Conditions: Tooth Erosion
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 33
Healthy volunteers: yes

Brief summary:
The purpose of this study is to investigate the ability of an experimental dentifrice containing 1150 parts per million (ppm) fluoride to remineralize acid-softened dental enamel and help prevent further demineralization compared to a 0 ppm fluoride placebo dentifrice and a marketed, fluoride-containing dentifrice (Reference Dentifrice).

Detailed description:
This will be a randomized, controlled, single center, single-blind, 3 period, 3 treatment, cross-over, in situ design study. Previously demineralized bovine enamel specimens will be placed intra orally using a palatal appliance and the remineralizing performance of the experimental, reference and placebo dentifrices will be evaluated at 4 and 12 hours post toothbrushing, based on surface micro hardness measurements of the bovine enamel specimens. At each treatment visit, once the palatal the appliance is fitted in the mouth, a five minute equilibration period will ensue following which each participant will brush their teeth with their assigned product. Participants will remove the appliance for 30 minutes at 4 and 8.5 hours post brushing and will remove and store the appliance 13 hours post brushing (12 hours intraoral exposure). Sufficient participants will be screened to randomize approximately 33 participants to study treatment to ensure approximately 30 participants complete the study.

Arms:
arm 1: Participants will brush the buccal surfaces of their natural teeth using 1.5+/- 0.1 grams (g) of the experimental dentifrice containing 1150 ppm fluoride and 5 percent (%) potassium nitrate (KNO3) for 25 timed seconds and then swish the resulting dentifrice slurry around the mouth, without further brushing, for a timed period of 95 seconds. Participants will use the dentifrice under supervision of the study staff while the intraoral appliance is in place in Treatment Periods 1 to 3. There will be a washout period of a minimum of 3 days prior to each treatment during which the participants will use their own dentifrice for at least one day, and a 0 ppm fluoride washout dentifrice for two days. arm 2: Participants will brush the buccal surfaces of their natural teeth using 1.5+/- 0.1 g of the placebo dentifrice containing 0 ppm fluoride and 5% KNO3 for 25 timed seconds and then swish the resulting dentifrice slurry around the mouth, without further brushing, for a timed period of 95 seconds. Participants will use the dentifrice under supervision of the study staff while the intraoral appliance is in place in Treatment Periods 1 to 3. There will be a washout period of a minimum of 3 days prior to each treatment during which the participants will use their own dentifrice for at least one day, and a 0 ppm fluoride washout dentifrice for two days. arm 3: Participants will brush the buccal surfaces of their natural teeth using 1.5+/- 0.1 g of the reference dentifrice containing 1100 ppm fluoride as stannous fluoride (SnF2) for 25 timed seconds and then swish the resulting dentifrice slurry around the mouth, without further brushing, for a timed period of 95 seconds. Participants will use the dentifrice under supervision of the study staff while the intraoral appliance is in place in Treatment Periods 1 to 3. There will be a washout period of a minimum of 3 days prior to each treatment during which the participants will use their own dentifrice for at least one day, and a 0 ppm fluoride washout dentifrice for two days.

Interventions: intervention 1: Experimental Dentifrice intervention 2: Placebo Control Dentifrice intervention 3: Reference Dentifrice
Intervention descriptions: intervention 1: Dentifrice containing 1150 ppm fluoride and 5% KNO3. intervention 2: Dentifrice containing 0 ppm fluoride and 5% KNO3. intervention 3: Dentifrice containing 1100 ppm fluoride as SnF2.

Protocol document:
Prot_000.pdf: 
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   
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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:  
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P h a s e:  
N/ A  
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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   
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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.   
 
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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  
 
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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  
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Sc he d ule of A cti vities  ............................................................................................ 1 4  
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I N T R O D U C TI O N ............................................................................................................. 1 6  
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St u d y Rati o nale  ...................................................................................................... 1 6  
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Bac k gr o u n d  ............................................................................................................ 1 7  
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Be nefit/ Ris k Assess me nt  ....................................................................................... 1 8  
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Mec ha nis m of Acti o n/I n dicati o n  ........................................................................... 1 8  
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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  
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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  
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J ustificati o n f or D ose ............................................................................................. 2 3  
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E n d of St u d y Defi niti o n  ......................................................................................... 2 3  
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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  
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Ra n d o mizati o n Criteria  .......................................................................................... 2 5  
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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  
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C o ntrace pti o n  ........................................................................................ 2 7  
5. 6  
Scree n Fail ures ....................................................................................................... 2 7  
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S p o ns or’s Q ualifie d Me dical Pers o n nel  ................................................................ 2 7  
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Cli nical Assess or Rater/ Cli nical Assess or Q ualificati o ns  ..................................... 2 7  
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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  
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I n v esti gati o nal/ St u d y Pr o d uct S u p plies ................................................................. 2 8  
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Me dical De vices  .................................................................................... 2 9  
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D osa ge F or m a n d Pac k a gi n g  ................................................................. 2 9  
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Pre parati o n a n d D is pe nsi n g................................................................... 3 0  
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I n v esti gati o nal/ St u d y Pr o d uct St ora ge .................................................................. 3 1  
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I n v esti gati o nal/ St u d y Pr o d uct Acc o u nta bilit y ....................................................... 3 1  
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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  
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Bli n di n g a n d All ocati o n/ Ra n d o mizati o n  ............................................................... 3 2  
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Brea ki n g t he Bli n d  ................................................................................................. 3 3  
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C o m plia nce  ............................................................................................................ 3 3  
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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  
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S T U D Y P R O C E D U R E S  ................................................................................................... 3 5  
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Visit 1/ Scree ni n g  ................................................................................................... 3 5  
8. 1. 1  
I nf or me d C o nse nt .................................................................................. 3 5  
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De m o gra p hics  ....................................................................................... 3 6  
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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  
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I n cl usi o n/ E xcl usi o n Criteria ................................................................. 3 6  
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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  
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Dis pe nse Was h -o ut Pr o d ucts a n d Diar y Car ds  ..................................... 3 7  
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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  
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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  
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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  
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Palatal a p plia nces i ntra oral p hase –  4 h o urs  ........................................ 3 9  
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Palatal a p plia nces i ntra oral p hase –  1 2 h o urs  ...................................... 4 0  
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St u d y C o ncl usi o n  .................................................................................. 4 0  
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F oll o w -u p Visit / P h o ne Call  ................................................................ 4 0  
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S T U D Y A S S E S S M E N T S  ................................................................................................. 4 0  
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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  
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Safet y a n d Ot her Assess me nts  ............................................................................... 4 1  
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Oral S oft Tiss ue ( O S T) E xa mi nati o n  .................................................... 4 1  
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Oral Har d Tiss ue ( O H T) E xa mi nati o n  .................................................. 4 1  
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Pre g na nc y T esti n g  ................................................................................. 4 2  
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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  
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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  
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Re p orti n g Pr oce d ures ............................................................................................. 4 5  
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Re p orti n g of a n A d verse E ve nt  ............................................................. 4 5  
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Re p orti n g of a Seri o us A d verse E ve nt  .................................................. 4 6  
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E val uati n g A d verse E ve nts  .................................................................................... 4 6  
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Assess me nt of I nte nsit y  ........................................................................ 4 6  
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Assess me nt of Ca usalit y  ....................................................................... 4 7  
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F oll o w -u p of A Es a n d S A Es .................................................................................. 4 7  
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Wit h dra wal D u e t o a n A d verse E ve nt  ................................................................... 4 8  
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Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ...................................................... 4 8  
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Pre g na nc y  .............................................................................................................. 4 8  
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Ti me Peri o d f or C ollecti n g Pre g na nc y I nf or mati o n.............................. 4 8  
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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  
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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  
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Case Re p ort F or m  .................................................................................................. 5 1  
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Data Ha n dli n g  ........................................................................................................ 5 2  
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Data Q ueries  .......................................................................................... 5 2  
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Pr ocessi n g Patie nt Re p orte d O utc o mes  ................................................................. 5 2  
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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  
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Sa m ple Size Deter mi nati o n  ................................................................................... 5 3  
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P o p ulati o ns f or A nal ysis  ........................................................................................ 5 3  
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Defi niti o ns of A nal ysis P o p ulati o ns  ..................................................... 5 3  
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E xcl usi o ns of Data fr o m A nal ysis ......................................................... 5 3  
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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  
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Statistical A nal yses  ................................................................................................ 5 4  
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Pri mar y A nal ysis  ................................................................................... 5 4  
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Sec o n dar y A n al yses  .............................................................................. 5 5  
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E x pl orat or y A nal ysis  ............................................................................. 5 5  
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Safet y A nal yses  ..................................................................................... 5 6  
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E xcl usi o n of Data fr o m A nal ysis  .......................................................... 5 6  
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De m o gra p hic a n d Baseli ne C haracteristics  ........................................... 5 6  
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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  
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Ha n dli n g of Dr o p o uts a n d Missi n g Data  .............................................. 5 6  
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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  
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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
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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 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  
[ A D A ( 2 0 2 2)] T o ot h br us hes. htt ps:// w w w.a da. or g/res o urces/r esearc h/sci e n ce -a n d -res earc h-
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
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 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
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 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
C CI
C CI
C CI


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

SAP_001.pdf: 
Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
Property of Haleon
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Haleon
Statistical Analysis Plan Template v7.0
Page 1 of 43
STATISTICAL ANALYSIS PLAN 
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
Protocol Number:
300057
Phase:
N/A
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IRUWKLVSXEOLFO\DYDLODEOHYHUVLRQ
CCI


Sodium Fluoride and Potassium Nitrate 
Protocol Number 300057 
 
 
 
 
 
Haleon Confidential 
 Statistical Analysis Plan Template v7.0 
Page 2 of 43 
 
 
Document History 
 
Document 
Version Date 
Summary of Changes (New analysis or 
Change in planned analysis) 
Original Analysis Plan 
23APR2024 
Not applicable (N/A) 
 
Amendments incorporate all revisions to date.   
 
 
CCI


Sodium Fluoride and Potassium Nitrate 
Protocol Number 300057 
 
 
 
 
 
Haleon Confidential 
 Statistical Analysis Plan Template v7.0 
Page 3 of 43 
 
 
Table of contents 
Document History ............................................................................................................... 2 
Table of contents ................................................................................................................. 3 
List of Tables ....................................................................................................................... 4 
Abbreviations.............................................................................................................................. 5 
1 
Summary of Key Protocol Information ............................................................................... 6 
1.1 
Study Design ............................................................................................................ 6 
1.2 
Study Objectives ...................................................................................................... 9 
1.3 
Treatments ............................................................................................................. 10 
1.4 
Sample Size Calculation ........................................................................................ 10 
2 
Planned Analyses ............................................................................................................... 11 
2.1 
Interim Analysis ..................................................................................................... 11 
2.2 
Final Analyses ....................................................................................................... 11 
3 
Considerations for data analyses and Data Handling Conventions ................................... 11 
3.1 
Baseline Definition ................................................................................................ 11 
3.2 
Timepoints and Visit Windows ............................................................................. 12 
4 
Data Analysis ..................................................................................................................... 12 
4.1 
Populations for Analysis ........................................................................................ 12 
4.1.1 
Subject Disposition ............................................................................... 12 
4.1.2 
Protocol Deviations ............................................................................... 12 
4.1.3 
Analysis Populations ............................................................................. 13 
4.2 
Subject Demographics and Other Baseline Characteristics ................................... 13 
4.2.1 
Demographic Characteristics ................................................................ 13 
4.2.2 
General Medical History ....................................................................... 13 
4.3 
Treatments (Study Product, Rescue Medication, other Concomitant 
Therapies, Compliance) ......................................................................................... 13 
4.3.1 
Study Product Compliance and Exposure ............................................. 13 
4.3.2 
Prior and Concomitant Medication ....................................................... 13 
4.3.3 
Medical Device Incidents and Malfunctions......................................... 13 
4.4 
Analysis of Efficacy .............................................................................................. 14 
4.4.1 
Primary Efficacy Endpoint - %SMHR at 4 hours (Test v Placebo) ...... 14 
4.4.2 
Secondary Efficacy Variables ............................................................... 15 
CCI


Sodium Fluoride and Potassium Nitrate 
Protocol Number 300057 
 
 
 
 
 
Haleon Confidential 
 Statistical Analysis Plan Template v7.0 
Page 4 of 43 
 
 
4.4.3 
Handling of Missing Values/Censoring/Discontinuations .................... 18 
4.5 
Analysis of Safety .................................................................................................. 18 
5 
Changes to the Protocol Defined Statistical Analysis Plan ............................................... 19 
Appendix 4: List of Data Displays .................................................................................... 20 
Appendix 5: Table Shells .................................................................................................. 24 
 
List of Tables 
No table of contents entries found. 
 
CCI


Sodium Fluoride and Potassium Nitrate 
Protocol Number 300057 
 
 
 
 
 
Haleon Confidential 
 Statistical Analysis Plan Template v7.0 
Page 5 of 43 
 
 
Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
SMHR 
Surface Microhardness Recovery 
RER 
Relative Erosion Resistance 
ARR 
Acid Resistance Ratio 
EFU 
Enamel Fluoride Uptake 
TEAEs 
Treatment-Emergent Adverse Events 
KNO3 
Potassium Nitrate 
BDR 
Blind Data Review 
PP 
Per Protocol 
ITT 
Intent to Treat 
SD 
Standard Deviation 
SE 
Standard Error 
CCI


Sodium Fluoride and Potassium Nitrate 
Protocol Number 300057 
 
 
 
 
 
Haleon Confidential 
 Statistical Analysis Plan Template v7.0 
Page 6 of 43 
 
 
The purpose of this Statistical Analysis Plan is to describe the planned analyses and outputs to 
be included in the Clinical Study Report for Protocol 300057. 
1 
Summary of Key Protocol Information 
This study will investigate the ability of an experimental dentifrice containing 1150ppm 
fluoride to remineralize acid-softened dental enamel and help prevent further demineralization 
compared to a 0ppm fluoride placebo dentifrice and a marketed, fluoride-containing dentifrice 
(Reference Dentifrice). The study will utilize an established in situ model where partially 
demineralized enamel specimens will be placed in a dental palatal appliance, treated intra orally 
then allowed to remineralize in situ for 4 and 12 hours. Efficacy will be evaluated through 
laboratory measurement of the surface microhardness recovery (SMHR), relative erosion 
resistance (RER), acid resistance ratio (ARR) and the enamel fluoride uptake (EFU). Safety 
will be demonstrated through tabulation of treatment-emergent adverse events (TEAEs). 
1.1 
Study Design 
This will be a randomized, controlled, single center, single- blind (to the dental examiner and 
specimen analysts), 3 period, 3 treatment, cross-over, in situ design. Previously demineralized 
bovine enamel specimens will be place intra orally using a palatal appliance and the 
remineralizing performance of the experimental, reference and placebo dentifrices evaluated at 
4 and 12 hours post toothbrushing, based on surface micro hardness measurements of the bovine 
enamel specimens. This study will be carried out in healthy adults who meet the study eligibility 
as detailed in the study protocol. There will be 7 visits as shown in the schedule of activities.  
The enamel specimens will be evaluated both prior to and after intra-oral exposure. Surface 
microhardness (SMH) will be used to evaluate changes in the mineral content of enamel and is 
used to calculate surface micro hardness recovery (%SMHR), relative erosion resistance 
(%RER) and acid resistance ratio (ARR). The incorporation of fluoride into the enamel 
specimens will be assessed by enamel fluoride uptake (EFU) measurements. For each treatment 
and subject, these measurements will be performed on the same enamel specimen as described 
in the Laboratory Procedure Document, in the four enamel specimens removed at each time 
point. The erosive acid challenges, with a commercially available grapefruit juice, will be 
carried out ex vivo and therefore does not pose a risk to the subject’s teeth. 
AEs and medical device incidents will be monitored throughout the study and recorded at every 
site visit following signing of informed consent. 
CCI


Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
Property of Haleon
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Haleon
Statistical Analysis Plan Template v7.0
Page 7 of 43
Schedule of Activities
Procedure/Assessment
Screening
Study Period 1
Study Period 2
Study Period 3
Visit 1
Visit 2
(Treatment)
Visit 3
(V2+1day)
Visit 4
(Treatment)
Visit 5
(V4+1day)
Visit 6
(Treatment)
Visit 7
(V6+1day)
Informed consent
X 
Minimum 3 days including a 2 days washout using 
supplied non-fluoride dentifrice
Minimum 3 days including a 2 days washout using 
supplied non-fluoride dentifrice
Minimum 3 days including a 2 days washout using 
supplied non-fluoride dentifrice
Demographics
X 
Medical history
X 
Current/prior/concomitant medication review
X 
X 
X 
X 
X 
X 
X 
OST Examination1
X 
X 
X 
X 
X 
X 
X 
OHT Examination
X 
X 
Assessment of stimulated and unstimulated 
saliva flow rate2
X 
Review of inclusion/exclusion criteria
X 
Try-in of palatal appliance
X 
Subject eligibility
X 
Dispense wash-out products and diary
X 
CCI


Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
Haleon Confidential
Statistical Analysis Plan Template v7.0
Page 8 of 43
Procedure/Assessment
Screening
Study Period 1
Study Period 2
Study Period 3
Visit 1
Visit 2
(Treatment)
Visit 3
(V2+1day)
Visit 4
(Treatment)
Visit 5
(V4+1day)
Visit 6
(Treatment)
Visit 7
(V6+1day)
Diary review
X 
X 
X 
X 
X 
X 
Subject continuance
X 
X 
X 
X 
X 
Randomization to treatment sequence
X 
Place palatal appliance fitted with enamel 
specimens into subject’s mouth3
X 
X 
X 
Supervised toothbrushing
X 
X 
X 
Intra oral phase 4 hours 3,4
X 
X 
X 
Intra oral phase 12 hours 3,5
X 
X 
X 
Adverse events review6
X 
X 
X 
X 
X 
X 
X 
Medical device incidents review1
X 
X 
X 
X 
X 
X 
Return wash-out products
X 
Return palatal appliance
X 
X 
X 
Study conclusion
X 
Abbreviations: OST: Oral Soft Tissue, OHT: Oral Hard Tissue. 
Footnotes:
1.
At Visits 2, 4 & 6 OST examination will be performed prior to insertion of the appliance and at Visits 3, 5 & 7 when the subject returns their palatal appliance. 
2.
Re-evaluation of saliva flow may be required within the study should the subject begin a treatment of medications likely to induce xerostomia.
3.
Laboratory analysis of enamel specimens performed prior to placing and after removing the specimens from the palatal appliance as described in the separate laboratory procedures document. 
4.
Four enamel specimens will be removed from the palatal appliance after wearing the appliance for 4 hours ± 10 min after toothbrushing.  Subject will be offered lunch to be eaten over a 30 ±10 minute 
period and then be allowed to leave the site with instructions on how and when to eat dinner (30 ±10 minute period between hours 8.5 and 9), and remove (hour 13), store and return their appliance.
5.
Subjects will remove their appliance after 12 hours ± 30 mins of wearing post toothbrushing (13 ±0.5 hours since brushing with product).  Subjects will then rinse and store the appliance as instructed by the 
site staff.  Subjects will return the appliance to the study site the following day.  The study site staff will recover the 4 remaining enamel sections, then the appliance will be cleaned, disinfected and stored at 
site until the next treatment visit.
6.
Adverse Events (AEs), Serious Adverse Events (SAEs) and medical device incidents collected from immediately after subject provides consent to participate in the study by the completion of the Informed 
Consent Form (ICF).  Medical device in this study is the supplied toothbrush.
CCI


Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
Property of Haleon
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Haleon
Statistical Analysis Plan Template v7.0
Page 9 of 43
1.2 
Study Objectives
Objectives
Endpoints
Primary Objective
Primary Endpoint
x
To investigate the efficacy of an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 to enhance remineralization of enamel compared to a 
placebo dentifrice (0ppm fluoride) after 4 hours of intra-oral exposure.
x
%SMHR at 4 hrs.
Secondary Objectives
Secondary Endpoints
Efficacy
x
To investigate the efficacy of an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 to inhibit demineralization of enamel compared to a 
placebo dentifrice (0ppm fluoride) after 4 hours of intra-oral exposure.
x
%RER at 4 hrs.
x
To investigate the efficacy of an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 to enhance remineralization of enamel compared to a 
marketed, reference dentifrice containing 1100ppm fluoride after 4 hours of 
intra-oral exposure.
x
%SMHR at 4 hrs.
x
To investigate the efficacy of an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 to enhance remineralization of enamel compared to a 
placebo dentifrice (0ppm fluoride) and a marketed, reference dentifrice
containing 1100ppm fluoride after 12 hours of intra-oral exposure.
x
%SMHR at 12 hrs.
x
To investigate the efficacy of an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 to inhibit demineralization of enamel compared to a 
reference dentifrice containing 1100ppm fluoride after 4 hours of intra-oral 
exposure.
x
%RER at 4 hrs.
x
To investigate the efficacy of an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 to inhibit demineralization of enamel compared to a 
placebo dentifrice (0ppm fluoride) and a marketed, reference dentifrice
containing 1100ppm fluoride after 12 hours of intra-oral exposure.
x
%RER 12 hrs.
x
To investigate the efficacy of an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 to promote fluoride uptake in enamel compared to a 
placebo dentifrice (0ppm fluoride) and a marketed, reference dentifrice
containing 1100ppm fluoride after 4 and 12 hours of intra-oral exposure.
x
EFU at 4 and 12 hrs.
x
To investigate the efficacy of an experimental dentifrice containing 1150 ppm 
fluoride and 5% KNO3 to reduce future acid-induced demineralization in
enamel compared to a placebo dentifrice (0ppm fluoride) and a marketed, 
x
ARR at 4 and 12 hrs.
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Objectives 
Endpoints 
reference dentifrice containing 1100ppm fluoride after 4 and 12 hours of intra-
oral exposure. 
x 
To investigate the efficacy of a marketed, reference dentifrice containing 
1100ppm fluoride. to enhance remineralization, inhibit demineralization, to 
reduce future acid-induced demineralization and to promote fluoride uptake in 
enamel compared to a placebo dentifrice (0ppm fluoride) after 4 and 12 hours 
of intra-oral exposure. 
x 
%SMHR, %RER, EFU, ARR 
at 4 and 12 hrs. 
Safety 
 
x 
To assess the oral tolerability of an experimental dentifrice containing 
1150ppm fluoride and 5% KNO3. 
x 
Treatment emergent 
adverse events 
Exploratory Objectives 
Exploratory Endpoints 
x 
To calculate the proportion of subjects who evidence a RER ratio (%RER 
0ppm fluoride placebo and 5% KNO3 : %RER experimental dentifrice 
containing 1150 ppm fluoride) >=3 and >=2.5 
x 
%RER at 4 and 12 hrs. 
1.3 
Treatments 
 
Test Dentifrice 
Placebo Control 
Reference Dentifrice 
Experimental Dentifrice containing 
1150ppm fluoride and 5% KNO3* 
0ppm fluoride dentifrice 
containing 5% KNO3 
Crest Pro-Health Densify 
Daily Protection 
* KNO3 is commonly used in other marketed anti sensitive toothpaste. 
All dentifrices will be applied in the same manner by brushing 1.5±0.1g of dentifrice on to 
the buccal surfaces of their natural teeth for 25 timed seconds and then swishing the 
resulting dentifrice slurry around the mouth, without further brushing, for a timed period of 
95 seconds. 
Subjects will use a 0ppm fluoride washout dentifrice twice daily for 2 days prior to each 
treatment visit in place of their usual oral hygiene practice. 
All subjects will be centrally randomized to 1 of 6 sequences using an Interactive Response 
Technology (IRT) based on a schedule consisting of randomized blocks of 6-sequences 
from a 3-treatment Williams Square design. 
All study site staff will be blinded except for those staff members directly dealing with 
dispensing study products. Site staff, study statistician(s), data management staff and other 
employees of the sponsor and vendors acting on behalf of the sponsor, who may influence 
study outcomes will be blinded to the product allocation. 
1.4 
Sample Size Calculation 
A sufficient number of healthy subjects will be screened to ensure that up to 33 subjects will be 
randomized to participate in the study to ensure at least 30 evaluable subjects complete the 
study. With a sample size of 30 subjects completing the study, there will be 97% power to detect 
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a difference in means of 7.5% in %SMHR at 12 hours, assuming a standard deviation (SD) of 
differences of 9.94% using a paired t-test with a 0.05 two-sided significance level. 
These differences and variability were observed when comparing a similar test product to a 
similar Placebo Control and Reference Dentifrice at 4 hours in GSKCH study 208166. In the 
absence of any historical studies with results at 12 hours, the result at 12 hours will be assumed 
to be similar to 4 hours for the purpose of sample size calculation. 
A recent network meta-analysis (Haleon study 300033) across 14 studies using the same design 
involving 22 different grouped type of study products suggests a SD of differences as high as 
12.16% at 4 hours. Even with such a higher SD, there would still be 90% (80%) power to detect 
a difference in means of 7.5% (6.5%) in %SMHR at 12 hours. 
Previous Haleon study 208166 and network meta-analysis 300033 suggest respective SD of 
differences for %RER between 17.5% and 20.3%. Such estimates of variability would give 90% 
(80%) power to detect respective difference in means of 10.7% and 12.4% (9.3% and 10.7%). 
2 
Planned Analyses 
2.1 
Interim Analysis 
No interim analysis is planned. 
2.2 
Final Analyses 
The final planned primary analyses will be performed after the completion of the following 
sequential steps: 
1. All subjects have completed the study as defined in the protocol. 
2. All required database cleaning activities including any external data reconciliation and a 
Blind Data Review (BDR) Meeting have been completed. 
3. Database has been locked. 
4. All criteria for unblinding the randomization codes have been met and the randomization 
codes have been distributed. 
3 
Considerations for data analyses and Data Handling 
Conventions 
3.1 
Baseline Definition 
Other than the Baseline indentation lengths (see section 4.4) there will be no definition of 
Baseline used in this study. 
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3.2 
Timepoints and Visit Windows 
Visits and assessments will be conducted in line with the Schedule of Activities (section 1.1) 
and any which are out-of-window will be recorded as protocol deviations and assessed for 
exclusion from the Per-Protocol (PP) Population (section 4.1.2). Otherwise, the results from 
each scheduled visit and assessment will directly represent the result at the respective time-
point in all analyses. 
4 
Data Analysis 
Data analysis will be performed by the 
. The statistical analysis software used will be SAS 
version 9.4 in Windows environment. 
Prior to database closure a Blind Data Review Meeting (BDRM) will be conducted in which 
various aspects of the trial will be discussed and agreed.  
Except as described below, all listings will be produced for all randomized subjects.   
4.1 
Populations for Analysis 
Tables described in this section will be produced for all randomized subjects.   
4.1.1 Subject Disposition 
Subject disposition will be summarized as the number and percentage of subjects who complete 
the study, with the number who discontinue broken down by reason for discontinuation, by 
treatment group across study treatment periods (Table 14.1.1) and by sequence group and period 
(Table 14.1.2). Subject disposition including the subject status (completer, Yes/No), critical 
demographic data (age, sex, race), the timing of the discontinuation, treatment sequence group, 
and the specific reason for discontinuation will be listed for all subjects in the Screened 
population in Listing 16.2.1.1.  
4.1.2 Protocol Deviations 
Protocol deviations will be tracked by the study team throughout the conduct of the study. Data 
will be reviewed prior to unblinding and closure of the database to ensure all important 
deviations are captured and categorised. 
Each PD will be assessed as part of the BDR, but possible PDs (list not exhaustive) which may 
impact the reliability of erosion parameters are non-compliance with the use of study product 
at the visit, lifestyle considerations or instructions for removal and return of palatal appliance, 
and therefore will be excluded from the per-protocol population (See Section 4.1.3). 
The number and percentage of subjects with any important protocol deviations and with each 
type of important protocol deviations will be presented by treatment (Table 14.1.3) and listed 
in Listing 16.2.2.2. 
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4.1.3 Analysis Populations 
The following analysis populations will be defined: 
x The Screened population will include all subjects who are screened. 
x The Intent-to-Treat (ITT) population will include all subjects who are randomized. Study 
product group will be assigned to each visit for analyses based on the study product 
sequence the subject was randomized to. 
x The Safety population will include all randomized subjects who receive at least 1 dose of 
study product. Study product group will be assigned for analyses based on the last known 
study product the subject actually received prior to the safety event. 
x The Per-Protocol (PP) population will include all subjects from the ITT population who 
have at least one visit with non-missing erosion parameters unaffected by protocol 
deviations. Study product group will be assigned to each visit for analyses based on the study 
product the subject received. 
Subjects excluded from any of the ITT, Safety and PP analysis populations will be listed for all 
subjects in the Screened population in Listing 16.2.3, with the reason for exclusion. 
4.2 
Subject Demographics and Other Baseline Characteristics 
4.2.1 Demographic Characteristics 
Demographic data (age, sex, race, ethnicity) will be summarized descriptively.  
4.2.2 General Medical History 
Medical history will be collected in the CRF. 
4.3 
Treatments (Study Product, Rescue Medication, other Concomitant 
Therapies, Compliance) 
4.3.1 Study Product Compliance and Exposure 
Non-compliance with study product will be captured as a PD and summarized. 
4.3.2 Prior and Concomitant Medication 
All prior and concomitant medications will be collected in the CRF. 
4.3.3 
Medical Device Incidents and Malfunctions  
The toothbrushes to be used in this study are medical devices. 
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All device deficiencies, (including malfunction, use error and inadequate labelling) shall be 
documented, and reported by the investigator throughout the clinical investigation and 
appropriately managed by the sponsor. 
4.4 
Analysis of Efficacy  
Statistical testing of all endpoints in this study will be conducted at a two-sided significance 
level of 0.05. A sequential testing strategy will be applied to preserve the overall type-1 error 
control for the respective sequential comparisons between the Experimental dentifrice and 
Placebo Control at 4 hours for the %SMHR (primary endpoint) and %RER (secondary 
endpoint). There will be no further adjustments for multiplicity. 
All analyses of erosion parameters will be primarily based on the ITT population. If there are 
more than a 10% of ITT population subjects with at least 1 visit with non-missing erosion 
parameters deemed to be affected by a protocol deviation, the PP analyses will also be 
performed as supportive analyses. 
Summary statistics including the counts (missing and non-missing), mean, SD, standard error 
(SE), median, minimum, and maximum will be presented by study product for each parameter 
for each time-point (4 and 12 hours). 
4.4.1 Primary Efficacy Endpoint - %SMHR at 4 hours (Test v Placebo) 
4.4.1.1 
Primary Efficacy Endpoint Definition 
The primary endpoint will be the %SMHR at 4 hours and the comparison between the 
Experimental dentifrice and Placebo Control. 
For each replicate within each specimen (collected after 4 hours in situ remineralization) within 
a particular study visit, the %SMHR (at the replicate level) will be derived as 
[(E1-R)/(E1-B)] * 100 
where: 
% LQGHQWDWLRQOHQJWKȝPRIVRXQGHQDPHODWEDVHOLQH 
E1 = indentation length ȝP after first erosive challenge 
R = indentation OHQJWKȝPDIWHU 4 hours in situ remineralization 
The %SMHR at the subject visit level (to be used in the analysis) will be derived as the mean 
of the specimen means (across evaluable replicate %SMHR within a specimen) within that visit. 
Missing data or data deemed as non-evaluable by the laboratory will not be used in these 
derivations. 
4.4.1.2 
Statistical Hypothesis, Model, and Method of Analysis 
The null and alternative hypotheses are: 
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x H0: there is no difference between the products. 
x H1: there is a difference between the products. 
A mixed model (including results across all 3 study products) will be used to analyze 
the %SMHR at 4 hours with fixed effects for treatment and study visit, as well as random effect 
for subject. Kenward Rogers degrees of freedom approach will be applied. The least square 
means for each study product will be presented along with the differences between least square 
means (Experimental dentifrice - Placebo Control; including two-sided p-value and 95% 
confidence interval) to test for a difference between products. 
The assumption of residual normality and variance homogeneity will be investigated from the 
mixed model through residual plots. If violated, a non-parametric method (Wilcoxon Signed 
Rank Test) will be performed for each pairwise comparison of interest as supportive analyses. 
4.4.2 Secondary Efficacy Variables 
4.4.2.1 
%SMHR at 4 hours (Test v Reference and Reference v Placebo) 
The results from the mixed model applied from the primary analysis for %SMHR at 4 hours 
will also be used to test and present the pairwise differences in %SMHR at 4 hours between the 
Experimental dentifrice versus the Reference dentifrice and the Reference dentifrice versus the 
Placebo Control. 
4.4.2.2 
%SMHR at 12 hours 
4.4.2.2.1 Secondary Efficacy Endpoint Definition 
%SMHR at 12 hours: %SMHR at the subject visit level (to be used in the analysis) will be 
derived from within specimen replicate results in similar fashion to the %SMHR at 4 hours. 
For each replicate within each specimen (collected after 12 hours in situ remineralization) within 
a particular study visit, the %SMHR (at the replicate level) will be derived as 
[(E1-R)/(E1-B)] * 100 
where: 
% LQGHQWDWLRQOHQJWKȝPRIVRXQGHQDPHODWbaseline 
E1 = indentation length ȝP after first erosive challenge 
R = indentation OHQJWKȝPDIWHU 12 hours in situ remineralization 
The %SMHR at the subject visit level (to be used in the analysis) will be derived as the mean 
of the specimen means (across evaluable replicate %SMHR within a specimen) within that visit. 
Missing data or data deemed as non-evaluable by the laboratory will not be used in these 
derivations. 
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4.4.2.2.2 Statistical Hypothesis, Model, and Method of Analysis 
The null and alternative hypotheses are: 
x H0: there is no difference between the products. 
x H1: there is a difference between the products. 
The same mixed model as applied for the primary analysis for %SMHR at 4 hours will be 
applied for the %SMHR at 12 hours. The same 3 pairwise comparisons of interest will be 
presented. 
4.4.2.3 
%RER at 4 and 12 hours 
4.4.2.3.1 Secondary Efficacy Endpoint Definition 
%RER at 4 hours and at 12 hours: The R in the derivation of each secondary endpoint represents 
the indentation length ȝP after the 4 or 12 hours in situ remineralization as appropriate. 
The %RER at the subject visit level (to be used in the analysis) will be derived from within 
specimen replicate results in similar fashion to the %SMHR. The %RER (at the replicate level) 
will be derived as 
>(í((í%@ * 100 
where: 
% LQGHQWDWLRQOHQJWKȝPRIVRXQGHQDPHODWEDVHOLQH 
E1 = indentation length ȝP after first erosive challenge 
( ,QGHQWDWLRQOHQJWKȝPDIWHUVHFRQGHURVLYHFKDOOHQJH 
The %RER at the subject visit level (to be used in the analysis) will be derived as the mean of 
the specimen means (across evaluable replicate %RER within a specimen) within that visit. 
Missing data or data deemed as non-evaluable by the laboratory will not be used in these 
derivations. 
4.4.2.3.2 Statistical Hypothesis, Model, and Method of Analysis 
The null and alternative hypotheses are: 
x H0: there is no difference between the products. 
x H1: there is a difference between the products. 
The same mixed model as applied for the primary analysis for %SMHR at 4 hours will be 
applied for %RER at 4 and 12 hours. The same 3 pairwise comparisons of interest will be 
presented. The residuals from each model will be examined and similar to the primary analysis, 
supporting non-parametric results be presented if required. 
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4.4.2.3.3 Exploratory Analysis  
The proportion of subjects who evidence a RER ratio (Placebo Control : Experimental 
dentifrice) >=3 and >=2.5 will be presented along with asymptotic 95% confidence intervals 
for both 4 and 12 hour time points. Assignments will be made in certain scenarios of RER 
values at the time point as follows: 
x Experimental dentifrice RER 0 and Placebo Control < 0 = Subject evidenced RER 
ratio 
x Placebo Control 0 = Subject did not evidence RER ratio 
4.4.2.4 
% ARR at 4 and 12 Hours 
4.4.2.4.1 Secondary Efficacy Endpoint Definition 
ARR at 4 hours and at 12 hours: The R in the derivation of each secondary endpoint represents 
the indentation length ȝP after the 4 or 12 hours in situ remineralization as appropriate. The 
ARR at the subject visit level (to be used in the analysis) will be derived from within specimen 
replicate results in similar fashion to the %SMHR. The ARR will be derived as 
1 í >(í5(í%@ 
where: 
% LQGHQWDWLRQOHQJWKȝPRIVRXQGHQDPHODWEDVHOLQH 
R = indentation OHQJWKȝPDIWHU 4 hours or 12 hours in situ remineralization 
E1 = indentation length ȝP after first erosive challenge 
( ,QGHQWDWLRQOHQJWKȝPDIWHUVHFRQGHURVLYHFKDOOHQJH 
The ARR at the subject visit level (to be used in the analysis) will be derived as the mean of the 
specimen means (across evaluable replicate ARR within a specimen) within that visit. Missing 
data or data deemed as non-evaluable by the laboratory will not be used in these derivations. 
4.4.2.4.2 Statistical Hypothesis, Model, and Method of Analysis 
The null and alternative hypotheses are: 
x H0: there is no difference between the products. 
x H1: there is a difference between the products. 
The same mixed model as applied for the primary analysis for %SMHR at 4 hours will be 
applied for the ARR at 4 and 12 hours. The same 3 pairwise comparisons of interest will be 
presented. The residuals from each model will be examined and similar to the primary analysis, 
supporting non-parametric results be presented if required. 
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4.4.2.5 
EFU at 4 and 12 Hours 
4.4.2.5.1 Secondary Efficacy Endpoint Definition 
EFU at 4 hours and at 12 hours: The EFU result will be received from the laboratory per 
specimen, pooled across multiple microdrill enamel biopsies within each specimen. The mean 
across specimens relating to a specific timepoint (4 or 12 hours) will be derived. The natural 
log of this mean will be used to represent the subject visit level EFU at the timepoint to be used 
in the analysis. 
Missing data or data deemed as non-evaluable by the laboratory will not be used in these 
derivations. 
4.4.2.5.2 Statistical Hypothesis, Model, and Method of Analysis 
The null and alternative hypotheses are: 
x H0: there is no difference between the products. 
x H1: there is a difference between the products. 
The same mixed model as applied for the primary analysis for %SMHR at 4 hours will be 
applied for the EFU at 4 and 12 hours. The same 3 pairwise comparisons of interest will be 
presented. The residuals from each model will be examined and similar to the primary analysis, 
supporting non-parametric results be presented if required. The back-transformed values will be 
presented to represent the least square geometric means and geometric mean ratio (and 95% 
CIs). 
4.4.3 
Handling of Missing Values/Censoring/Discontinuations 
Exclusions of any data from the analyses will be determined during a Blinded Data 
Review (BDR) meeting prior to database lock and unblinding. 
If it is not possible to derive the erosion parameter at the visit level due to missing data 
from specimens not collected and/or data deemed to be non-evaluable by the laboratory, 
the data will be treated as missing in the Intent-To-Treat (ITT) analyses. 
4.5 
Analysis of Safety 
AEs will be regarded as treatment emergent if they occur on or after the date of first use of study 
product in the study. In this crossover trial, events will be assigned to the study product being 
received at the onset of the event. Treatment-emergent adverse events (TEAEs) with an onset 
date/time between visits will be assigned to the study product received in the previous period. 
TEAEs with an onset after last use of any study product will be assigned to the last study product 
used. 
The number of distinct events and the number and percentage of subjects having at least one 
event will be presented by study product and overall for the following: 
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x AEs (overall only) 
x SAEs (overall only) 
x TEAEs 
x Serious TEAEs 
x Oral TEAEs 
x Product Related TEAEs 
x Device related AEs 
x Device Incidents 
All AEs and device incidents will be listed providing all relevant details collected in the CRF. 
5 
Changes to the Protocol Defined Statistical Analysis Plan 
There were no changes or deviations to the originally planned statistical analysis specified in 
the protocol/protocol amendment (Dated: DD/MMM/YYYY). 
 
 
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Appendix 4: List of Data Displays 
 
  
Type 
Number 
Title 
Population 
Topline Output 
Tables and Figures 
 
14.1 Demographic Data Summary figures and tables.  
 
  
Table 
14.1.1 
Subject Disposition by Treatment Group Across Study Treatment Periods 
ITT Population 
 
  
Table 
14.1.2 
Subject Disposition by Sequence Group and Period 
ITT Population 
 
  
Table 
14.1.3 
Incidence of Important Protocol Deviations 
ITT Population 
 
  
Table 
14.1.4.1 
Demographic Characteristics 
Safety Population 
 
  
Table 
14.1.4.2 
Demographic Characteristics 
ITT Population 
 
  
Table 
14.1.4.3 
Demographic Characteristics 
PP Population 
 
14.2 Objectives Data Summary figures and tables. 
 
  
Table 
14.2.1.1.1 
Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 4 Hours by Treatment 
Group 
ITT Population 
Yes 
  
Table 
14.2.1.1.2 
Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 4 Hours by Treatment 
Group 
PP Population 
Yes 
  
Table 
14.2.1.2.1 
Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 12 Hours by 
Treatment Group 
ITT Population 
Yes 
  
Table 
14.2.1.2.2 
Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 12 Hours by 
Treatment Group 
PP Population 
Yes 


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Figure
14.2.1.3
Bar Chart with Error Bars (±SE) for Adjusted Mean Surface Microhardness Recovery 
(%SMHR) at 4 and 12 hours
ITT Population
Table 
14.2.2.1.1
Statistical Analysis of Relative Erosion Resistance (%RER) at 4 Hours by Treatment Group
ITT Population
Yes
Table 
14.2.2.1.2
Statistical Analysis of % Relative Erosion Resistance (%RER) at 4 Hours by Treatment 
Group
PP Population
Yes
Table 
14.2.2.2.1
Statistical Analysis of % Relative Erosion Resistance (%RER) at 12 Hours by Treatment 
Group
ITT Population
Yes
Table 
14.2.2.2.2
Statistical Analysis of % Relative Erosion Resistance (%RER) at 12 Hours by Treatment 
Group
PP Population
Yes
Figure
14.2.2.3
Bar Chart with Error Bars (±SE) for Adjusted Mean Relative Erosion Resistance (%RER) 
by Treatment Group
ITT Population
Table
14.2.3.1.1
Statistical Analysis of Acid Resistance Ratio (ARR) at 4 Hours by Treatment Group
ITT Population
Table
14.2.3.1.2
Statistical Analysis of Acid Resistance Ratio (ARR) at 4 Hours by Treatment Group
PP Population
Table
14.2.3.2.1
Statistical Analysis of Acid Resistance Ratio (ARR) at 12 Hours by Treatment Group
ITT Population
Table
14.2.3.2.2
Statistical Analysis of Acid Resistance Ratio (ARR) at 12 Hours by Treatment Group
PP Population
Figure
14.2.3.3
Bar Chart with Error Bars (±SE) for Adjusted Mean Acid Resistance Ratio (ARR) at 4 and 
12 hours
ITT Population
Table
14.2.4
Summary Table of Indents Measures (B/E1/R/E2) by Timepoint and Treatment Group
ITT Population
Table
14.2.5.1
Statistical Analysis of Enamel Fluoride Uptake (EFU) at 4 Hours by Treatment Group
ITT Population
Table
14.2.5.2
Statistical Analysis of Enamel Fluoride Uptake (EFU) at 12 Hours by Treatment Group
ITT Population
Figure
14.2.5.3
Bar Chart with 95% CI for Adjusted Geometric Mean Enamel Fluoride Uptake (EFU)
ITT Population
14.3 Safety Data
14.3.1 Displays of Adverse Events
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Table
14.3.1
Summary of Adverse Events and Device Incidents Overall and by Treatment Group
Safety Population
SAS Output
16.1.9 Documentation of statistical methods.
SAS Output 
File
16.1.9.1
Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 4 Hours by Treatment 
Group
ITT Population
Yes
SAS Output 
File
16.1.9.2
Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 4 Hours by Treatment 
Group
PP Population
Yes
SAS Output 
File
16.1.9.3
Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 12 Hours by 
Treatment Group
ITT Population
Yes
SAS Output 
File
16.1.9.4
Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 12 Hours by 
Treatment Group
PP Population
Yes
SAS Output 
File
16.1.9.5
Statistical Analysis of Relative Erosion Resistance (%RER) at 4 Hours by Treatment Group
ITT Population
Yes
SAS Output 
File
16.1.9.6
Statistical Analysis of % Relative Erosion Resistance (%RER) at 4 Hours by Treatment 
Group
PP Population
Yes
SAS Output 
File
16.1.9.7
Statistical Analysis of % Relative Erosion Resistance (%RER) at 12 Hours by Treatment 
Group
ITT Population
Yes
SAS Output 
File
16.1.9.8
Statistical Analysis of % Relative Erosion Resistance (%RER) at 12 Hours by Treatment 
Group
PP Population
Yes
SAS Output 
File
16.1.9.9
Statistical Analysis of Acid Resistance Ratio (ARR) at 4 Hours by Treatment Group
ITT Population
SAS Output 
File
16.1.9.10
Statistical Analysis of Acid Resistance Ratio (ARR) at 4 Hours by Treatment Group
PP Population
SAS Output 
File
16.1.9.11
Statistical Analysis of Acid Resistance Ratio (ARR) at 12 Hours by Treatment Group
ITT Population
SAS Output 
File
16.1.9.12
Statistical Analysis of Acid Resistance Ratio (ARR) at 12 Hours by Treatment Group
PP Population
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SAS Output 
File
16.1.9.13
Statistical Analysis of Enamel Fluoride Uptake (EFU) at 4 Hours by Treatment Group
ITT Population
SAS Output 
File
16.1.9.14
Statistical Analysis of Enamel Fluoride Uptake (EFU) at 12 Hours by Treatment Group
ITT Population
16.2 Patient Data Listings
16.2.1 Discontinued patients.
Listing
16.2.1
Subject Disposition
Screened Population
16.2.2 Protocol deviations.
Listing
16.2.2
Protocol Deviations
ITT Population
16.2.3 Patients excluded from the efficacy analysis.
Listing
16.2.3
Exclusions from Efficacy Analysis
ITT Population
16.2.7 Adverse event listings
Listing
16.2.7.1
Adverse Events
ITT Population
Listing 
16.2.7.2
Device Incidents
ITT Population
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
Haleon Confidential
Statistical Analysis Plan Template v7.0
Page 24 of 43
Appendix 5: Table Shells
Each table when output from the SAS analysis program will include the program run date in the top right header and the program name in the 
bottom left footnote.
Table 14.1.1, Subject Disposition by Treatment Group Across Study Treatment Periods, ITT Population
Study Period
Test
Reference 
Placebo
Overall
1
Randomized
N
Discontinued Study Prior To Visit
n (x.x%)
     <reason n>
Attended Visit
Evaluable Erosion Data
     <reason if not n>
: :3
: :Overall
Randomized
Discontinued Study Prior To Visit
     <reason n>
Attended Visit
Evaluable Erosion Data
Percentages are based on all subjects randomized to each specific period based on randomized sequence. 
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Table 14.1.2, Subject Disposition by Sequence Group and Period, ITT Population
Study 
Period
ABC (N=X)
ACB (N=X)
BAC (N=X)
BCA (N=X)
CAB (N=X)
CBA (N=X)
Overall (N=XX)
1
Discontinued Study Prior To Visit
n (x.x%)
     <reason n>
Attended Visit
    Evaluable Erosion Data
     <reason if not n>
: :
3
: :
Overall
Completed Study
Discontinued Study
     <reason n>
A = Test, B = Reference, C= Placebo
Percentages are based on all subjects randomized within each specific sequence.
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Statistical Analysis Plan Template v7.0
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Table 14.1.3, Incidence of Important Protocol Deviations, ITT Population
Test
Reference
Placebo
Overall (N=XXX)
Any Important Protocol Deviation
n (x.x%)
     <PD type 1>
           : :
     <PD type n>
Any Important Protocol Deviation Leading to Data 
Exclusion from PP analysis
     <PD type 1>
           : :
     <PD type n>
Percentages are based on all subjects randomized in the ITT population.
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Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Table 14.1.4, Demographic Characteristics, ITT Population  
Overall (N=XXX)
Age
n, Mean (SD), Median, min-max
x, x.x (x.x), x.x, x-x
Sex
Female
n (x.x%)
Male
n (x.x%)
Race
American Indian or Alaska Native
n (x.x%)
Asian
n (x.x%)
Black or African American
n (x.x%)
Native Hawaiian or Other Pacific Islander
n (x.x%)
White
n (x.x%)
Multiracial
n (x.x%)
Other
n (x.x%)
Ethnicity
Hispanic or Latino
n (x.x%)
Not Hispanic or Latino
n (x.x%)
Percentages are based on all subjects randomized in the ITT population.
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Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Table 14.2.1.1.1, Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 4 Hours by Treatment Group, ITT Population (similar table for PP 
Population if necessary)
Parameter
Test
Reference 
Placebo
%SMHR at 4 hours (N=XXX)
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
Adjusted Mean (SE, 95% CI)*
x.xx (x.xxx, x.xxx to x.xxx)
x.xx (x.xxx, x.xxx to x.xxx)
x.xx (x.xxx, x.xxx to x.xxx)
    vs Placebo (SE)
x.xx (x.xxx)
x.xx (x.xxx)
      95% CI
x.xxx to x.xxx
x.xxx to x.xxx
      p-value
x.xxxx
x.xxxx
    vs Reference (SE)
x.xx (x.xxx)
      95% CI
x.xxx to x.xxx
p-value
x.xxxx
*A mixed model with fixed effects for treatment and study visit, and random effect for subject.
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
Haleon Confidential
Statistical Analysis Plan Template v7.0
Page 30 of 43
All of the tables listed below will be similar to 14.2.1.1.1 (other than decimal places used: SMHR/RER/EFU 2 decimal places for mean, 3 for sd/se/ci; 
ARR 3 decimals for mean and 4 for sd/se/ci):
Table 14.2.1.2.1, Statistical Analysis of Surface Microhardness Recovery (%SMHR) at 12 Hours by Treatment Group, ITT Population (similar table for PP 
Population if necessary)
Table 14.2.3.1.1, Statistical Analysis of Acid Resistance Ratio (ARR) at 4 Hours by Treatment Group, ITT Population (similar table for PP Population if 
necessary) 
Table 14.2.3.2.1, Statistical Analysis of Acid Resistance Ratio (ARR) at 12 Hours by Treatment Group, ITT Population (similar table for PP Population if 
necessary) 
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Table 14.2.2.1.1, Statistical Analysis of Relative Erosion Resistance (%RER) at 4 Hours by Treatment Group, ITT Population (similar table for PP 
Population if necessary); Similar table for 14.2.2.2.1, Statistical Analysis of % Relative Erosion Resistance (%RER) at 12 Hours by Treatment Group, ITT 
Population (similar table for PP Population if necessary)
Parameter
Test
Reference 
Placebo
%RER at 4 hours  (N=XXX)
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
Adjusted Mean (SE, 95% CI)*
x.xx (x.xxx, x.xxx to x.xxx)
x.xx (x.xxx, x.xxx to x.xxx)
x.xx (x.xxx, x.xxx to x.xxx)
    vs Placebo (SE)
x.xx (x.xxx)
x.xx (x.xxx)
      95% CI
x.xxx to x.xxx
x.xxx to x.xxx
      p-value
x.xxxx
x.xxxx
      RER Ratio >= 3
x.x% (x.x% to x.x%)
      RER Ratio >=2.5 (95% CI)
x.x% (x.x% to x.x%)
    vs Reference (SE)
x.xx (x.xxx)
      95% CI
x.xxx to x.xxx
      p-value
x.xxxx
*A mixed model with fixed effects for treatment and study visit, and random effect for subject.
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Table 14.2.5.1, Statistical Analysis of Enamel Fluoride Uptake (EFU) at 4 Hours by Treatment Group, ITT Population; Similar table for 14.2.5.2, Statistical 
Analysis of Enamel Fluoride Uptake (EFU) at 12 Hours by Treatment Group, ITT Population
Parameter
Test
Reference 
Placebo
EFU at 4 hours (ug F/cm2) (N=XXX)
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
Adjusted Geometric Mean (95% CI)*
x.xx (x.xxx to x.xxx)
x.xx (x.xxx, x.xxx to x.xxx)
x.xx (x.xxx, x.xxx to x.xxx)
    vs Placebo, Geometric Mean Ratio (95% CI)
x.xx (x.xxx to x.xxx)
x.xx (x.xxx to x.xxx)
      p-value
x.xxxx
x.xxxx
    vs Reference, Geometric Mean Ratio (95% CI)
x.xx (x.xxx)
      p-value
x.xxxx
*A mixed model on log transformed EFU with fixed effects for treatment and study visit, and random effect for subject. Estimates are back-
transformed.
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Figure 14.2.1.3, Bar Chart with Error Bars (±SE) for Adjusted Mean Surface Microhardness Recovery (%SMHR) at 4 and 12 hours, ITT Population
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
Page 34 of 43
All of the figures listed below will be similar to 14.2.1.3: 
Figure 14.2.2.3, Bar Chart with Error Bars (±SE) for Adjusted Mean Relative Erosion Resistance (%RER) by Treatment Group, ITT Population
Figure 14.2.3.3, Bar Chart with Error Bars (±SE) for Adjusted Mean Acid Resistance Ratio (ARR) at 4 and 12 hours, ITT Population
Figure 14.2.5.3, Bar Chart with 95% CI for Adjusted Geometric Mean Enamel Fluoride Uptake (EFU), ITT Population
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
Haleon Confidential
Statistical Analysis Plan Template v7.0
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Table 14.2.4, Summary Table of Indents Measures (B/E1/R/E2) by Timepoint and Treatment Group, ITT Population
Parameter
Test
Reference 
Placebo
(N=XXX)
B at 4 hours
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
B at 12 hours
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
E1 at 4 hours
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
E1 at 12 hours
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
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Sodium Fluoride and Potassium Nitrate
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Statistical Analysis Plan Template v7.0
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Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
R at 4 hours
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
R at 12 hours
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
E2 at 4 hours
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
E2 at 12 hours
n
x
x
x
Mean (SD, SE)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
x.xx (x.xxx, x.xxx)
Median
x.xx
x.xx
x.xx
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Minimum to Maximum
x.xx to x.xx
x.xx to x.xx
x.xx to x.xx
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Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Table 14.3.1, Summary of Adverse Events and Device Incidents Overall and by Treatment Group, Safety Population
Test (N=XXX)
Reference (N=XXX)
Placebo (N=XXX)
Overall (N=XXX)
Any Adverse Event
n (x.x%)
Any Serious Adverse Event
n (x.x%)
Any Treatment Emergent Adverse Event (TEAE)
n (x.x%)
n (x.x%)
n (x.x%)
n (x.x%)
Any Serious TEAE
n (x.x%)
n (x.x%)
n (x.x%)
n (x.x%)
Any Oral TEAE
n (x.x%)
n (x.x%)
n (x.x%)
n (x.x%)
Any Product Related TEAE
n (x.x%)
n (x.x%)
n (x.x%)
n (x.x%)
Any Device Related AE
n (x.x%)
Any Device Incidents
n (x.x%)
Percentages are based on all subjects in the Safety population according to the study product received.
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
Haleon Confidential
Statistical Analysis Plan Template v7.0
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Listing 16.2.1, Subject Disposition, Screened Population
ID
Age / Sex 
/ Race / 
Ethnicity
Visit 
Dates
Treatment 
Sequence 
Group
Analysis 
population
Completer
Reason for 
Discontinue
Date of 
Discontinue
Age / 
Female or 
Male / 
Race / 
Ethnicity
V1: Date 1
V2: Date 2
V3: Date 3
V4: Date 4
V5: Date 5
V6: Date 6
V7: Date 7
ABC
ITT / SAF / 
PP
Yes or No
xxxxxxxxxxxxxxxx
DDMMMYYYY
A = Test, B = Reference, C= Placebo
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Sodium Fluoride and Potassium Nitrate
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Statistical Analysis Plan Template v7.0
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Listing, 16.2.2 Protocol Deviations, ITT Population
ID
Visit Dates
Treatment Sequence 
Group
Date of PD
Protocol 
Deviation (PD)
Important PD
Important PD affect efficacy and 
Visit data exclusion from PP analysis 
V1: Date 1
V2: Date 2
V3: Date 3
V4: Date 4
V5: Date 5
V6: Date 6
V7: Date 7
ABC
DDMMMYYYY
xxxxxxxxxxxxxxxx
Yes or No
Yes or No, Vx
A = Test, B = Reference, C= Placebo
PP = Per-Protocol
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Listing 16.2.3, Exclusions from Efficacy Analysis, ITT Population
ID
Treatment Sequence Group
Study Periods 
Excluded from PP 
analysis
Reason for Exclusion
ABC
P1/P2/P3
xxxxxxxxxxxxxxxxxxx
A = Test, B = Reference, C= Placebo
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Listing 16.2.7.1, Adverse Events, ITT Population
ID
Visit Dates
Treatment 
Sequence 
Group
AE Description
AE Dates
Start-Stop
TEAE / 
Last Study 
Product 
Used 
Serious/ 
Severity / 
Related to 
Study Product 
/ 
Oral 
Frequency/
Outcome/
Action/
Withdraw 
from study
V1: Date 1
V2: Date 2
V3: Date 3
V4: Date 4
V5: Date 5
V6: Date 6
V7: Date 7
ABC
xxxxxxxxxxxxxxxxxxx
DDMMMYYYY-
DDMMMYYYY
Yes or No, 
A 
Serious or 
Not Serious /
Mild or 
Moderate or 
Severe /
Related or 
Not Related /
Oral or Not 
Oral
Xxxxx/
Xxxxx/
Xxxxx/
Yes or No
A = Test, B = Reference, C= Placebo
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Sodium Fluoride and Potassium Nitrate
Protocol Number 300057
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Statistical Analysis Plan Template v7.0
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Listing 16.2.7.2, Device Incidents, Non-Randomized Subjects
ID
Visit Dates
Treatment Sequence 
Group
Incident Date
Incident Description
Incident related to AE
V1: Date 1
V2: Date 2
V3: Date 3
V4: Date 4
V5: Date 5
V6: Date 6
V7: Date 7
ABC
DDMMMYYYY
xxxxxxxxxxxxxxxxxxx
Yes or No
A = Test, B = Reference, C= Placebo
CCI