be treate d as missi n g i n t he I nte nt -T o -Treat (I T T) a nal yses. D ue  t o t he i n sit u nat ure a n d desi g n 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
of t he st u d y, t he li keli h o o d of missi n g data ha vi n g a ‘ missi n g n ot at ra n d o m’ mec ha nis m is ver y 
u nli kel y a n d is n ot rel e va nt t o t he st u d y o bjecti ves. As s uc h t his met h o d t o h a n dle missi n g data 
is dee me d a de q u ate. 
T he mi xe d m o d el a n al ysis met h o ds will e ns ure t hat s u bjects wit h s o me missi n g or e xcl u de d 
res ults f or o ne or m ore of t he st u d y pr o d ucts will still c o ntri b ute t o t he res ults b ut wit h m uc h 
l o wer wei g hti n g c o m pare d t o s u bjects wit h c o m plete data. H o we ver, t he i nclusi o n of s uc h data 
i n t he a nal ysis f or d ata ‘ missi n g at ra n d o m’ is u n biase d a n d a d ds sli g htl y i m pr o ve d precisi o n t o 
st u d y res ults. If t he n u m b er of s u bjects wit h c o m plete data is ver y l o w i n eit her t he I T T a n d/ or 
P P a nal yses, it ma y be deci de d at t he B D R m eeti n g t o als o i ncl u de ‘c o m plete case’ a n al yses as 
necessar y s u p p orti n g e vi de nce.  
1 2. 3. 9  
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 3  
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 3. 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 -p art 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 C R F will ser ve as t h e 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 act i vit y t o verif y t hat t h e: 
•  Data are a ut he ntic, acc urate, a n d c o m plete.  
•  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 ory 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 be des cri be d i n a writte n m o nit ori n g pla n o n file at 
Hale o n . T he i n vesti gat or ( or desi g ne e) 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 3. 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 ura 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 va 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.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 6 3  
T he i n vesti gat or(s) will n otif y Hale o n or its a g e nts i m me diatel y of a n y re g ulat or y i ns pecti 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 s t 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 feasi 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 ulator y a ut h orit y, t he i n vesti gat or will pr o vi de Hale o n  or its a g e 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 3. 3  
R e g ul at or y a n d Et hi c al C o n si d er at i o n s 
1 3. 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 d oc u m e nts, i n vesti gat or br oc h ure/safet y state me nt 
(i ncl u di n g a n y u p d ates) a n d ot her rele va nt d o c u me nts, e. g. recr uit me nt a d vertise me nts, if 
a p plica ble, fr o 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 h e 
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 ue nt a me n d me nts t o t he pr ot oc ol are ma de. 
T he o nl y circ u msta n ce i n w hic h a n a me n d me nt ma y be 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 g e 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 me diatel y after t h e 
i m ple me ntati o n. 
1 3. 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 nati o nal Et hical G ui deli nes 
f or Bi o me dical 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 
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 ma ns (I C H, N o v 2 0 1 6), g ui deli nes f or G C P (I C H, 1 9 9 6), a n d t he Declarati o n of 
Helsi n ki (W orl d Me dic al 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 ulat or y re q uire me nts a n d la ws.  
1 3. 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 xce pt w here re q uire d 
b y la ws.  
W he n st u d y data 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 d ata will be re pl ace d b y n u merical c o des b ase d o n a 
n u m beri n g s yste m pr o vi de d b y Hale o n i n or d er 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 lis t 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 of 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. 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 9  of 6 3  
T he i nf or me d c o nse nt d oc u me nts use 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 of t he st u d y a n d p ossi ble ris ks ass ociate d wi t h partici pati o n.  
1 3. 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, g e 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 neric q uesti o n naire ma y be 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 nit 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 bjects bef ore s uc h materi als are us e d.  
1 3. 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 ni fica 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 g e 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 o n 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 mpete 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 ne 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 uct, Hale o n s h o ul d b e i nf or me d i m me diatel y.  
I n a d diti o n, t he i n vestigat 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 he 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 3. 4  
P o st i 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 vaila 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 n al 
researc hers f or s cie ntific a nal yses or t o c o n d uct 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 tr ial 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 3. 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 the 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.  
Ha le 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 nc 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 bjects, 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.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 0  of 6 3  
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 3. 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 retrie val, w he n 
nee de d (e. g. f or a Hale o n a u dit or re g ulat or y i ns pecti o n) a n d m ust be a vaila ble f or re vie 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 yste ms, a n d rele va nt site staff.  
W here per mitte d b y l ocal la ws/re g u lati o ns or i nstit uti o nal 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, s ca n ne d, el ectr o nic); 
h o we ver, ca uti o n nee ds t o be e xercise 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 o c 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. 
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 ntract 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 mar 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 be a bl e t o i nf or m t he S p o ns or at a n y ti me as t o t he 
l ocati o n of t he st u d y rec or ds. 
1 3. 7  
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 occ 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 .  I n a d diti o n, Hale o n  retai ns t he ri g ht t o disc o nti n ue de vel o p me nt of t he e x peri me ntal 
de ntifrice  at a n y ti me.  
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 materials 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 he 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 h e ter mi nati o n or s us pe nsi o n.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 1  of 6 3  
If t he 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 u res. 
1 4  
R E F E R E N C E S  
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i nstit ute/ oral-he alt h-t o pics/t o ot h br us hes: E xtracte d 2 6 A pril 2 0 2 2. 
[ Atti n T 2 0 0 6] Met h o ds f or assess me nt of de nt al er osi o n. Kar ger M o n o gra p hs i n Oral 
Scie nce.  
[ Barl o w A P, S ufi F, Mas o n S C ( 2 0 0 9)] E val uati o n of differe nt fl u ori date d de ntifrice 
f or m ulati o ns usi n g a n i n sit u er osi o n re mi neralizati o n m o del. J Cli n De nt; 2 0( 6): 1 9 2 -8.  
[ Bartize k R D, Gerlac h R W, Faller R V, et al. ( 2 0 0 1)] Re d ucti o n i n de ntal caries wit h f o ur 
c o nce ntr ati o ns of s o di u m fl u ori de i n a de ntifri ce: a meta -a nal ysis e v al uati o n. J Cli n De nt; 
1 2( 3): 5 7 -6 2.  
[Br u nelle J A, Carl os J P ( 1 9 9 0)] Rece nt tre n ds i n de ntal cari es i n U. S. c hil dre n a n d t he effect 
of water fl u ori dati o n. J D e nt Res; 6 9 S pec N o: 7 2 3 -7; disc ussi o n 8 2 0 -3.  
[ C h o w L C ( 1 9 9 0)] T o ot h-b o u n d fl u ori de a n d d e ntal caries. J D e nt Res; 6 9 S pec N o: 5 9 5 -6 0 0; 
disc ussi o n 3 4 -6.  
[ C oc hra ne NJ, Zer o D T, Re y n ol ds E C ( 2 0 1 2)] Re mi neralizati o n m o dels. A d v De nt Res; 
2 4( 2): 1 2 9 -3 2.  
[ Creet h J E, B ur nett G R, S o u verai n A, et al. ( 2 0 2 0)] I n sit u effi cac y of a n e x peri me ntal 
t o ot h paste o n e na mel re h ar de ni n g a n d pre ve nti o n of de mi neralisati o n: a ra n d o mise d, 
c o ntr olle d trial. B M C Oral Healt h; 2 0( 1): 1 1 8.  
[ Creet h J E, K ell y S A, Marti nez-Mier E A, et al. ( 2 0 1 5)] D ose -res p o nse effect of fl u ori de 
de ntifrice o n re mi neralis ati o n a n d f urt her de mi neralisati o n of er osi ve lesi o ns: A ra n d o mise d  
i n sit u cli nical st u d y. J De nt; 4 3( 7): 8 2 3-3 1.  
[ Creet h J E, Par ki ns o n C R, B ur nett G R, et al. ( 2 0 1 8)] Effects of a s o di u m fl u ori de-a n d 
p h ytate -c o ntai ni n g de ntifrice o n re mi neralisati o n of e na mel er osi ve lesi o ns — a n i n sit u 
ra n d o mise d cli nical st u d y. Cli nical oral i n vesti gati o ns; 2 2: 2 5 4 3 -5 2.  
[ Feat herst o ne J D, Gle na R, S hariati M, et al. ( 1 9 9 0)] De p e n de nce of i n vitr o de mi neralizati o n 
of a patite a n d re mi neralizati o n of de ntal e n a mel o n fl u ori de c o nce ntrati o n. J De nt Res; 6 9 
S pec N o: 6 2 0 -5; disc ussi o n 3 4 -6.  
[ F owler C, Wills o n R, Rees G D ( 2 0 0 6)] I n vitr o micr o har d ness st u dies o n a ne w a nti -er osi o n 
dese nsitizi n g t o ot h paste. J Cli n De nt; 1 7( 4): 1 0 0 -5.  
[ F o wler C E, Gracia L, E d war ds MI, et al. ( 2 0 0 9)] I n hi biti o n of e n a mel er osi o n a n d pr o m oti o n 
of lesi o n re har de ni n g b y fl u ori de: a w hite li g ht i nterfer o metr y a n d micr oi n de ntati o n st u d y. J 
Cli n De nt; 2 0( 6): 1 7 8 -8 5.  
[ Gilla m D G ( 1 9 9 6)] Effi cac y of a p otassi u m nitrate m o ut h was h i n alle viati n g cer vical de nti ne 
se nsiti vit y ( C D S). J o ur nal of Cli nical Peri o d o nt ol o g y; 2 3( 1 1): 9 9 3-7.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
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C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 2  of 6 3  
[I C H ( 1 9 9 6)] G E N E R A L C O N SI D E R A TI O N S F O R C LI NI C A L T RI A L S E 8. 
[I C H ( N o v 2 0 1 6)] T o pic E 6 ( R 2) G ui deli ne f or G o o d Cli nical Practice. 
[ Li p pert F, L y n c h RJ ( 2 0 1 4)] C o m paris o n of K n o o p a n d Vic kers s urface micr o har d ness a n d 
tra ns verse micr ora di o gr a ph y f or t he st u d y of earl y caries lesi o n f or mati o n i n h u ma n a n d 
b o vi ne e na mel. Arc h Oral Bi ol; 5 9( 7): 7 0 4 -1 0.  
[ Ma g gi o B, G ui bert R G, Mas o n S C, et al. ( 2 0 1 0)] E val uati o n of m o ut hri nse a n d de ntifrice 
re gi me ns i n a n i n sit u er osi o n re mi neralisati o n m o del. J o urnal of De ntistr y; 3 8: S 3 7 -S 4 4.  
[ Ne h me M, Jeffer y P, Mas o n S, et al. ( 2 0 1 6)] Er osi o n re mi neralizati o n effi cac y of gel-t o-
f oa m fl u ori de t o ot h pastes i n sit u: A ra n d o mize d cli nical trial. Caries Res.; 5 0( 1): 6 2-7 0.  
[ Ne h me M, Par ki ns o n C, Zer o D, et al. ( 2 0 1 9)] Ra n d o mise d st u d y of t he effects of fl u ori de 
a n d ti me o n i n sit u re mi neralisati o n of aci d -s ofte n e d e na mel. Cli nical Oral I n v esti gati o ns; 2 3: 
4 4 5 5 -6 3.  
[ Sa ma nt A, Mali k C, C ha bra S, et al. ( 1 9 7 6)] Gi n gi vitis a n d peri o d o ntal disease i n pr e g na nc y. 
4 7( 7): 4 1 5 -8 . 
[ Sc hiff T, D ots o n M, C o he n S, et al. ( 1 9 9 4)] Efficac y of a d e ntifrice c o ntai ni n g p otassi u m 
nitrate, s ol u ble p yr o p h os p hate, P V M/ M A c o p ol y mer, a n d s o di u m fl u ori de o n de nti nal 
h y perse nsiti vit y: A t wel ve -wee k cli nical st u d y. J o ur nal of Cli nical De ntistr y; 5( S P E C. I S S.): 
8 7 -9 2.  
[ S hellis R P, Ga nss C, Re n Y, et al. ( 2 0 1 1)] Met h o d ol o g y a n d m o dels i n er osi o n researc h: 
disc ussi o n a n d c o ncl usi o ns. Caries Res; 4 5 S u p pl 1: 6 9 -7 7.  
[ Ste p he n K W ( 1 9 9 3)] D e ntifrices: rece nt cli nical fi n di n gs a n d i m plicati o ns f or use. I nt De nt J; 
4 3( 6 S u p pl 1): 5 4 9 -5 3.  
[ U S F D A ( 2 0 0 5)] G UI D A N C E F O R I N D U S T R Y: C O L L E C TI O N O F R A C E A N D 
E T H NI CI T Y D A T A I N C LI NI C A L T RI A L S.  
[ W hite AJ, Y orat h C, Te n He n gel V, et al. ( 2 0 1 0)] H u ma n a n d b o vi ne e na mel er osi o n u n der 
‘ si n gle‐ dri n k ’ c o n diti o ns. E ur o pea n j o ur na l of oral scie nces; 1 1 8( 6): 6 0 4-9.  
[ W orl d Me dic al Ass ociati o n ( 2 0 1 3)] Declarati o n of Helsi n ki, 6 4t h Ge neral Asse m bl y, 
F ortale za.  
[ Zer o D T ( 1 9 9 5)] I n sit u caries m o dels. A d v De nt Res; 9( 3): 2 1 4-3 0; disc ussi o n 3 1 -4.  
[ Zer o D T, Hara A T, K ell y S A, et al. ( 2 0 0 6)] E v al uati o n of a dese nsitizi n g test de ntifrice usi n g 
a n i n sit u er osi o n re mi neralizati o n m o del. J Cli n De nt; 1 7( 4): 1 1 2 -6.  
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
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Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 0 5 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot be 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 3  of 6 3  
1 5  
A P P E N DI CI E S  
1 5. 1  
A b br e vi ati 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 5 -1  
A b br e vi ati o n s  
A b br e vi ati o n  
T er m  
A E  
A d v er s e e v e nt  
A R R  
A ci d r e si st a n c e r ati o  
B D R  
Bli n d e d d at a r e vi e w  
CI  
C o nfi d e n c e i nt er v al  
C R F  
C a s e r e p ort f or m  
e C R F  
El e ctr o ni c c a s e re p ort for m  
E F U  
E n a m el fl u ori d e u pt a k e  
G C P  
G o o d c li ni c al p r a cti c 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 R B 
In stit uti o n al r e vi e w b o ar d  
N/ A  
N ot a p pli c a bl e  
 
 
O H T  
Or al h ar d ti s s u e  
O S T  
Or al s oft ti s s u e  
PI  
P er s o n al i nf or m ati o n 
R E R  
R el ati v e er o si o n r e si st a n c e  
S A E  
S eri o u s a d v er s e e v e nt  
S O P  
St a n d ar d o p er ati n g pr o c e d ur e  
S M H R  
S urf a c e mi cr o h ar d n e s s r e c o v er y  
S S  
S af et y st at e m e nt  
T E A E  
Tr e at m e nt e m er g e nt a d v er s e e v e nt  
U S  
U nit e d St at e s  
 
 
3 0 0 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
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C CI
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Si g nat ure Pa ge f or  3 0 0 0 5 7 T M F- 2 4 2 9 9 8 v 3. 0
Si g nat ure Pa ge f or T M F- 2 4 2 9 9 8 v 3. 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 0 5 7 Pr ot oc ol  1 4 Mar 2 0 2 4 | T M F- 2 4 2 9 9 8 | 3. 0
P P D
P P D