Clinical trial NCT06143670
Conditions: Gingivitis
Sponsor: HALEON
Start date: 2023-11-29; Completion date: 2024-03-12
Enrollment: 159 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this clinical study is to investigate the efficacy of a dentifrice containing 0.454 percent (%) weight by weight (w/w) stannous fluoride (SnF2), on gingivitis treatment and plaque reduction, compared to a regular fluoride dentifrice after 12 weeks twice daily brushing in a population of clinically diagnosed gingivitis without undergoing dental prophylaxis.

Detailed description:
This will be a single center, randomized, controlled, single blind (examiner blind), two-treatment arm, parallel study. Study participants will be over 18 years old, non-smokers, in good general health with clinically measurable levels of gingivitis that meet all study criteria at the Screening and Baseline visits. Approximately 160 participants (approximately 80 per group) will be randomized to ensure approximately 144 evaluable participants (approximately 72 per group) complete the study.

Arms: arm 1: Participants will be instructed to brush their teeth with full ribbon of toothpaste (0.454% w/w SnF2) on head of toothbrush provided for at least one (timed) minute twice a day (morning and evening) for 12 weeks. arm 2: Participants will be instructed to brush their teeth with full ribbon of toothpaste (0.243% w/w Sodium fluoride) on head of toothbrush provided for at least one (timed) minute twice a day (morning and evening) for 12 weeks.
Interventions: intervention 1: Stannous fluoride toothpaste intervention 2: Sodium fluoride toothpaste
Intervention descriptions: intervention 1: 0.454% w/w SnF2 intervention 2: 0.243% w/w Sodium fluoride

Protocol documents:
Prot_000.pdf: 
Hale o n  
Cli nical Pr ot oc ol  
Pr ot oc ol N u m ber : 3 0 0 1 0 7  
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
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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, C o ntr oll e d, E x a mi n er -Bli n d Cli ni c al St u d y 
I n v e sti g ati n g t h e Eff e ct s  of a  D e ntifri c e C o nt ai ni n g 0. 4 5 4 % w/ w 
St a n n o u s Fl u ori d e o n Gi n gi viti s Tr e at m e nt a n d Pl a q u e R e d u cti o n 
W h e n U s e d T wi c e D ail y f or 1 2 W e e k s   
Pr ot o c ol N u m b er:  
3 0 0 1 0 7  
C o m p o u n d/ Pr o d u ct N a m e:  
0. 4 5 4 % W ei g ht/ W ei g ht ( w/ w) St a n n o u s 
Fl u ori d e  (S n F 2 ) 
U nit e d St at e s ( U S) I n v e sti g ati o n al 
N e w Dr u g (I N D) N u m b er:  
N/ A  
E ur o p e a n Cli ni c al Tri al s D at a b a s e 
( E u dr a C T) N u m b er: 
N/ A  
Ot h er R e g ul at or y A g e n c y I d e ntifi e d 
N u m b er:  
N/ A  
P h a s e:  
N/ A  
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T his d oc u me nt c o ntai ns c o nfi de ntialit y state me nts t hat are n ot rele va nt 
f or t his p u blicl y a vaila ble versi o n
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Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
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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 d,  
W arr e n, N e w J er s e y ( N J) 0 7 0 5 9,  
U nit e d St at e s ( U S)  
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Pr o pert y of Hal e o n - C o nfi de ntial   
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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)  
N e w V er si o n  
2. 0  
•  Cl arifi e d A E a n d m e di c al d e vi c e i n ci d e nt m o nit ori n g 
i n st u d y d e si g n s y n o p si s a n d o v er all st u d y 
d e si g n  ( s e cti o n 4. 1) 
•  Cl arifi e d st ati sti c al a n al y s e s  
•  T y p o gr a p hi c al a d mi ni str ati v e c h a n g e s  
A m e n d m e nt 1  
 
 
A m e n d m e nt 2  
 
 
 
 
 
A me n d me nts i nc or p orate all re visi o ns t o dat e, i ncl u di n g a me n d m e nts ma de at t he re q u est of 
c o u ntr y h ealt h a ut h orities, i nstit uti o nal re vie w b oar ds/et hics c o m mittees (I R Bs/ E Cs), etc.   
 
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Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
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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  a n d a p pli ca ble p orti o ns of E U M D R 2 0 1 7/ 7 4 5 a n d 
E ur o pea n N ati o n I nter n ati o nal O r ga nisati o n f or St a n dar disati o n (I S O) 1 4 1 5 5: 2 0 1 1 a n d 
I S O 1 4 1 5 5: 2 0 2 0.  
•  I ac k n o wle d ge t hat I a m res p o nsi ble f or o verall st u d y c o n d u ct. I a gree t o p ers o nall y 
c o n d uct or s u per vise t he descri be d st u d y.  
•  I a gree t o e ns ure t hat all ass ociates, c ollea g ues a n d e m pl oyees assisti n g i n t he c o n d uct of 
t he st u d y are i nf or m e d a b o ut t heir o bli gati o ns. Mec ha nis ms are i n place t o e ns ure site staff 
recei v es all a p pr o priate i nf or mati o n t hr o u g h o ut t h e st u d y. 
•  I a gree t o c o n d uct t his st u d y i n f ull c o nf or ma nce wit h t he la ws a n d re gul 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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P P D
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Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
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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 ge  ................................................................ 4  
Ta ble of C o nte nts  ................................................................................................................ 5  
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P R O T O C O L S U M M A R Y  ................................................................................................ 1 0  
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S y n o psis  ................................................................................................................. 1 0  
1. 2  
Sc he d ule of A cti vities  ............................................................................................ 1 4  
2  
I N T R O D U C TI O N ............................................................................................................. 1 7  
2. 1  
St u d y R ati o nale  ...................................................................................................... 1 7  
2. 2  
Be nefit/ Ris k Assess me nt  ....................................................................................... 1 8  
2. 3  
Mec ha nis m of Acti o n/I n dicati o n  ........................................................................... 1 8  
3  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S  .................................................................... 1 9  
4  
S T U D Y D E SI G N  .............................................................................................................. 2 0  
4. 1  
O verall Desi g n  ....................................................................................................... 2 0  
4. 2  
Scie ntific Rati o nale f or St u d y Desi g n  ................................................................... 2 1  
4. 3  
J ustificati o n f or D ose ............................................................................................. 2 3  
4. 4  
E n d of St u d y Defi niti o n  ......................................................................................... 2 3  
5  
S T U D Y P O P U L A TI O N  .................................................................................................... 2 3  
5. 1  
T y pe a n d Pla n ne d N u m b er of S u bjects  ................................................................. 2 3  
5. 2  
I n cl usi o n Criteria ................................................................................................... 2 4  
5. 3  
E x cl usi o n Criteria  .................................................................................................. 2 4  
5. 4  
Ra n d o mizati o n Criteria  .......................................................................................... 2 7  
5. 5  
Lif est yle C o nsi derati o ns  ........................................................................................ 2 7  
5. 5. 1  
Meals a n d Dietar y Restri cti o ns  ............................................................. 2 7  
5. 5. 2  
Alc o h ol, Caffei ne a n d C he wi n g g u m  .................................................... 2 7  
5. 5. 3  
De ntal Pr o d uct/ Treat me nt a n d Oral H y gie ne Res tricti o ns ................... 2 7  
5. 5. 4  
Me dicati o n a n d Treat me nt Restricti o n  .................................................. 2 8  
5. 5. 5  
C o ntrace pti o n  ........................................................................................ 2 8  
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C O VI D -1 9  ............................................................................................. 2 8  
5. 6  
Scree n Fail ures ....................................................................................................... 2 8  
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S p o ns or’s Q ualifie d Me dical Pers o n nel  ................................................................ 2 8  
5. 8  
Cli nical Assess or Q ualificati o ns  ............................................................................ 2 8  
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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 9  
6. 1  
I n v esti gati o nal/ St u d y Pr o d uct S u p plies ................................................................. 2 9  
6. 1. 1  
Me dical De vices (if a p plica ble –  del ete if n ot nee d e d)  ......................... 3 1  
6. 1. 2  
D osa ge F or m a n d Pac k a gi n g  ................................................................. 3 1  
6. 1. 3  
Pre parati o n a n d Dis pe nsi n g ................................................................... 3 1  
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A d mi nistrati o n  ....................................................................................................... 3 2  
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Cli nical Pr ot oc ol  
 
 
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Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
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Me dicati o n/ D osi n g Err ors  ..................................................................... 3 2  
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O ver d ose  ............................................................................................... 3 3  
6. 3  
I n v esti gati o nal/ St u d y Pr o d uct St ora ge .................................................................. 3 3  
6. 4  
I n v esti gati o nal/ St ud y Pr o d uct Acc o u nta bilit y  ....................................................... 3 3  
6. 4. 1  
Destr ucti o n of I n v esti gati o nal/ St u d y Pr o d uct S u p plies  ........................ 3 4  
6. 5  
Bli n di n g a n d All ocati o n/ Ra n d o mizati o n  ............................................................... 3 4  
6. 6  
Brea ki n g t he Bli n d  ................................................................................................. 3 5  
6. 7  
C o m plia nce  ............................................................................................................ 3 5  
6. 8  
C o nc o mita nt Me dicati o n/ Treat me nt(s)  .................................................................. 3 5  
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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 6  
7. 1  
S u bject Disc o nti n uati o n/ Wit h dra wal  ..................................................................... 3 6  
7. 2  
L ost t o F oll o w u p  ................................................................................................... 3 6  
8  
S T U D Y P R O C E D U R E S  ................................................................................................... 3 7  
8. 1  
Visit 1/ Scree ni n g  ................................................................................................... 3 7  
8. 1. 1  
I nf or me d C o nse nt .................................................................................. 3 7  
8. 1. 2  
De m o gra p hics  ....................................................................................... 3 8  
8. 1. 3  
Me dical Hist or y a n d Pri or Me dicati o n/ Treat me nt  ................................ 3 8  
8. 1. 4  
Oral E x a mi nati o n/ Assess me nt  .............................................................. 3 8  
8. 1. 5  
I n cl usi o n/ E x cl usi o n Criteria ................................................................. 3 8  
8. 1. 6  
S u bject Eli gi bilit y  ................................................................................. 3 9  
8. 1. 7  
Dis pe nse Was h o ut Pr o d ucts  .................................................................. 3 9  
8. 2  
St u d y Peri o d  .......................................................................................................... 3 9  
8. 2. 1  
Baseli ne: Visit 2 ( Da y 0)  ....................................................................... 3 9  
8. 2. 2  
Visit 3 a n d 4 ( Da y 2 1 ± 3 da y a n d 4 2 ± 4 da y)  ....................................... 4 0  
8. 2. 3  
Visit 5 ( Da y 8 4 ± 4 d a y)  ......................................................................... 4 0  
8. 3  
Diar y Re vie w  ......................................................................................................... 4 1  
8. 4  
St u d y C o n cl usi o n  ................................................................................................... 4 1  
8. 5  
F oll o w -u p Visit/ P h o ne Call  ................................................................................... 4 2  
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S T U D Y A S S E S S M E N T S  ................................................................................................. 4 2  
9. 1  
Scree ni n g Assess me nts  .......................................................................................... 4 2  
9. 1. 1  
Gr oss Assess me nt of Gi n gi val Healt h  .................................................. 4 2  
9. 1. 2  
P oc ket De pt h Meas ure m e nt  .................................................................. 4 2  
9. 2  
Efficac y Assess me nts  ............................................................................................ 4 2  
9. 2. 1  
M GI Assess me n t ( L o be n e et al, 1 9 8 6) .................................................. 4 3  
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BI Assess me nt ( Sa xt o n a n d va n der O u d eraa, 1 9 8 9)  ............................ 4 3  
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Pla q ue Discl os ure  .................................................................................. 4 4  
9. 2. 4  
T PI Assess me nt ( L o be ne et al, 1 9 8 2)  ................................................... 4 4  
9. 2. 5  
Re peata bilit y Ass ess me nts  .................................................................... 4 5  
9. 3  
Safet y a n d Ot her Assess me nts  ............................................................................... 4 5  
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Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
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O S T E x a mi nati o n  .................................................................................. 4 5  
9. 3. 2  
O H T E x a mi nati o n  ................................................................................. 4 6  
9. 3. 3  
Pre g n a nc y T esti n g  ................................................................................. 4 6  
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 6  
1 0. 1  
Defi niti o n of a n A d verse E ve nt ( A E)  .................................................................... 4 6  
1 0. 2  
Defi niti o n of a Seri o us A d verse E ve nt ( S A E)  ....................................................... 4 7  
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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 8  
1 0. 4  
Re p orti n g Pr oce d ures ............................................................................................. 4 9  
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Re p orti n g of a n A d verse E ve nt  ............................................................. 4 9  
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Re p orti n g of a Seri o us A d verse E ve nt  .................................................. 5 0  
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E val uati n g A d v erse E ve nts  .................................................................................... 5 0  
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Assess me nt of I nte nsit y  ........................................................................ 5 0  
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Assess me nt of Ca usalit y  ....................................................................... 5 1  
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F oll o w -u p of A Es a n d S A Es .................................................................................. 5 1  
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Wit h dra wal D ue t o a n A d verse E ve nt  ................................................................... 5 2  
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Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ...................................................... 5 2  
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Pre g n a nc y  .............................................................................................................. 5 2  
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Ti me Peri o d f or C ollecti n g Pre g n a nc y I nf or mati o n .............................. 5 2  
1 0. 9. 2  
Acti o n t o be Ta ke n if Pre g na n c y Occ urs  .............................................. 5 3  
1 0. 1 0  Me dical De vic e I n ci de nts  ...................................................................................... 5 3  
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Defi niti o n of a n I nci d e nt  ....................................................................... 5 3  
1 0. 1 1  Re p orti n g of I nci de nts a n d Malf u ncti o ns  .............................................................. 5 4  
1 0. 1 2  F oll o w -u p of Me di cal De vice I nci de nts  ................................................................ 5 5  
1 0. 1 3  Re g ulat or y Re p orti n g Re q uire m e nts f or Me dical De vice I n ci de nts ...................... 5 5  
1 1  D A T A M A N A G E M E N T  .................................................................................................. 5 5  
1 1. 1  
Case  Re p ort F or m  .................................................................................................. 5 5  
1 1. 2  
Data Ha n dli n g  ........................................................................................................ 5 6  
1 1. 2. 1  
Data Q ueries  .......................................................................................... 5 6  
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 7  
1 2. 1  
Sa m ple Siz e Deter mi nat i o n ................................................................................... 5 7  
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P o p ulati o ns f or A nal ysis  ........................................................................................ 5 7  
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Statistical A nal yses  ................................................................................................ 5 7  
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Pri mar y A n al ysis(es)  ............................................................................. 5 8  
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Sec o n dar y A nal ysis(es)  ......................................................................... 5 8  
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E x pl orat or y A nal ysis(es)  ....................................................................... 5 9  
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Safet y A nal ysis(es) ................................................................................ 5 9  
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Ot her A nal ysis(es)  ................................................................................. 5 9  
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De m o gra p hic a n d Baseli ne C haracteristics  ........................................... 6 0  
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St u d y Dr u g/ Pr o d uct C o m plia nce  .......................................................... 6 0  
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Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
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Ha n dli n g of Dr o p o uts a n d Missi n g Data  .............................................. 6 1  
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I nteri m A nal ysis .................................................................................... 6 1  
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 .............................................................. 6 1  
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Q ualit y C o ntr ol  ...................................................................................................... 6 1  
1 3. 2  
Q ualit y Ass ura nce  .................................................................................................. 6 1  
1 3. 3  
Re g ulat or y a n d Et hical C o nsi derati o ns  ................................................................. 6 2  
1 3. 3. 1  
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee..................................... 6 2  
1 3. 3. 2  
Et hical C o n d uct of t he St u d y  ................................................................ 6 2  
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S u bject I nf or mati o n a n d C o nse nt  .......................................................... 6 2  
1 3. 3. 4  
S u bject Recr uit me nt  .............................................................................. 6 3  
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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 ............................................................................................... 6 3  
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  ................. 6 3  
1 3. 5  
Pr o visi o n of St u d y Res ults t o I n vesti gat ors  ........................................................... 6 3  
1 3. 6  
Rec or ds Rete nti o n  .................................................................................................. 6 4  
1 3. 7  
C o n diti o ns f or Ter mi nati n g t he St u d y  ................................................................... 6 4  
1 4  R E F E R E N C E S  .................................................................................................................. 6 5  
1 5  A P P E N DI CI E S .................................................................................................................. 6 8  
1 5. 1  
A B B R E VI A TI O N S  ............................................................................................... 6 8  
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Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
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Li st of i n t e xt t a bl e s  
Ta ble 1 -1  
Sc he d ule of Acti vities  ........................................................................... 1 5  
Ta ble 3 -1  
St u d y O bjecti ves a n d E n d p oi nts  ........................................................... 1 9  
Ta ble 6 -1  
I n v esti gati o nal/ St u d y Pr o d uct S u p plies ................................................ 2 9  
Ta ble 6 -2  
Was h o ut/ Accli matizati o n Pr o d uct S u p plies  .......................................... 3 0  
Ta ble 6 -3  
S u n dr y Ite ms  ......................................................................................... 3 0  
Ta ble 1 5 -1  
A b bre viati o ns  ........................................................................................ 6 8  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 0  of 7 0  
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  
B a c k gr o u n d a n d R ati o n al e : 
T his cli nical st u d y will i n vesti gate t he efficac y of a d e ntifrice c o ntai ni n g 0. 4 5 4 % sta n n o us 
fl u ori de ( S n F2), o n gi n gi vitis treat me nt a n d pla q ue re d u cti o n, c o m pare d t o a re g ular fl u ori de 
de ntifrice after 1 2 wee ks t wice dail y br us hi n g i n a p o p ulati o n of cli nicall y dia g n ose d gi n gi vitis  
wit h o ut u n der g oi n g d e nt al pr o p h yl a xis . Gi n gi val healt h a n d pla q ue re d ucti o n will be e val u ate d 
usi n g blee di n g i n de x ( BI), n u m ber of blee di n g sites  ( N B S), m o difie d gi n gi v al i n de x ( M GI) a n d 
T ures k y m o dificati o n of t he Q ui gle y Hei n Pla q ue I n d e x ( T PI).  
O bj e cti v e s a n d E n d p oi nt s : 
O bjecti ves  
E n d p oi nts  
Pri m ar y  
T o assess t he perf or ma nce of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
gi n gi vitis, as meas ure d b y N B S , after 1 2 
wee ks t wice d ail y t o ot h br us hi n g.  
At Week 1 2:  
•  C ha n ge fr o m B aseli ne i n N B S  
 
Sec o n d ar y  
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 %  w/ w  S n F 2 i n re d uci n g 
gi n gi vitis,  as meas ur e d b y N B S , c o m p are d t o 
a ne gati ve c o ntr ol  after 1 2 wee ks t wice d ail y 
t o ot h br us hi n g. 
At Week 1 2:  
•  C ha n ge fr o m B aseli ne i n N B S  
 
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w  S n F 2  i n re d uci n g 
gi n gi vitis, as meas ur e d b y N B S , c o m p are d t o  
a ne gati ve c o ntr ol, after 3 a n d 6 wee ks t wice 
dail y t o ot h br us hi n g. 
At Weeks 3 & 6:  
•  C ha n ge fr o m B aseli ne i n N B S  
 
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2  i n re d uci n g 
pla q ue acc u m ulati o n, as meas ure d b y t he T PI  
(o verall a n d i nter pr o xi mal), c o m pare d t o  a 
ne gati ve c o ntr ol, after 3, 6 a n d 1 2 wee ks 
t wice dail y t o ot h br us hi n g.  
At Weeks 3, 6 & 1 2:  
•  C ha n ge fr o m B as eli ne i n Mea n T PI 
( o verall a n d i nter pr o xi mal)  
 
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
gi n gi vitis, as meas ure d b y BI,  c o m p are d t o a 
ne gati ve c o ntr ol,  after 3, 6 a n d 1 2 wee ks 
t wice dail y t o ot h br us hi n g.  
At Weeks 3, 6 & 1 2:  
•  C ha n ge fr o m B aseli ne i n BI  
 
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
gi n gi vitis, as meas ur e d b y M GI, c o m pare d t o  
At Weeks 3, 6 & 1 2:  
•  C ha n ge fr o m B aseli ne i n M GI  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 1  of 7 0  
a ne gati ve c o ntr ol,  after 3, 6 a n d 1 2 wee ks 
t wice dail y t o ot h br us hi n g.  
 
E x pl or at or y  
 
T o e x pl ore t he effic ac y of a de ntifri ce 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
gi n gi vitis, as meas ure d b y N B S , BI  a n d M G I, 
c o m pare d t o  a n e gati ve c o ntr ol , after 3, 6 a n d 
1 2 wee ks t wice dail y t o ot h br us hi n g,  
i n t he l o w a n d hi g h baseli ne mea n M GI 
s u b gr o u p:  
•  L o w: M GI ≤ 2  
•  Hi g h: M GI >  2  
At Weeks 3, 6 & 1 2:  
C ha n ge fr o m Baseli ne i n  
•  N B S  
•  Mea n BI  
•  Mea n M GI  
F or eac h M GI s u b gr o u p  
 
T o e x pl ore t he effic ac y of a de ntifri ce 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
pla q ue acc u m ulati o n, as meas ure d b y T PI, 
c o m pare d t o a n e gati ve c o ntr ol , after 3, 6 a n d 
1 2 wee ks t wice dail y t o ot h br us hi n g,  
i n t he l o w a n d hi g h baseli ne mea n M GI 
s u b gr o u p:  
• 
L o w: M GI ≤ 2  
• 
Hi g h: M GI >  2  
At Weeks 3, 6 & 1 2:  
C ha n ge fr o m Baseli ne i n  
•  Mea n T PI ( o verall a n d i nter pr o xi mal)  
F or eac h M GI s u b gr o u p  
 
S afet y  
T o assess t he oral t olera bilit y of de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2, o ver 1 2 wee ks 
t wice dail y use. 
Treat me nt -e mer ge nt a d v erse e ve nts o v er 1 2 
wee ks  
St u d y D e si g n : 
T his will be a si n gle ce nt er, ra n d o mize d, c o ntr olle d, si n gle bli n d (e x a mi ner bli n d), ra n d o mize d, 
t w o-treat me nt ar m, p arallel st u d y. St u d y s u bj ects will be o v er 1 8 years ol d, n o n-s m o kers, i n 
g o o d ge neral healt h wit h cli nicall y meas ura ble le vels of gi n gi vitis t hat meet all st u d y criteri a at 
t he Scree ni n g a n d Baseli ne visits.   
A p pr o xi matel y 1 6 0 s u bj ects ( ap pr o xi matel y 8 0 per gr o u p) will be ra n d o mize d t o e ns ure 
a p pr o xi matel y 1 4 4 e val u a ble s u bjects ( a p pr o xi matel y 7 2 per gr o u p) c o m plete t he st u d y.   
T his st u d y will c o nsist of 5 st u d y visits: Scree ni n g, Baseli ne, Wee k 3, 6 a n d 1 2. Gi n gi vitis will 
be assesse d usi n g M GI ( L o be n e et al, 1 9 8 6 ) a n d BI (Sa xt o n a n d va n der O u deraa, 1 9 8 9 ) (T h e 
N B S  is deri ve d fr o m  t he BI assess me nt ). Pla q ue will be asses se d usi n g  T PI ( L o be n e et al, 1 9 8 2 ).  
All e val ua ble te et h (i n relati o n t o t he i ncl usi o n/ e x cl usi o n ge neral de ntiti o n criteria) will be 
assesse d.  
At Scree ni n g visit ( Visit 1), s u bjects will pr o vi de t heir writte n i nf or me d c o nse n t t o partici pate 
i n t he st u d y. D e m o gra p hics, me dical hist or y, a n d c urre nt me dicati o ns will be rec or de d, 
f oll o we d b y a n oral e x a mi nati o n ( oral s oft tiss ue ( O S T) e x a mi nati o n , oral har d tiss ue ( O H T) 
e x a mi nati o n , de ntiti o n e x cl usi o ns , a gr oss gi n gi v al assess me nt  a n d p oc k et de pt h ass ess me nt . 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 2  of 7 0  
Eli gi ble s u bjects will be gi ve n a w as h o ut de ntifrice  a n d t o ot h br us h t o use i n bet wee n Scree ni n g 
a n d Bas eli ne Visits.  T he y will als o be iss ue d wit h a st u d y diar y t o rec or d pr o d uct usa ge.   
Wit hi n 1 4 ± 3 da ys of Scree ni n g ( Visit 1), eli gi ble s u bjects will ret ur n t o t he site f or t he Baseli n e 
visit ( Visit 2) wit h o ver ni g ht pla q ue (s u bjects will be i nstr ucte d t o a bstai n fr o m oral h y gie ne f or 
1 2 h o urs [ + 6 h o urs; -2 h o urs] i m me diatel y b ef ore t he visit).  
At t he Baseli ne visit,  s u bjects will u n der g o, i n t he f oll o wi n g or der, a f ull O S T e x a mi nati o n, 
gi n gi val i nfla m mati o n ( M GI), gi n gi val blee di n g ( BI), s u pra-gi n gi val pla q ue ( T PI). S u bjects 
wit h blee di n g sites % (d eri ve d  fr o m BI assess me nt) or T PI s c ore o utsi de t h e i ncl usi o n criteria 
ra n ge will be disc o nti n ue d fr o m t he st u d y at t his visit.  Eli gi ble s u bjects will be stratifie d 
acc or di n g t o t heir se x (male or fe mal e)  t o e ns ure a bala nce of se x acr oss b ot h  treat me nt gr o u ps 
a n d t he n ra n d o mize d t o st u d y pr o d u ct. T he s u bjects will t he n be i nstr ucte d t o br us h f or at least 
o ne  (ti me d) mi n ute at site wit h t heir assi g ne d st u d y pr o d uct (s u per vis e d br us hi n g) after w hic h  
t he y will be i nstr ucte d t o c o nti n ue usi n g t h eir pr o d uct t wice dail y ( m or ni n g a n d e ve ni n g u ntil 
t heir ne xt visit), at least o ne (ti me d) mi n ute /eac h ti me.  
After usi n g t he st u d y d e ntifrice f or 3, 6, a n d 1 2 wee ks, s u bjects will ret ur n t o t he st u d y site 
( Visits 3, 4, a n d 5, res pecti vel y) wit h o ver ni g ht pla q ue (s u bjects will be i nstr ucte d t o a bstai n 
fr o m o ver ni g ht t o ot h br us hi n g f or 1 2 h o urs [ + 6 h o urs; -2 h o urs] i m me diatel y bef ore eac h 
assess me nt visit), at a p pr o xi matel y t he s a me ti me of d a y as t he Bas eli ne visit. T he st u d y 
de ntifrice a n d t he di ar y will be re vie we d t o deter mi ne treat me nt c o m plia nce. S u bjects will ha v e 
a f ull O S T e x a mi nati o n a n d t he n u n der g o, i n t h e f oll o wi n g or der, M GI, BI, a n d T PI.  At Visit 5, 
s u bjects will als o ha ve a f ull O H T e x a mi nati o n, ret ur n all st u d y s u p plies a n d ha v e a de ntal 
pr o p h yla xis if dee me d a p pr o priate b y t he i n vesti gat or or e x a mi ner.  
At Visits 2, 3, 4, a n d 5, re peata bilit y d ata wi ll be ge n erat e d f or M GI a n d T PI assess me nts fr o m 
re plicate e x a mi nati o ns o n t he sa me s u bject (t he s u bject f or t he M GI re peat assess me nt a n d t he 
s u bject f or t he T PI assess me nt ca n be differe nt). De pe n di n g o n s u bject visit sc he d uli n g, e ver y 
eff ort will be ma d e t o c o m plete o ne re p eata bilit y e x a mi nati o n f or eac h cli nical meas ure d uri n g 
eac h cli nical assess me nt da y, t hat is, at least o n e M GI, a n d o ne T PI re p eat assess me nt o n eac h 
assess me nt da y. Re p eata bilit y e x a mi nati o ns will be se parate d b y a mi ni m u m of 1 0 mi n u tes a n d, 
w here p ossi ble, se p arat e d b y a n ot her s u bject. D ue t o t he i n vasi ve nat ure of t he BI assess me nt, 
it is n ot feasi ble t o c o n d uct a n acc urat e re p eata bilit y assess me nt f or t his i n de x.   
Safet y a n d oral t olera bilit y of t he st u d y d e ntifrices will be m o nit ore d o ver t he 1 2 -wee k usa ge 
peri o d b y re vie w of T E A Es. Me dical de vi ce i nci d e nts will be rec or de d (t h e me dical d e vice i n 
t his st u d y is t he ma n u al t o ot h br us h use d t o a p pl y t he st u d y t o ot h pastes) t hr o u g h o ut t he st u d y. 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 3  of 7 0  
St u d y Pr o d u ct s : 
 
 
Was h o ut De ntifrice  
Tes t De ntifrice 
Refere n ce De ntifrice  
( ne gati ve c o ntr ol) 
Pr o d uct N a me  
C ol gate Ca vit y 
Pr otecti o n   
(0. 7 6 % w/ w S o di u m 
M o n ofl u or o p h os p hate 
a n d 0. 1 % w/ w S o di u m 
F l u ori de  
Par o d o nta x C o m plete 
Pr otecti o n De ntifrice  
( 0. 4 5 4 % S n F 2)  
Crest Ca vit y 
Pr otecti o n  
(0. 2 4 3 % s o di u m 
fl u ori de) 
 
Pr o d uct M aster 
F or m ul ati o n 
C o de ( M F C)  
  
N/ A  
 
 
  
N/ A  
D ose/ A p plic ati o n  
Visit 1 -2:  
S u bjects will use t he 
pr o vi de d was h o ut 
pr o d uct.  
S u bjects will br us h t heir 
teet h acc or di n g t o t heir 
n or mal br us hi n g h a bits 
t wice dail y  ( m or ni n g a n d 
e ve ni n g). 
Visit 2 -5:  
S u bjects will use t heir all ocate d st u d y pr o d uct.  
S u bjects will br us h f or at least o ne (ti me d) 
mi n ute  t wice dail y ( m or ni n g a n d e ve ni n g). 
 
S u bjects will d ose t he t o ot h br us h pr o vi de d wit h a ri b b o n of paste t o c o ver 
t he br us h hea d (a f ull br us h hea d) o n eac h br us hi n g occasi o n. Eac h 
br us hi n g occasi o n will be rec or de d b y t he s u bject i n t heir diar y t o e na ble  
assess me nt of treat me nt c o m plia nce.  
R o ute of 
A d mi nistr ati o n  
Oral t o pical  
Ret ur n 
Re q uire me nts  
All use d/ u n use d sa m ples  t o be ret ur ne d 
 
T y p e a n d Pl a n n e d N u m b er of S u bj e ct s : 
A p pr o xi matel y 1 6 0 s u bj ects ( a p pr o xi matel y 8 0 per gr o u p) will be ra n d o mize d t o e ns ure 
ap pr o xi matel y 1 4 4 e v al ua ble s u bjects ( a p pr o xi matel y 7 2 per gr o u p) c o m plete t he st u d y , 
all o wi n g f or a p pr o xi matel y 1 0 %  dr o p o uts.     
Base d o n pre vi o us, si milar Hal e o n st u dies e v al uati n g pla q ue re d u cti o n a n d gi n gi vitis treat me nt 
pr o vi de d b y dail y -us e of 0. 4 5 % w/ w S n F 2  de ntifrice , a p pr o xi matel y 7 2 e val ua ble s u bjects per 
pr o d uct gr o u p is c o nsi dere d s ufficie nt f or t his st u d y. 
St ati sti c al A n al y si s:  
A m o difie d I nte nt -T o -Treat ( mI T T) p o p ulati o n will be use d f or t he efficac y a nal yses (all 
ra n d o mize d s u bjects w h o c o m plete at least o ne use of st u d y pr o d uct a n d ha v e at least o ne p ost-
b aseli ne cli nical effic ac y assess me nt)  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 4  of 7 0  
T he pri mar y  e n d p oi nt is N B S  ( N B S is deri ve d fr o m t he BI a n d it is t he n u m ber of e val ua bl e 
sites wit h a BI sc ore of eit her 1 or 2) at Wee k 1 2 . T he pri mar y c o m paris o n is c ha n ge fr o m 
Baseli ne at W ee k  1 2 f or t he test de ntifrice .  
A mi x e d m o del wit h re peate d meas ures ( M M R M) will be perf or me d o n t he c ha n ge fr o m 
baseli ne wit h pr o d uct (test or refere nce), ti me p oi nt a n d pr o d uct b y ti me p oi nt i nteracti o n as 
fi x e d effects, a n d b aseli n e N B S as a c o variate. 
T he ke y sec o n d ar y c o m p aris o n is  c ha n ge fr o m Baseli ne at Wee k 1 2 f or t he t est de ntifrice vers us 
t he refere nce de ntifrice ( ne gati ve c o ntr ol) a n d will be a nal yz e d usi n g t he sa me M M R M fr o m 
t he pri mar y a n al ysis  
All p -val ues will be t w o -si de d a n d assesse d at t he 5 % si g nifica nce le vel. A dj uste d mea ns f or 
b ot h treat me nts a n d treat me nt differe n ces will be pr o vi de d al o n g wit h 9 5 % c o nfi de nce i nter vals 
( CIs), as a p pr o priate. 
1. 2  
S c h e d ul e of A cti viti e s  
T he S c he d ule of A cti 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 s c he d ule visits ( 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 well -bei n g 
of t he s u bject.  
 
 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 5  of 7 0  
T a bl e 1 -1  
S c h e d ul e of A cti viti e s  
 
 
Pr oce d ure/ Assess me nt   
Scree ni n g    
St u d y Visits  
Visit 1   
  
Visit 2   
Da y 0  
Baseli ne 1 
Visit 3   
Da y 2 1 ± 3  
( Wee k 3)1   
Visit 4  
Da y 4 2 ± 4    
( Wee k 6)1 
Visit 5   
Da y 8 4 ± 4  
( Wee k 1 2)1  
I nf or me d c o nse nt  
X   
Was h o ut peri o d  1 4 da ys ± 3 da ys   
  
  
  
  
  
Me dical hist or y    
X   
  
  
  
  
De m o gra p hics    
X   
  
  
  
  
C urre nt/ pri or/c o nc o mita nt 
me dicati o n re vie w   
X   
X   
X   
X   
X   
O S T E xa mi nati o n   
X   
X   
X   
X   
X   
O H T E xa mi nati o n   
X   
 
  
  
X   
Gr oss gi n gi val 
assess me nt 2  
X   
  
  
  
  
P oc ket De pt h 
Assess me nt 2 
X  
 
 
 
 
Re vie w of 
I ncl usi o n/e xcl usi o n 
Criteria   
X   
X   
  
  
  
S u bj ect eli gi bilit y   
X   
X   
  
  
  
S u bj ect c o nti n ua nce   
  
  
X   
X   
X   
Dis pe nse t o ot h br us h 
was h o ut t o ot h paste, a n d 
was h o ut diar y 3  
X   
  
  
  
  
Ret ur n W as h o ut 
T o ot h paste/ T o ot h br us h   
  
X   
  
  
  
M o difie d Gi n gi val I n de x 
( M GI) assess me nt 
  
X   
X   
X   
X   
M GI re p eata bilit y 
assess me nt 4  
  
X   
X   
X   
X   
Blee di n g I n de x ( BI) 
assess me nt 5  
  
X   
X   
X   
X   
Pla q ue discl os ure a n d 
pla q ue i n de x ( T PI) 
assess me nts   
 
X  
X  
X  
X  
T PI re peata bilit y 
assess me nt 6 
 
 
X  
X  
X  
X  
Ra n d o mizati o n   
 
 
X  
 
 
 
Dis pe nse st u d y pr o d ucts, 
ti mer, a n d st u d y diar y  
  
  
X   
  
 
  
Oral h y gie ne i nstr ucti o n 
& s u per vise d br us hi n g 
wit h st u d y de ntifrice 7  
  
  
X   
X   
X   
  
Re vie w diar y c o m pleti o n  
 
 
X  
X  
X  
      X  
C ollect st u d y pr o d ucts, 
assess c o m plia nce, a n d 
ret ur n t o s u bj ect  
  
  
  
X   
X   
 
Ret ur n st u d y pr o d ucts 
(e n d of st u d y) 
  
 
  
  
  
X   
E n d of st u d y de ntal 
pr o p h yla xis ( o pti o nal)   
  
  
  
  
X   
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 6  of 7 0  
A d verse e ve nts re vie w 8  
X   
X   
X   
X   
X   
Me dical de vice i nci de nts 
re vie w 
  
X   
X   
X   
X   
St u d y c o ncl usi 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, M GI: M o difie d Gi n gi vitis I n de x, BI: blee di n g i n de x; T PI: T ures k y Pla q ue 
I n de x. 
F o ot n otes:   
1: S u bjects will a bstai n fr o m o ver ni g ht t o ot h br us hi n g f or a mi ni m u m of 1 2 hrs ( + 6 hr, -2 hr) i m me diatel y pri or t o t he assess me nt visits ( Visits 2, 
3, 4 a n d 5)  
2: I n relati o n t o t he ge neral de ntiti o n i ncl usi o n/ e xcl usi o n criteria  
3: N o i nstr ucti o n or  s u per vise d br us hi n g at scree ni n g visit  
4: Mi ni m u m  o ne M GI re peata bilit y assess me nts d uri n g eac h cli nical assess me nt da y ; M GI r e peata bilit y assess me nt at Baseli ne visit will be  
c o n d ucte d  after t he su bject ’s eli gi bilit y has b ee n c o nfir me d . 
5: N B S  a n d blee di n g sites % are deri ve d fr o m BI assess me nt  
6: Mi ni m u m o ne T PI r e peata bilit y assess me nts d uri n g eac h cli nical assess me nt da y ; T PI re peata bilit y assess me nt at Baseli ne visit will be  
c o n d ucte d after t he s u bject’s eli gi bilit y has b ee n c o nfir me d . 
7:  At B aseli ne visit, site will co nfir m t hat 2 n d t o ot h br us h has n ot bee n use d  bef ore t he s u per vise d br us hi n g  
8 : A d verse E ve nts ( A Es), S eri o us A d vers e E ve nts ( S A Es) a n d me dical de vice i nci de nts c ollecte d 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 m e d C o nse nt F or m (I C F).   
 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 7  of 7 0  
2  
I N T R O D U C TI O N 
De ntal pla q ue is a s oft, stic k y, c ol orless d e p osit of bacteria w hic h c ollects o n t he teet h a n d al o n g 
t he gi n gi val mar gi n. It is a ca usati ve a ge nt of gi n gi vitis a n d peri o d o ntitis (Sil ness a n d L o e 1 9 6 4,  
T heila de et al 1 9 6 6 , Ki na ne a n d H o d ge 2 0 0 1 , Da vies 2 0 0 8 , C ha p ple et al 2 0 1 5 ). Gi n gi vitis is 
a n i nfla m mat or y res p o ns e t o t he prese n ce of de nt al pla q ue ( Ki n a ne a n d H o d ge 2 0 0 1 ), w hic h 
t y picall y pres e nts as re d ness, s welli n g (o e d e ma), a n d/ or blee di n g of t he g u ms at t he gi n gi val 
mar gi n s urr o u n di n g t h e t o ot h. Gi n gi vitis is a re v ersi ble c o n diti o n b ut, if left u ntreate d, ca n 
pr o gress t o  t he irre v ersi bl e p hase of p eri o d o ntitis, w here i nfl a m mati o n e xte n ds t o t he u n derl yi n g 
tiss ues, peri o d o ntal li ga me nt, a n d al ve olar b o ne. T he res ulti n g l oss of t hese str uct ures ca n 
e ve nt uall y lea d t o t o ot h l oss t hr o u g h destr u cti o n of t he peri o d o ntal tiss ues  s u p p orti n g t he t o ot h. 
Peri o d o ntitis is re p orte d t o affect 5 t o 2 0 % of t h e w orl d’s p o p ulati o n ( Peterse n a n d O ga wa 
2 0 1 2 ). T he mai nte na nce of g o o d gi n gi val healt h is t heref ore i m p orta nt i n pre ve nti n g gi n gi vitis 
a n d t he de vel o p m e nt of p eri o d o ntal disease ( C ha p ple et al., 2 0 1 5 ). 
Ma n y pe o ple are u na ble t o ac hie v e a d e q uate pl a q u e c o ntr ol b y t o ot h br us hi n g al o ne. T he effect 
of t o ot h br us hi n g ca n b e a u g m e nte d b y t he us e of de ntifrice ( Da vi es, 2 0 0 8 ) a n d a nti micr o bial 
i n gre di e nts. 
A nti micr o bial a ge nts (s uc h as 
metal salts, cet yl p yri di ni u m c hl ori de a n d 
c hl or he xi di ne) ha ve bee n i ncl u de d i n dail y use de ntifrice a n d m o ut h ri nse f or m ulati o ns f or 
ma n y years, wit h a vie w t o deli veri n g i m pr o ve d pla q ue c o ntr ol a n d g u m healt h be nefits 
(C ha p ple et al, 2 0 1 5 ). T h e y c o m ple me nt mec ha ni cal pla q ue re m o val b y i n hi biti n g t he gr o wt h 
of bact eria ( via bacteri ost atic a n d/ or b acterici dal acti vit y) i n areas of t he m o ut h less accessi ble 
t o t he t o ot h br us h a n d b y i nterferi n g wit h t he re-c ol o nisati o n of pla q ue bacteria ( Teles a n d Teles, 
2 0 0 9 ). 
S n F 2 is a well-k n o w n c he m ot hera pe utic a ge nt w hic h has bee n i nc or p orate d i nt o de ntifrices 
si nce t he 1 9 4 0s f or its oral healt h be n efits (Ma ki n, 2 0 1 3 ; Miller et al , 1 9 9 4; Va n L o vere n, 
1 9 9 0a ; Va n L o v ere n, 2 0 0 1 ). T he sta n n o us i o n ( S n[II]) is a br oa d-s pectr u m a nti micr o bial a ge nt 
w hic h has bee n s h o w n t o re d uce bact erial bi o mass/ vir ule nce a n d i n hi bit bacterial meta b olis m 
(Arc hila et al, 2 0 0 4 ; Bell a m y et al, 2 0 1 2 ; He et al, 2 0 1 2 ; Ti na n off, 1 9 9 0 ; Ti na n off, 1 9 9 5 ). S n 
[II] i o ns ra pi dl y o xi dize t o “i nacti ve” sta n nic i o ns ( S n [I V]) a n d h y dr ol yse t o f or m i ns ol u ble ti n 
c o m p o u n ds (f or e x a m ple, sta n n o u s h y dr o xi de) i n t he prese n ce of water (a n d sali va) a n d sali va-
deri ve d i o ns ( Ma ki n, 2 0 1 3 ). T o ma xi mise t he deli ver y of bi oa vaila ble S n[II] i o ns t o t he oral 
ca vit y, S n F 2 de ntifric es are ofte n “sta bilize d” b y t he a d diti o n of c o m ple xi n g a ge nts or de v el o pe d 
as l o w water c o nte nt/a n h y dr o us f or m ulati o ns.  
N u mer o us cli nical st u dies re p orte d i n t he scie ntific literat ur e de m o nstrate t he a nti -
gi n gi vitis/a nti -pla q ue effi cac y of 0. 4 -0 . 4 5 4 % S n F2 de ntifrices , f or e x a m ple, (Mallatt et al, 2 0 0 7 ; 
Ma n k o di et al, 1 9 9 7 ; Ma n k o di et al, 2 0 0 5 ; Par ki ns o n et al, 2 0 1 4 ; Par ki ns o n et al, 2 0 1 5 ; 
Par ki ns o n et al, 2 0 1 8a ; Par ki ns o n et al, 2 0 1 8 b ) i n a p o p ulati o n wit h mil d-m o derate pla q ue -
i n d uce d gi n gi vitis at ti me p oi nts ra n gi n g fr o m 4 t o 2 4 weeks.  
T his 1 2 -wee k ra n d o mize d c o ntr olle d cli nical st u d y is t o assess t h e efficac y of pla q ue re d ucti o n 
a n d gi n gi vitis  treat me nt f oll o wi n g t wi ce d ail y us e of a 0. 4 5 4 % S n F 2  de ntifrice  (p ar o d o nta x 
C o m plete Pr otecti o n de ntifrice , n o n-a q ue o us f or m ula) i n c o m paris o n wit h a sta n d ar d fl u ori de 
de ntifrice  i n a p o p ulati o n of s u bjects wit h cli nicall y meas ura ble le vels of gi n gi vitis wit h o ut pre -
treat me nt de ntal  pr o p h yl a xis.   
2. 1  
St u d y R ati o n al e  
Dail y de ntifri ce s c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 ( 0.1 5 % w/ v F i o n) ha ve bee n i nc or p orate d i nt o 
de ntifrices si nce t he 1 9 4 0s a n d mar kete d b y se v eral oral healt h c o m pa nies , t hese pr o d ucts are 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 8  of 7 0  
u n der t he F D A O T C m o n o gra p h. T he U S F D A rec o g nizes its a nti -pl a q ue a n d gi n gi vitis 
effic ac y. (Oral H ealt h Care Dr u g Pr o d ucts f or O ver -t he-C o u nter H u ma n Us e., ( 1 9 9 1)   
Hale o n ha s e x ec ute d a n u m ber of cli nical effi cac y st u dies o n t wice dail y use of 0. 4 5 4 % w/ w 
S n F 2 de ntifrice  f or m ulati o ns. All st u dies were e x ec ute d as ra n d o mize d c o ntr olle d cli nical trials 
i n well-defi ne d p o p ulati o ns of healt h y v ol u nteers wit h gi n gi vitis a n d all of t hese st u dies ha d a 
de ntal pr o p h yla xis o nce s u bjects ha ve b ee n e nr olle d i nt o t he cli nical st u d y .  T h e se st u dies 
de m o nstrate d t he efficac y of S n F 2 i n re d u ci n g gi n gi val i nfla m mati o n a n d pla q ue acc u m ulati o n 
i n s u bjects wit h mil d t o m o derate gi n gi vitis  f oll o wi n g pr o p h yla xis pr oce d ure . (Par ki ns o n et al., 
2 0 1 4 , Par ki ns o n et al., 2 0 1 5 , Par ki ns o n et al., 2 0 1 8a , Par ki ns o n et al., 2 0 1 8 b,  Hale o n St u d y 
2 0 7 0 1 4, 2 0 1 8 , Ac her k o u k et al., 2 0 2 1 ).  
I n all of t hese st u dies s u bjects recei v e d a de ntal pr o p h yla xis o nce e nr olle d i nt o t he cli nical st u d y 
f oll o wi n g A D A/ F D A g ui da nce  wit h  f or re d uci n g t he i nci de n ce of gi n gi vitis (F D A., 2 0 0 5 ). 
S u bjects recei ve a de ntal pr o p h yl a xis t o rest ore gi n gi val healt h a n d t he e n d p oi nt pr o vi de a n 
assess me nt  t he rea p peara nce of gi n gi vitis after a set peri o d of ti me. (F D A ., 2 00 5 ) 
S u bjects w h o alrea d y h a v e meas ur a ble gi n gi vitis b ef ore tr eat me nt ma y e x pe rie nce a si g nifi ca nt 
re d ucti o n i n t he gi n gi vitis a n d blee di n g sc ores o v er ti me wit h t wice d ail y use a n d c o m pare d t o 
a c o ntr ol pr o d uct. T his re d ucti o n i n dicates t hat t he test pr o d uct re d u ces t h e s e verit y of gi n gi vitis. 
(F D A., 2 0 0 5 ). T h eref ore, t his pla q ue  red ucti o n  a n d gi n gi vitis treat me nt st u d y (wit h n o 
pr o p h yla xis  bef ore  c o m m e nci n g  treat me nt) will ge nerate e vi de nce t o s u p p ort t he effect of S n F 2 
o n e xisti n g pla q ue a n d gi n gi vitis a n d will pr o vi de a d diti o nal e vi de nce i nt o t he effects of usi n g 
S n F 2 par o d o nta x o ver a 1 2 -wee k p eri o d.   
2. 2  
B e n efit/ Ri s k A s s e s s m e nt  
St u d y pr o d ucts are c o m m erciall y a v aila ble dail y us e t o ot h pastes w hic h c o ntai n o nl y i n gre die n ts 
wit h a hist or y of safe use i n oral healt hcare pr o d ucts. S u m mar y s afet y i nf or mati o n f or t he 
accli matiz ati o n a n d st u d y pr o d ucts will be pr o vi de d o n t he pr o d uct la bels.  
2. 3  
M e c h a ni s m of A cti o n/I n di c ati o n  
T he sta n n o us i o n ( S n [II]) is a br oa d -s pectr u m a nti micr obial a ge nt w hic h has bee n s h o w n t o 
re d uce b acteri al bi o mass/ vir ule nce a n d i n hi bit bacterial meta b olis m (Arc hila et al., 2 0 0 4 , 
Bella m y et al., 2 0 1 2 , H e et al., 2 0 1 2 , Ti na n off, 1 9 9 0 , Ti na n off, 1 9 9 5 , Haraszt h y et al., 2 0 1 9 ). 
It has b ee n s h o w n t o i nt erfere wit h t he d e vel o p me nt a n d mat urati o n of t he pla q ue bi ofil m, 
i n hi biti n g bacterial a d here nce a n d c ol o nizati o n of t he oral s urfaces, a n d p e netrati n g t he cell wall 
t o i nterfere wit h bacteri al meta b olis m. (Ti na n off, 1 9 9 0 ; Wils o n a n d Pratte n, 1 9 9 9)   
 
 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 1 9  of 7 0  
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 bjecti ves  
E n d p oi nts  
Pri m ar y  
T o assess t he perf or ma nce of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
gi n gi vitis, as meas ure d b y N B S , after 1 2 
wee ks t wice d ail y t o ot h br us hi n g.  
At Week 1 2:  
•  C ha n ge fr o m Baseli ne i n N B S  
 
Sec o n d ar y  
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 %  w/ w  S n F 2 i n re d uci n g 
gi n gi vitis,  as meas ur e d b y N B S , c o mp are d t o 
a ne gati ve c o ntr ol  after 1 2 wee ks t wice d ail y 
t o ot h br us hi n g. 
At Week 1 2:  
•  C ha n ge fr o m Baseli ne i n N B S  
 
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2  i n re d uci n g 
gi n gi vitis, as meas ur e d b y N B S , c o m p are d t o  
a ne gati ve c o ntr ol, after 3 a n d 6 wee ks t wice 
dail y t o ot h br us hi n g.  
At Weeks 3 & 6:  
•  C ha n ge fr o m Baseli ne i n N B S  
 
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2  i n re d uci n g 
pla q ue acc u m ulati o n, as meas ure d b y t he T PI  
(o verall a n d i nter pr o xi mal), c o m pare d t o a 
ne gati ve c o ntr ol, after 3, 6 a n d 1 2 wee ks 
t wice dail y t o ot h br us hi n g.  
At Weeks 3, 6 & 1 2:  
•  C ha n ge fr o m Bas eli ne i n Mea n T PI 
( o verall a n d i nter pr o xi mal)  
 
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
gi n gi vitis, as me as ure d b y BI,  c o m p are d t o  a 
ne gati ve c o ntr ol,  after 3, 6 a n d 1 2 wee ks 
t wice dail y t o ot h br us hi n g.  
At Weeks 3, 6 & 1 2:  
•  C ha n ge fr o m Baseli ne i n BI  
 
T o e val uate t he efficac y of a de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
gi n gi vitis, as meas ur e d b y M GI, c o m pare d t o  
a ne gati ve c o ntr ol,  after 3, 6 a n d 1 2 wee ks 
t wice dail y t o ot h br us hi n g.  
At Weeks 3, 6 & 1 2:  
•  C ha n ge fr o m Baseli ne i n M GI  
 
E x pl or at or y  
 
T o e x pl ore t he effic ac y of a de ntifri ce 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
gi n gi vitis, as meas ure d b y N B S , BI  a n d M GI, 
c o m pare d t o  a n e gati ve c o ntr ol , after 3, 6 a n d 
1 2 wee ks t wice dail y t o ot h br us hi n g,  
At Weeks 3, 6 & 1 2:  
C ha n ge fr o m Baseli ne i n  
•  N B S  
•  Mea n BI  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 0  of 7 0  
i n t he l o w a n d hi g h baseli ne mea n M GI 
s u b gr o u p:  
•  L o w: M GI ≤ 2  
•  Hi g h: M GI > 2  
•  Mea n M GI  
F or eac h M GI s u b gr o u p  
 
T o e x pl ore t he effic ac y of a de ntifri ce 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2 i n re d uci n g 
pla q ue acc u m ulati o n, as meas ure d b y T PI, 
c o m pare d t o a n e gati ve c o ntr ol , after 3, 6 a n d 
1 2 wee ks t wice dail y t o ot h br us hi n g,  
i n t he l o w a n d hi g h baseli ne mea n M GI 
s u b gr o u p:  
• 
L o w: M GI ≤ 2  
• 
Hi g h: M GI >  2  
At Weeks 3, 6 & 1 2:  
C ha n ge fr o m Baseli ne i n  
•  Mea n T PI ( o verall a n d i nter pr o xi mal)  
F or eac h M GI s u b gr o u p  
 
S afet y  
T o assess t he oral t olera bilit y of de ntifrice 
c o ntai ni n g 0. 4 5 4 % w/ w S n F 2, o ver 1 2 wee ks 
t wice dail y use. 
Treat me nt -e mer ge nt a d v erse e ve nts o v er 1 2 
wee ks  
T his st u d y will b e c o nsi d ere d s u ccessf ul if t here is a statisticall y si g nifica nt differe nce i n N B S 
after 1 2 wee ks of t wice d ail y br us hi n g wit h t he S n F2 de ntifrice c o m pare d t o its baseli ne a n d t he 
differe n ce is i n fa v or of t he S n F 2 de ntifrice.  
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 si n gle ce nter, c o ntr olle d, si n gle bli n d (e x a mi ner bli n d),  ra n d o mize d, t w o-
treat me nt ar m, parallel st u d y. St u d y s u bjects will be o ver 1 8 years ol d, n o n-s m o kers, i n g o o d 
ge n eral h ealt h wit h cli ni call y m eas ura ble le vels of gi n gi vitis t hat meet all st u d y criteria at t he 
Scree ni n g a n d Bas eli ne visits.   
A p pr o xi matel y 1 6 0 s u bj ects  (a p pr o xi matel y n = 8 0 per gr o u p) will be ra n d o mize d t o e ns ure 
a p pr o xi matel y 1 4 4 e val u a ble s u bjects (a p pr o xi matel y 7 2 per gr o u p) c o m plete t he st u d y.   
A s per s y n o psis, this st u d y will c o nsist of 5 st u d y visits: Scree ni n g, Baseli ne, Wee k 3, 6 a n d 
1 2. Gi n gi vi tis will be assesse d usi n g M GI (L o be ne et al, 1 9 8 6 ) a n d BI (Sa xt o n a n d va n der 
O u deraa, 1 9 8 9 ) ( T h e N B S will be  deri ve d fr o m  t he BI assess me nt). Pla q ue will be assesse d 
usi n g T PI ( L o b e ne et al, 1 9 8 2 ).  
All e val ua ble te et h (i n relati o n t o t he i ncl usi o n/ e x cl usi o n ge neral de ntiti o n criteria) will be 
assesse d.  
At Scree ni n g visit ( Visit 1; i n relati o n t o s u bject scree ni n g), s u bjects will pr o vi de 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 hics, me dical hist or y, a n d c urre nt 
me dicati o ns will be rec or de d, f oll o we d b y a n oral e x a mi nati o n ( oral s oft tiss ue ( O S T)  
e x a mi nati o n , oral har d tiss ue ( O H T) e x a mi nati o n, de ntiti o n e x cl usi o ns, a gr oss gi n gi v al 
assess me nt a n d p oc ket de pt h assess me nt . Eli gi ble s u bjects will be gi ve n a was h o ut de ntifrice  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 1  of 7 0  
a n d t o ot h br us h t o use i n bet wee n Scree ni n g a n d Baseli ne Visits.  T he y will als o be iss ue d wit h 
a st u d y diar y t o rec or d pr o d uct usa ge.  
Wit hi n 1 4 ± 3 da ys of  Scree ni n g ( Visit 1), eli gi ble s u bjects will ret ur n t o t he site f or t he Baseli n e 
visit ( Visit 2) wit h o ver ni g ht pla q ue (s u bjects will be i nstr ucte d t o a bstai n fr o m oral h y gie ne f or 
1 2 h o urs [ + 6 h o urs; -2 h o urs] i m me diatel y b ef ore t he visit).  
At Baseli ne v isit, the was h o ut  de ntifrice a n d t he diar y will be re vi e we d t o deter mi n e 
c o m plia nce.  At t he Baseli ne visit,  s u bjects will als o u n der g o, i n t he f oll o wi n g or der, a f ull O S T 
e x a mi nati o n, gi n gi val i nfla m mati o n ( M GI), gi n gi val blee di n g ( BI), s u pra -gi n gi val pla q ue 
( T PI). S u bjects wit h blee di n g sites % ( deri ve d fr o m BI assess me nt) or T PI sc ore o utsi de t he 
i ncl usi o n criteria ra n ge will be disc o nti n ue d fr o m t he st u d y at t his visit. Eli gi ble s u bjects will 
be stratifie d acc or di n g t o t heir se x (male or fe m ale) t o e ns ure a b ala nce of se x acr oss b ot h 
treat me nt gr o u ps a n d t he n ra n d o mize d t o st u d y pr o d uct. T he s u bjects will t he n be i nstr ucte d t o 
br us h f or a t le ast o ne (ti me d) mi n ute at site wit h t heir assi g n e d st u d y pr o d uct (s u per vis e d 
br us hi n g) after w hic h t he y will b e i nstr ucte d t o c o nti n ue usi n g t heir pr o d uct t wice d ail y 
( m or ni n g a n d e v e ni n g u ntil t heir ne xt visit), at least o ne (ti me d) mi n ute /eac h ti me f or t he ne xt 
1 2 wee ks .  
After usi n g t he st u d y d e ntifrice f or 3, 6, a n d 1 2 wee ks, s u bjects will ret ur n t o t he st u d y  site 
( Visits 3, 4, a n d 5, res pecti vel y) wit h o ver ni g ht pla q ue (s u bjects will be i nstr ucte d t o a bstai n 
fr o m o ver ni g ht t o ot h br us hi n g f or 1 2 h o urs [ + 6 h o urs; -2 h o urs]  i m me diatel y bef ore eac h 
assess me nt visit), at a p pr o xi matel y t he s a me ti me of d a y as t he Ba s eli ne visit. T he st u d y 
de ntifrice a n d t he di ar y will be re vie we d t o deter mi ne treat me nt c o m plia nce. S u bjects will ha v e 
a f ull O S T e x a mi nati o n a n d t he n u n der g o, i n t he f oll o wi n g or der, M GI, BI, a n d T PI.  At Visit 5, 
s u bjects will als o ha v e a f ull O H T e x a mi nati o n, ret ur n all st u d y s u p plies a n d will be offere d  a 
de ntal pr o p h yl a xis if dee me d a p pr o priat e b y t he i n vesti gat or or e x a mi ner.  
At Visits 2, 3, 4, a n d 5, re peata bilit y d ata will be ge n erat e d f or M GI a n d T PI assess me nts fr o m 
re plicate e x a mi nati o ns o n t he sa me s u bject (t he s u bject f or t he M GI re peat assess me nt a n d t he 
s u bject f or t he T PI assess me nt ca n be differe nt). De pe n di n g o n s u bject visit sc he d uli n g, e ver y 
eff ort will be ma d e t o c o m plete o ne re p eata bilit y e x a mi nati o n f or eac h cli nical meas ure d uri n g 
eac h cli nical assess me nt da y, t hat is, at least o n e M GI, a n d o ne T PI re p eat assess me nt o n eac h 
assess me nt da y. Re p eata bilit y e x a mi nati o ns will be se parate d b y a mi ni m u m of 1 0 mi n utes a n d, 
w here p ossi ble, se p arat e d b y a n ot her s u bject. D ue t o t he i n vasi ve nat u re of t he BI assess me nt, 
it is n ot feasi ble t o c o n d uct a n acc urat e re p eata bilit y assess me nt f or t his i n de x.   
Safet y a n d oral t olera bilit y of t he st u d y d e ntifrices will be m o nit ore d o ver t he 1 2 -wee k usa ge 
peri o d b y re vie w of T E A Es. Me dical de vi ce i nci d e nts  will be rec or de d (t h e me dical d e vice i n 
t his st u d y is t he ma n u al t o ot h br us h use d t o a p pl y t he st u d y t o ot h pastes) t hr o u g h o ut t he st u d y. 
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 g oal of t his st u d y is t o e val uate a n d c o m p are t he efficac y of a n o n-mar ket de n tifrice 
c o ntai ni n g 0. 4 5 4 %  w/ w S n F 2  t o a re g ul ar fl u ori de de ntifrice o n treati n g gi n gi val bl ee di n g a n d 
gi n gi val i nfla m mati o n as well as re d u ci n g pla q ue acc u m ulati o n i n a p o p ulati o n wit h  cli nicall y 
meas ura ble l e vels of gi n gi vitis after 1 2 wee ks use.  
T his st u d y desi g n f oll o ws t he F D A g ui deli nes f or treat me nt of gi n gi vitis, w here s u bjects ha ve 
meas ura ble le vels of gi n gi vitis bef ore treat me nt 
a n d d o n ot recei ve pr ofessi o nal de nt al 
pr o p h yla xis pri or t o c o m me nci n g pr o d uct usa ge.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 2  of 7 0  
 St u d y s u bjects wit h a pre -s pecifie d l e vel of gi n gi vitis are stratifie d acc or di n g t o t heir se x (male 
or fe mal e) a n d  t he n ra n d o mize d t o t he st u d y pr o d uct; efficac y is d eter mi n e d after a peri o d of 
t wice-dail y br us hi n g, c o m pare d t o a c o ntr ol/c o m parat or d e ntifrice.  
A  1 2 -w ee k tr eat me nt d urat i o n has b ee n s electe d i n t his st u d y t o e na ble s ufficie nt ti me t o o bser ve 
pr o d uct effect  (Par ki ns o n et al ., 2 0 1 4 ; Par ki ns o n  et al., 2 0 1 8 b ; Par ki ns o n et al ., 2 0 2 0).  T he 
earlier ti me p oi nts, 3 w ee ks a n d 6 wee ks are c o nsi dere d t o hel p o bt ai n i nf or mati o n o n t he 
pr o gress  of gi n gi vitis res ol uti o ns . 
Healt h y s u bjects wit h cli nicall y m eas ura ble le vels of gi n gi vitis ( blee di n g sites  1 0 -3 0 % ) will be 
i ncl u de d i n t his st u d y. T he g i n gi vitis stat us i ncl usi o n a n d e x cl usi o n criteria will f oll o w t he ne w 
classificati o n ( 2 0 1 7 W orl d W or ks h o p o n t he Classificati o n of Peri o d o ntal a n d Peri -I m pla nt 
Diseases a n d C o n diti o n ( C ha p ple et al., 2 0 1 8 ), a n d t his will hel p t o mi ni mize t he ris k of a n 
at y pic al or p ote ntial lac k of treat me nt res p o nse f or s u bjects wit h se ver gi n gi v al healt h 
c o n diti o n s t hat ma y ot her wise be ma na ge d pr ofessi o nall y rat her t ha n s olel y via h o me use of a 
t wice-dail y d e ntifric e.  De ntal pla q ue is a  pre -re q uisite f or pla q ue-i n d uce d gi n gi vitis. T h us, 
eli gi ble s u bjects will be re q uire d t o ha ve a q ualif yi n g mi ni m u m le vel of s u pra -gi n gi val pla q ue 
( o verall me a n T PI ≥1. 5) after a p pr o xi matel y o ver ni g ht a bsti ne n ce fr o m oral h y gie ne pr oce d ures 
t o be ra n d o mized t o treat me nt . 
T he M GI a n d t he BI are esta blis he d cli nical meas ures of gi n gi val i nfla m mati o n a n d gi n gi val 
blee di n g, res p ecti vel y (i. e., gi n gi v al healt h , F D A., 2 0 0 5 ); t he T PI is a n esta blis he d cli nical 
meas ure of s u pra gi n gi v al pla q ue acc u m ulati o n  (F D A., 2 0 0 5 ).  
T he sa me e x a mi ner will perf or m ass ess me nts f or t he d urati o n of t he  st u d y t o eli mi nate t h e 
p ossi bilit y of i nter -e x a mi ner vari a bilit y.  
T o assess e x a mi ner re pr o d uci bilit y acr oss t he treat me n t peri o d, re peat 
M GI a n d T PI 
assess me nts will be perf or me d o n selecte d s u bjects t hr o u g h o ut t he st u d y. D ue t o t he i n vasi ve 
nat ure of t he i n d e x, re peata bilit y assess me nts are n ot feasi ble f or t h e BI.  
Base d o n wi del y rec o m m e n de d oral h y gi e ne practices a n d t y p ical c o ns u mer ha bits, all s u bjects 
will f oll o w t he s a me d osa ge re gi me n of t wice -d ail y treat me nt ( m or ni n g a n d e ve ni n g). T o 
facilitate c o m plia nce wit h pr o d uct usa ge t hr o u g h o ut t he st u d y a n d t o e na ble staff t o c o nfir m 
c orrect d osi n g, a s u per vise d br us hi n g wil l be perf or me d o n-site at t he e n d of Visits 2 -4. S u bjects 
will als o be re q uire d t o rec or d eac h br us hi n g i n t he diar y pr o vi d e d, i ncl u di n g t he ti me of t he 
last br us hi n g bef ore ret ur ni n g f or t he site assess m e nt visits. D uri n g t he was h o ut peri o d f or t his 
st u d y ( 1 4± 3 da ys ), eli gi ble s u bjects will use a mar kete d, re g ular fl u ori de de ntifrice  a n d 
t o ot h br us h (as pr o vi de d). Usi n g t hese pr o d ucts bef ore t he Baseli ne visit will hel p fa miliarize 
s u bjects wit h t he d osi n g/ diar y c o m pleti o n re q uire me nts. It will als o ser ve as a ‘ was h o ut’ fr o m 
a n y a nti -pla q ue i n gre die nts c o ntai ne d i n t he s u bject’s o w n oral h y gie ne pr o d ucts .  
A parallel gr o u p desi g n h as bee n sele cte d as m ost a p pr o priate f or t his i n vesti gati o n.  A ntici pate d 
differe ntial c h a n ges i n cli nical varia bles a m o n g treat m e nt gr o u ps c o ul d lea d t o carr y o ver effects 
a n d a n altere d oral healt h state, w hic h ma kes a cr oss o ver desi g n i na p pr o priate f or t his st u d y.  
T he d osa ge re gi me n of t wice dail y use ( m or ni n g a n d e ve ni n g) will be t he sa me f or eac h 
treat me nt gr o u p.  
S m o kers will b e e x cl u de d fr o m t his i n vesti gati o n beca use of t he m as ki n g  effect of s m o ki n g o n 
g u m ble e di n g. Base d o n t he literat ure, s m o ki n g d ecreases t he bl o o d fl o w wit hi n t he gi n gi val 
micr o vasc ulat ure a n d i nterferes wit h ne utr o p hil f u ncti o n, s u p pressi n g t he i nfla m mat or y 
res p o nse t o de ntal pla q ue a n d mas ki n g t he cli nical si g ns of peri o d o ntal disease (Mac h u ca et al, 
2 0 0 0;  O bei d a n d Berc y, 2 0 0 0 ).  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 3  of 7 0  
Ge n der is a k n o w n m o difier of t he i nitiati o n a n d o utc o me of gi n gi vitis. Q ualif ie d s u bjects will 
be stratifie d b y ge n der t o e ns ure fe male s u bj ects are bal a nce d bet w ee n t he treat me nt gr o u ps . 
H or m o nal fl uct uati o ns t hr o u g h t he fe mal e me nstr ual c ycl e ( Ra ber D url ac her et al 1 9 9 4 ) a n d 
h or m o nal c h a n ges d uri n g pre g n a nc y ma y affect t he res p o nse of t he gi n gi val tiss ue t o pla q ue 
bacteria a n d c o ul d i m pact t he gi n gi vitis efficac y meas ure me nts ( Fi g uer o et al., 2 0 1 0 ). W hilst 
t he st u d y pr o d ucts are n ot c o ntrai n dicat e d f or pre gn a nc y a n d breastf ee di n g, pre g na nt a n d/ or 
lactati n g fe males will be e x cl u de d fr o m t his st u d y d ue t o t he i ncrease d pre v ale nce a n d se verit y 
of gi n gi vitis a n d peri o d o ntal disease o bser ve d d uri n g pre g na n c y ( Sa ma nt et al., 1 9 7 6 ) a n d 
breastfee di n g (A g h aza de h et al, 2 0 1 9 ) w hic h, t o get her wit h t he i ncrease d a m o u nts of calc ul us 
a n d pla q ue o bser ve d d uri n g pre g na nc y, ma y i m pact st u d y o utc o mes.  
Acc or di n g t o t he I nter n ati 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 x a 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 de d as t o t he treat me nt t he s u bject recei v es, b ut t he pr o d ucts u n der test 
m ust be i de ntical i n e ver y wa y (c ol or, fl a v or, a p peara nce, pac ka gi n g). Gi ve n  it is al m ost 
i m p ossi ble t o e ns ure i de ntical a p peara nce, taste, a n d pac ka gi n g f or t he de ntifrices e val uate d i n 
t his oral care st u d y, t he l e vel of bli n d ness f or t his st u d y is descri b e d as “e x a mi ner bli n d.” 
4. 3  
J u stifi c ati o n f or D o s e  
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 br us h. T he d osa ge re gi me n of t wice dail y treat me nt 
( m or ni n g a n d e ve ni n g) will be t he sa m e f or all s u bjects a n d is b ase d o n wi del y rec o m me n de d 
oral h y gi e ne  practice a n d t y pical c o ns u m er ha bit.  St u d y s u bjects will be i nstr ucte d t o  br us h f or 
at least o ne (ti me d) mi n ute wit h t heir assi g ne d st u d y de ntifrice o n eac h br us hi n g occasi o n. After 
1 2 wee ks ( 8 4 ± 4  da ys) t wice dail y tr eat me nt, eac h s u bject s h o ul d c o m plete a p pr o xi matel y  1 6 8  
treat me nt a p plicati o ns. E ac h s u bject will c o m plet e a s u per vise d br us hi n g wit h t heir assi g ne d 
st u d y de ntifrice at t he e n d of st u d y visit 2, 3, a n d 4 ( w hile still at t he st u d y site) t o e na bl e staff 
t o c hec k c orrect d osi n g a n d e nc o ura ge c o m plia nce wit h pr o d uct usa ge t hr o u g h o ut t he st u d y. 
4. 4  
E n d of St u d y D efi niti o n  
A s u bject is c o nsi dere d t o ha ve c o m plete d t he st u d y if he or s he has 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 sc he d ul e d pr oce d ure s h o w n i n t he Sc h e d ule of Acti vities.  
T he e n d of t his st u d y is d efi ne d as t he d ate of t he l ast visit of t he last s u bject i n t he st u d y.  
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  
S ufficie nt s u bjects will be scree n e d t o ra n d o mize a p pr o xi matel y  1 6 0  s u bjects t o e ns ure 
a p pr o xi matel y 1 4 4  e v al u a ble s u bjects (a p pr o xi matel y 7 2 s u bj ects/ gr o u p) 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 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 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 4  of 7 0  
c o nsi dere d a p pr o priate.  All rele va nt me dical a n d n o n -me dical c o n diti o ns s h o ul d be ta ke n i nt o 
c o nsi derati o n w he n d eci di n g w het h er a s u bject is s uita ble f or t his pr ot oc ol.   
S u bject eli gi bilit y t o parti ci 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 t ea m bef 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 
Eli gi ble s u bjects are e x pecte d t o 
meet t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble 
f or e nr oll me nt i nt o t he st u d y:    
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 n t d o c u me nt i n dicati n g t hat 
t he s u bject has bee n i nf or me d of all perti ne nt as p ects of t he st u d y bef ore a n y 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 he ti me of scree ni n g, is at least 1 8 years ol d, 
i ncl usi ve.  
3. A s u bject  w h o is willi n g a n d a bl e t o c o m pl y wit h sc he d ule d visits, treat me nt pla n, a n d ot h er 
st u d y pr oce d ures.  
4. A s u bject 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 d esi g nee, n o cli nicall y si g nifica nt/rele va nt a b n or malities i n me dical hist or y 
or u p o n oral e x a 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 oral healt h t hat meets all t he f oll o wi n g:   
A T S C R E E NI N G ( Visit 1):  
a. S u bject wit h at least 2 0 nat ural, per m a ne nt teet h.    
b. S u bject wit h at least 4 0 e val ua ble s urfaces f or M GI, BI, a n d T PI.  
A n ev al u a ble s urf ace is d efi ne d as h a vi n g 2/ 3r ds of t he n at ur al t o ot h s urf ace gr a d a ble 
f or t he selecte d cli nic al i n dices. T he f oll o wi n g s h o ul d n ot be i ncl u de d i n t he ev al u a ble 
s urf ace c o u nt: t hir d m ol ars; f ully cr o w ne d/exte nsively rest ore d, gr ossly c ari o us, 
ort h o d o ntic ally b a n de d/ b o n de d or a b ut me nt teet h; s urf aces wit h c alc ul us de p osits 
w hic h, i n t he o pi ni o n of t he cli nic al ex a mi n er, w o ul d i nterfere wit h t he b aseli ne 
assess me nts of t he select e d cli nic al i n dices.  
c. A s u bject wit h pla q ue -i n d uce d gi n gi vitis, i n t he o pi ni on of t he cli nical e x a mi ner, as 
c o nfir me d b y a gr oss vis ual e x a mi nati o n.   
A T B A S E LI N E ( Visit 2):  
d. A s u bject wit h o n g oi n g h ar d tiss ue eli gi bilit y a n d, i n t he o pi ni o n of t he cli nical e x a mi ner, 
at least 4 0 e val ua bl e s urfaces.  
e. A s u bject wit h 1 0 % - 3 0 % ble e di n g sites (f oll o wi n g BI) 
f. A s u bject wit h mea n w h ole m o ut h T PI sc ore ≥1. 5. 
5. 3  
E x cl u si o n Crit eri a  
S u bjects w h o meet a n y of t he f oll o wi n g e x cl usi o n criteria were n ot eli gi ble f or e nr oll me nt i nt o 
t he st u d y:  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 5  of 7 0  
1. A s u bject w h o is a n e m pl o yee of t he i n v esti gati o nal site, eit her directl y i n v ol ve d i n t h e 
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 s p o ns or’s e mpl o yee 
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.   
2. A s u bject w h o has partici pate d i n ot her st u dies (i ncl u di n g n o n -me dici n al 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. A s u bject wit h, i n t he o pi ni o n of t he i n vesti gat or or me dicall y q ualifie d desi g nee, a n ac ute 
or c hr o nic me di cal or ps yc hiatric c o n diti o n or la b orat or y a b n or m alit y t hat ma y i ncreas e 
t he ris k ass ociate d wit h st u d y partici p ati 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 pret ati 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 m e dicall y q ualifie d desi g nee, w o ul d ma ke t he s u bject i na p pr o priate f or 
e ntr y i nt o t his st u d y.   
4. A s u bject w h o has a n y ot her cli nical seri o us or u nsta ble c o n diti o ns (e. g., car di o vas c ular 
diseases, dia b etes, li ver dis or ders, a n d ki d ne y dis or ders) w hic h c o ul d ha v e affect e d st u d y 
o ut c o mes a n d/ or s u bject safet y.    
5. A s u bject w h o is a pre g na nt fe male (self -re p orte d) or is i nte n di n g t o bec o me pre g na nt o ver 
t he d urati o n of t he st u d y. 
6. A s u bject w h o is a breastfee di n g fe male.   
7. A s u bject w h o is k n o w n or s us pect e d i nt olera nce or h y p erse nsiti vit y t o t he st u d y mat erials 
( 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.   
8. A s u bject w h o is 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   
9. S u bject w h o is a c urre nt s m o ker or a n e x -s m o ker w h o st o p pe d wit hi n 6 m o nt hs of Scree ni n g.  
1 0. S u bject w h o is usi n g s m o keless f or ms of t o bacc o ( e. g., c h e wi n g t o bacc o, g ut k ha, p a n 
c o ntai ni n g t o ba cc o, nic oti ne -base d e -ci garettes).   
1 1. A s u bject w h o is dia g n ose d x er ost o mia or is t a ki n g a n y me dicati o n t hat i n t he vie w of t he 
i n vesti gat or is c a usi n g x er ost o mia.   
1 2. A s u bject w h o has a me dical c o n dit i o n w hi c h c o ul d h a ve dir ectl y i nfl ue nce d gi n gi v al 
blee di n g  (e. g., t y pe 2 dia betes).  
1 3. A s u bject w h o has a blee di n g dis or der t hat c o ul d ha ve affect e d st u d y o utc o mes a n d/ or 
s u bject safet y.  
1 4. A s u bject w h o has a rece nt hist or y ( wit hi n t he last year) of alc o h ol or ot h er s u bsta nce  a b use.  
1 5. A s u bject w h o has a s e vere oral c o n diti o n (e. g., ac ute necr otizi n g ulcerati ve gi n gi vitis or  oral 
or peri -oral ulc erati o n i ncl u di n g her petic lesi o ns) t hat c o ul d, i n t he o pi ni o n of 
t he i n vesti gat or, c o m pr o mise st u d y o utc o mes or t he oral healt h of t he s u bject/e x a mi ner  if 
t he y p artici pate i n t he st u d y.   
1 6. Prese nce of a t o n g u e or li p pierci n g, or a n y ot her oral feat ure t hat c o ul d i nterfere  wit h t he 
usa ge of a t o ot h br us h.   
1 7 . Me dic ati o n e xcl usi o ns:  
At scree ni n g ( Visit 1 ):  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 6  of 7 0  
a. A s u bject usi n g a n y a nti bi otic me dicati o n wit hi n 1 4 da ys pri or t o scree ni n g or at a n y 
ti me d uri n g t he st u d y.  
b. A s u bject c urre ntl y ta ki n g a n a nti -i nfla m mat or y me dicati o n w hic h, i n t he o pi ni o n of 
t he I n v esti gat or, c o ul d affect gi n gi val c o n diti o n.   
c. A s u bject c urre ntl y t a ki n g a s yste mic me dicati o n (e. g., a nti -i nfl a m mat or y, a nti-
c oa g ula nt, i m m u n os u p pressa nts) or tra diti o nal/ her bal re me d y w hi c h, i n t h e o pi ni o n 
of t he I n v esti gat or, c o ul d affect pla q ue/ gi n gi val c o n diti o n (e. g., i b u pr ofe n, as piri n, 
w arfari n, c ycl os p ori n, p he n yt oi n, calci u m c ha n n el bl oc kers).    
1 8 . Me dic ati o n e xcl usi o ns   
At B aseli ne ( Visit 2):    
a. A s u bject w h o h as ta ke n (i n t he pre vi o us 1 4 da ys), a n y a nti bi otics.    
b. A s u bject w h o has ta ke n (i n t he pre vi o us 1 4 da ys) a s yste mic me dicati o n (e. g., a nti -
i nfla m mat or y, a nti-c o a g ula nt, i m m u n os u p pressa nts) or tr a diti o nal/ her bal re me d y 
w hic h, i n t he o pi ni o n of t he I n vesti gat or, c o ul d affect pla q ue/ gi n gi val c o n diti o n 
(e. g., i b u pr ofe n, as piri n, 
warfari n, c ycl os p ori n, p he n yt oi n, cal ci u m cha n n el 
bl oc kers).    
c. A s u bj ect w h o has use d a n a nti bacteri al de ntifri ce or m o ut h was h (e. g., c hl or he xi di ne) 
or a n y oral care pr o d uct t hat i n t he vie w of t he i n vesti gat or c o ul d i nterfere wit h 
pla q ue f or mati o n or meas ures of gi n gi vitis, i n t he peri o d bet wee n Scree ni n g a n d t he 
Baseli ne visit.   
1 9 . Peri o d o nt al e xcl usi o ns  
a. A s u bject w h o s h o ws si g ns of acti ve peri o d o ntitis ( wit h pr o bi n g p oc k et de pt hs > 3 
m m).  
b. A s u bject w h o is recei vi n g or has recei ve d treat me nt f or peri o d o ntal disease 
(i ncl u di n g s ur ger y) wit hi n 1 2 m o nt hs of Scree ni n g.  
c. A s u bject w h o h as gi n gi vitis, w hic h i n t he o pi ni o n of t he i n vesti gat or, is n ot 
e x pecte d t o res p o n d t o tr eat me nt wit h a n o ver t h e c o u nter ( O T C) de ntifrice.    
2 0 . De nt al E xcl usi o ns  
a. A s u bject w h o has acti ve caries t hat c o ul d, i n t he o pi ni o n of t h e i n vesti gat or, 
c o m pr o mise st u d y o utc o mes or t he oral healt h of t he s u bject if t he y parti ci pate i n 
t he st u d y.   
b. A s u bject w h o has de nt ures ( partial or f ull).   
c. A s u bject w h o has a n ort h o d o ntic a p plia nce ( ba n ds, a p plia nces, or fi x e d/ re m o va ble 
retai ners).  
d. A s u bject w h o recei ve d ort h o d o ntic t hera p y wit hi n 3 m o nt hs of Scree ni n g.    
e. A s u bject w h o h as n u mer o us rest or ati o ns i n a p o or state of re pair.    
f. A s u bject w h o has a n y de ntal c o n diti o n (e. g., o v ercr o w di n g) t hat c o ul d, in t he o pi ni o n 
of t he i n vesti gat or, c o m pr o mise st u d y o ut c o mes or t he oral h ealt h of t he s u bj ect if t h e y 
partici pate i n t he st u d y.    
g. A s u bject w h o has ha d de ntal pr o p h yl a xis wit hi n 1 2 wee ks of Scree ni n g.   
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 7  of 7 0  
h. A s u bject w h o has ha d teet h bleac hi n g wit hi n 1 2  wee ks of Scree ni n g.    
i. A s u bject w h o h as hi g h le vels of e xtri nsic stai n or calc ul us de p osits, i n t he o pi ni o n of 
t he i n vesti gat or, t h at c o ul d ha ve i nterfere d wit h pla q ue assess me nts.   
2 1 . A s u bject w h o has pr e vi o usl y bee n e nr olle d i n t his st u d y.   
2 2 . A s u bject w h o, i n t h e o pi ni o n of t he i n vesti gat or or me dicall y q u alifie d desi g nee, s h o ul d 
n ot partici pate i n t he st u d y.   
5. 4  
R a n d o mi z ati o n Crit eri a  
S u bjects w h o satisf y t he st u d y sele cti o n criteria will be stratifie d acc or di n g t o t heir se x  ( male 
or fe male) a n d ra n d o mize d t o st u d y treat me nt.  
5. 5  
Lif e st yl e C o n si d er ati o n s  
T he site ma y c o ntact s u bjects pri or t o st u d y visits, as a re mi n der of t he a p pr oac hi n g sc h e d ule d 
visit a n d a n y a p plica ble lifest yle restricti o ns.  
5. 5. 1  
M e al s a n d Di et ar y R e stri cti o n s  
Fr o m Scree ni n g ( Visit 1 ) t o t he S u bject’s L ast St u d y Visit  
 
S u bjects s h o ul d n ot c he w g u m or c o ns u m e a n y c o nfecti o ner y c o nt ai ni n g x ylit ol (e. g., 
mi nts).    
Bef ore Cli nic al Effic ac y Assess me nt Visits: B as eli ne ( Visit 2) t o L ast St u d y Visit   
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) f or at least 4 hrs pri or t o 
t heir sc he d ule d assess me nt visits a n d u ntil all assess me nts are c o m plete d uri n g visit 
da ys. Water is per mitte d u ntil 1 h o ur pri or t o t heir sc he d ule d st u d y visits.  
5. 5. 2  
Al c o h ol, C aff ei n e a n d C h e wi n g g u m  
•  S u bjects will n ot be per mitte d t o use c he wi n g g u m fr o m scree ni n g t o t he e n d of 
t he st u d y. 
5. 5. 3  
D e nt al Pr o d u ct/ Tr e at m e nt a n d Or al H y gi e n e R e stri cti o n s  
Fr o m Scree ni n g ( Visit 1) t o t he S u bject’s L ast St u d y Visit  
•  S u bjects will  n ot  be  p er mitte d t o use a n y oral care pr o d ucts  (e. g., de ntifrices, 
t o ot h br us hes, m o ut h ri nses) ot her t ha n t h ose pr o vi de d d uri n g t he st u d y.   
•  S u bjects will n ot be per mitte d t o use a n y  d e ntal fl oss, t o ot h pic ks, water pic ks, or 
i nter-de ntal br us hes (e x ce pt f or t he re m o val of i m pact e d f o o d 
wit h n o n -
a nti micr o bial pr o d ucts o nl y).   
•  S u bjects will be i nstr ucte d t o dela y a n y n o n -e mer ge nc y de ntal treat me nt u ntil 
st u d y c o m pleti o n (i ncl u di n g d e ntal pr o p h yla xis). T he y will be re q uir e d t o i nf or m 
site staff of a n y e mer ge n c y tr eat me nt t he y recei ve d uri n g t he st u d y.  
Bef ore Cli nic al Effic ac y Assess me nt Visits:   
S u bjects s h o ul d refrai n fr o m oral h y gie ne pr oce d ures f or 1 2 h o urs ( + 6 h o urs, -2 h o urs) 
bef ore t h eir visit , a n d atte n d t he st u d y site wit h o ver ni g ht pla q u e gr o wt h.   
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 8  of 7 0  
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  
T he f oll o wi n g m e dicati o n a n d treat me nt r estricti o ns a p pl y f or t he d urati o n of t he st u d y:  
•  If c urre nt/ c o nc o mita nt 
me dicati o ns/ treat me nts or tra diti o nal h er bal i n gre die nts/ 
treat me nts are use d d uri n g t he st u d y, t heir i de ntit y, as well as t heir d osa ge a n d fre q ue n c y, 
start a n d st o p dates m ust be re p ort e d t o t he I n vesti gat or a n d rec or de d i n t he C R F.  
F or m ore i nf or mati o n o n c o nc o mita nt me dicati o ns, please refer t o  Secti o n 6. 8.  
5. 5. 5  
C o ntr a c e pti o n  
T he are n o c o ntr ace pti o n re q uire me nts  for s u bjects e ntere d i nt o t his st u d y.  Fe males of c hil d -
beari n g p ote 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 bec o me 
pre g na nt.  
5. 5. 6  
C O VI D -1 9  
I n acc or da n ce wit h t he cli nical site pr oce d ures, a n d at t he i n vesti gat or’s discreti o n, s u bjects will 
be re q uire d t o si g n t he site’s c o nse nt f or m f or C o vi d-1 9 . S u bjects will nee d t o pass t he site’s 
pre -a p p oi nt me nt t ele p h o ne scree ni n g a n d will p erf or m  re-assess me nt pri or t o or w hile atte n di n g 
eac h st u d y visit. 
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 p are nt re p orti n g of s cree n fail ure s u bject s, a 
mi ni mal set of scree n fail ure i nf or mati o n will i ncl u de de m o gra p h y, scree n fail ure det ails (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 v erse e v e nts or 
i nci de 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 m e dical/ de nt al pers o n nel f or t he 
st u d y is d oc u me nt e d i n t he St u d y C o ntact List l ocate d i n t he i n vesti gat or st u d y master file h el d 
at t he st u d y site.  
T he c o ntact n u m ber is o nl y t o be use d b y i n vesti gati o nal staff see ki n g a d vice o n me dical/ de ntal 
q uesti o ns or pr o ble ms i n t he e v e nt t hat t he esta blis he d c o m m u nicati o n pat h wa ys bet w e e n t h e 
i n vesti gati o nal site a n d t he st u d y te a m are n ot a vaila ble.   
T he c o ntact n u m b er is n ot i nte n de d f or direct us e b y st u d y s u bjects.  T o facilitate access t o 
a p pr o priatel y q ualifie d me dical/ de ntal pers o n nel o n st u d y -rel ate d me dical/ de ntal q uesti o ns or 
pr o ble ms, s u bjects will be pr o vi de d wit h a c o p y of I C F w hic h h as c o n nect n u m ber liste d .   
5. 8  
Cli ni c al A s s e s s or Q u alifi c ati o n s  
Cli nical e x a mi ner (s) i n v ol ve d i n t he scree ni n g, safet y a n d efficac y assess me nts will be 
a p pr o priatel y q u alifie d d e ntal pr ofessi o nals , re gistere d t o pr actice i n t he U S.  
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 n ce 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 x a mi ner(s), wit h pri or 
rele va nt cli nical e x perie n ce.   
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 2 9  of 7 0  
6  
I N V ES 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 ui deli nes, a n d H ale o n  p olic y, st u d y i nter ve nti o n is defi ne d as an y i n vesti gati o nal 
i nter ve nti o n(s), mar 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 o c ol. 
T his i ncl u des a pr o d uct wit h a mar keti n g a ut h ori zati o n w he n use d or ass e m ble d (f or m ulate d or 
pac ka ge d) i n a wa y differe nt fr o m t he a p pr o ve d f or m, or w he n use d f or a n  u na p pr o ve d 
i n dicati o n, or w he n use d t o gai n f urt her i nf or m ati o n a b o ut a n a p pr o ve d use.  
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 
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 Pr o d uct  
Refere n ce Pr o d uct  
( ne gati ve c o ntr ol) 
Pr o d uct N a me  
p ar o d o nta x C o m plete 
Pr otecti o n  
( 0. 4 5 4 % w/ w S n F 2) 
Crest Ca vit y Pr otecti o n 
( 0. 2 4 3 % w/ w  s o di u m 
fl u ori de) 
P ac k D esi g n  
Cart o n of 6 o ver -wra p p e d 
t u bes 
Cart o n of 6 o ver -wra p p e d 
t u bes 
Dis pe nsi n g Det ails  
O ne cart o n –  baseli ne visit  
O ne cart o n –  baseli ne visit  
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)  
C o m mercial Pr o d uct  
D ose/ A p plic ati o n  
F ull ri b b o n of de ntifrice  o n 
hea d of t o ot h br us h pr o vi de d  
F ull ri b b o n of de ntifrice  o n 
hea d of t o ot h br us h pr o vi de d  
R o ute of A d mi nistr ati o n  
Oral  
Oral  
Us a ge I nstr ucti o ns  
S u bjects will br us h t heir teet h 
f or at least o ne (ti me d) mi n ute 
t wice a da y ( m or ni n g a n d 
e ve ni n g)  
S u bjects will br us h t heir teet h 
f or at least o ne (ti me d) mi n ute 
t wice a da y ( m or ni n g a n d 
e ve ni n g)  
Ret ur n Re q uire me nts  
All use d/ u n use d sa m ples t o be 
ret ur ne d 
All use d/ u n use d sa m ples t o be 
ret ur ne d 
 
 
 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 0  of 7 0  
T a bl e 6 -2  
W a s h o ut/ A c cli m ati z ati o n Pr o d u ct S u p pli e s  
 
Was h o ut de ntifrice  
Pr o d uct N a me  
C ol gate Ca vit y Pr otecti o n  
P ac k D esi g n  
O ne t u be  
Dis pe nsi n g Det ails  
O ne  t u be –  scree ni n g visit 
Pr o d uct M aster F or m ul ati o n C o de ( M F C)  
N/ A - c o m mercial pr o d u ct  
D ose/ A p plic ati o n  
A p pl y a f ull ri b b o n of de ntifrice  o n t he hea d of 
t o ot h br us h pr o vi de d 
R o ute of A d mi nistr ati o n  
T o pical oral use  
Us a ge  I nstr ucti o ns 
S u bjects will br us h t heir teet h acc or di n g t o 
t heir n or mal br us hi n g ha bits t wice a da y 
( m or ni n g a n d e ve ni n g). 
Ret ur n Re q uire me nts  
All use d/ u n use d sa m ples t o be ret ur ne d  
 
T 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:  
Ite m 
S u p plie d 
B y  
P ac k Desi g n  
Dis pe nsi n g 
Det ails  
Ret ur n/ Dis p os al Det ails  
 
 
 
 
Use d 
S a m ples  
U n use d 
S a m ples  
Se ns o d y ne 
Se nsiti ve Care s oft -
bristle d 
T o ot h br us hes 
( U S 
mar ket place)  
Hale o n  
C o m mercial 
pac k  (2 
br us hes/ pac k)  
–  1 pac k  per 
s u bject 
1 pac k at 
scree ni n g.  
S u bjects will  
use 1  br us h  
d uri n g was h o ut 
peri o d  
 S u bjects will  
use t he 2 n d  
br us h d uri n g  
st u d y peri o d  
Destr o y at 
site usi n g site 
dis p osal 
pr oce d ures  
 
Ret ur n  
C o u nt d o w n Ti mer  
Hale o n  
I n di vi d ual 
c o m mercial 
Baseli ne visit  
S u bject t o 
kee p or 
Ret ur n  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 1  of 7 0  
pac k –  1 per 
s u bject 
destr o ye d at 
site usi n g site 
dis p osal 
pr oce d ures  
 
O pa q ue Ba gs  
Hale o n  
C o m mercial 
Pac k  
 
Scree ni n g Visit 
a n d baseli ne 
visit  
S u bject t o 
kee p or 
destr o ye d at 
site usi n g site 
dis p osal 
pr oce d ure  
Ret ur n  
Detaile d i nstr ucti o ns f or t he ret ur n of st u d y pr o d uct/st u d y s u p plies f or t he acc o u nta bilit y c hec ks 
a n d s u bse q ue nt destr ucti o n w hic h will be pr o vi de d b y Hale o n  d uri n g  t he st u d y i n ti me f or st u d y 
cl ose o ut visit.  
6. 1. 1  
M e di c al D e vi c e s  (if a p pli c a bl e –  d el et e if n ot n e e d e d)  
T he t o ot h br us hes t o be use d i n t his st u d y are m e dical de vices . 
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: 2 0 2 0  
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 was h o ut a n d st u d y pr o d ucts are de ntifrices 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 t he pr o vi de d ma n ual t o ot h br us h.  
T he was h o ut de ntifric es will be s u p plie d i n t heir c o m mercial t u bes . T h e test a n d refere nce 
de ntifrices will be s u p pli e d i n t heir c o m mercial t u bes b ut o ver -wra p p e d i n w hite o pa q ue vi n yl 
i n or der t o mas k t heir i de ntit y as m uc h as p ossi ble.  All i n vesti gati o nal s a m ples will ha ve a 
st u d y la bel affi x e d a n d will be pr o vi de d i n la b elle d pr o d uct cart o ns c o ntai ni n g s uffici e nt 
sa m ples f or t he d urati o n of t he use peri o d. Was h o ut sa m ples will ha ve a st u d y la bel affi x e d t o 
eac h t u be.  
T he c o nte nt of t he pr o d uct la bels will be i n acc or da nce wit h all a p plica 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 Cli nical S u p plies gr 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 use a n d st ora ge 
re q uire me nts. 
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 -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 n ot t o 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 pr o d ucts i n acc or da n ce wit h t he ra n d o mizati o n sc he d ule ge nerate d 
b y a  H ale o n a p pr o ve d v e n d or, pri or t o t he start of t he st u d y, usi n g vali date d s oft ware.  
St u d y pr o d uct 
will be dis pe nse d b y q ualifie d site pers o n nel ( u n bli n de d) per t h e 
d osa ge/a d mi nistrati o n i nstr ucti o ns. T hese staff me m bers will n ot be i n v ol ve d i n a n y s afet y, 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 2  of 7 0  
effic ac y ass ess me nts or ot her as pects of t he st u d y t hat c o ul d be i nfl ue n ce 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 use. A n a d diti o nal me m ber of site sta ff s h o ul d e ns ure t he 
dis pe nsi n g pr oce d ures are c o m plete d acc uratel y.  
T he st u d y d e ntifrice  will be dis pe nse d i n a bli n de d fas hi o n t o t he s u bject.  T he st u d y site will be 
pr o vi de d wit h o pa q ue b a gs i n w hic h t h e st u d y pr o d ucts a n d pr o d uct us a ge i nstr ucti o ns wi ll be 
place d i n t he ba g pri or t o t he s u bject lea vi n g t he dis pe nsi n g area. S u bjects s h o ul d be a d vise d as 
t o c orrect pr o d uct usa ge i n acc or da n ce wit h t he Pr o d uct Usa ge I nstr u cti o ns at visit 2, 3, a n d 4. 
All ra n d o mize d s u bjects s h o ul d recei ve sta n d ar d oral ca re a d vi ce at Visit 2 (secti o n 8. 2. 1). 
6. 2  
A d mi ni str ati o n  
O nl y s u bjects e nr olle d i n t he st 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 b e 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 ge 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. 
After was h o ut peri o d, s u bjects will be i nstr ucte d t o self -a dmi 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. S u bjects will recei ve a br us hi n g i nstr ucti o n a n d 
st u d y diar y s heet. T his will o utli ne t he br us hi n g i nstr ucti o ns a n d will be use d t o rec or d t he dat e 
a n d ti me of eac h br us hi n g occasi o n d uri n g t he treat me nt peri o d. S u bjects will als o be as ke d t o 
n ote a n y misse d br us hi n gs, a n d t o use t he diar y t o rec or d a n y c ha n ges i n me dicati o ns, or ne w 
me dicati o ns, or t o diet. T o e ns ure t hat s u bjects u n dersta n d t he d ose of de ntifrice t o be use d, 
staff will de m o nstr ate w h at is mea nt b y a ‘f ull ri b b o n’ (i.e., c o veri n g t he l e n gt h of t he t o ot h br us h 
hea d) a n d pr o vi de d etaile d oral h y gie ne i nstr ucti o n d uri n g t he s u per vise d t o ot h br us hi n g i n 
a gree m e nt wit h t he st u d y sc he d ule a n d pr o d uct us a ge i nstr ucti o ns.  
6. 2. 1  
M e di c ati o n/ D o si n g Err or s  
Me dicati o n/ d osi n g 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 me dicati o n/ d osi n g err ors occ urri n g t o a st u d y s u bj ect are t o be ca pt ure d i n t h e C R F.  I n 
t he e ve nt of me di cati o n d osi n g err or, t he s p o ns or s h o ul d be n otifie d i m me di atel y a n d u n der 
n o circ u mst a nce s h o ul d t his e xcee d 2 4 h o urs . 
Me dicati o n/ d osi n g 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: 
•  Me dicati o n/ d osi n g err ors i n v ol vi n g s u bject e x p os ure t o a n y of t he st u d y pr o d ucts.  
•  P ote ntial me dicati o n/ d osi n g 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 me dicati o n/ d osi n g err or is acc o m p a nie d b y a n A E, as deter mi ne d b y t he i n vesti gat or, t h e 
me dicati o n/ d osi n g err or a n d, a n y ass ociate d a d verse e ve nt(s) are t o be ca pt ure d i n t he C R F A E 
f or m.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 3  of 7 0  
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.  
Li mite d q ua ntities of t he st u d y pr o d uct(s) will be s u p plie d, a n d cl osel y m o nit ore d b y t he site 
f or eac h s u bject. 
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 st u d y pr o d uct s 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 br us h. 
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ur e c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y pr o d ucts  recei ve d a n d a n y discre p a ncies are re p orte d a n d 
res ol ve d bef ore us e acc or di n g t o t he s u p plie d s hi p pi n g d oc u me nt ati o n . 
T he i n vesti gat or, or d esi g nee, will e ns ure t hat all st u d y pr o d ucts are st ore d i n a s ec ure d area 
wit h c o ntr olle d access u n der re q uire d st or a ge c o n diti o ns a n d i n acc or da n ce wit h a p plica ble 
re g ulat or y re q uire me nts a n d t he pr o d uct la b el.   
Site s yst e ms m ust be 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 ns (as 
a p plica ble, i ncl u di n g fr o ze n, refri gerate d, a n d/ or r o o m -te m perat ure pr o d ucts).  T his s h o ul d be 
ca pt ure d 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 v e dail y e val u ati o n f or e x c ursi o ns 
s h o ul d be a v aila ble.  T he o perati o n of t h e te m perat ure-m o nit ori n g de vice a n d st ora ge u nit (f or 
e x a m ple, refri gerat or), as a p plica ble, s h o ul d b e re g ularl y i ns pecte d t o e ns ure it is mai ntai ne d i n 
w or ki n g or der.  
A n y e x c ursi o ns fr o m t he pr o d uct -la bel st ora ge c o n diti o ns s h o ul d be re p orte d t o a p pr o priate sit e 
staff u p o n disc o ver y a n d c o m m 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 ge re q uir e me nts, i ncl u di n g a n y acti o ns ta ke n, 
m ust be d oc u me nte d as a pr ot oc ol de viati o n a n d re p orte d t o t he S p o ns or.   
O nce a n e x c ursi o n is i de ntifie d, t he affect e d pr o d uct ( or pr o d ucts) m ust be q uara nti ne d a n d n ot 
use d u ntil t he s p o ns or pr o vi des d oc u me ntati o n of per missi o n t o use. Use of a n y of t he affecte d 
pr o d uct(s) pri or t o s p o ns or a p pr o val will be c o nsi dere d a pr ot oc ol de viati o n.    
Site staff will i nstr uct s u bjects o n t he pr o per st ora ge re q uir e me nts f or all ta ke -h o me pr o d u cts.  
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  at t he st u d y sites, ha n dle d a n d st or e d 
safel y a n d pr o perl y, a n d ke pt i n a sec ure d l ocati o n t o w hic h o nl y t he staff ha ve access. U p o n 
recei pt, all st u d y pr o d ucts s h o ul d be st or e d acc or di n g t o t he i nstr ucti o ns s p ecifie d o n t he pr o d uct 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 4  of 7 0  
la bels. St u d y pr o d ucts are t o be dis pe nse d o nl y t o s u bjects e nr olle d i n t he st u d y i n acc or da n ce 
wit h t he pr ot oc ol, b y a ut h orize d site staff.  
T he i n vesti gati ve site m ust mai ntai n a de q uate rec or ds d oc u me nti n g t he recei pt, use, l oss, or 
ot her dis p ositi o n of all t he pr o d uct s u p plie s. All st u d y pr o d u cts will be acc o u nte d f or usi n g t he 
i n vesti gati o nal/st u d y pr o d uct acc o u nta bilit y f or m/rec or d. T he i n vesti gat or is res p o nsi ble f or 
st u d y pr o d uct acc o u nt a bilit y, rec o n ciliati o n, a n d rec or d mai nte n a nce.  
T he acc o u nt a bilit y rec or ds m ust be a v aila ble f or i ns pecti o n b y t h e st u d y m o nit or d uri n g t he 
st u d y. M o nit ori n g of pr o d uct acc o u nta bilit y will b e perf or me d b y t he m o nit or d uri n g site visits 
a n d at t he c o m pleti o n of t he st u d y.  
S u bjects will ret ur n use d a n d u n use d t u bes of t he was h o ut de ntifrice  t o t he st u d y site at t heir 
Baseli ne visit ( Visit 2). S u bjects will ret ur n use d a n d u n use d t u b es of t heir assi g ne d st u d y 
de ntifrice t o t he st u d y site at t heir last visits (f or m ost s u bjects t his will be Visit 5). St u d y pr o d uct 
ret ur n will be d oc u me nt e d usin g t he i n vesti gati o n al/st u d y pr o d uct acc o u nt a bilit y f or m/rec or d.  
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 p al I n vesti gat or or a n a p pr o priate desi g n ee, a n d a 
re pres e ntati ve of Hal e o n  (st u d y m o nit or) will i n ve nt or y all use d a n d u n use d st u d y pr o d ucts a n d 
s u n dr y ite ms.  T he i n vesti gati o nal/st u d y pr o d uct acc o u nta bilit y rec or d f or ret ur ne d st u d y 
pr o d ucts will t he n 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 
(incl u di n g e m pt y c o ntai ners),  will be ret ur ne d f or destr ucti o n t o t he Hale o n  Cli nical S u p plies 
De part me nt or d esi g n ate 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 Hale o n  d uri n g t he st u d y i n ti me f or st u d y cl ose o ut visit.  
Ret ur n a n d destr ucti o n i nstr ucti o ns f or s u n dr y ite ms are pr o vi de d i n T a ble 6 -3.  
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 t o o ne of t he tw o  st u d y pr o d ucts 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 nitiate d, trai ni n g, l o gi n i nf or mati o n a n d 
directi o ns f or t he I R T will be pr o vi de d. St u d y pr o d ucts will be dis pe nse d acc or di n g t o t he 
i nstr ucti o n recei ve d t hr o u g h t he I R T at t he a p pr o priate st u d y visits. 
Ret ur ne d st u d y pr o d ucts s h o ul d n ot be re -dis pe nse d t o a n y s u bject.  
T his st u d y is des cri be d as e x a mi ner -bli n d (t he i n vesti gat or, cli nical e x a mi ner a n d m o nit or will 
be bli n de d t o pr o d uct recei ve d). Site staff, t he st u d y statisticia n, data ma na ge m e nt staff, ot her 
e m pl o yees of t he S p 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 als o be bli n de d t o t he pr o d uct all ocati o n. T o e ns ure t he cli nical e x a mi ner re mai ns 
bli n de d t hr o u g h o ut t he st u d y:  
• site staff i n v ol ve d i n t he dis pe nsi n g of st u d y pr o d uct a n d t he s u per visi o n of o nsite pr o d uct 
u sa ge will w or k i n a se p arate area;  
• t he e x a mi ner will n ot be per mitte d i n a n y area w here st u d y pr o d uct is st ore d, dis pe nse d, or i n 
use;  
• st u d y s u bjects will be i nstr ucte d n ot t o re m o ve st u d y pr o d uct fr o m t he o p a q ue ba gs pr o vi de d 
o utsi de of t he dis pe nsi n g r o o m, w hile at t he st u d y site;  
• dis pe nsi n g staff a n d o n-site br us hi n g s u per vis ors will n ot be i n v ol ve d i n a n y safet y/ pr o d uct 
perf or ma n ce assess me nts d uri n g t he st u d y.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 5  of 7 0  
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 det er mi ni n g if u n bli n di n g  of a 
s u bject’s pr o d uct assi g n me nt is warra nte d. S u bject safet y m ust al wa ys b e t he first c o nsi derati o n 
i n ma ki n g s uc h a d eter mi nati o n. If t he i n v esti gat or deci des t hat u n bli n di n g is warra nte d, t h e 
i n vesti gat or s h o ul d ma k e e ver y eff ort t o c o ntact t he s p o ns or pri or t o u n bli n di n g a s u bject’s 
pr o d uct assi g n me nt u nless t his c o ul d dela y e mer ge nc y tr eat me nt of t h e s u bject.  
If a s u bject’s pr o d uct assi g n me nt is u n bli n de d, t he s p o ns or m ust be n otifie d wit hi n 2 4 h o urs 
after brea ki n g t he bli n d. T he date a n d reas o n t hat  t he bli n d was br o ke n m ust be rec or de d i n t he 
s 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 o ciate d wit h brea ki n g t he bli n d m ust be rec or de d a n d re p orte d as s pecifie d i n t his 
pr ot oc ol. T he st u d y site ma y als o be re q uire d b e re q uire d t o i nf or m t h e I R B/ E C 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 p er visi o n of i n vesti gat or site pers o n nel.  
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 ure details of pr o d uct use t hr o u g h o ut 
t he st u d y p eri o d. 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 dicati 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 be re vie we d b y t he i n vesti gat or 
( or s uita bl y q u alifie d desi g nee) wit h t he s u bjects a n d tra nscri be 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 or d oses 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 uire m e nts a n d diar y c o m pleti o n as nee d e d.  
A rec or d of t he n u m ber of de ntifrice t u bes dis pe nse d t o a n d ta ke n b y eac h s u bject m ust b e 
mai ntai ne d a n d rec o ncile d wit h st u d y i nter ve nti o n a n d c o m plia nce rec or ds. I nter v e nti o n start 
a n d st o p dates, i ncl u di n g d ates f or i nter ve nti o n dela ys a n d/ or d ose r e d u cti o ns will als o be 
rec or de d i n t he C R F. 
S u per vise d br us hi n gs will be carrie d o ut at t he st u d y site i n a gree me nt wit h t he Sc he d ul e of 
Acti vities, t o facilitate s u bject c o m plia nce wit h d osi n g a n d br us hi n g i nstr ucti o ns.  
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 ni t 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 n s/treat me nts at 
eac h site visit.  
Me dicati o n/treat me nts ta ke n wit hi n 
2 8  da ys of si g ni n g t he i nf or me d c o nse nt f or m will b e 
d oc u me nte d as a pri or me dicati o n/treat me nt.  Me dicati o ns/treat me nts t a 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 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 6  of 7 0  
7  
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 T I 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 dr a w fr o m t he st u d y at a n y ti me at his or her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or or s p o ns or f or safet y, b e ha vi oral 
reas o ns, or t he i na bilit y of t he s u bject t o c o m pl y wit h t he pr ot oc ol -re q uir e d sc he d ule of st u d y 
visits or pr oce d ures.   
T he f oll o wi n g circ u msta nces re q uire disc o nti n uati o n of st u d y pr o d uct a n d/ or pre m at ure s u bject 
wit h dra wal:  
•  Pr ot oc ol vi olati o n t hat ma y i m pact t he s u bject’s s afet y  
•  Wit h dra wal of i nf or me d c o nse nt  
•  S u bject l ost t o f oll o w -u p  
•  U n bli n di n g of t he s u bject  
•  Pre g n a nc y  
If a s u bj ect is disc o nti n ue d or pre mat urel y wit h dra ws fr o m t he st u d y, t he reas o n(s) f or 
disc o nti n uati o n or wit h dra wal a n d t h e ass ociate d date m ust be d oc u me nt e d i n t he rele va nt 
secti o n(s) of t he 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 sit e. Bef ore a s u bject is dee me d l ost t o f oll o w 
u p, t he i n vesti gat 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 t h at t he y h a d b ee n dis pe ns e d a n d if a p pr o priate re q uest t h at 
t he s u bject ret ur n f or a fi nal visit a n d f oll o w-u p wit h t he s u bject re gar di n g a n y u nres ol ve d 
a d verse e ve nts ( A Es).  
Fi nal safet y assess me nts ma y be carrie d o ut w he n t he s u bject ret ur ns t o t he st u d y site, at t h e 
i n vesti gat or’s discreti o n, w hic h c o ul d i ncl u de 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 nreac h a ble, h e/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr o m t he st u d y a n d l ost t o f oll o w u p.  
Lac k of c o m pleti o n of all or a n y of t he earl y ter mi nati o n pr oce d ures will n ot be vie we d as 
pr ot oc ol de viati o ns s o l o n g as t he s u bj ect’s safet y w as pres er ve d.  
If t he s u bject wit h dra ws fr o m t he st u d y a n d wit h dra ws c o ns e nt f or discl os ure of f ut ure 
i nf or mati o n, n o f urt her e val uati o ns s h o ul d be p erf or me d, a n d n o a d diti o nal data s h o ul d be 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 7  of 7 0  
c ollecte d.  T he s p o ns or ma y retai n a n d c o nti n ue t o use a n y d ata c ollecte d bef ore s uc h 
wit h dra wal of c o nse nt.  
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 all pr oce d ures are esse ntial a n d re q uire d 
f or st u d y c o n d uct. 
8. 1  
Vi sit 1/ S cr e e ni n g  
Scree ni n g pr oce d ures will be c o n d ucte d b y t he I n v esti gat or, or s uita bl y q u alifie d desi g n ee.  
S u bjects will be scree ne d wit hi n  1 4 ± 3 da ys pri or t o a d mi nistrati o n of t he i n vesti gati o nal /st u d y 
pr o d uct t o c o nfir m t hat t he y m eet t he s u bject s electi o n criteria f or t he st u d y.   
T he f oll o wi n g s cree ni 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 ver 
p ossi ble), a n d t he fi n di n gs will be rec or de d i n t he C R F: 
 
1.  I nf or me d c o ns e nt 
2.  De m o gra p hics, 
me dical 
hist or y 
(i ncl u di n g 
s m o ki n g) 
a n d 
pri or/c o nc o mita nt 
me dicati o n/treat me nt  
3.  O S T e x a mi nati o n (Secti o n 9. 3. 1 )  
4.  O H T e x a mi nati o n ( Secti o n 9. 3. 2 )  
5.  Gr oss gi n gi val assess me nt ( Secti o n 9. 1. 1 ) 
6.   P oc ket de pt h assess me nt (secti o n 9. 1.2 ) 
7.  Re vie w of i ncl usi o n/e x cl usi o n criteria  
8.  S u bject eli gi bilit y  
9.  Dis pe nse was h o ut pr o d u cts/ de ntifrice, t o ot h br us h  a n d diar y  (i ncl u di n g instr uct i o n o n   
diar y c o m pleti o n ). Re mi n d s u bject t o use 1 t o ot h br us h d uri n g was h o ut a n d bri n g b ot h 
t he use d a n d ne w br us hes at baseli ne visit.  
1 0.  Rec or d A d verse e v e nts & I nci d e nts ( Secti o n 1 0 ) 
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 aft er a de q u ate e x pla nati o n of t he ai ms, met h o ds, o bjecti ves, a n d p ote ntial hazar ds of 
t he st u d y. T w o c o pies of t he i nf or me d c o nse nt f or m (I C F) will be si g n e d a n d date d b y t h e 
s u bject, t he s u bject will r etai n o ne c o p y a n d t he ot her will be ke pt at site.  
T he i n vesti gat or, or desi g nee, m ust als o e x plai n t o t he s u bjects t hat t h e y are c o m pletel y free t o 
ref use t o e nter t he st u d y or t o wit h dra w fr o m it at a n y ti me.  A p pr o priat e f or ms f or d oc u me nti n g 
a si g ne d a n d date d c o nse nt will be pr o vi de d b y eit her t he i n vesti gat or or b y Hale o n . 
T he i n vesti gat or, or desi g nee, s h o ul d si g n a n d date eac h c o p y of t he I C F t o c o nfir m t hat t he 
c o nse nt pr ocess was c o m plete d c orrect l y aft er t he s u bject has si g n e d.   
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 8  of 7 0  
T he ti me t he s u bject si g ne d t he i nf or me d c o nse nt f or m will be ca pt ure d as t his is t he p oi nt at 
w hic h all A d verse E ve nts will be ca pt ure d fr o m. T he date a n d ti me of c o nse nt will be ca pt ure d  
i n t he 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 
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 nee) t o partici pate i n t he st u d y t he s u bject is c o nsi d ere d 
e nr olle d i n t he st u dy. 
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, se x (male 
or fe m ale)  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 nce f or I n d ustr y: C ollecti o n of R ace a n d Et h nicity D at a i n Cli nic al Tri als, 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 o ne  years), i ncl u di n g aller gies or 
dr u g s e nsiti vit y, will be d oc u me nte d i n t he e 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 3 0  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 e C R F.  
8. 1. 4  
Or al E x a mi n ati o n/ A s s e s s m e nt  
 
T he f oll o wi n g pr oce d ures will be c o m plete d, a n d data rec or de d i n t he C R F. T he f oll o wi n g 
scree ni n g pr oce d ures s h o ul d be carrie d o ut b y a q u alifie d de ntal pr ofessi o nal: 
•  
O S T e x a mi nati o n as descri be d ( Secti o n 9. 3. 1 ) 
•  
O H T e x a mi nati o n as descri be d i n ( Secti o n 9. 3. 2.)  
•  
Gr oss assess me nt of gi n gi val healt h ( Secti o n 9. 1. 2 ).   
•  
P oc ket de pt h assess me nt (secti o n 9. 1.2 ) 
T he oral e x a mi nati o ns/assess me nts s h o ul d be carri e d o ut as des cri be d i n Secti o n 9 . All fi n di n gs 
will be  rec or de d i n t he C R F. 
Fi n di n gs fr o m t his e x a mi nati o n perf or m e d at t h e Scree ni n g Visit will be use d t o d eter mi ne 
s u bject eli gi bilit y. 
8. 1. 5  
I n cl u si o n/ E x cl u si o n Crit eri a 
I n cl usi o n a n d e x cl usi o n criteria i nf or mati o n will be d oc u me nte d i n t he C R F. 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 3 9  of 7 0  
8. 1. 6  
S u bj e ct Eli gi bilit y  
T he i n vesti gat or a n d/ or me dicall y q u alifie d desi g nee will re vie w i ncl usi o n/e xcl usi o n criteria, 
me dical hist or y, pri or me dicati o ns t o c o nfir m s u bject eli gi bilit y t o partici pate i n t he cli nical 
trial. T his will be d oc u me nte d i n t he C R F. 
T o pre par e f or st u d y partici pati o n, s u bjects will be i nstr ucte d i n t he Lif est 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. 7  
Di s p e n s e W a s h o ut Pr o d u ct s  
Eli gi ble s u bjects will be pr o vi de d wit h t he was h o ut de ntifrice , t o ot h br us hes a n d diar y t o use 
d uri n g t h e w as h o ut peri o d ( 1 4 ± 3 da ys). S u bjects will be i nstr ucte d t o us e o nl y t heir s u p plie d 
oral care pr o d ucts ( was h o ut pr o d ucts) acc or di n g t o t heir n or mal ha bit u ntil t heir ne xt 
a p p oi nt me nt. C o m pleti o n of all pr oce d ures will be d oc u me nte d i n t he C R F.  
8. 2  
St u d y P eri o d  
8. 2. 1  
B a s eli n e: Vi sit 2  (D a y 0 )   
S u bjects will visit t he cli nical st u d y site 1 4  ± 3 d a ys after t he Scree ni n g visit. T he f oll o wi n g 
pr oce d ures/ assess me nts will ta ke p lace i n t he or der liste d bel o w as m uc h as p ossi ble a n d be 
rec or de d i n t he C R F: 
1.  C ollect  was h o ut pr o d ucts/ c o m plia nce c hec ks i ncl u di n g diar y re vie w  
2.  C o nfir m t hat 2 n d t o ot h br us h has n ot bee n use d 
3.  Re vie w of c o nc o mita nt me dicati o n or n o n -dr u g treat me nts/ pr oce d ures, a d verse e ve nts, 
i nci de nts a n d lifest yl e restricti o ns.  
o  C o nc o mita nt me dicati o ns/ treat me nts (Secti o n 6. 8 )  
4.  O S T e x a mi nati o n ( Secti o n 9. 3. 1 ) 
5.  M GI assess me nt ( Secti o n 9. 2. 1 ) 
6.  Gi n gi val ble e di n g  
o  BI ass ess me nt ( Secti o n 9. 2. 2 ) (i ncl u di n g blee di n g  sites %  w hic h is deri ve d fr o m 
BI ass ess me nt ) 
7.  Pla q ue discl os ure ( Secti o n 9. 2. 3 ) 
8.  T PI ass ess me nt ( Secti o n 9. 2. 4 ) 
9.  I n cl usi o n/e x cl usi o n criteria 
1 0.  S u bject eli gi bilit y  
1 1.  M GI re p eata bilit y assess me nt  (w here a p plica bl e ) (Secti o n 9. 2. 1 ) 
1 2.  T PI re peat a bilit y assess m e nt  (w here a p plica ble)  (S ecti o n 9. 2. 4 ) 
1 3.  Ra n d o mizati o n  
1 4.  Dis pe nse st u d y d e ntifrice,  st u d y i nstr ucti o ns & di ar y a n d ti mer  
1 5.  Oral h y gi e ne i nstr ucti o n s a n d/ i ncl u di n g diar y c o m pleti o n i nstr ucti o ns 
1 6.  S u per vise d br us hi n g at site  usi n g t he 2 n d t o ot h br us h 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 0  of 7 0  
1 7.  Rec or d  A d ver se e v e nts & I nci d e nts (Secti o n 1 0 ) 
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 m e nte d i n 
t he C R F.  
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 bj ects t o res p o n d  t o a 
n o n -lea di n g q uesti o n s u c h as “ H o w d o y o u feel? ” will be assess e d a n d a n y A Es rec or de d i n t he 
C R F.  
8. 2. 2  
Vi sit 3  a n d 4 (D a y 2 1 ± 3  d a y a n d 4 2 ± 4  d a y )  
T he f oll o wi n g pr oce d ures/ assess me nts will ta ke place i n t he or der liste d bel o w a n d be rec or de d 
i n t he C R F: 
1.  C ollect st u d y de ntifric e, t o ot h br us h & diar y fr o m s u bject  
2.  Re vie w of c o nc o mita nt me dicati o ns a n d n o n -dr u g treat me nts/ pr oce d ures, a d v erse 
e ve nts, i nci de nts a n d lifest yl e restricti o ns  
o  C o nc o mita nt me dicati o ns/ treat me nts (Secti o n 6. 8 ) 
3.  C o m plia nce c hec ks i n cl u di n g diar y re vie w  
4.  S u bject c o nti n ua nce  
5.  O S T e x a mi nati o n ( Secti o n 9. 3. 1 ) 
6.  M GI assess me nt ( & re peata bilit y assess me nt, w here a p plica bl e) ( Secti o n 9. 2. 1 ) 
7.  BI ass ess me nt ( Secti o n 9. 2. 2 ) 
8.  Pla q ue discl os ure ( Secti o n 9. 2. 3 ) 
9.  T PI ass ess me nt ( & re p eata bilit y assess me nt, w here a p plica ble) ( Secti o n 9. 2. 4 ) 
1 0.  Ret ur n st u d y de ntifri ce, t o ot h br us h, st u d y i nstr ucti o ns a n d diar y t o s u bject  
1 1.  Oral h y gie n e i nstr ucti o n re vie w / c o m plia nce c h ec ks i ncl u di n g diar y c o m pl eti o n re vie w 
wit h s u bject  
1 2.  S u per vise d br us hi n g at site  
1 3.  Rec or d A d verse e v e nts & I nci d e nts ( Secti o n 1 0 ) 
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 m e nte d i n 
t he C R F.  
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 bj ects t o res p o n d t o a 
n o n -lea di n g q uesti o n s u c h as “ H o w d o y o u feel? ” will be assess e d a n d a n y A Es rec or de d i n t he 
C R F.  
8. 2. 3  
Vi sit 5 (D a y 8 4 ± 4  d a y )  
T he f oll o wi n g pr oce d ures/ assess me nts will ta ke place i n t he or der liste d bel o w a n d be rec or de d 
i n t he C R F: 
1.  C ollect st u d y de ntifric e, t o ot h br us h, diar y & ti mer (all st u d y s u p plies) fr o m s u bject  
2.  Re vie w of c o nc o mita nt me dicati o ns a n d n o n -dr u g treat me nts/ pr oce d ures, a d v erse 
e ve nts, i nci de nts a n d lifest yl e restricti o ns  
o  C o nc o mita nt me dicati o ns  / treat me nts (Secti o n 6. 8 ) 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 1  of 7 0  
3.  C o m plia nce c hec ks i n cl u di n g diar y re vie w  
4.  S u bject c o nti n ua nce  
5.  O S T e x a mi nati o n ( Secti o n 9. 3. 1 ) 
6.  O H T e x a mi nati o n ( Secti o n 9. 3. 2 ) 
7.  M GI assess me nt ( & re peata bilit y assess me nt, w here a p plica bl e) ( Secti o n 9 . 2. 1) 
8.  BI ass ess me nt ( Secti o n 9. 2. 2 ) 
9.  Pla q ue discl os ure ( Secti o n 9. 2. 3 ) 
1 0.  T PI ass ess me nt ( & re p eata bilit y assess me nt, w here a p plica ble) ( Secti o n 9. 2. 4 ) 
1 1.  C o m plete o pti o nal de ntal pr o p h yla xis (as/ if dee m e d necessar y b y e x a mi ner)  
1 2.  Rec or d A d verse e v e nts & I nci d e nts ( Secti o n 1 0 ) 
1 3.  St u d y c o ncl usi o n ( Secti o n 8. 4 ) 
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 m e nte d i n 
t he C R F.  
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 bj ects t o res p o n d t o a 
n o n -lea di n g q uesti o n s u c h as “ H o w d o y o u feel? ” will be assess e d a n d a n y A Es rec or de d i n t he 
C R F.  
8. 3  
Di ar y R e vi e w  
T he diar y s h o ul d b e re vi e we d at e ver y visit b y t h e i n vesti gat or, or s uita bl y q ualifie d desi g nee, 
a n d t he s u bject. A n y s u bject c o m me nt ca pt ur e d i n t he diar y w hi c h is c o nsi dere d a n a d v erse 
e ve nt will be assesse d a n d re p orte d as per t he defi ne d pr oce d ure i n t his pr ot oc ol. A d verse e ve nt 
re p orti n g pr oce d ures are s u m marize d i n A d verse E ve nt a n d Seri o us A d verse E ve nts .  
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 pr o d uct a p plicati o ns will be c o nsi dere d d e 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.  
8. 4  
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 all s u bjects w het her t he y 
c o m plete d all st u d y pr oce d ures or if t he y were disc o nti n ue d fr o m t he st u d y earl y.  If t he s u bject 
disc o nti n ue d earl y, at a n y p oi nt d uri n g t he st u d y, t he pri mar y  reas o n f 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 H ale o n  me dical  m o nit or ( or desi g nate d re pres e ntati ve) s h o ul d be n otifie d a n d, t h e 
s u bject ma y be as ke d t o re mai n at t he cli nical site or be as k e d t o ret ur n f or a f oll o w -u p visit t o 
e ns ure a n y iss ue is r es ol v e d or dee m e d n ot cli nicall y si g nifica nt.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 2  of 7 0  
8. 5  
F oll o w -u p Vi sit / P h o n e C all 
T he st u d y site ma y c o nta ct a s u bject t o f oll o w u p a n A E  p ost -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 e x a mi nati o ns ma y be carri e 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 cir c u msta nces, 
o utsi de t he c o ntr ol of t he i n vesti gat or t hat ma y m a ke it u nfeasi ble t o c o m plete a n assess me nt.  
I n t hes e cas es, t he i n vesti gat or m ust ta ke all ste ps necessar y t o e ns ure t h e safet y a n d well-bei n g 
of t he s u bject.  W he n a pr ot oc ol -re q uir e d assess me nt ca n n ot be p erf or me d, t he i n vesti gat or ( or 
desi g nee) will d oc u me nt t he reas o n f or t he miss e d assess me nt as a pr ot oc ol de viati o n a n d a n y 
c orrecti ve a n d pre v e ntati ve acti o ns t hat he or s he has ta ke n t o e ns ure t hat re q uire d pr ocesses are 
a d here d t o as s o o n as p ossi ble.  T he S p o ns or m ust be i nf or me d of a n y misse d assess me nts i n a 
ti mel y ma n ner. 
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 n e d staff/ cli nical e x a mi ners at 
t he ti mes, a n d i n t he or der, defi ne d i n t he St u d y Pr oce d ures  s ecti o n of t his pr ot oc ol. A si n gle 
e x a mi ner w ill be res p o nsi ble f or t he c o n d u ct of t he cli nical meas ures of gi n gi vitis/ pla q ue 
acc u m ulati o n f or t h e d urati o n of t he st u d y.  
Eli gi ble t o ot h assess me nts will be acc o m plis he d b y oral e x a mi nati o n a n d will e val uate de ntiti o n 
e x cl usi o ns al o n g wit h a gr oss gi n gi val assess me nt i n relati o n t o t he ge neral de ntiti o n i ncl usi o n/ 
e x cl usi o n criteria.  
Assess me nts will be carri e d o ut b y t he i n vesti gat or, or q ualifie d desi g nee, a gai nst t he i ncl usi o n/ 
e x cl usi o n criteria. I neli gi ble s u bjects will n ot be re -scree ne d.   
Fi n d i n gs fr o m t hese e x a mi nati o ns will be use d t o deter mi ne s u bject eli gi bilit y. 
9. 1. 1  
Gr o s s A s s e s s m e nt of Gi n gi v al H e alt h  
Vis ual assess me nt of gi n gi val healt h will be perf or me d t o rec or d t he prese nce/a bse n ce of 
pla q ue -i n d uce d gi n gi vitis as per t he i ncl usi o n criteria d uri n g Scree ni n g visit ( Visit 1).   
9. 1. 2  
P o c k et D e pt h M e a s ur e m e nt  
P oc ket de pt h assess me nt will be perf or me d d uri n g S cree ni n g visit. Mic hi ga n “ O” pr o be wit h 
Willia ms Mar ki n gs w ill be use d as a "se nsi n g" i nstr u me nt t o deter mi ne p oc ket de pt h. T he pr o be 
ti p will be i nserte d ge ntl y i nt o t he gi n gi val s ulc us or p oc ket a n d t he t otal e xte nt of t he s ulc us or 
p oc ket will be assess e d.  
9. 2  
E ffi c a cy A s s e s s m e nt s  
T he f oll o wi n g assess me nts will be perf or me d b y a p pr o priatel y tr ai ne d staff/ cli nical e x a mi ners, 
at t he ti mes a n d i n t he or der defi n e d i n t he St u d y Pr oce d ures  s ecti o n of t his pr ot oc ol. 
If i n t he o pi ni o n of t he e x a mi ner a s u bject is bet wee n defi ne d  gra des/sc ores , a c o nser vati v e 
a p pr oac h s h o ul d be use d  t o pr o vi de t he fi nal sc ore.  T he sa me a p pr oac h s h o ul d be a p plie d 
t hr o u g h o ut t he st u d y t o e ns ure c o nsiste nc y i n t he gra di n g of t he sc ores at all ti me p oi nts.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 3  of 7 0  
T he sa me e x a mi ner will be use d t hr o u g h o ut t he st u d y f or eac h cli nical i n de x t o eli mi nate t he 
p ossi bilit y of i nter -e x a mi ner vari a bilit y.  
At Baseli ne visit, s u bjects wit h blee di n g sites % ( deri ve d fr o m BI ass ess me nt) or T PI sc ore 
o utsi de t he i nc l usi o n criteria ra n ge will be disc o nti n ue d fr o m t he st u d y.  
9. 2. 1  
M GI A s s e s s m e nt ( L o b e n e et al, 1 9 8 6 ) 
T he M GI assess me nt is a n o n -i n vasi ve e val u ati o n w hic h f oc uses o n t he vis ual s y m pt o ms of 
gi n gi vitis (f or e x a m ple, re d ness, te xt ure, e de ma). T he M GI will be assesse d o n t he facial a n d 
li n g ual s urfaces of eac h sc ora ble t o ot h (sec o n d per ma ne nt m olar t o sec o n d per ma ne nt m olar i n 
eac h arc h) b y a n a p pr o priatel y q ualifie d e x a mi ner. 
T w o sc ores 
will be rec or de d 
b uccall y/la biall y ( pa pilla a n d mar gi n) a n d t w o sc ores li n g uall y/ palat all y ( pa pilla a n d mar gi n). 
T he sc ori n g of t he M GI will be perf or m e d u n der de ntal office c o n diti o ns usi n g a sta n dar d de ntal 
li g ht f or ill u mi nati n g t he oral ca vit y.  
T he M GI sc ori n g s yste m will be as f oll o ws:  
T a bl e 9 -1 M o difi e d Gi n gi v al I n d e x S c ori n g S y st e m  
Sc ore Des cri pti o n  
0  
A bse nce of i nfla m mati o n  
1  
Mil d i nfla m mati o n; sli g ht c ha n ge i n c ol o ur, little c ha n ge i n c ol o ur; little c ha n ge i n 
te xt ure of a n y p orti o n of t he mar gi nal or pa pillar y gi n gi val u nit 
2  
Mil d i nfla m mati o n; criteria as a b o v e b ut i n v ol vi n g t he e ntire mar gi nal or pa pillar y 
gi n gi val u nit  
3  
M o derate i nfla m mati o n; glazi n g, re d ness, e de ma, a n d/ or h y p ertr o p h y of t he mar gi nal 
or pa pillar y gi n gi val u nit  
4  
Se vere i nfla m mati o n; mar ke d re d ness, e de m a a n d / or h y pertr o p h y of t he mar gi nal or 
pa pillar y gi n gi val u nit, s p o nta ne o us blee di n g, c o n gesti o n, or ulcerati o n.  
T he M GI will be assesse d b y t he s a me e x a mi ner o n all e val ua ble t eet h fr o m Baseli ne o n war ds 
as i n dicate d i n t he Sc he d ule of Acti vities.  
9. 2. 2  
BI A s s e s s m e nt ( S a xt o n a n d v a n d er O u d er a a, 1 9 8 9 ) 
T he BI assesses t he n u m ber of blee di n g p oi nts elicite d o n pr o bi n g as a m eas ure of gi n gi v al 
c o n diti o n. T he gi n gi va e will be air drie d a n d t he n t he e x a mi ner will use P C P 1 1. 5 B H u -Frie d y 
Q uli x C ol or C o de d pr o be  t o assess blee di n g.  T he pr o be will b e ge ntl y i ns erte d i nt o t he gi n gi val 
cre vic e t o a de pt h of a p pr o xi matel y 1 milli meter ( m m) a n d t he n r u n ar o u n d t he t o ot h (at a n gle 
of ~ 6 0º t o t he l o n g a xis of t he t o ot h), ge ntl y str etc hi n g t he e p it heli u m w hile s wee pi n g fr o m 
i nter pr o xi mal t o i nter pr o xi mal al o n g t he s ulc ular e pit heli u m. Mi ni m u m f orce s h o ul d be use d t o 
a v oi d da ma ge t o t he gi n gi val tiss ue. T he BI will be assesse d o n t h e facial a n d li n g ual gi n gi val 
s urfaces of eac h sc ora ble t o ot h (sec on d m olar t o s ec o n d m olar ). T hree sc ores (acc or di n g t o t he 
scale b el o w) s h o ul d b e rec or de d b uccall y/la bi all y ( distal, b o d y, mesial sites) a n d t hr ee s c ores 
li n g uall y/ p alatall y. All s c ora ble t eet h i n o ne q u a dra nt s h o ul d be pr o be d first (a p pr o xi matel y 3 0 
sec o nds) bef ore rec or di n g t he n u m ber of gi n gi val u nits w hic h blee d.  
T he BI s c ori n g s yste m will be as f oll o ws:  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 4  of 7 0  
T a bl e 9 -2 Bl e e di n g I n d e x s c ori n g s y st e m  
Sc ore Des cri pti o n  
0  
N o blee di n g after 3 0 sec o n ds  
1  
Blee di n g o bser ve d wit hi n 3 0 sec o n ds of pr o bi n g  
2  
Blee di n g o bser ve d i m me diatel y o n pr o bi n g  
T he BI will be ass esse d b y t he s a me e x a mi ner o n all e val ua ble teet h fr o m Baseli ne o n war ds as 
i n dicate d i n t he Sc he d ule of Acti vities.  
T he n u m ber of blee di n g sites f or eac h s u bject at eac h visit is calc ulat e d as t he  n u m ber of 
e val ua ble t o ot h sites wit h a BI s c ore of eit her 1 or 2 . 
Blee di n g site s % = the n u m ber of blee di n g sites / t otal sites e x a mi ne d 
Re pe at a bilit y e xercise will n ot be perf or me d f or BI.  
9. 2. 3  
Pl a q u e Di s cl o s ur e  
De ntal pla q ue is c ol orless a n d s o is us uall y di s cl ose d (‘stai ne d’) pri or t o assess me nt. T he 
discl osi n g s ol uti o n will be use d acc or di n g t o t he ma n ufact ur er’s i nstr ucti o ns.  
•  At t he re q uest of t he s u bject, t he cli nicia n ma y a p pl y a t hi n la yer of p etr ole u m jell y t o 
t he s u bject’s li ps, as a barrier t o hel p mi ni mize stai ni n g b y t he discl osi n g s ol uti o n. Care 
s h o ul d be ta ke n t o e ns ure n o petr ole u m jell y c o m es i nt o c o ntact wit h t he la bial s urfaces 
of t he a nteri or t eet h as t his c o ul d i m pact cli nical assess me nts i n t his re gi o n.  
•  T he s u bject will ri nse t heir m o ut h w it h 1 0 m L ta p water f or 1 0 sec o n ds t o re m o ve a n y 
f o o d de bris a n d e x pect orate. 
•  T he cli nicia n will t he n a p pl y t he pla q ue discl osi n g s ol uti o n as per t he la bel i nstr ucti o ns. 
Care will be ta ke n n ot t o disl o d ge t he pla q ue d uri n g t his pr ocess. T he s u bject will t h e n 
ri nse wit h 1 0 m L ta p wat er f or 1 0 s ec o n ds a n d e x pect orate t o re m o ve e x cess s ol uti o n. 
Pla q ue ma y b e re discl os e d bet w ee n t he T PI a n d re p eat assess me nts at t he discreti o n of t h e 
cli nical e x a mi ner.  
9. 2. 4  
T PI A s s e s s m e nt ( L o b e n e et  al, 1 9 8 2 ) 
T he T ures k y M o dificati o n of t he Q ui gle y Hei n Pla q ue I n de x ( L o be ne et al, 1 9 8 2 ) will be use d 
t o assess pla q ue o n all gra da ble t eet h meeti n g t he i ncl usi o n/ e x cl usi o n criteria, a n d will be 
perf or me d b y a n a p pr o priatel y q u alifie d e x a mi ner. O nl y nat ur al teet h ca n be assesse d. T his 
mea ns n o cr o w ns, bri d ges, a n d teet h wit h filli n gs (s urface t hat has 5 0 % of t he s urface gra da bl e 
or n o m ore t ha n 5 0 % of t he s urface fille d) w hic h, i n t he e x a mi ner’s j u d g m e nt, w o ul d pre ve nt 
a n ac c urate gra di n g s h o ul d be assesse d. T hir d m ol ars s h o ul d n ot be assesse d.  
T he pla q ue will first be discl ose d usi n g a pl a q ue discl osi n g d ye s ol uti o n, i n a gree m e nt wit h t he 
ma n ufact ur er’s i nstr ucti o ns. T he T PI will be assesse d o n t he facial a n d li n g ual s urfac es of eac h 
sc ora ble t o ot h (s ec o n d m olar t o sec o n d m olar). T hree sc ores s h o ul d be rec or de d b u ccall y/ 
la biall y ( distal, b o d y, mesial sites) a n d t hree sc ores li n g uall y / palat all y ( distal, b o d y, mesial 
sites). 
 Discl ose d pla q ue will be sc ore d as f oll o ws:  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 5  of 7 0  
T a bl e 9 -3 T ur e s k y Pl a q u e I n d e x S c ori n g S y st e m  
Sc ore Des cri pti o n  
0  
N o pla q ue  
1  
Se parate flec ks of pl a q ue at t he cer vi cal mar gi n  
2  
T hi n c o nti n u o us ba n d of pla q ue ( u p t o 1 m m) at t h e cer vi cal mar gi n  
3  
 Ba n d of pl a q ue wi der t ha n 1 m m b ut c o veri n g < 1/ 3 of  t he t o ot h s urface 
4  
Pla q ue c o veri n g ≥ 1/ 3 b ut < 2/ 3 of t he t o ot h s urface  
5  
Pla q ue c o veri n g ≥ 2/ 3 of t he t o ot h s urface  
T he T PI will be assess e d b y t he s a me e x a mi ner o n all e val ua ble teet h fr o m Baseli ne o n war ds 
as i n dicate d i n t he Sc he d ule of Acti vities.  
9. 2. 5  
R e p e at a bilit y A s s e s s m e nt s  
T he cli nical e x a mi ner selecte d f or t his st u d y will ha ve d e m o nstrate d t heir a bilit y t o re plicate 
t heir o w n sc ores (i ntra-e x a mi ner re peata bilit y/reli a bilit y) o n a t o ot h site -b y -t o ot h site basis i n 
pre vi o us st u dies a n d/ or cali brati o n  e x ercises. Re peat 
M GI a n d T PI assess me nts will be 
perf or me d b y t he cli nical e x a mi ner at Visits 2 - 5. At least 1 re peat assess me nt s h o ul d be 
perf or me d f or eac h i n d e x o n eac h cli nical ass ess me nt da y, t h at is, at least o n e M GI a n d o n e T PI 
re peat assess me nt o n eac h assess me nt da y. ‘ Re peat’ s u bjects will be selecte d at ra n d o m fr o m 
t h ose i n atte n da n ce. Differe nt s u bjects ca n be us e d f or re p eat M GI a n d T PI assess me nts. At 
Baseli ne visit, M GI a n d T PI re peata bilit y will be o nl y assesse d o n s u bjects wit h c o nfir me d 
st u d y eli gi bilit y.  
T here s h o ul d be a dela y of at least 1 0 mi n utes bet wee n ori gi nal a n d re p eat assess me nts f or a 
gi ve n s u bject a n d i de all y se parat e d b y a n ot her s u bj ect. N o ot her pr oce d ure o n t he s u bject s h o ul d 
be carrie d o ut bet w ee n t h e first a n d t he re pea t assess me nt. W here p ossi ble, t he cli nical e x a mi ner 
s h o ul d assess a differe nt s u bject i n t he i nter ve ni n g peri o d.  
Sc ores fr o m t he first ass ess me nt m ust n ot be visi ble t o t he e x a mi ner/scri be w he n t he re p eat 
assess me nt is carrie d o ut.  
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 x a mi ners, at t he ti mes a n d i n t he or der defi ne d i n t he St u d y Pr oce d ures  secti o n of t his pr ot oc ol.   
9. 3. 1  
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 x a mi ner.  T he O S T 
e x a mi nati o n will be acc o m plis he d b y direct o bser vati o n a n d pal pati o n wit h retracti o n ai ds, as 
a p pr o priate. T he e x a 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 u bli n g ual area, s u b ma n di b ular area a n d sali var y gla n ds.  Fi n di n gs fr o m t he 
e x a mi nati o n will be rec or de d i n t he C R F as eit her n or mal or a b n or mal, wit h details of a n y 
a b n or malities. T he res ults of t he O S T e x a 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 gi bilit y. A n y n e w O S T a b n or malit y or w orse ni n g of a pre -e xisti n g 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 6  of 7 0  
c o n diti o n o bser ve d b y t he cli nical e x a mi ner or re p orte d b y t h e s u bject after t he scree ni n g 
e x a 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  
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 nce d cli nica l e x a mi ner.  T he O H T 
e x a mi nati o n will be acc o m plis he d b y dir ect o bs er 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 deca 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 x e d or re m o va ble de nt ures, fi x e d or re m o va ble ort h o d o ntic 
braces/ b a n ds, fi x e d ort h o d o ntic retai ners, f ull cr o w ns or ve neers will be rec or de d. O bser vati o ns 
will be liste d as eit h er 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 x a mi ner or re p orte d b y t he s u bject after t he 
scree ni n g e x a 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 x a mi nati o n perf or me 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.  
9. 3. 3  
Pr e g n a n c y T e sti n g  
F or t his st u d y, t he i n di vi d ual pr o d ucts bei n g teste d are n ot c o ntr a -i n dicat e d f or pre g n a nc y or 
i nte n de d t o be c o ntr a-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 
har m eit her t o t he m ot her or fet us.  A pre g n a nc y t est is t heref ore n ot re q uire d.  H o we ver, 
s u bjects of c hil d-beari n g p ote ntial will be as ke d t o pr o vi de ver bal c o nfir m ati 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 n a 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 na n c y, t he s u bject will be 
wit h dra w n fr o m t he st u d y.  
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 he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
re p orti n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g 
u p A Es t hat are s eri o us, c o nsi dere d relate d t o t he st u d y pr o d uct  or t he st u d y, or t hat ca use d t he 
s u bject t o disc o nti n ue t he st u d y pr o d uct or st u d y. 
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 oci ate d 
wit h t he use of a st u d y pr o d uct i ncl u di n g a n y 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 x acer bate d) te m p orall y ass ociate d wit h t he 
use of a st u d y pr o d uct i n cl u di n g a n y was h o ut or l ea d -i n pr o d u ct ( or me dical de vice). 
E ve nts Meeti n g  t he A E Defi niti o n:   
•  A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or 
ot her safet y assess me nts (e. g. , E C G, ra di ol o gical sca ns, vital si g n meas ure me nts), 
i ncl u di n g t h ose t hat w ors e n fr o m baseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he 
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C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 7  of 7 0  
me dical a n d scie ntific j u d g me nt of t he i n v esti gat or (i.e., n ot relat e d t o pr o gressi o n of 
u n derl yi n g dise ase).  
•  E x acer bati o n of a c hr o ni c or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n 
i ncreas e i n fre q u e nc y a n d/ or i nte nsit y of t he c o n diti o n. 
•  Ne w c o n diti o ns detect e d or di a g n os e 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 v e bee n prese nt bef ore t h e start of t he st u d y. 
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose  of eit her st u d y 
pr o d uct or a c o nc o mita nt me dicati o n. O ver d ose per se will n ot be re p ort e d as a n 
A E/ S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble s uici dal/self -har mi n g 
i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of se q uelae. 
•  " Lac k of effic ac y" or "fail ure of e x pecte d p har mac ol o gical acti o n" p er se will n ot be 
re p orte d as a n A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y ass ess me nts. 
H o we ver, t he si g ns, s y m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of 
effic ac y will be re p orte d as A E if t he y f ulfill t he d efi niti o n of a n A E.  
E ve nts N O T  meeti n g t he A E defi niti o n:  
•  A n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs (if a p plica ble) or ot her a b n or mal 
safet y assess me nts w hic h are ass ociat e d wit h t he u n derl yi n g diseas e, u nl ess j u d ge d b y 
t he i n vesti gat or t o b e m ore se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n.  
•  T he diseas e/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease/ dis or der b ei n g st u die d, u nless m ore se v ere t ha n e x pecte d f or t he s u bject’s 
c o n diti o n.  
•  Me dical or s ur gic al pr oce d ure (e. g. , e n d os c o p y, a p pe n d ect o m y) is n ot t he A E . T he 
c o n diti o n t hat lea ds t o t he pr oce d ure is a n A E (e. g. , a p pe n dicitis).  
•  Sit uati o ns w here a n u nt o war d 
me dical occ urre nce di d n ot o cc ur (s ocial a n d/ or 
c o n ve nie nce a d missi o n t o a h os pital).  
•  A ntici pate d da y -t o-da y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) pres e nt or 
detecte d at t he start of t h e st u d y t hat d o n ot w ors e n.  
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 w ar d me dical occ urre nce a t a n y d ose t h at: 
•  Res ults i n de at h  
•  Is lif e-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 t he 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   
▪ I n ge 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 v er ni g ht sta y) at t he h ospital or e mer ge nc y war d f or 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 8  of 7 0  
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 office or o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g 
h os pitaliz ati 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 pitaliz ati o n” occ urre d, or was necessar y, t he A E s h o ul d be c o nsi dere d 
seri o us. 
▪ H os pitalizati o n f or electi 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 ase li ne is n ot c o nsi dere d a n A E. 
•  Res ults i n persiste nt or si g nific a nt dis a bilit y/i nc a p acit y  
▪ T he ter m disa bilit y me a ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct 
n or mal 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 re lati vel y mi n or me dical 
si g nifica n ce s uc h as u nc o m plicate d hea dac he, 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 x ercise 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 hreateni n g or res ult i n deat h or h os pitalizati o n b ut 
ma y je o p ar dize t he s u bject or ma y re q uir e me dical or s ur gi cal 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 d ere d seri o us. 
▪ E x a m ples of s u c h e ve 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 n c h os pas m, bl o o d 
d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or de vel o p me nt of 
dr u g d e pe n de nc y or dr u g a b use.  
N ote:  Cl assificati 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 aft er a s u bject pr o vi des c o nse nt 
t o partici pate i n t h e st u d y b y t h e c o m pleti o n (si g nat ure) of t he I C F a n d u ntil 5  da ys f oll o wi n g 
last a d mi nistrati o n of t he st u d y pr o d uct ( or last pr oce 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 diatel y a n d u n der n o 
circ u msta nce s h o ul d t his e x cee d 2 4 h o urs. T he i n v esti gat or will s u b mit a n y u p date d S A E data 
t o t he s p o ns or wit hi n 2 4 h o urs of it b ei n g a vaila bl e . 
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k A Es or S A Es after t he c o ncl usi o n of t he st u d y 
partici pati o n . H o we ver, if t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h, at an y ti me 
after a s u bject has bee n disc har ge d fr o m t he st u d y,  a n d he/s he c o nsi ders t he e ve nt t o be 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 4 9  of 7 0  
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 m e nti n g a n d re p orti n g 
e ve nts t hat meet t he defi niti o n of a n A E a n d re mai n res p o nsi ble f or f oll o wi n g u p o n A Es t hat 
are seri o us, c o nsi dere d relate d t o t he st u d y pr o d uct(s), 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 bj ect will b e 
q uesti o ne d a b o ut A Es.   
Eac h A E is t o be assesse d t o deter mi ne if it m eets t he criteria f or a S A E.  If a n S A E occ urs, 
e x pe dite d re p orti n g will f oll o w l ocal a n d i nter nati o nal re g ulati o ns, as a p pr o priate.  
W he n a n A E 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 n ee) 
t o re vie w all d oc u me ntatio n (e. g. , h os pital pr o gress n otes, la b orat or y, a n d dia g n ostics re p orts) 
relate d t o t he e v e nt. 
T he i n vesti gat or or site staff will t he n rec or d all rele va nt i nf or m ati o n re gar di n g a n A E i n t he 
C R F a n d all details relati n g t o a n S A E i n t he pa p er S A E F or m pr o vi de d.  
It is n ot  acce pta ble f or t he i n vesti gat or ( or m e dicall y q ualifi e d desi g nee) t o se n d p h ot oc o pies 
of t he s u bject’s me dical rec or ds t o 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 cer tai 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 h e A E/ S A E were k n o w n a n d n ot t he i n di vi d ual si g ns/s y m pt o ms. (e. g. , u p per 
res pirat or y tr act i nfecti o n, seas o nal aller g y, etc. i nstea d of r u n n y n ose).  
A Es elicite d b y t h e i n vesti gat or ( or me dicall y q ualifie d desi g nee) i n a sta n dar d ma n ner at t he 
st u d y visits s h o ul d als o be rec or de d i n t he A E 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 ges i n t heir healt h. O pe n -e n d e d a n d n o n -lea di n g v er bal 
q uesti o ni n g s h o ul d be us e d.  
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 staff.  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 here 
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 x a m ple, t he sa me A E ter m s h o ul d be use 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 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 0  of 7 0  
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 AE 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.  PI will be r es p o nsi ble f or n otif yi n g t he I R B/I E C of S A Es t hat occ ur d uri n g t he 
st u d y.  
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 bl e  
•  I n v esti gat or o pi ni o n of relati o ns hi p t o st u d y pr o d uct ( or st u d y pr oce d ure, if a p pr o priate)  
•  Criteri o n f or seri o us ness.  
T he f oll o wi n g are desir a ble a n d are of partic ular rele va n ce f or i n vesti gat or a n d Hale o n  
assess me nt of t he S A E re p ort:  
•  Date of o nset of A E  
•  Date A E st o p pe d, if rele v a nt 
•  St u d y pr o d uct start dat e  
•  St u d y pr o d uct e n d d ate if rele va nt  
•  Acti o n ta ke n i n relati o n t o t he st u d y pr o d u ct  
•  O utc o me if k n o w n  
T he S A E f or m, c o m plete d as f ull y as p ossi ble, m ust be sca n ne d a n d e -maile d t o t he Case 
Ma na ge me nt Gr o u p  mail b o x 
, wit h c o p y t o t he a p pr o priate 
St u d y M a na ger , wit h t he st u d y n u m ber a n d s u bject n u m ber i n t he s u bject li ne of t he e mail 
i m me di atel y a n d u n der n o circ u mst a nce s h o ul d t his e xcee d 2 4 h o urs after st u d y site 
pers o n nel l ear n of t he e v e nt. T he i n vesti gat or will s u b mit a n y u p d ate d S A E data t o t he s p o ns or, 
i m me di atel y a n d u n der n o circ u mst a nce s h o ul d t his e xcee d 2 4 h o urs of it bei n g a v aila ble.  
T he i nitial re p ort will be f oll o we d u p wit h m ore i nf or mati o n as rele va nt, or as re q ueste d b y t h e 
st u d y ma na ger.  
T he St u d y  Ma n a ger will be res p o nsi ble f or f or war di n g t he S A E f or m t o ot h er Hale o n  p ers o n nel 
as a p pr o priat e.  
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 n t of I nt e n sit y 
T he i n vesti gat or or me dicall y q u alifie d desi g nee will ma ke a n assess me nt of i nte nsit y f or eac h 
A E re p orte d d uri n g t he st u d y a n d will assi g n it t o o ne of t he f oll o wi n g cate g ories:  
•  Mil d:  A n e ve nt t hat is easil y t olerat e d b y t he s u bject, ca usi n g mi ni mal disc o mf ort a n d 
n ot i nterferi n g wit h e ver y d a y acti vities.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI
P P D


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 1  of 7 0  
•  M o derate:  A n e ve nt t hat is s ufficie ntl y disc o mf orti n g t o i nterfere wit h n or m al e ver y da y 
acti vities  
•  Se vere:  A n e ve nt t hat pr e ve nts n or mal e ver y da y acti vities.  
N O T E: A n A E t hat is assesse d as se vere s h o ul d n ot be c o nf use d wit h a n S A E. Se vere is a 
cate g or y utilize d f or rati n g t he i nte nsit y of a n e v e nt; a n d b ot h n o n -seri o us A Es a n d S A Es ca n 
be assesse d as se vere. F or e x a m ple, a hea d ac he m a y b e se v ere (i nterferes si g nifica ntl y wit h t he 
s u bject's us u al f u ncti o n) b ut w o ul d n ot be classifi e d as seri o us u nless it met o ne of t he criteria 
f or S A Es, liste d a b o ve. A n e ve nt is defi ne d as ‘seri o us’ w he n it meets at least 1 of t he pre defi ne d 
o utc o mes as descri be d i n t he defi niti o n of a n S A E, N O T w he n it is rate d as se vere. 
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 ass ess me nt is o ne of t he criteria use d w he n d eter mi ni n g re g ul at or y re p orti n g 
re q uire me nts.  
F or eac h A E (seri o us a n d n o n -seri o us), t he i n vesti gat or ( or me di call y q ualifie d desi g n ee) m ust  
pr o vi de a n assess me nt of ca usalit y o n t he A E 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 otes t hat he/s he 
has re vie we d t he A E a n d assesse d ca usalit y, w here a p plica ble.  
A “reas o na ble p ossi bi lit 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 Pr o d uct I nf or m ati o n  f or mar kete d pr o d ucts, i n t he deter mi nati o n of his/ her assess me nt.  
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, ot her ris k fact ors, a n d 
t he te m p oral relati o ns hi p of t he e ve nt t o t he st u d y pr o d uct will be c o nsi dere d a n d i n vesti gat e d. 
F or eac h A E/ S A E, t h e i n vesti gat or m ust d oc u me nt i n t he me di cal n otes t hat he/s he has re vie we d 
t he A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y. 
T he i n vesti gat or’s assess me nt of ca usalit y m ust be pr o vi d e d f or all A Es (seri o us a n d n o n -
seri o us); t he i n vesti gat or m ust rec or d t he ca usal relati o ns hi p i n t he 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 h as mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o Hale o n .  H o w e ver, it is ver y i m p ort a nt t h at t he 
i n vesti g at or al w a ys m a ke a n assessme nt of c a us alit y f or e ver y e ve nt pri or t o t he i niti al 
tr a ns missi o n of t he S A E d at a t o Hale o n . T h e i n vesti gat or ma y c ha n ge his/ her o pi ni o n of 
ca usalit y i n li g ht of f oll o w -u p i nf or mati o n a n d se n d a n S A E f oll o w -u p re p ort wit h t he u p date d 
ca usalit y assess me nt .  
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 ge f or t he c o n d uct of  s u p ple me ntal 
meas ure me nts a n d/ or e v al uati o ns as ma y be i n dicate d or as re q uest e d b y Hale o n  t o el uci date as 
f ull y as p ossi ble t he nat ure a n d/ or ca usalit y of t h e A E. T his ma y i n cl u de a d diti o nal la b orat or y 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 2  of 7 0  
tests or i n vesti gati o ns, hist o pat h ol o gical e x a mi natio ns, or c o ns ultati o n wit h ot her healt h care 
pr ofessi o nals.  
Ne w or u p 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. 
I n v esti gat ors are n ot o bli ge d t o acti vel y see k A Es i n f or mer s u bjects.  H o we v er, if t he 
i n vesti gat or le ar ns of a S A E, i ncl u di n g d eat h, at a n y ti me after a s u bject h as bee n dis c har ge d 
fr o m t he st u d y, a n d c o nsi ders t he e vent reas o n a bl y rel ate d t o t he st u d y pr o d uct or st u d y 
partici pati o n, t he i n vesti gat or will pr o m ptl y n otif y Hale o n  b y e maili n g t h e i nf or mati o n t o t he 
Case Ma na ge me nt Gr o u p  mail b o x at Hale o n  
, wit h c o p y t o 
t he a p pr o priat e   St u d y Ma na ger . 
T he i n vesti gat or will s u b mit a n y u p d ate d S A E dat a t o Hale o n  wit hi n t he desi g nat e d re p orti n g 
ti me fra mes. 
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 gal res p o nsi bilit y t o n otif y, as a p pr o priate, t he l ocal re g ul at or y a ut h orit y a n d 
ot her re g ulat or y a ut h orities a b o ut t he safet y of a pr o d uct u n der cli nical i n vesti gati o n.  Pr o m pt 
n otificati o n of S A Es b y t he i n vesti gat or t o Hale o n  is esse ntial s o t hat le gal o bli gati o ns a n d 
et hical res p o nsi bilities t o war ds t he safet y of s u bjects are met.  
Hale o n  will  c o m pl y wit h c o u ntr y s pecific re g ulat or y re q uire me nts 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 pecte d seri o us a d verse reacti o ns 
( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire m e nts a n d s p o ns or p olic y a n d f or war de d t o 
i n vesti gat ors as n ecessar y. 
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a S A E or ot her s pecific 
safet y i nf or mati o n e. g., s u m mar y or listi n g of S A E fr o m t he s p o ns or will re vie w a n d t h e n file 
it al o n g wit h t he I n vesti gat or’s Br oc h ure i n t he i n vesti gat or st u d y master file, a n d will n otif y 
t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts. 
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 n a nc y i nf or mati o n will be c ollecte d o n all pre g na nci es re p orte d w hile  a fe male s u bject is 
partici pati n g i n t he st u d y fr o m t he si g ni n g of i nf or me d c o ns e nt u ntil 5  da ys aft er last 
a d mi nistrati o n of st u d y pr o d uct.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI
P P D


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 3  of 7 0  
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 h e 
a p pr o priate St u d y Ma na ger . Ori gi n al pre g n a nc y i nf or mati o n f or ms will be retai ne d i n t h e 
i n vesti gat or st u d y master file.  
T he s u bject will be f oll o we d t o deter mi ne t he o ut c o me of t he pre g n a nc y. I nf or mati o n o n t he 
stat us of t he m ot her a n d i nfa nt / ne o n ate (i ncl u di n g c o nc o mita nt me dicati o ns ta ke n b y t h e 
m ot her d uri n g t he pre g n a nc y) will be f or war de d b y t he i n vesti gat or t o t he C ase Ma na ge me nt 
Gr o u p mail b o x at Hale o n  
 wit h c o p y t o t he a p pr o priat e   
St u d y M a na ger . Ge nerall y, f oll o w-u p will be n o l o n ger t ha n 6 t o 8 wee ks f oll o wi n g t h e 
esti mate d deli ver y date. A n y ter mi nati o n of t he pre g n a nc y will be re p orte d.  
W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E, a b n or mal pre g na n c y o utc o m es (e. g. , 
s p o nta ne o us a b orti o n, fet al deat h, still birt h, c o n ge nital a n o malies, ect o pic pre g na nc y) are, a n d 
s h o ul d be rec or de d as a n S A E. 
A n y fe male s u bject w h o bec o mes pr e 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 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 he alt 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 h a ve bee n d u e t o ot her f ort u n ate circ u msta nces or t o t he i nter ve nti o n of healt h care 
pers o n nel.  
It is s ufficie nt t h at: 
A n i nci de nt ass ociate d wit h a de vice h a p pe ne d a n d  
•  T he i nci de nt was s uc h t 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:  
•  Lif e -t hreate ni n g ill ness 
•  Per ma ne nt i m pair me nt of b o d y f u ncti o n or per ma n e nt da ma ge t o b o d y str uct ure  
•  C o n diti o n necessitati n g me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he 
a b o ve  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI
P P D
P P D


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 4  of 7 0  
•  Fetal distress, f etal deat h, or a n y c o n ge nital a b n or malit y or birt h defects  
E x a m ples of i nci de nts:  
•  A s u bject, user, care gi ver, or healt hcare pr ofessi o nal is i nj ure d as a res ult of a me dical 
de vice fail ure or its mis use.  
•  A s u bject’s st u d y treat me nt is i nterr u pte d or c o m pr o mise d b y a me di cal de vi ce fail ure.  
•  A mis dia g n osis d ue t o m e dical de vice fail 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.  
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 R e 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 plet e d as t h or o u g hl y as p ossi ble a n d si g ne d b y t he 
i n vesti gat or bef ore tr a ns mittal t o Hale o n .  It is ver y i m p orta nt t hat t he i n vesti gat or d escri bes 
a n y c orrecti ve or re me di al acti o ns ta ke n t o pr e ve nt rec urre nce of t he i nci de nt.  
T he c o m plete d I nci d e nt 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 ge me nt 
Gr o u p  mail b o x 
, wit h c o p y t o t he a p pr o priate   St u d y 
Ma na ger , wit h  t he st u d y n u m b er a n d s u bject n u m ber i n t he s u bject li ne of t he e mail 
i m me di atel y a n d u n der n o circ u msta nce s h o ul d t his e xcee d 2 4 h o urs after st u d y site 
pers o n nel lear n of t he e ve nt. If t here is a n S A E, t he c o m plete d S A E f or m s h o ul d be se nt t o get her 
wit h t his re p ort f or m.  H o we ver, if a c o p y of t he S A E re p ort is se nt wit h t his f or m, t his d oes n ot 
re place t he pr oce d ure t o re p ort a n S A E.  T h e ori gi nal I nci de nt Re p ort F or m will be retai ne d i n 
t he i n vesti gat or st u d y master file.  
T he i nitial re p ort will be f oll o we d u p wit h m ore i nf or mati o n as rele va nt, or as re q ueste d b y t h e   
st u d y ma na ger. 
T he i n vesti gat or wil l f oll o w t he f oll o wi n g directi o ns re gar di n g t h e re p orti n g of a de vi ce fail ure 
( malf u ncti o n): 
•  N otif y H ale o n i m me diatel y ( b y f oll o wi n g t he pr o cess descri be d a b o ve). 
•  Sc he d ule t he s u bject t o ret ur n t o t he site pr o m ptl y t o ret ur n t he faile d d e vice.  
•  Rec or d a n y i nci d e nts o n t he 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 ucti o ns gi ve n 
i n t he secti o n a b o ve. 
•  F or a n y i nci d e nt/ malf u ncti o n occ urri n g wit h a me dical de vice (i ncl u di n g t h ose t hat are 
part of c o m bi nati o n pr o d ucts) s u p plie d b y Hale o n , ret ur n t he faile d de vic e t o t he s p o ns or 
as s o o n as p ossi ble, i ncl u di n g d oc u me nt ati o n of t he details of t he fail ure .  
•  F or a n y i nci d e nt /malf u ncti o n  occ urri n g wit h a me dical de vice  (i ncl u di n g t h ose t hat are 
part of c o m bi nati o n pr o d ucts)  s u p plie d b y t he I n vesti gat or site, re p ort t he i n ci de nt t o t he 
de vice ma n ufact ur er  a n d f oll o w t he ma n ufact urer i nstr ucti o ns f or t he ret ur n of t he faile d 
de vice  ( w hilst ke e pi n g H ale o n  i nf or me d). 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI
P P D


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 5  of 7 0  
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 de s a n y s u p ple me nt al 
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 n ci de nt. 
Ne w or u p date d i nf or mati o n will be rec or de d o n t h e ori gi nall y c o m plete d I n ci de nt Re p ort f or m 
wit h all c ha n ges si g ne d a n d date d b y t he i n vesti gat or.  
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 h e defi niti o ns of i nci de nt or malf u ncti o n t hat 
occ ur d uri n g all peri o ds of t he st u d y i n w hic h t h e me dical de vice is us e d.  
T he i n vesti gat or will pr o m ptl y re p ort all i nci de nts occ urri n g wit h a n y me di cal de vice pr o vi de d 
f or use i n t he st u d y i n or der f or t h e s p o ns or t o f ulfill t he le gal res p o nsi bilit y t o n otif y a p pr o priate 
re g ulat or y a ut h orities a n d ot her e ntities a b o ut certai n safet y i nf or mati o n relati n g t o me dical 
de vices bei n g use d i n cli nical st u dies.  
T he i n vesti gat or, or res p o nsi ble pers o n acc or di n g t o l ocal re q uire me nts (e. g. , t he hea d of t h e 
me dical i nstit uti o n), will c o m pl y wit h t he a p plica 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 o r b ot h, de pe n di n g o n t h e d ata c ollecti o n met h o d.  
F or t his st u d y, s u bject data will be e ntere d i nt o a n electr o nic C R F (e C R F), usi n g a v ali date d 
s yste m. Dat a relati n g t o S A Es, pre g na nc y a n d i nci de nts will als o be c ollecte d o n pa per f or ms . 
T he i n vesti gat or i s 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 n etic 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 dat a rec or de d i n t he C R F s h o ul d  be s pecifie d .  T h e C R F  a n d or diar y ca n 
be use d as a s o urce d o c u me nt at t he discreti o n of data ma na ge me nt.  
Eac h s u bject will be assi g ne d a n d i d e nti fie 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 
i nf or mati o n t o be re p ort e d t o t he s p o ns or o n eac h trial s u bject. 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 6  of 7 0  
F or eac h s u bject w h o h as gi ve n i nf or me d c o nse nt/asse nt t he C R F m ust b e c o m plete d a n d si g ne d 
b y t he Pri nci pal I n v esti gat or ( or a ut h orize d desi g nee) t o certif y t hat t he data are  c o m plete a n d 
c orrect.  T he i n v esti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce dat a) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e C R F. 
Ma na ge me nt of cli nical data will be perf or me d i n acc or da n ce wit h T hir d Part y Bi ostatistics a n d 
Data M a na ge m e nt  (B D M ) Ve n d or a p plica ble sta n dar ds a n d d ata clea ni n g pr oce d ures wit h 
o versi g ht b y H ale 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 n a me 
or i nitials or f ull birt h date) is t o be rec or de d i n t he C R F or as part of t h e q u er y te xt.  
All C R F pa ges s h o ul d be c o m plete d d uri n g a s u bject assess me nt w he n t he C R F h as b ee n 
desi g nat e d as t he s o urce.  Data t hat is s o urce d else w here s h o ul d be e ntere d i nt o t he C R F i n a n 
a gree d u p o n ti mefra me b et wee n t he I n vesti gat or a n d S p o ns or.   
Hale o n  will o btai n a n d retai n all C R Fs a n d ass ociate d st u d y data as a p plica bl e at t he c o m pleti o n 
of t he st u d y.  
1 1. 2  
D at a H a n dli n g  
D oc u me ntati o n of all d ata ma na ge m e nt acti vities s h o ul d all o w ste p -b y -ste p retr os p ecti ve 
assess me nt of data q u alit y a n d st u d y p erf or m a nce.  
A n y c h a n ges or c orrecti o ns t o data will be perf or me d i n t he Electr o nic Data Ca pt ure ( E D C) 
S yste m, a n d it will i ncl u d e rati o nale f or c ha n ges. T he E D C s yste m has a n a u dit trail, w hic h will 
pr o vi de a c o m plete rec or d of t he c ha n ges a n d c orrecti o ns e n d orse d b y t he I n vesti gat or.  
A d verse e v e nts will be c o de d usi n g Me di cal Di cti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
a n d a n y c o n c o mita nt me dicati o ns ter ms (if a p plica ble) usi n g a n i nter nal v ali date d me dicati o n 
dicti o nar y , W H O Dr u g .   
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 n erat e d a ut o maticall y, as t he d ata are bei n g e nt ere d i nt o t he 
s yste m. Re p orts a n d listi n gs o n t he 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 Cli nical Dicti o nar y De vel o p me nt a n d Ma n a ge me nt Gr o u p will 
raise q u eries as n ee d e d o n safet y data t o c o de t he ter ms ( A Es a n d Dr u gs or c o nc o mita nt 
me dicati o n) a p pr o priatel y.  
T he st u d y m o nit or will perf or m  o n g oi n g re vie w t he of t he C R Fs i n acc or da n ce wit h t he 
m o nit ori n g pla n, t o c o nfir m t hat data e ntere d i nt o t he C R F b y a ut h orize d site pers o n nel are 
acc urate, c o m plet e, a n d verifia ble fr o m s o urce d oc u me nts; t hat t he safet y a n d ri g hts of 
partici pa nts are bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d uct e d i n acc or da n ce wit h t he 
c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her st u d y a gree m e nts, I C H G C P, a n d all a p plica bl e 
re g ulat or y re q uire me nts. 
A n y q u eries will be ge nerate d i n t he E D C S yste m t o t he I n vesti gat or o r desi g nee, e na bli n g t he 
err ors t o be a d dress e d i n parallel wit h Data Ma n a ge m e nt re vie w. T h e st u d y m o nit or ca n als o 
r u n re p orts a n d listi n gs o n t he C R Fs, t o raise ma n ual q ueries as nee d e d f or site clarificati o n or 
c orrecti o n.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 7  of 7 0  
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 ati o n  
T he pri mar y e n d p oi nt f or t his st u d y is “ C ha n ge fr o m Baseli ne i n N B S at Wee k 1 2 f or t he test 
pr o d uct (c o ntai ni n g 0. 4 5 4 % w/ w S n F 2)”. T here were n o pre vi o us si milar st u dies w here t h e sa me 
acti ve i n gre die nt i n t he test pr o d uct was use d wit h o ut pre -pr o p h yla xis. T h us, d ue t o t he 
u ncertai nt y of w h at w o ul d be e x pecte d i n ter ms of c ha n ge fr o m bas eli ne f or t he test pr o d uct 
gi ve n t he af ore me nti o ne d para meters, treat me nt efficac y esti mates f or t he ke y s ec o n dar y 
o bjecti ve (test d e ntifric e c o m pare d t o t he refere nce de ntifrice) were use d i nstea d.   T w o s p o ns or 
cli nical st u dies t hat i ncl u de d pre - pr o p h yla xis ( Par ki ns o n et al, 2 0 1 4  a n d Hale o n St u d y 2 1 2 5 3 7 ) 
were us e d as refer e n ce t o esti mate efficac y of test de ntifrice ( 0. 4 5 %  w/ w  S n F 2) c o m pare d t o 
refere nce d e ntifrice ( ne gati ve c o ntr ol).  I n t h ese t w o st u dies, t he mea n differe nce ( S D) bet w ee n 
t he test a n d refere n ce pr o d uct re p ort e d a m ea n differe nce i n BI of 0. 0 7 bet wee n gr o u ps wit h 
sta n dar d de viati o n ra n gi n g fr o m 0. 0 4 t o 0. 1 2 8 at 1 2 wee ks. D ue t o t he u ncert ai nt y of w hat w o ul d 
be e x pecte d i n ter ms of t he ra n ge of mea n differe nces w he n s u bjects d o n ot u n der g o a pre -
pr o p h yla xis, a hi g h er S D of 0. 1 2 8 was use d t o cal c ulate t he sa m p le size f or t his st u d y. 
T he perce nt differe nces fr o m c o ntr ol i n t he refere n ce st u dies re mai ne d c o nsiste nt ( ~ 4 0 % - 6 0 % 
i n fa v or of t he test de ntifrice) i n t he st u dies me nti o ne d a b o ve, t h us a n ass u m pti o n was ma de 
t hat t hese n u m bers w o ul d n ot fall far fr o m that ra n ge i n t his st u d y.  
Base d o n  t he ass u m pti o ns o utli ne d a b o ve, a s a m ple siz e of a p pr o xi matel y 1 6 0 s u bjects 
(a p pr o xi matel y 8 0 p er gr o u p) will be ra n d o mize d t o e ns ure a p pr o xi matel y 1 4 4 e v al ua bl e 
s u bjects (a p pr o xi matel y 7 2 per gr o u p) c o m plete t he st u d y (as s u mi n g a 1 0 % dr o p o ut rate); t his 
will pr o vi de s ufficie nt p o wer ( 9 0 %) t o ac hie ve statistical si g nifica n ce (at t he 5 %, t w o -si de d 
le vel) f or t he k e y sec o n d ar y o utc o me.  
1 2. 2  
P o p ul ati o n s  for A n al y si s  
• T he Safet y p o p ulati o n will c o m prise all ra n d o mize d s u bjects w h o r ecei v e at least o ne d ose 
of t he st u d y pr o d uct. T his p o p ulati o n will be base d o n t he pr o d uct t he s u bject act u all y 
recei v e d. 
• T he m o difie d I nte nt -T o -Treat ( mI T T) p o p ulati o n will i ncl u de all ra n d o mize d s u bjects w h o 
c o m plete at least o ne use of st u d y pr o d uct a n d ha ve at least o ne p ost baseli ne cli nical 
perf or ma n ce assess me nt. T his p o p ulati o n will be base d o n t he st u d y pr o d uct t o w hic h t he 
s u bject was ra n d o mize d. A n y s u bject w h o recei ves a ra n d o mizati o n n u m ber will be 
c o nsi dere d t o ha v e bee n ra n d o mize d.  
• T he Per -P r ot o c ol ( P P) p o p ulati o n will i ncl u de all ra n d o mize d s u bjects w h o d o n ot ha ve a n y 
pr ot oc ol de viati o ns .  
• T he re p eata bilit y p o p ulati o n f or M GI is defi ne d as all s u bjects w h o h a ve at least o ne re peat 
M GI cli nical assess me nt at a n y visit.  
• T he re p eata bilit y p o p u lati o n f or T PI is defi ne d as all s u bjects w h o ha v e at l east o ne re peat 
T PI cli nic al assess me nt at a n y visit.  
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 o c u me nte d i n t he statistical 
re p orti n g a n d a n al ysis pl a n (S A P), w hic h will b e writte n f oll o wi n g fi n alizati o n of t he pr ot oc ol 
a n d pri or t o st u d y u n bli n di n g/a nal ysis (as a p pr o priate).  T his secti o n is a s u m mar y of t he pla n ne d 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 8  of 7 0  
statistical a nal yses of t h e 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 ke y sec o n d ar y 
e n dp oi nts.  
T he mI T T p o p ulati o n will be use d f or all efficac y a nal ys es. N o re peat assess me nt data is t o be 
use d i n a n y efficac y a nal ys es.  
Statistical a nal yses of t he e n d p oi nts will be perf or me d usi n g t he c ha n ge fr o m baseli ne, i n or der 
t o prese nt direct esti mates f or t he wit hi n-treat me nt mea n c ha n ges fr o m baseli ne (e. g., t h e 
pri mar y e n d p oi nt).  Descri pti ve s u m mar y statistics will be prese nte d f or t he act ual a n d c ha n ge 
fr o m baseli ne val u es at e ac h ti me p oi nt. 
All p -val ues prese nt e d will be t w o -si de d a n d assess e d at t h e 5 % si g nifi ca nce le vel. A s e q ue ntial 
testi n g strate g y will be use d t o a dj ust f or m ulti plicit y f or t he c o m paris o n bet wee n test a n d 
refere nce pr o d ucts i n t he n u m ber of blee di n g sites at wee k 1 2. T his will o nl y b e assesse d f or 
c o nfir mat or y e vi d e nce if t h e pri mar y e n d p oi nt (c h a n ge fr o m b aseli ne wit hi n t he test pr o d uct at 
wee k 1 2) ac hie v es a statisticall y si g nifica n ce re d ucti o n. T here will b e n o f urt her a dj ust me nts 
f or m ulti plicit y f or a n y ot her sec o n d ar y e n d p oi nts. 
1 2. 3. 1  
Pri m ar y A n al y si s( e s)  
A mi x e d m o del wit h r e peate d meas ures ( M M R M) will be perf or me d o n t he c ha n ge fr o m 
baseli ne wit h pr o d uct (test or refere nce), ti me p oi nt a n d pr o d uct b y ti me p oi nt i nteracti o n as 
fi x e d effects, a n d baseli n e N B S as a c o variate. S u bject will be fitte d as a re peate d meas ure wit h 
u n str uct ure d c o v aria n ce. Ke n war d-R o ger de grees of free d o m will be use d.  
F or t he pri mar y o bjecti v e, t o test t he n ull h y p ot hesis ( H 0: T here is n o Mea n C ha n ge fr o m 
Baseli ne f or t he test de ntifrice ( delta = 0) ) vs. t he alter nati ve h y p ot hesis ( H1: T here is Mea n 
C ha n ge fr o m baseli ne f or t he test D e ntifrice ( delta ≠ 0 )), t he res ults fr o m t h e M M R M m o del at 
Wee k 1 2 f or t he t est pr o d uct gr o u p will b e use d. P -val ues a n d 9 5 % c o nfi d e nce i nter vals ( CI) 
will be pr o vi de d.  
1 2. 3. 2  
S e c o n d ar y A n al y si s( e s)  
T he ke y sec o n dar y o bje cti ve is t o e val uate t he effi cac y of a de ntifri ce c o nt ai ni n g 0. 4 5 4 % w/ w 
S n F 2, c o m pare d t o ne gati ve c o ntr ol, as meas ure d b y N B S, after 1 2 wee ks t wice dail y 
t o ot h br us hi n g.  T he ke y s ec o n dar y e n d p oi nt is t he N B S at 1 2 wee ks a n d will be a nal yz e d 
usi n g t he sa me M M R M fr o m t he pri mar y a n al ysis.   
Ot her sec o n d ar y ti me p oi nts ( wee k 3 a n d 6) f or N B S will be a nal yz e d usi n g t he sa m e M M R M 
fr o m t he pri mar y a nal ysis. Esti mates of treat me nt effect (c h a n ges fr o m bas eli ne at 3, 6 a n d 1 2 
wee ks) a n d treat me nt c o m paris o ns will be base d o n l east s q uares me a ns ( L S mea ns) ge nerate d 
b y a p pr o priate c o ntrast st ate me nts.  P -val ues a n d 9 5 % c o nfi de n ce i nter vals ( CI) will be 
pr o vi de d.  
I n a d diti o n t o N B S, ot her sec o n dar y e n d p oi nts  i ncl u de c ha n ge fr o m bas eli ne assess me nts aft er 
3, 6, a n d 1 2 wee ks f or BI,  M GI, a n d T PI.  
F or t he c ha n ge fr o m baseli ne f or eac h e n d p oi nt a b o ve, t he sa me M M R M as a p plie d f or t he 
N B S (i n pri mar y o bje cti ve) will als o be a p plie d b ut i ncl u di n g t he res p ecti ve baseli ne as 
c o variate i nstea d of t he b aseli ne N B S. Res ults wit hi n a n d bet wee n  tr eat me nts at eac h ti me 
p oi nt will als o be o btai ne d a n d prese nt e d i n t he sa me ma n ner.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 5 9  of 7 0  
1 2. 3. 3  
E x pl or at or y A n al y si s( e s)  
Res ults bet wee n treat me nts ( mea n differe n ce fr o m baseli ne f or treat me nt vs mea n differe nce 
fr o m baseli ne f or refere n ce) at eac h ti me p oi nt will als o be o btai ne d a n d prese nte d i n a si milar 
ma n ner as i n t he pri mar y o bjecti ve  i n t he l o w a n d hi g h baseli ne M GI s u b gr o u ps: 
•  L o w: M GI ≤ 2  
•  Hi g h: M GI > 2  
Esti mates of treat me nt c o m paris o ns will be base d o n least s q uares mea ns ( L S mea ns) ge nerate d 
b y a p pr o priate c o ntrast state me nts. P -val ues a n d 9 5 % c o nfi de n ce i nt er vals ( CI) will be 
pr o vi de d.  
1 2. 3. 4  
S af et y A n al y si s( e s)  
T he Safet y p o p ulati o n will be use d f or safet y a nal ys es. Safet y a n al ys es will be perf or me d 
acc or di n g t o pr o d u ct recei ve d. All A Es will be re vie we d b y  t he Cli nical Researc h 
Scie ntist, or desi g nee, pri or  t o data base l oc k a n d u n bli n di n g a n d will be c o d e d usi n g t he 
Me d D R A. D uri n g t his re vie w sta ge, A Es will be f urt her cate g orize d as oral or n o n -oral. 
A Es will be liste d a n d s u m mariz e d  b y  pr o d uct  receive d.  S A Es  will  als o be  liste d. A Es  
will  be  re gar de d as ‘treat me nt’ e mer ge nt if t he y o cc ur o n or after t he first pr o d uct use at 
t he Bas eli ne visit. 
T he  f oll o wi n g A Es ta bles will  be  pr o d uce d, pres e nte d b y  pr o d uct  gr o u p:  
•  listi n g of all  A Es  (ra n d o mize d s u bjects a n d n o n-ra n d o mize d s u bjects); 
•  s u m mar y of  A Es;  
•  treat me nt e mer ge nt  A Es  b y  Oral/ N o n -Oral  a n d Preferre d  Ter m  ( P T); 
•  treat me nt e mer ge nt  A Es b y  S yste m  Or ga n  Class  ( S O C) a n d P T;  
•  treat me nt rel ate d A Es  b y  Oral/ N o n -Oral  a n d P T;  
•  listi n g of seri o us A Es (if t he re are n o S A Es, a n ull listi n g  will be pr o d uce d; if 
t here are m ore t ha n 5 treat me nt e mer ge nt seri o us A Es ( S A Es), a ta ble will b e 
pr o d uce d i n place of t he listi n g b y S O C a n d P T);  
•  n o n -seri o us treat me nt e mer ge nt A Es b y S O C a n d P T ( o nl y pr o d uce d if t here 
are m ore t ha n 5 A Es).  
T he res ults of t he O S T a n d O H T e x a mi nati o ns will be liste d a n d t he res ults of t he O S T 
e x a mi nati o ns will be ta b ulate d.  
1 2. 3. 5  
Ot h er A n al y si s( e s)  
F or des cri pti ve p ur p oses o nl y, t he perce nt c ha n ge fr o m baseli ne at w ee ks 3, 6 a n d 1 2, i n 
eac h ar m se pa ratel y, will be calc ul ate d a n d re p ort e d f or eac h pri mar y a n d s ec o n dar y 
o utc o me varia ble. A d diti o nall y, t he n u m ber a n d p erce nt of patie nts i m pr o vi n g, re m ai ni n g 
t he sa me, or w orse ni n g (c o m pare d t o bas eli ne) at wee ks 3, 6 a n d 1 2, i n eac h ar m 
se parat el y, will be calc ul ate d a n d  re p orte d f or eac h pri mar y  a n d sec o n dar y o utc o me  
varia ble. T h ese  a n al ys es  will o nl y us e t he o bser ve d data a n d n ot t he L O C F i m p ute d data.  
Re pe at a bility  of  t he e x a mi ner 
T he re p eata bilit y of t he e x a mi ner i n c o n d ucti n g t h e M GI a n d T PI assess me nts will als o 
be perf or me d. T he re peat pla q ue a n d M GI assess me nts will be c o m pare d t o t he ori gi nal 
assess me nts. T he re peat assess me nt is n ot t o be use d i n a n y effi cac y a nal ysis. T he fi rst 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 0  of 7 0  
a n d sec o n d  ass ess me nts  of  eac h i n de x will  be  a nal yze d  wit h  a Fleiss -C o he n  
wei g ht e d  ka p pa c o effi cie nt  ( κ), al o n g wit h  t he 9 5 %  CI,  t o assess  t he i ntra-e x a mi ner  
relia bilit y. Relia bilit y  will be  dee me d: E x celle nt  if κ >  0. 7 5, Fair  t o g o o d if 0. 4 ≤ κ  ≤ 0. 7 5  
a n d P o or if  κ < 0. 4.  
T his a nal ysis will be c o n d ucte d o n eac h res p ecti v e i n de x re peata bilit y p o p ulati o n ( M GI 
p o p ulati o n a n d T PI p o p ulati o n).  
Missi n g  d at a  
M M R M a nal yses acc o u nt f or missi n g data usi n g ‘a missi n g at ra n d o m’ ass u m pti o n, i.e., 
t here is a s yste matic relati o ns hi p bet wee n t he pr o p e nsit y f or missi n g val ues a n d t he 
o bser ve d dat a, b ut n ot t he missi n g data. U n d er s uc h ass u m pti o ns, M M R M is s h o w n t o 
pr o v i de u n biase d esti mat es of t he treat me nt effect, w hilst t he a nal ysis of o nl y c o m plete 
cases usi n g A N C O V A are biase d ( Bar o n et al, 2 0 0 8 ; As h bec k et al, 2 0 1 6 ). S uc h 
c o m plete cas e a nal ysis re q uires a ‘ missi n g c o m pletel y at r a n d o m’ ass u m pti o n t o re mai n 
u n biase d a n d t his is u nli kel y t o h ol d, i.e., t he fact t hat t he data are missi n g is i n de pe n de nt 
of t he o bser ve d a n d u n o bser ve d dat a.  
Usi n g a n M M R M, it will t heref ore be ass u me d t hat a s u bject wit h missi n g data at o ne 
p ost -Baseli ne visit w o ul d ha ve o btai ne d a si milar efficac y res ult at t hat visit c o m pare d t o 
a s u bject usi n g t h e sa me st u d y pr o d uct wit h si milar n o n -missi n g res ults at ot her 
ti me p oi nts ( Baseli ne a n d t he ot her p ost-Baseli ne visit). Se nsiti vit y a nal yses will prese nt 
res ults fr o m t he se parate A N C O V A m o dels usi n g o nl y n o n-missi n g v al ues at eac h si n gle 
ti me p oi nt. A d diti o nal se nsiti vit y a n al ys es ma y be a d de d t o t he S A P pri or t o u n bli n di n g 
i n case of hi g h dr o p-o ut r ates a n d/ or e x cl usi o n fr o m P P p o p ul ati o n. 
E xcl usi o n of D at a fr o m A n alysis  
E x cl usi o n of a n y data fr o m t he a nal ys es will be deter mi ne d d uri n g a Bli n d Data Re vie w  
( B D R) M eeti n g pri or t o data base l oc k. A n y reas o ns f or e x cl usi o n fr o m a n a 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  
A ge a n d ot her c o nti n u o us varia bles will be s u m marize d usi n g des cri pti ve statistics i ncl u di n g 
mea n, sta n d ar d d e viati o n, me dia n, mi ni m u m, a n d ma xi m u m. Ge n der, race a n d ot her cate g orical 
varia bles will be s u m mariz e d us i n g fre q ue n c y c o u nts a n d perce nta ges f or t he safet y a n d mI T T 
p o p ulati o ns. Me dical hist or y a n d c urre nt me dical c o n diti o ns will be liste d.   
1 2. 3. 7  
St u d y Dr u g/ Pr o d u ct C o m pli a n c e  
N u m ber of br us hi n gs, br us hi n g c o m plia nce ( %), n u m ber of misse d br us hi n gs, n u m ber of 
a d diti o nal br us hi n gs o ver 1 2  wee ks will be s u m marize d usi n g descri pti ve statistics.  
N u m ber of br us hi n gs is d efi ne d as: [( dat e of Visit  5  –  date of Visit 2) m ulti plie d b y 2 –  n u m ber 
of missi n g br us hi n gs + n u m ber of a d diti o nal br us hi n gs].  
Br us hi n g c o m plia nce ( %) is defi ne d as: [ 1 0 0 x ( N u m ber of br us hi n gs / E x pecte d n u m ber of 
br us hi n gs)], w here e x pecte d n u m ber of br us hi n gs is defi ne d as: [( date of Visit 5  –  date of Visit 
2) m ulti plie d b y 2].  
1 2. 3. 7. 1  Pri or a n d C o n c o mit a nt M e di c ati o n s  
Pri or a n d C o nc o mita nt Me dicati o ns wil l be liste d o nl y. 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 1  of 7 0  
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  
S u bjects w h o wit h dra w fr o m t he st u d y earl y will b e i ncl u de d i n t he statistical a nal ysis u p t o t he 
p oi nt of wit h dra wal. S u bjects w h o wit h dra w will n ot be re place d. F or t he pri mar y a nal yses, n o 
data will be i m p ute d i n t h e case of dr o p o uts or missi n g d ata. H o we ver, se nsiti vit y a n al ys es usi n g 
L O C F are pla n ne d as det aile d i n secti o n 1 2. 3. 5 . 
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-part y ve n d or) m o nit ors will c o ntact t he site pri or t o t he start of t he st u d y t o 
re vie w wit h t he site staff t he pr ot oc ol, st u d y re q uire me nts, a n d t h eir res p o nsi bilities t o satisf y 
re g ulat or y, et hical, a n d H ale o n  re q uir e me nts. 
W he n re vie wi n g data c ollecti o n pr oce d ures, t he disc ussi o n 
will i ncl u de i de ntificati o n, 
a gree m e nt a n d d oc u me ntati o n of data ite ms f or w hic h t he 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 ac ti vit y t o v erif y t hat t h e: 
•  Data are a ut he ntic, acc urate, a n d c o m plete.  
•  Safet y a n d ri g hts of s u bjects are b ei n g pr otecte d.  
•  St u d y is c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y ot her 
st u d y a gree me nts, G C P, a n d all a p plica ble re g ulat or y re q uire m e nts. 
T he e xte nt a n d n at ure of m o nit ori n g will b e des cri be d i n a writte n m o nit ori n g pl a n o n file at 
Hale o n . T he i n vesti gat or ( or desi g nee) a grees t o all o w t he m o nit or direct access t o all rele va nt 
d oc u me nts a n d a grees t o c o -o perate wit h t he m o ni t 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 ur a nce assess me nt a n d/ or a u dit of t h e site rec or ds, a n d t he re g ulat or y 
a ge ncies ma y c o n d u ct a re g ulat or y i ns pe cti o n at a n y ti me d uri n g or aft er c o m pleti o n of t he 
st u d y.  
I n t he e v e nt of a n assess me nt, a u dit or i ns pecti o n, t he i n vesti gat or (a n d i nstit uti o n) m ust a gree 
t o gra nt t he a d vis or(s), a u dit or(s) a n d i ns pect or(s) direct access t o all rele va nt d oc u me nts a n d 
t o all ocate t heir ti me a n d t he ti me of t heir staff t o disc uss t he c o n d uct of t he st u d y, a n y 
fi n di n gs/rele v a nt iss ues a n d t o i m ple me nt a n y c orrecti ve a n d/ or pre ve ntati v e acti o ns t o a d dress 
a n y fi n di n gs/iss ues i de ntifie d.  
T he i n vesti gat or(s) will n otif y H ale o n  or its a ge nts i m me diatel y of a n y re g ulat or y i ns p ecti o n 
n otificati o n i n relati o n t o t he st u d y. F urt her m ore, t he i n vesti gat or will c o o perate wit h Hale o n  
or its a ge nts t o pre pare t he st u d y site f or t he i ns pecti o n a n d will all o w Hale o n  or its a ge nt, 
w he ne ver 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 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 2  of 7 0  
c o pies of t he i ns pe cti o n fi n di n g t o Hale o n  or its a ge nt. Bef ore res p o nse s u b missi o n t o t h e 
re g ulat or y a ut h orit y, t he i n vesti gat or will pr o vi de Hale o n  or its a ge nts wit h a n o p p ort u nit y t o 
re vie w a n d c o m me nt o n r es p o nses t o a n y s uc h fi n di n gs.  
T he s p o ns or will be a vail a ble t o hel p i n vesti gat ors pre p are 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 ati 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  a n d i nf or me d c o ns e nt d oc u me nts, i n vesti gat or br oc h ure/safet y st ate me nt 
(i ncl u di n g a n y u p dates) a n d ot her rele va nt d oc 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/ EC 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 b e i nitiate d pri or t o I R B/ E C a p pr o val is 
w here t h e c h a n ge is ne ces sar 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 n ati o nal Et hical G ui deli nes 
f or Bi o me di cal Researc h I n v ol vi n g H u m a n S u bjects ( C o u ncil f or I nt er nati o nal Or ga nizati o ns 
of 
Me dical Scie n ces 2 0 0 2), I nter nati o nal Et hical G ui deli nes f or Healt h -Relate d Researc h 
I n v ol vi n g H u m a ns ( C o u ncil f or I nter nati o nal Or ga nizati o ns of 
Me dical Scie nces, 2 0 1 6), 
g ui deli nes f or G C P (I C H 1 9 9 6 a n d re visi o n 2), a n d t he Declarati o n of Helsi n ki ( W orl d Me dical 
Ass ociati o n 2 0 1 3).  
In 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 p plica ble p orti o n of E U M D R 2 0 1 7/ 7 4 5, I S O 1 4 1 5 5: 2 0 1 1 a n d I S O 1 4 1 5 5: 2 0 2 0 , a n d 
a p plica ble l ocal re g ulat or y re q uire me nts a n d l a 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 x ce 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 d e d b y Hale o n  i n or d er t o de-i de ntif y st u d y s u bj ects.   
T he st u d y site will mai nt ai n a c o nfi de nt ial list of s u bjects w h o partici pate d i n t he st u d y, li n ki n g 
eac h s u bject’s n u merical c o de t o his or her act ual i de ntit y.  I n case of data tr a nsfer, Hale o n  will 
mai ntai n hi g h sta n dar ds of c o nfi de ntialit y a n d pr otecti o n 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 me d c o ns e nt d o c u me nts m ust be i n c o m plia nce wit h I C H G C P, a p plica ble p orti o n of 
I S O 1 4 1 5 5, l ocal re g ulat or y re q uir e me nts, a n d l e gal re q uir e me nts, i ncl u di n g a p plica ble pri vac y 
la ws. 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 3  of 7 0  
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 wit 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 m ittee a p pr o ve d, ge neric, prescree ni n g q uesti o n naire t o assess 
basic s u bject c haracteristics t o deter mi ne ge neral eli gi bilit y f or t his st u d y is all o we d.   T his 
ge n eric q uesti o n naire ma y b e use d b y sites as a p h o ne scri pt a n d/ or t o re vie w i nter nal d ata bas es 
to 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 bj ects 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 o l or 
I C H G C P  
Wit hi n Hale o n  a seri o us breac h is defi ne d as a breac h li kel y t o affect t o a si g nifica nt de gree t he 
safet y a n d ri g hts of a s u bject or t he relia bilit y a n d r o b ust ness of t he data ge nerate d i n Hale o n  -
s p o ns ore d h u ma n s u bject researc h st u dies.  
I n t he e ve nt of a n y pr o hi biti 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 m pete nt a ut h orit y i n a n y area of t he w orl d, or if t he i n vesti gat or is a ware of a n y n e w 
i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be n efits a n d ris ks of t he i n vesti gati o nal 
pr o d 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 vesti gat or will i nf or m Hale o n  i m me diatel y of a n y ur ge nt safet y meas ures 
ta ke n b y t h e i n vesti gat or t o pr otect t he st u d y s u bjects a gai nst a n y i m me diate hazar d, a n d of an 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 sti n g of I nf or m ati o n o n P u bli cl y A v ail a bl e Cli ni c al Tri al 
R e gi st er s  
St u d y i nf or mati o n fr o m t his pr ot oc ol will be p oste d o n p u blicl y a v aila ble cli nical trial re gist ers 
bef ore e nr oll me nt of s u bj ects be gi ns i n acc or da n ce wit h a p plica ble Hal e o n  pr ocesses . 
Hale o n  i nte n ds t o ma k e a n o n y mize d s u bject-le vel data fr o m t his trial a vaila ble t o e xter nal 
researc hers f or s cie ntific a nal ys es or t o c o n d u ct f urt her researc h t hat ca n hel p a d va nce m e dical 
scie nce or i m pr o ve patie nt care. T his hel ps e ns ure t he d ata pr o vi d e d b y trial partici pa nts are 
use d t o ma xi m u m effect i n t he creati o n of k n o wle d ge a n d u n derst a n di n g.  
1 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 t he cli nical st u d y re p ort.  T he i n vesti gat or will be pr o vi de d 
reas o na bl e access t o statistical ta bles, fi g ures, a n d rele va nt re p orts a n d will ha ve t he o p p ort u nit y 
t o re vie w t he c o m plet e st u d y res ults at a Hale o n  site or ot her m ut uall y-a greea ble l ocati o n.  
Hale o n  will  als o pr o vi d e t he i n vesti gat or wit h t he f ull s u m mar y of t he st u d y res ults.  T he 
i n vesti gat or is e n c o ura ge d t o s hare t he s u m mar y res ults wit h t he st u d y su bj ects, as a p pr o priate.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 4  of 7 0  
T he pr oce d ures a n d ti mi n g f or p u blic discl os ure of t he res ults s u m mar y a n d f or de vel o p me nt of 
a ma n uscri pt f or p u blicati o n will be i n acc or da n ce wit h Hale o n  P olic y . 
A ma n uscri pt will be pr o gresse d f or p u blicati o n i n t he scie ntific literat ur e if t he res ults pr o vi d e 
i m p orta nt scie ntific or me dical k n o wle d ge. 
1 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 Hal e o n  a u dit or re g ulat or y i ns pecti o n) a n d m ust be a v aila ble f or re vi e w i n 
c o nj u ncti o n wit h assess me nt of t he facilit y, s u p p orti n g s yst e ms, a n d rel e va nt site staff.  
W here per mitte d b y l ocal la ws/re g ulati o ns or i nstit uti o 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, sca n ne d, electr o nic); 
h o we ve r, ca uti o n nee ds t o be e x ercise d bef ore s u c h acti o n is ta ke n.  
T he i n vesti gat or m ust e ns ure t hat all re pr o d ucti o ns are le gi ble a n d are a tr u e a n d acc urate c o p y 
of t he ori gi nal a n d meet accessi bilit y a n d retrie v al sta n dar ds, i ncl u di n g re -ge nerati n g a h ar d 
co 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 mi t y will be mai ntai ne d.  O n C R Fs or ot her 
d oc u me nts s u b mitte d t o Hale o n , s u bjects s h o ul d n ot be i de ntifie d b y t heir n a mes or i nitials, b ut 
b y a n i de ntificati o n c o d e. T he i n vesti gat or s h o ul d kee p a se p arat e l o g of s u bjects’ c o d es, na m es 
a n d a d dresses.  D oc u m e 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 ntr act ual a gree me nt, fr o m t he iss ue of t he fi nal 
Cli nical St u d y Re p ort ( C S R) or e q ui vale nt s u m mar y,  u nless l ocal r e g ulati o ns or i nstit uti o nal 
p olicies re q uir e a l o n ger rete nti o n peri o d. T he mi ni m u m rete nti o n ti me will meet t he strictest 
sta n dar d a p plica bl e t o t hat site f or t he st u d y, as dictate d b y a n y i nstit uti o nal re q uire me nts or 
l ocal la ws or re g ulati o ns, Hale o n  sta n dar ds/ pr oce d ures, a n d/ or i nstit uti o nal re q uire me nts.   
N o st u d y d oc u me nt s h o ul d be d estr o ye d wit h o ut a pri or writte n a gree me nt b et wee n Hale o n  a n d 
t he i n vesti gat or. T h e i n vesti gat or 
m ust n otif y Hale o n  of a n y c ha n ges i n t he arc hi v al 
arra n ge me nts, i ncl u di n g, b ut n ot li mite d t o, arc hi val at a n off -site facilit y or tra nsfer of 
o w ners hi p of t he rec or ds i n t he e ve nt t he i n vesti gat or is n o l o n ger ass ociate d wit h t he site.  
1 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 o cc ur beca us e 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, H ale o n  retai ns t he ri g ht t o disc o nti n ue de vel o p me nt of Par o d o nta x 
C o m plete Pr otecti o n De ntifrice  at a n y t i 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 mat erials m ust 
be c ollecte d a n d all C R F’s  c o m plete d t o t he greatest e xte nt p ossi ble. W here re q uire d b y t h e 
a p plica ble re g ulat or y re q uire me nts, Hale o n  s h o ul d i nf or m t he re g ulat or y a ut h orit y(ies) a n d t he 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 5  of 7 0  
i n vesti gat or s h o ul d pr o m ptl y i nfor m t h e I R B/ E C a n d pr o vi de t he I R B/ E C a det aile d writte n 
e x pla nati o n of t he ter mi nati o n or s us pe nsi o n.  
If t h e I R B/ E C ter mi nates or s us pe n ds its a p pr o val/fa v ora ble o pi ni o n of a trial, t he i n vesti gat or 
s h o ul d pr o m ptl y n otif y t he Hale o n  a n d pr o vi de Hale o n   w it h a detaile d writte n e x pla nati o n of 
t he ter mi nati o n or s us pe nsi o n. 
U p o n c o m pleti o n or pre mat ure disc o nti n uati o n of t he st u d y, t he Hale o n  m o nit or will c o n d uct 
site cl os ure acti vities wit h t he i n vesti gat or or site staff, as a p pr o priate, i n acc or da nce wit h 
a p plica ble re g ulati o ns i ncl u di n g G C P, a n d Hale o n  Sta n dar d O perati n g Pr oce d ures.  
1 4  
R E F E R E N C E S  
[Ac her k o u k  A, Pat el N , B utler A, A mi ni P ( 2 0 2 1)] A ra n d o mise d cli nical st u d y i n vesti gati n g 
effic ac y of a sta n n o us fl u ori de t o ot h paste i n i m pr o vi n g gi n gi val healt h after 3 wee ks’ us e. B M C 
Oral Healt h B M C Oral H ealt h 2 0 2 1 Se p 1 2; 2 1( 1): 4 4 1  
[ A D A ( 2 0 2 2)] T o ot h br us hes. htt ps:// w w w.a da. or g/r es o urces/researc h/scie nce -a n d-researc h-
i nstit ute/ oral-healt h -t o pics/t o ot h br us hes: E xtracte d 2 6 A pril 2 0 2 2. 
[ Arc hila L, Bartize k R D, Wi nst o n J L, et al. ( 2 0 0 4)] T he c o m parati ve efficac y of sta bilize d 
sta n n o us  
fl u ori de/s o di u m  
he x a meta p h os p hate  
de ntifrice  
a n d  
s o di u m 
fl u ori de/tricl osa n/c o p ol y mer de ntifri ce f or t h e c o ntr ol of gi n gi vitis: A 6-m o nt h ra n d o mize d 
cli nical st u d y. J o ur nal of peri o d o nt ol o g y; 7 5( 1 2): 1 5 9 2 -9.  
[A g haza de h  Z , Be hr o ozia n A , et al ( 2 0 1 9)] C o m paris o n of Gi n gi val a n d De ntal I n dices i n 
Lactati n g a n d N o n -Lactati n g  M ot hers D uri n g First 6 M o nt h After Deli ver y . Pes q uisa Brasileir a 
e m O d o nt o pe diatria e Clí nica I nte gra da 2 0 1 9; 1 9:e 4 5 8 6  
[ As h bec k E. L., Bell M. L. ( 2 0 1 6)]  Si n gle ti me p oi nt c o m paris o ns i n l o n git u di nal ra n d o mize d 
c o ntr olle d trials: p o wer a n d bias i n t he pres e nce of missi n g data. B M C Me d Res Met h o d ol, 
2 0 1 6, 1 6, 4 3.  
[ Bar o n G., Ra v a u d P., Sa ms o n A., et al. ( 2 0 1 6)]  Missi n g data i n ra n d o mize d c o ntr olle d trials 
of r he u m at oi d art hritis wit h ra di o gra p hi c o utc o mes: A si m ulati o n st u d y. Art hritis R he u m -
Art hritis Care Res. 2 0 0 8; 5 9: 2 5 – 3 1  
[ Bella m y P, B o ul di n g A, Far m er S, et al. ( 2 0 1 2)] Ra n d o mize d di gital pla q ue i ma gi n g trial 
e val uati n g pla q u e i n hi biti o n effi cac y of a n o v el sta bilize d sta n n o us fl u ori de de ntifrice c o m pare d 
wit h a n a mi ne fl u ori de/st a n n o us fl u ori de de ntifri c e. J o ur nal of Cli nical De ntistr y; 2 3( 3): 7 1 -5.  
[ C u m mi ns D, Creet h J ( 1 9 9 2)] Deli ver y of a nti pla q ue a ge nts fr o m de ntifrices, gels, a n d 
m o ut h was hes. J o ur nal of de ntal researc h; 7 1( 7): 1 4 3 9 -4 9  
[ C ha p ple I L, Va n der Weij de n F, D oerfer C, et al ( 2 0 1 5)] Pri mar y p re v e nti o n of peri o d o ntitis: 
Ma na gi n g gi n gi vitis. J o ur nal of cli nical peri o d o nt ol o g y. 2 0 1 5; 4 2  
[ Da vies R M ( 2 0 0 8)] T o ot h paste i n t he c o ntr ol of pla q ue/ gi n gi vitis a n d peri o d o ntitis. 
Peri o d o nt ol o g y 2 0 0 0; 4 8( 1): 2 3 -3 0.  
F D A: G ui da n ce f or I n d ustr y Gi n gi vitis: De ve l o p me nt a n d E val uati o n of Dr u gs f or Treat me nt  
or Pre ve nti o n.   
[ Fi g uer o E, Carrill o-de -Al b or n oz A, Herrera D, et al.( 2 0 1 0)] Gi n gi val c h a n ges d uri n g 
pre g na nc y: I. I nfl ue n ce of h or m o nal variati o ns o n cli nical a n d i m m u n ol o gical para met ers. 
J o ur nal of cli nical peri o d o nt ol o g y. 2 0 1 0; 3 7( 3): 2 2 0-9.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 6  of 7 0  
[ Gall o b, J et al. ( 2 0 2 1)] Efficac y of Sta n n o us Fl u ori de T o ot h paste o n Pla q ue a n d Gi n gi vitis 
Re d ucti o n. 2 0 2 1 I A D R/ A A D R/ C A D R Ge neral Sessi o n  
[Hale o n St u d y 2 0 7 0 1 4 ( 2 0 1 8)] A Cli nical St u d y I n vesti gati n g t he Gi n gi vitis Effica c y of a 
Sta n n o us Fl u ori de De ntifrice i n a C hi nese P o p ulati o n  
[Hale o n  Cli nical St u d y 2 1 2 5 3 7 ( 2 0 2 0)] A Ra n d o mize d, E x a mi ner Bli n d, Cli nical St u d y 
I n v esti gati n g t he Effic ac y of a Sta n n o us Fl u ori de De ntifrice i n i m pr o vi n g gi n gi val healt h after 
3 wee ks use. ( G S K data o n file)  
[ He T, Bar ker M L, G o yal C R, et al. ( 2 0 1 2)] A nti-gi n gi vitis effects of a n o v el 0. 4 5 4 % 
sta bilize d sta n n o us fl u ori de de ntifrice relati ve t o a p ositi ve c o ntr ol. A merica n j o ur nal of 
de ntistr y; 2 5( 3): 1 3 6 -4 0.  
[ Haraszt h y VI, Ra yl ae C C, Sree ni vasa n P K ( 2 0 1 9)] A nti micr o bial effects of a sta n n o us 
fl u ori de t o ot h paste i n disti nct oral micr oe n vir o n m e nts. T he J o ur nal of t he A merica n De ntal 
Ass ociati o n; 1 5 0( 4): S 1 4 -S 2 4.  
I C H T o pi c E 6 ( R 2) G ui d eli ne f or G o o d Cli nical Practice, N o v 2 0 1 6. 
[ Ki na ne D F ( 2 0 0 1)] Peri o d o ntal disease i n c hil dre n a n d a d olesce nts: i ntr o d ucti o n a n d 
classificati o n. Peri o d o nt ol o g y 2 0 0 0; 2 6( 1): 7 -1 5.  
[ L o b e ne R R, Weat herf or d T, R oss N M, et al. ( 1 9 8 6)] A m o difie d gi n gi val i n de x f or use i n 
cli nical trials. Cli nical pre ve nti ve de ntistr y. 1 9 8 6 ; 8( 1): 3-6.  
[ L o b e ne R R, S o par kar P M, Ne w ma n M B ( 1 9 8 2)]. Use of de ntal fl oss. Effect o n pla q ue a n d 
gi n gi vitis. Cli nical pre ve nti ve de ntistr y. 1 9 8 2; 4( 1): 5 -8.  
[Mac h uca G, R osales I, Lacalle J R, et al . ( 2 0 0 0)] Effect of ci garette s m o ki n g o n peri o d o ntal 
stat us of healt h y y o u n g a d ults. T he J o ur nal of peri o d o nt ol o g y. 2 0 0 0; 7 1( 1): 7 3 -8  
[ Ma ki n S A ( 2 0 1 3)] Sta n n o us fl u ori de de ntifrices. A merica n j o ur n al of de ntistr y; 2 6( S pIss A): 
3 A -9 A  
[ Mallatt M, Ma n k o di S, Ba ur ot h K, et al. ( 2 0 0 7)] A c o ntr olle d 6‐ m o nt h cli nical trial t o st u d y 
t he effects of a sta n n o us fl u ori de de ntifrice o n gi n gi vitis. J o ur nal of cli nical peri o d o nt ol o g y; 
3 4( 9): 7 6 2 -7.  
[ Ma n k o di S, Bartize k R D, Wi nst o n J L, et al. ( 2 0 0 5)] A nti‐ gi n gi vitis efficac y of a st a bilize d 
0. 4 5 4 % sta n n o us fl u ori d e/s o di u m he xa meta p h os p hate de ntifrice. J o ur nal of cli nical 
peri o d o nt ol o g y; 3 2( 1): 7 5 -8 0.  
[ Ma n k o di S, Petr o ne D, Battista G, et al. ( 1 9 9 7)] Cli nical efficac y of a n o pti mize d sta n n o us 
fl u ori de de ntifric e, Part 2: A 6-m o nt h pla q ue/ gi n gi vitis cli nical st u d y, n ort heast U S A. 
C o m pe n di u m of c o nti n ui n g e d u cati o n i n de ntistr y; 1 8( -): 1 0-5.  
[ Miller S, Tr u o n g T, He u R, et al. ( 1 9 9 4)] Rece nt a d va nces i n sta n n o us fl u ori de tec h n ol o g y: 
a nti bacterial effic ac y a n d mec ha nis m of acti o n t o war ds h y perse nsiti vit y. I nter nati o nal de ntal 
j o ur nal; 4 4( S u p pl. 1): 8 3-9 8.  
[O bei d P, Berc y P  ( 2 0 0 0)] Effects of s m o ki n g o n p eri o d o ntal healt h: A re vie w. A d va n ces i n 
t hera p y. 2 0 0 0; 1 7( 5): 2 3 0-7.  
[ Oral Healt h Care Dr u g Pr o d ucts f or O ver-t he-C o u nter H u ma n Use ( 1 9 9 1)] A m e n d me nt t o 
Te ntati ve Fi nal M o n o gra p h t o I ncl u d e O T C Relief of Oral Disc o mf ort Dr u g Pr o d ucts. Fe deral 
Re gister 5 6( 1 8 5): 4 8 3 0 2 -4 7, at 3 5.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 7  of 7 0  
[ Par ki ns o n et al ( 2 0 1 5)] R C Ts of Sta n n o us Fl u ori de T o ot h paste A nti micr o bial Acti vit y; 
E val uati o n of t he Pla q ue Gl yc ol ysi s a n d Re gr o wt h M o del (J De nt Res 9 4 B: A bstract # 3 4). 
B S O D R. Car diff, U K.  
[ Par ki ns o n C R, Tar gett D, G ui bert R, et al. ( 2 0 1 4)] Cli nical St u d y I n vesti gati n g t he Gi n gi vitis 
Efficac y of a n E x peri me ntal T o ot h paste ( A bstract # 1 3 6 3). A A D R/ C A D R A n n ual Meeti n g. 
C ha rl otte, N ort h Car oli na 
[ Par ki ns o n C, A mi ni P, W u J, et al. ( 2 0 1 8a)] A 2 4-wee k ra n d o mize d cli nical st u d y 
i n vesti gati n g t he a nti-gi n gi vitis efficac y of a 0. 4 5 4 % w/ w sta n n o us fl u ori d e t o ot h paste. 
A merica n j o ur n al of de ntistr y; 3 1( 1): 1 7 -2 3.  
[ Par ki ns o n C R, A mini P, J ose A, et al. ( 2 0 1 8 b)] A 1 2-wee k ra n d o mize d cli nical st u d y 
i n vesti gati n g t he a nti-gi n gi vitis efficac y of a 0. 4 5 4 % w/ w sta n n o us fl u ori d e de ntifrice. 
A merica n j o ur n al of de ntistr y; 3 1( 2): 8 1 -5  
[ Par ki ns o n C R, Mille ma n, K R, et al ( 2 0 2 0)]. Gi n gi vitis eff icac y of a 0. 4 5 4 % w/ w sta n n o us 
fl u ori de de ntifric e: a 2 4-wee k ra n d o mize d c o ntr olle d trial. B M C Oral H ealt h 2 0, 8 9 ( 2 0 2 0).  
htt ps:// d oi. or g/ 1 0. 1 1 8 6/s 1 2 9 0 3 -0 2 0 -0 1 0 7 9 -6  
[Peterse n P E, O ga wa H  ( 2 0 0 0)] T he gl o bal b ur d e n of peri o d o ntal diseas e: T o war ds 
i nte grati o n wit h c hr o nic disease pre v e nti o n a n d c o ntr ol. Peri o d o nt ol o g y 2 0 0 0. 2 0 1 2; 6 0( 1): 1 5-
3 9.  
[ Ra ber-D urlac h er J E, va n Stee n ber ge n TJ, Va n d er Vel de n U, et al ( 1 9 9 4)] E x peri me ntal 
gi n gi vitis d uri n g pre g n a n c y a n d p ost -part u m: Cli nical, e n d ocri n ol o gical, a n d micr o bi ol o gical 
as pects. J o ur nal of cli nic al peri o d o nt ol o g y. 1 9 9 4; 2 1( 8): 5 4 9 -5 8. E p u b 1 9 9 4/ 0 9/ 0 1. P u b Me d 
P MI D: 7 9 8 9 6 1 9  
[ R ose na uer, T et al ( 2 0 2 2)] Direct a n d i n direct effects of differe nt de ntifrices o n t he i nitial 
bacterial c ol o nizati o n of e na mel i n sit u o ver ni g ht. I nter nati o nal j o ur nal of de ntal h y gi e ne 
N L M ( Me dli ne). (J a n 2 4, 2 0 2 2)  
[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 pre g n a nc y. 
1 9 7 6; 4 7( 7): 4 1 5 -8.  
[Sil ness J, L oe H ( 1 9 6 4)] Peri o d o ntal disease i n pr e g n a nc y. II. C orrel ati o n bet wee n oral 
h y gie n e a n d peri o d o ntal c o n diti o n. Acta O d o nt ol Sca n d. 1 9 6 4; 2 2: 1 2 1 -3 5  
[ S ne ha N, Sri ni vas R, Sri ni vas P ( 2 0 2 2)] A nti pla q ue effi cac y of t o ot h paste –  A s yste matic 
re vie w a n d m eta-a nal ysis of ra n d o mize d c o ntr olle d trials. J o ur nal of I n dia n Ass ociati o n of 
P u blic Healt h De ntistr y 2 0. 1 ( 2 0 2 2): 1 6 -2 4  
[ Sa xt o n C A, va n der O u deraa FJ] T he effect of a d e ntifrice c o ntai ni n g zi nc citrate a n d 
tricl osa n o n de vel o pi n g gi n gi vitis. J o ur nal of peri o d o ntal researc h. 1 9 8 9; 2 4( 1): 7 5-8 0.  
[ S u n o m o, H et al ( 2 0 2 1)] T he Effecti ve ness of t h e Use of Fl u ori date d T o ot h paste o n 
Re d ucti o n of Pla q ue Sc ore: A S yste m atic Lit erat ure Re vie w. Al o h a I nter n ati o nal J o ur nal of 
Healt h A d va n ce me nt 4. 1 2 ( 2 0 2 1): 2 7 6 -2 8 1  
[ R ose n ber g M, Se pt o n I, Eli I, et al. ( 1 9 9 1)] Halit osis meas ure me nt b y a n i n d ustrial s ul p hi de 
m o nit or. J o ur nal of peri o d o nt ol o g y; 6 2( 8): 4 8 7 -9.  
[ Teles R P, Teles F R F ( 2 0 0 9)] A nti micr o bial a ge nts use d i n t he c o ntr ol of peri o d o ntal 
bi ofil ms: effecti ve a dj u n cts t o mec ha nical pla q u e c o ntr ol? Brazilia n Oral Researc h; 
2 3( S u p pl. 1): 3 9 -4 8.  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 8  of 7 0  
[T heila de E, Wri g ht W H, J e nse n S B, et al  ( 1 9 9 6)]. E x peri me ntal gi n gi vitis i n ma n. II. A 
l o n git u di nal cli nical a n d bacteri ol o gical i n vesti gati o n. J Peri o d o ntal Res; 1 9 6 6; 1: 1-1 3.  
[ Ti na n off N ( 1 9 9 0)] Re vie w of t he a nti micr o bi al acti o n of sta n n o us fl u ori de. T he J o ur nal of 
cli nical de ntistr y; 2( 1): 2 2 -7.  
[ Ti na n off N ( 1 9 9 5)] Pr o gress re gar di n g t he use of sta n n o us fl u ori de i n cli nical de ntistr y. T he 
J o ur nal of cli nical de ntistr y; 6: 3 7-4 0.  
[ Val ke n b ur g C, Else Sl ot D, Va n der Weij de n G ( 2 0 2 0)] W hat is t he effect of acti ve 
i n gre di e nts i n de ntifrice o n i n hi biti n g t he re gr o wt h of o ver ni g ht pla q ue? A s yste matic re vie w. 
I nter nati o nal j o ur nal of de ntal h y gi e ne 1 8: 1 2 8-4 1.  
[ va n L o vere n C ( 1 9 9 0)] T he a nti micr o bial acti o n of fl u ori de a n d its r ole i n caries i n hi biti o n. 
J o ur nal of de ntal researc h; 6 9( S u p pl. 2): 6 7 6-8 1.  
[ va n L o vere n C ( 2 0 0 1)] A nti micr o bial acti vit y of fl u ori de a n d its i n vi v o i m p orta nce: 
i de ntificati o n of res earc h q uesti o ns. Caries researc h; 3 5( S u p pl. 1): 6 5-7 0.  
[ Willia ms C, Mc Bri de S, B ol de n T, et al. ( 1 9 9 7)] Cli nical efficac y of a n o pti mize d sta n n o us 
fl u ori de de ntifric e, Part 3: A 6-m o nt h pla q ue/ gi n gi vitis cli nical st u d y, s o ut h east U S A. 
C o m pe n di u m of c o nti n ui n g e d u cati o n i n de ntistr y;  1 8( -): 1 6-2 0  
[ Wils o n M, Pratte n J, e dit ors. ( 1 9 9 9)] La b orat or y assess me nt of a nti micr o bials f or pla q ue-
relate d dise ases 
1 5  
A P P E N DI CI E S  
1 5. 1  
A B B R E VI A TI O N S  
T he f oll o wi n g is a list of a b bre viati o ns t hat ma y b e use d i n t he pr ot oc ol.  
T a bl e 1 5 -1  
A b br e vi ati o n s  
A b bre vi ati o n  
Ter m  
A E  
A d verse e ve nt  
A N C O V A  
A nal ysis of c o vari a nce  
B D M  
Bi ostatistics a n d Data M a na ge me nt  
B D R  
Bli n de d data re vie w  
BI  
Blee di n g i n de x  
CI  
c o nfi de nce i nter val  
C R F  
case re p ort f or m  
C R S  
Cli nical Researc h Scie ntist  
C S R  
Cli nical st u d y re p ort  
Da  
Dalt o n  
D M S  
Data ma na ge me nt s yste m  
E C  
et hics c o m mittee  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 6 9  of 7 0  
A b bre vi ati o n  
Ter m  
E C G  
ec h ocar di o gra m  
E D C  
Electr o nic D ata Ca pt ure  
E u dra C T  
E ur o pea n Cli nical Trials Data base  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S F V  
First s u bject first visit  
G C P  
G o o d Cli nical Practice  
GI  
gi n gi val i n de x  
hrs  
h o urs  
I B 
i n vesti gat or’s br oc h ure 
I C F 
I nf or me d c o ns e nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I R B 
i nstit uti o nal re vie w b oar d 
I T T 
I nte nt t o treat 
I o M T 
I nter net of M e dical T hi n gs 
L L C  
li mite d lia bilit y c o m pa n y 
Me d D R A  
me dical Dicti o nar y f or R e g ul at or y Acti vities  
M F C  
Ma n ufact uri n g f or m ulati o n c o de  
M GI  
M o difie d gi n gi val i n de x  
mI T T  
M o difie d I nte nt -t o-Treat  
m m  
Milli meter  
N/ A  
N ot a p plica ble  
N B S  
n u m ber of blee di n g sites  
N o.  
N u m ber  
O H  
Oral healt h  
O H T  
Oral har d tiss ue  
O S T  
Oral s oft tiss ue  
PI  
Pri nci pal i n vesti gat or  
PI  
Pers o nal i nf or mati o n  
P P  
Per pr ot oc ol  
P R O  
Patie nt re p orte d o utc o me  
R A P  
Re p orti n g a n d a nal ysis pla n  
R E C  
Researc h et hics c o m mittee  
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 7   
 
Pr o pert y of Hal e o n - C o nfi de ntial   
Ma y n ot b e use d, di v ul ge d, p u blis he d or ot her wise discl ose d wit h o ut t he c o nse nt of Hale o n  
 Cli nical Pr ot oc ol Te m plate v 1 0 . 0 
Pa ge 7 0  of 7 0  
A b bre vi ati o n  
Ter m  
S A E  
seri o us a d verse e v e nt 
S D  
Sta n dar d de viati o n  
S E  
Sta n dar d err or  
Sta n n o us 
Fl u ori de  
S n F 2 
S O P  
sta n dar d o perati n g pr oce d ure 
S R S D  
Si n gle refere nce st u d y d o c u me nt  
S S  
Safet y st ate me nt  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o n  
T PI  
T ures k y m o dificati o n of t he Q ui gle y Hei n Pla q ue I n d e x  
U K  
U nite d Ki n g d o m  
w/ w  
Wei g ht f or w ei g ht  
 
 
 
 
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
C CI


Si g nat ure Pa ge f or  3 0 0 1 0 7 T M F- 2 4 7 1 5 8 v 2. 0
Si g nat ure Pa ge f or T M F- 2 4 7 1 5 8 v 2. 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure:
G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me: 
R ole: A p pr o ver
Date of si g nat ure: 
G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me:
R ole: A p pr o ver
Date of si g nat ure:
G M T + 0 0 0 0
3 0 0 1 0 7 Pr ot oc ol  1 0 Oct 2 0 2 3 | T M F- 2 4 7 1 5 8 | 2. 0
P P D
P P D
P P D
P P D
P P D
P P D

SAP_001.pdf: 
0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
Pr o p ert y of H al e o n  
C o nfi d e nti al  
M a y n ot b e u s e d, di v ul g e d, p u bli s h e d , or ot h er wi s e di s cl o s e d  
wit h o ut t h e c o n s e nt of H al e o n  
 St ati sti c al A n al y si s P l a n T e m pl at e v 7 . 0 
P a g e 1 of 4 5  
S T A TI S TI C A L A N A L Y SI S P L A N 
A R a n d o mi z e d, C o ntr oll e d, E x a mi n er -Bli n d Cli ni c al St u d y  
I n v e sti g ati n g t h e Eff e ct s of a D e ntifri c e C o nt ai ni n g 0. 4 5 4 % w/ w  
St a n n o u s Fl u ori d e o n Gi n gi viti s Tr e at m e nt a n d Pl a q u e R e d u cti o n  
W h e n U s e d T wi c e D ail y f or 1 2 W e e k s  
Pr ot o c ol N u m b er:  3 0 0 1 0 7  
P h a s e:  
N/ A  
T hi s d o c u m e nt c o nt ai n s c o nfi d e nti alit y st at e m e nt s t h at ar e n ot r el e v a nt 
f or t hi s p u bli cl y a v ail a bl e v er si o n
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2  of 4 5  
D o c u m e nt Hi st or y 
 
 
D oc u m e nt  
Versi o n D ate  
S u m m ar y of C h a n ges ( Ne w a n al ysis or 
C h a n ge i n pl a n ne d a n al ysis)  
Ori gi nal A nal ysis Pla n  
2 4- Ja n-2 0 2 4  
N ot a p plica ble ( N/ A)  
 
 
 
 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 3  of 4 5  
T a bl e of c o nt e nt s 
D oc u me nt Hist or y ............................................................................................................... 2  
Ta ble of c o nt e nts  ................................................................................................................. 3  
List of Ta bles  ....................................................................................................................... 4  
A b bre viati o ns .............................................................................................................................. 5  
1  
S u m mar y of Ke y Pr ot oc ol I nf or mati o n  ............................................................................... 6  
1. 1  
St u d y Desi g n  ............................................................................................................ 6  
1. 2  
St u d y O bjecti ves  .................................................................................................... 1 0  
1. 3  
Treat me nts  ............................................................................................................. 1 1  
1. 4  
Sa m ple Size Calc ulati o n  ........................................................................................ 1 2  
2  
Pla n ne d A nal yses  ............................................................................................................... 1 2  
2. 1  
I nteri m A nal ysis ..................................................................................................... 1 2  
2. 2  
Fi nal A nal yses  ....................................................................................................... 1 2  
3  
C o nsi derati o ns f or Data A nal yses a n d D ata Ha n dli n g C o n ve nti o ns ................................. 1 3  
3. 1  
Baseli ne Defi niti o n  ................................................................................................ 1 3  
3. 2  
S u b gr o u ps/ Stratificati o ns  ....................................................................................... 1 3  
3. 3  
Ce nters P o ols  ......................................................................................................... 1 3  
3. 4  
Ti me p oi nts a n d Visit Wi n d o ws  ............................................................................. 1 3  
4  
Data A nal ysis  ..................................................................................................................... 1 3  
4. 1  
P o p ulati o ns f or A nal ysis  ........................................................................................ 1 4  
4. 1. 1  
S u bject Dis p ositi o n  ............................................................................... 1 4  
4. 1. 2  
Pr ot oc ol De viati o ns ............................................................................... 1 4  
4. 1. 3  
A nal ysis P o p ulati o ns ............................................................................. 1 5  
4. 2  
S u bject De m o gra p hics a n d Ot her Baseli ne C haracteristics  ................................... 1 6  
4. 2. 1  
De m o gra p hic C haract eristics  ................................................................ 1 6  
4. 2. 2  
Ge ner al Me dical Hist or y  ....................................................................... 1 6  
4. 3  
Treat me nts ( St u d y Pr o d uct, Resc ue Me dicati o n, ot her C o nc o mita nt 
T hera pies, C o m plia nce)  ......................................................................................... 1 6  
4. 3. 1  
St u d y Pr o d uct C o m plia nce a n d E x p os ure  ............................................. 1 7  
4. 3. 2  
Pri or a n d C o nc o mita nt Me dicati o n  ....................................................... 1 7  
4. 4  
A nal ysis of Efficac y  .............................................................................................. 1 8  
4. 4. 1  
Pri mar y Efficac y E n d p oi nt  .................................................................... 1 8  
4. 4. 2  
Sec o n dar y Efficac y E n d p oi nts  .............................................................. 2 0  
4. 4. 3  
E x pl orat or y Effi cac y Varia bles  ............................................................. 2 6  
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 4  of 4 5  
4. 4. 4  
Ha n dli n g of Missi n g Val ues/ Ce ns ori n g/ Disc o nti n uati o ns  .................... 2 7  
4. 5  
A nal ysis of Safet y  .................................................................................................. 2 8  
4. 5. 1  
A d verse E v e nts a n d Seri o us A d verse E v e nts  ........................................ 2 8  
4. 5. 2  
Ot her Safet y V aria bles  .......................................................................... 2 8  
4. 6  
A nal ysis of Ot her V aria bles  ................................................................................... 2 9  
4. 6. 1  
Re peata bilit y of t he E xa mi ner  ............................................................... 2 9  
5  
C ha n ges t o t he Pr ot oc ol Defi ne d Statistical A nal ysis Pla n  ............................................... 3 0  
A p pe n di x 1: List of Data Dis pla ys .................................................................................... 3 3  
 
Li st of T a bl e s  
Ta ble 1 - 1 
Sc he d ule of A cti vities  ............................................................................. 8 
Ta ble 1 - 2 
St u d y O bjecti ves a n d E n d p oi nts ........................................................... 1 0  
Ta ble 1 - 3 
I n v esti gati o nal/ St u d y Pr o d uct S u p plies ................................................ 1 1 
Ta ble 4 - 1 
Blee di n g I n d e x Sc ori n g S yste m ............................................................ 1 8  
Ta ble 4 - 2 
M o difie d Gi n gi val I n d e x Sc ori n g S yste m............................................. 2 3  
Ta ble 4 - 3 
T ures k y Pla q ue I n d e x Sc ori n g S yste m ................................................. 2 4  
Ta ble 5 - 1 
C ha n ges t o t he Pr ot oc ol Defi ne d Statistical A nal ysis Pla n  ................... 3 1 
 
 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 5  of 4 5  
A b br e vi ati o n s  
A E  
A d v er s e E v e nt  
A N C O V A  
A n al y si s of C o v ari a n c e  
B D R M  
Bli n d D at a R e vi e w M e eti n g  
BI  
Bl e e di n g I n d e x  
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  
C S  
C o m p o u n d S y m m etr y  
I C F 
I nf or m e d C o n s e nt F or m 
L O C F  
L a st O b s er v ati o n C arri e d F or w ar d  
L S  
L e a st S q u ar e  
M e d D R A  
M e di c al Di cti o n ar y f or R e g ul at or y A cti viti e s  
M F C  
M a st er F or m ul ati o n C o d e  
M GI  
M o difi e d Gi n gi v al I n d e x  
mI T T  
M o difi e d I nt e nt -t o-Tr e at  
M M R M  
Mi x e d M o d el f or R e p e at e d M e a s ur e s  
N B S  
N u m b er of Bl e e di n g Sit e s  
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  
P P  
P er -Pr ot o c ol  
P T  
Pr ef err e d T er m  
S A E  
S eri o u s A d v er s e E v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
S D  
St a n d ar d D e vi ati o n  
S E  
St a n d ar d Err or  
S O C  
S y st e m Or g a n Cl a s s  
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  
T PI  
T ur e s k y Pl a q u e I n d e x  
w/ w  
W ei g ht f or W ei g ht  
W H O D D  
W orl d H e alt h Or g a ni z ati o n Dr u g Di cti o n ar y  
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Pa ge 6  of 4 5  
T he p ur p ose of t his Statistical A nal ysis Pla n  ( S A P) is t o descri be t he pla n ne d a nal yses a n d 
o ut p uts t o be i ncl u de d i n t he Cli nical St u d y Re p ort f or Pr ot oc ol 3 0 0 1 0 7 ( Versi o n 2. 0, d ate d 
1 0- Oct - 2 0 2 3). 
1 
S u m m ar y of K e y Pr ot o c ol I nf or m ati o n  
T he p ur p ose of t his tri al is t o de m o nstrate t he efficac y a n d s afet y of a d e ntifrice c o ntai ni n g 
0. 4 5 4 % sta n n o us fl u ori d e ( S n F 2), o n gi n gi vitis treat me nt a n d pla q u e re d u cti o n, c o m pare d t o a 
re g ular fl u ori de d e ntifrice after 1 2 w ee ks t wi ce dail y br us hi n g i n a p o p ulati o n of cli nicall y 
dia g n ose d  gi n gi vitis  wit h o ut  u n der g oi n g  de ntal  pr o p h yla xis.  Gi n gi val  healt h  a n d  pla q ue  
re d ucti o n  will  be  e val u ate d  usi n g  blee di n g  i n d e x  ( BI),  n u m b er  of  blee di n g  sites  ( N B S),  
m o difie d gi n gi val i n de x ( M GI) a n d  T ures k y m o dificati o n of t he Q ui gle y Hei n Pla q ue I n de x 
( T PI). 
T he st u d y will f oll o w a ra n d o mize d, c o ntr olle d, si n gle bli n d (e xa mi ner bli n d), t w o -treat me nt 
ar m, parallel st u d y. St u d y s u bjects will be o ver 1 8 years ol d, n o n -s m o kers, i n g o o d ge neral 
healt h wit h cli nicall y meas ura ble le vels of gi n gi vitis t hat meet all st u d y criteria at t he Scree ni n g 
a n d Baseli ne visits.   
A p pr o xi matel y  1 6 0  s u bj ects  (a p pr o xi matel y  8 0  per  gr o u p)  will  be  ra n d o mize d  t o  e ns ure  
a p pr o xi matel y 1 4 4 e val u a ble s u bjects (a p pr o xi matel y 7 2 per gr o u p) c o m plete t he st u d y. 
1. 1   
St u d y De si g n  
T his  will  be  a  si n gle  ce nter,  c o ntr olle d,  si n gle  bli n d  (e x a mi ner  bli n d),  ra n d o mize d,  
t w o--treat me nt ar m, par allel st u d y. St u d y s u bjects will be o ver 1 8 years ol d, n o n -s m o kers, i n 
g o o d ge neral healt h wit h cli nicall y meas ura ble le v els of gi n gi vitis t hat meet all st u d y criteria at 
t he Scree ni n g  a n d B aseli ne visits.  
A p pr o xi matel y 1 6 0 s u bjects (a p pr o xi matel y n = 8 0 per gr o u p) will be ra n d o mize d t o e ns ure  
a p pr o xi matel y 1 4 4 e val u a ble s u bjects (a p pr o xi matel y 7 2 per gr o u p) c o m plete t he st u d y. 
T his st u d y will c o nsist of 5 st u d y visits: Scree ni n g, Baseli ne, Wee k 3, 6 a n d  1 2. Gi n gi vitis will 
be assess e d usi n g M GI ( L o be ne et al, 1 9 8 6 ) a n d BI (Sa xt o n a n d va n d er  O u deraa, 1 9 8 9 ). ( T h e 
N B S will be deri ve d fr o m BI assess me nt). Pla q u e will be ass esse d usi n g  T PI ( L o be ne et al, 
1 9 8 2 ). 
All e val ua ble teet h (i n r elati o n t o t he i ncl usi o n/ e xcl usi o n ge neral de ntiti o n criteria) will be  
assesse d.  
At t he Scr ee ni n g  visit  ( Visit  1),  s u bjects  will  pr o vi de  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 gr a p hics,  me dical  hist or y,  a n d  c urre nt  m e dicati o ns  will  be  
rec or d e d, f oll o we d b y a n oral e xa mi nati o n ( oral s oft tiss ue ( O S T) e xa mi nati o n, oral har d tiss ue 
( O H T) e x a mi nati o n, de ntiti o n   e xcl usi o ns,  a  gr oss  gi n gi val assess me nt  a n d  p oc ket  de pt h 
assess me nt ). 
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Eli gi ble  s u bjects will  be gi ve n a was h o ut d e ntifrice  a n d t o ot h br us h t o use i n bet wee n  Scree ni n g 
a n d Baseli ne Visits.   T he y will als o be iss ue d wit h a st u d y diar y t o rec or d pr o d uct usa ge. 
Wit hi n  1 4 ± 3 da ys of Scr ee ni n g  ( Visit 1),  eli gi ble s u bjects will  ret ur n t o t he site f or t h e Bas eli ne 
visit  ( Visit 2) wit h  o ver ni g ht pla q ue (s u bjects will  be i nstr ucte d t o a bstai n fr o m oral  h y gie ne f or 
1 2 h o urs [ + 6 h o urs; - 2 h o urs] i m me diatel y bef ore t he visit). 
At t he Baseli ne visit, s u bjects will u n der g o, i n t he f oll o wi n g or der, a f ull O S T e xa mi nati o n, 
gi n gi val i nfla m mati o n ( M GI), gi n gi val blee di n g ( BI), s u pra-gi n gi val pla q ue ( T PI). S u bjects 
wit h blee di n g sites % ( deri ve d fr o m BI assess me nt) or T PI  sc ore o utsi de t he i ncl usi o n criteri a 
ra n ge will be disc o nti n ue d fr o m t he st u d y at t his visit. Eli gi ble s u bjects will be stratifie d 
acc or di n g  t o t heir se x ( m ale or f e male) t o e ns ure a bala nce  of se x acr oss b ot h treat me nt gr o u ps 
a n d t he n ra n d o mize d t o st u d y pr o d uct. T he  s u bjects will  t he n be i nstr ucte d t o br us h f or  at l east 
o ne (ti me d) mi n ute at site wit h t heir assi g ne d st u d y  pr o d uct (s u per vise d br us hi n g) after w hic h 
t he y will be i nstr ucte d t o c o nti n ue usi n g t heir pr o d uct t wice dail y ( m or ni n g a n d e ve ni n g u ntil 
t heir ne xt visit), at least o ne (ti me d) mi n ute eac h ti me. 
After usi n g t he st u d y de ntifrice f or 3, 6, a n d 1 2 wee ks, s u bjects will ret ur n t o t he st u d y site 
( Visits 3, 4, a n d 5, res pecti vel y) wit h o ver ni g ht pla q ue (s u bjects will be i nstr ucte d t o a bstai n 
fr o m  o ver ni g ht  t o ot h br us hi n g f or 1 2  h o urs [ + 6  h o urs;  -2 h o urs] i m me diatel y  bef ore eac h  
assess me nt visit), at a p pr o xi matel y t he s a me ti me of d a y as t he Bas eli ne visit. T he st u d y 
de ntifrice  a n d t he diar y  will  be r e vie we d t o deter mi ne  treat me nt c o m plia nce.  S u bjects  will  ha v e 
a f ull O S T  e xa mi nati o n  a n d t he n u n der g o, i n t he f oll o wi n g or der,  M GI,  BI,  a n d T PI.  At  Visit  5, 
s u bjects will als o ha ve a f ull O H T e xa mi nati o n, ret ur n all st u d y s u p plies a n d ha v e a de ntal 
pr o p h yla xis if dee me d a p pr o priate b y t he i n vesti gat or or e xa mi ner. 
At  Visits  2, 3, 4, a n d 5, r e peata bilit y data  will  be ge nerat e d  f or M GI  a n d T PI  assess me nts  fr o m 
re plicate e x a mi nati o ns o n t he sa me s u bject (t he s u bject f or t he M GI  re peat assess me nt a n d t he 
s u bject f or t he T PI re peat assess me nt ca n b e differe nt). De p e n di n g o n s u bject visit sc he d uli n g, 
e ver y eff ort  will  be ma d e  t o c o m plete o n e re p eat a bilit y e xa mi nati o n  f or eac h cli nical meas ure  
d uri n g eac h cli nical assess me nt da y, t hat is, at least o ne M GI, a n d o ne  T PI  re peat assess me nt 
o n eac h assess me nt   da y. Re peata bilit y  e xa mi nati o ns will   be se parate d  b y a mi ni m u m   of  1 0 
mi n utes  a n d, w here p ossi ble, se parate d b y a n ot her s u bject. D ue t o t he i n vasi ve nat ure of t he BI 
assess me nt, it is n ot feasi ble t o c o n d uct a n acc urat e re peata bilit y assess me nt f or t his i n de x.  
Safet y a n d oral t olera bilit y of t he st u d y de ntifrices will be m o nit ore d o ver t he 1 2 -wee k usa ge 
peri o d b y r e vie w of T E A Es. Me dical de vi ce i nci d e nts will be rec or de d (t h e me dical d e vice i n 
t his st u d y is t he ma n ual t o ot h br us h use d t o a p pl y t he st u d y t o ot h pastes) t hr o u g h o ut t he st u d y. 
Ta ble 1 - 1 pr ese nts t he sc he d ule of acti vities. 
 
 
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Pa ge 8  of 4 5  
T a bl e 1- 1 
S c h e d ul e of A cti viti e s  
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  Vi sit s  
 
Vi sit  1 
 
Vi sit  2 
D a y  0 
B a s eli n e 1 
Vi sit  3 
D a y  2 1 ± 3  
( W e e k 3) 1 
Vi sit  4 
D a y  4 2 ± 4  
( W e e k 6) 1 
Vi sit  5 
D a y  8 4 ± 4  
( W e e k 1 2) 1 
I nf or m e d c o n s e nt  
X 
W a s h o ut  p eri o d  1 4  d a y s ± 3  d a y s  
 
 
 
 
M e di c al  hi st or y  
X 
 
 
 
 
D e m o gr a p hi c s  
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 
O S T  E x a mi n ati o n  
X 
X 
X 
X 
X 
O H T  E x a mi n ati o n  
X 
 
 
 
X 
Gr o s s  gi n gi v al 
a s s e s s m e nt 2 
X 
 
 
 
 
P o c k et  D e pt h A s s e s s m e nt 2  
X 
 
 
 
 
R e vi e w  of 
I n cl u si o n/ e x cl u si o n Crit eri a 
 
X 
 
X 
 
 
 
S u bj e ct  eli gi bilit y  
X 
X 
 
 
 
S u bj e ct  c o nti n u a n c e  
 
 
X 
X 
X 
Di s p e n s e t o ot h br u s h 
w a s h o ut  t o ot h p a st e, a n d 
w a s h o ut di ar y 3 
 
X 
 
 
 
 
R et ur n W a s h o ut 
T o ot h p a st e/ T o ot h br u s h  
 
X 
 
 
 
M o difi e d  Gi n gi v al  I n d e x 
( M GI) a s s e s s m e nt 
 
X 
X 
X 
X 
M GI  r e p e at a bilit y 
a s s e s s m e nt 4 
 
X 
X 
X 
X 
Bl e e di n g  I n d e x ( BI) 
a s s e s s m e nt 5 
 
X 
X 
X 
X 
Pl a q u e  di s cl o s ur e  a n d 
pl a q u e i n d e x ( T PI) 
a s s e s s m e nt s  
 
 
X 
 
X 
 
X 
 
X 
T PI  r e p e at a bilit y 
a s s e s s m e nt 6 
 
X 
X 
X 
X 
R a n d o mi z ati o n  
 
X 
 
 
 
Di s p e n s e  st u d y  pr o d u ct s, 
ti m er, a n d st u d y di ar y 
 
X 
 
 
 
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Or al  h y gi e n e  i n str u cti o n & 
s u p er vi s e d br u s hi n g wit h 
st u d y d e ntifri c e 7 
 
 
X 
 
X 
 
X 
 
R e vi e w  di ar y  c o m pl eti o n  
 
X 
X 
X 
X 
C oll e ct  st u d y  pr o d u ct s,  
a s s e s s  c o m pli a n c e,  a n d 
r et ur n t o s u bj e ct 
 
 
 
X 
 
X 
 
R et ur n  st u d y  pr o d u ct s ( e n d 
of st u d y)  
 
 
 
 
X 
E n d of st u d y d e nt al 
pr o p h yl a xi s  ( o pti o n al) 
 
 
 
 
X 
A d v er s e  e v e nt s  r e vi e w8  
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 
 
X 
X 
X 
X 
St u d y  c o n cl u si o n  
 
 
 
 
X 
A b br e vi ati o n s:  O S T: Or al S oft Ti s s u e, O H T: Or al H ar d Ti s s u e, M GI: M o difi e d Gi n gi viti s I n d e x, BI: 
bl e e di n g i n d e x; T PI: T ur e s k y Pl a q u e  I n d e x. 
F o ot n ot e s:  
1:   S u bj e ct s  will  a b st ai n  fr o m o v er ni g ht  t o ot h br u s hi n g f or a mi ni m u m  of  1 2 hr s  ( + 6 hr, -2 hr)  i m m e di at el y 
pri or  t o t h e a s s e s s m e nt  vi sit s  ( Vi sit s 2,  3, 4 a n d 5)  
2:   I n r el ati o n t o t h e g e n er al  d e ntiti o n  i n cl u si o n/ e x cl u si o n  crit eri a   
3:  N o i n str u cti o n or s u p er vi s e d br u s hi n g at s cr e e ni n g vi sit  
4:   Mi ni m u m  o n e  M GI  r e p e at a bilit y a s s e s s m e nt s  d uri n g  e a c h  cli ni c al  a s s e s s m e nt  d a y; M GI  
r e p e at a bilit y a s s e s s m e nt  at  B a s eli n e  vi sit will  b e  c o n d u ct e d aft er t h e s u bj e ct’ s eli gi bilit y h a s b e e n 
c o nfir m e d.  
5:   N B S  a n d  bl e e di n g  sit e s %  ar e  d eri v e d  fr o m BI  a s s e s s m e nt  
6:  Mi ni m u m o n e T PI r e p e at a bilit y a s s e s s m e nt s d uri n g e a c h cli ni c al a s s e s s m e nt d a y;  T PI r e p e at a bilit y 
a s s e s s m e nt at B a s eli n e vi sit  will b e  c o n d u ct e d aft er t h e s u bj e ct’ s eli gi bilit y h a s b e e n c o nfir m e d.  
7:   At  B a s eli n e  vi sit,  sit e  will  c o nfir m  t h at 2 n d  t o ot h br u s h h a s  n ot  b e e n  u s e d  b ef or e  t h e s u p er vi s e d  
br u s hi n g  
8:   A d v er s e  E v e nt s ( A E s), S eri o u s A d v er s e  E v e nt s ( S A E s)  a n d m e di c al  d e vi c e  i n ci d e nt s c oll e ct e d 
i m m e di at el y aft er  s u bj e ct pr o vi d e s c o n s e nt  t o p arti ci p at e i n t h e st u d y b y t h e c o m pl eti o n of t h e 
I nf or m e d C o n s e nt F or m (I C F). 
 
 
 
 
 
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1. 2   
St u d y Obj e cti v e s  
St u d y o bjecti ves a n d e n d p oi nts are defi ne d i n T a ble 1 - 2. 
T a bl e 1- 2 
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 ve s  
E n d p oi nt s  
Pri m ary O bj ecti ve  
Pri m ary E n d p oi nt  
T o a s s e s s t h e p erf or m a n c e of a d e ntifri c e  
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2  i n r e d u ci n g 
gi n gi viti s, a s m e a s ur e d b y N B S, aft er 1 2  
w e e k s t wi c e d ail y t o ot h br u s hi n g.  
At W e e k 1 2:  
•  
C h a n g e fr o m B a s eli n e i n N B S  
S e c o n d ary O bje cti ve s  
S e c o n d ary  E n d p oi nt s 
Effi c a c y  
 
T o e v al u at e t h e effi c a c y of a d e ntifri c e 
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2  i n r e d u ci n g 
gi n gi viti s, a s m e a s ur e d b y N B S, c o m p ar e d t o 
a n e g ati v e c o ntr ol aft er 1 2 w e e k s t wi c e d ail y 
t o ot h br u s hi n g. 
At W e e k 1 2:  
•  
C h a n g e fr o m B a s eli n e i n N B S  
T o e v al u at e t h e effi c a c y of a d e ntifri c e 
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2  i n r e d u ci n g 
gi n gi viti s, a s m e a s ur e d b y N B S, c o m p ar e d t o 
a n e g ati v e c o ntr ol, aft er 3 a n d 6 w e e k s t wi c e 
d ail y t o ot h br u s hi n g.  
At W e e k s 3 & 6:  
•  
C h a n g e fr o m B a s eli n e i n N B S  
T o e v al u at e t h e effi c a c y of a d e ntifri c e 
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2  i n r e d u ci n g 
pl a q u e a c c u m ul ati o n, a s m e a s ur e d b y t h e 
T PI ( o v er all a n d i nt er pr o xi m al), c o m p ar e d t o 
a n e g ati v e c o ntr ol, aft er 3, 6 a n d 1 2 w e e k s 
t wi c e d ail y t o ot h br u s hi n g. 
At W e e k s 3, 6 & 1 2:  
•  
C h a n g e fr o m B a s eli n e i n M e a n T PI  
      ( o v er all a n d i nt er pr o xi m al) 
T o e v al u at e t h e effi c a c y of a d e ntifri c e  
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2  i n r e d u ci n g 
gi n gi viti s, a s m e a s ur e d b y BI, c o m p ar e d t o a 
n e g ati v e c o ntr ol, aft er 3, 6 a n d 1 2 w e e k s  
t wi c e d ail y t o ot h br u s hi n g. 
At W e e k s 3, 6 & 1 2:  
•  
C h a n g e fr o m B a s eli n e i n BI  
T o e v al u at e t h e effi c a c y of a d e ntifri c e  
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2  i n r e d u ci n g 
gi n gi viti s, a s m e a s ur e d b y M GI, c o m p ar e d t o 
a n e g ati v e c o ntr ol, aft er 3, 6 a n d 1 2 w e e k s 
t wi c e d ail y t o ot h br u s hi n g. 
At W e e k s 3, 6 & 1 2:  
•  
C h a n g e fr o m B a s eli n e i n M GI  
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 d e ntifri c e 
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2 , o v er 1 2 w e e k s 
t wi c e d ail y u s e. 
Tr e at m e nt -e m er g e nt a d v er s e e v e nt s o v er 1 2  
w e e k s  
E x pl or at or y O bj ecti v es  
E x pl or at or y E n d p oi nt s  
T o e x pl or e t h e effi c a c y of a d e ntifri c e  
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2  i n r e d u ci n g 
gi n gi viti s, a s m e a s ur e d b y N B S, BI a n d M GI, 
c o m p ar e d t o a n e g ati v e c o ntr ol, aft er 3, 6 
At W e e k s 3, 6 & 1 2:  
C h a n g e fr o m B a s eli n e i n  
•  
N B S  
•  
M e a n BI  
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O bj e cti ve s  
E n d p oi nt s  
a n d 1 2 w e e k s t wi c e d ail y t o ot h br u s hi n g,  i n 
t h e l o w a n d hi g h b a s eli n e M GI s u b gr o u p: 
 
•  
L o w: M GI ≤ 2 
•  
Hi g h: M GI >  2  
•  
M e a n M GI  
F or e a c h M GI s u b gr o u p  
T o e x pl or e t h e effi c a c y of a d e ntifri c e  
c o nt ai ni n g 0. 4 5 4 % w/ w S n F 2  i n r e d u ci n g 
pl a q u e a c c u m ul ati o n, a s m e a s ur e d b y T PI, 
c o m p ar e d t o a n e g ati v e c o ntr ol, aft er 3, 6 
a n d 1 2 w e e k s t wi c e d ail y t o ot h br u s hi n g,  i n 
t h e l o w a n d hi g h b a s eli n e M GI s u b gr o u p: 
 
•  
L o w: M GI ≤ 2 
•  
Hi g h: M GI >  2  
At W e e k s 3, 6 & 1 2:  
C h a n g e fr o m B a s eli n e i n  
•  
M e a n T PI ( o v er all a n d i nt er pr o xi m al)  
F or e a c h M GI s u b gr o u p  
 
T his st u d y will be c o nsi d ere d s u ccessf ul if t here is a statisticall y si g nifica nt differe nce i n N B S 
after 1 2 wee ks of t wi ce dail y br us hi n g wit h t he S n F 2  de ntifrice c o m pare d t o its baseli ne a n d 
t he differ e nce is i n f a v or of t he S nF 2  de ntifrice.  
1. 3   
Tr e at m e nt s 
Ta ble 1 - 3 pr ese nts t he st u d y pr o d ucts. 
T a bl e 1- 3 
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 
Pr o d u ct D e s cri pti o n  
T e st Pr o d u ct  
R ef er e n c e Pr o d u ct  
( n e g ati v e c o ntr ol) 
Pr o d u ct N a m e  
P ar o d o nt a x C o m pl et e  Pr ot e cti o n  
( 0. 4 5 4 % w/ w S n F2 ) 
Cr e st C a vit y Pr ot e cti o n  ( 0. 2 4 3 % 
w/ w s o di u m  fl u ori d e) 
P a c k D e si g n  
C art o n of 6 o v er -wr a p p e d  t u b e s 
C art o n of 6 o v er -wr a p p e d  t u b e s 
Di s p e n si n g D et ail s  
O n e c art o n –  b a s eli n e vi sit  
O n e c art o n –  b a s eli n e vi sit  
Pr o d u ct M a st er  
F or m ul ati o n C o d e 
( M F C) 
 ( C o m m er ci al Pr o d u ct)  
C o m m er ci al Pr o d u ct  
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 
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  
Or 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  f or 
at l e a st o n e (ti m e d) mi n ut e  t wi c e a 
d a y ( m or ni n g a n d  e v e ni n g)  
S u bj e ct s will br u s h t h eir t e et h  f or 
at l e a st o n e (ti m e d) mi n ut e  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  
All u s e d/ u n u s e d s a m pl e s t o b e  
r et ur n e d 
All u s e d/ u n u s e d s a m pl e s t o b e  
r et ur n e d 
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Pa ge 1 2  of 4 5  
Detaile d i nstr ucti o ns f or t he ret ur n of st u d y pr o d uct/st u d y s u p plies f or t he acc o u nta bilit y c hec ks  
a n d s u bse q ue nt destr ucti o n w hic h will be pr o vi de d b y Hale o n d uri n g t he st u d y i n ti me f or st u d y  
cl ose o ut visit.  
1. 4   
S a m pl e Si z e C al c ul ati o n 
T he pri mar y e n d p oi nt f or t his st u d y is “ C ha n ge fr o m Baseli ne i n N B S at Wee k 1 2 f or t he test  
pr o d uct (c o ntai ni n g 0. 4 5 4 % w/ w S n F 2)”. T h ere w ere n o pre vi o us si milar st u dies w here b ot h a 
n o n- pre -pr o p h yla xis w as use d i n c o nj u ncti o n wit h t he sa me or si milar acti ve i n gre die nt i n t he 
test pr o d uct. T h us, d ue t o t he u ncertai nt y of w hat w o ul d be e x pecte d i n ter ms of c ha n ge fr o m 
baseli ne f or t he test pr o d uct  gi ve n t he af ore me nti o ne d para meters, treat me nt efficac y esti mates 
f or t he sec o n d ar y o bjecti ve ( c ha n g e fr o m b aseli ne i n BI f or t est de ntifrice  c o m pare d t o c ha n g e 
fr o m baseli ne i n BI f or r efer e nce de ntifrice ) were use d i nstea d. T w o s p o ns or  cli nical st u dies 
t hat i ncl u de d pr e-pr o p h yla xis ( Par ki ns o n et al, 2 0 1 4 a n d H ale o n St u d y 2 1 2 5 3 7)  were us e d as 
refere nce t o  esti mate efficac y  of  t est  de ntifrice  ( 0. 4 5 % w/ w  S n F2) c o m pare d  t o refere nce 
de ntifrice ( n e gati ve c o ntr ol). I n t hes e t w o st u dies, t he mea n differe n ce b et wee n  t he test a n d 
refere nce pr o d u ct r e p ort e d a m ea n differe nce i n BI of 0. 0 7 bet wee n gr o u ps wit h sta n dar d 
de viati o n ( S D) ra n gi n g fr o m 0. 0 4 t o 0. 1 2 8 at 1 2 w ee ks. D ue t o t h e u ncertai nt y of w hat w o ul d 
be e x pecte d i n ter ms of t he ra n g e of mea n differe nces w he n s u bjects d o n ot u n der g o a pre -
pr o p h yla xis, a hi g her S D of 0. 1 2 8 was use d t o cal c ulate t he sa m ple size f or t his st u d y. 
T he perce nt differ e nces fr o m c o ntr ol i n t he refere n ce st u dies re mai ne d c o nsiste nt ( ~ 4 0 % - 6 0 % 
i n fa v or of t he test de ntifrice) i n t he st u dies me nti o ne d a b o ve, t h us a n ass u m pti o n was ma de 
t hat t hese n u m bers w o ul d n ot fall far fr o m t hat ra n ge i n t his st u d y. 
Base d  o n  t he  ass u m pti o ns  o utli ne d  a b o ve,  a  s a m ple  size  of  a p pr o xi matel y  1 6 0  s u bjects  
(a p pr o xi matel y  8 0  p er  gr o u p)  will  be  ra n d o mize d  t o  e ns ure  a p pr o xi matel y  1 4 4  e v al ua bl e 
s u bjects (a p pr o xi matel y 7 2 per gr o u p) c o m plete t he st u d y (ass u mi n g a 1 0 % dr o p o ut rate); t his  
will pr o vi de s ufficie nt p o wer ( 9 0 %) t o ac hie ve statistical si g nifica nce (at t he 5 %, t w o -si de d 
le vel) f or t he k e y sec o n d ar y o utc o me.  
2 
Pl a n n e d A n al y s e s  
2. 1   
I nt eri m A n al y si s 
N o i nteri m a nal ysis is pla n ne d. 
2. 2   
Fi n al A n al y s e s 
T he fi nal pla n n e d pri mar y a nal yses will be perf or me d aft er t he c o m pleti o n of t he f oll o wi n g 
se q ue ntial ste ps: 
1.  All s u bjects ha ve c o m plete d t he st u d y as defi ne d i n t he pr ot oc ol. 
2.  All re q uire d dat a base clea ni n g acti vities i ncl u di n g a n y e xter n al data rec o nciliati o n ha ve 
bee n c o m plete d a n d data base has bee n l oc ke d. 
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Pa ge 1 3  of 4 5  
3.  All criteria f or u n bli n di n g t he ra nd o mizati o n  c o d es ha ve bee n m et a n d t he ra n d o mizati o n 
c o des ha ve b ee n distri b ut e d. 
3  
C o n si d er ati o n s f or D at a A n al y s e s  a n d D at a  H a n dli n g 
C o n v e nti o n s  
3. 1   
B a s eli n e D efi niti o n 
F or all e n d p oi nts, t he bas eli ne val ue will be t he Da y 0 ( Visit 2) pre -br us hi n g assess me nt wit h a 
n o n- missi n g val ue.  
U nless ot her wise state d, if baseli ne data is missi n g n o deri vati o n will be perf or me d a n d t he 
baseli ne val ue will be s et t o missi n g.  
3. 2   
S u b gr o u p s/ Str atifi c ati o n s 
S u bjects  w h o satisf y t he st u d y selecti o n criteria  will be stratifie d acc or di n g t o t heir  se x ( male 
or fe male) a n d r a n d o mize d t o st u d y treat me nt.   
E x pl orat or y s u b gr o u p a n al yses will be c o n d ucte d t o e val uate a n d c o m p are N B S , mea n BI, mea n  
M GI  a n d mea n T PI ( o verall a n d i nter pr o xi mal)  i n t he l o w ( ≤ 2) a n d hi g h ( > 2) baseli ne mea n 
M GI s u b gr o u ps. 
3. 3   
C e nt er s P o ol s 
Si nce t his is a si n gle ce nter st u d y, p o oli n g of ce nters is n ot a p plica ble. 
3. 4   
Ti m e p oi nt s a n d Vi sit Wi n d o w s 
T he ti me p oi nts a n d visits f or t his st u d y are defi ne d i n Ta ble 1 - 1 “ Sc he d ule of Acti vities”. A n y 
de viati o n fr o m t he st u d y sc he d ule ma y b e re vi e we d o n a cas e - b y-case b asis at t he Bli n d Data 
Re vie w Meeti n g ( B D R M) t o deter mi ne w h et her t he d ata s h o ul d b e e x cl u de d fr o m t he Per 
Pr ot oc ol ( P P) p o p ulati o n. 
4 
D at a A n al y si s  
Data a nal ysis will be perf or me d b y 
 wit h o versi g ht fr o m Hale o n. T he statistical 
a nal ysis s oft war e use d will be S A S versi o n 9. 4 or hi g her.   
Pri or t o data base cl os ur e a B D R M will be c o n d ucte d i n w hic h vari o us as pects of t he trial will 
be disc usse d a n d a gree d.  
E xce pt as des cri be d b el o w, all listi n gs will be pr o d uce d f or all ra n d o mize d s u bjects.   
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Pa ge 1 4  of 4 5  
4. 1   
P o p ul ati o n s f or An al y si s  
4. 1. 1  
S u bj e ct D i s p o siti o n 
Scree n f ail ures ar e 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. A n e nr olle d s u bject is a s u bject w h o has si g ne d i nf or me d c o nse nt 
a n d is eli gi ble t o pr ocee d be y o n d t he scree ni n g visit. 
T he n u m ber of s u bjects scree n e d, e nr olle d, a n d ra n d o mize d will be prese nt e d i n  Ta ble 1 4. 1. 1 . 
T he n u m ber a n d perce nt a ge of scr ee n fail ure s u bjects (s u bjects n ot ra n d o mize d) wit h reas o ns 
w h y s u bjects are n ot ra n d o mize d will be dis pla ye d. Perce nta ges f or scree n fail ure s u bjects will 
be base d o n t he t otal n u m ber of s u bjects scree n e d.  
T he n u m ber a n d per ce nt a ge of ra n d o mize d s u bjects w h o c o m plete a n d disc o nti n ue t he st u d y, 
br o ke n d o w n b y reas o n f or disc o nti n uati o n, will be prese nte d b y st u d y pr o d uct a n d o verall,  i n 
Ta ble  1 4. 1. 1. T he p erce nta ges will be base d o n t h e n u m ber of s u bjects ra n d o mize d. 
Ta ble 1 4. 1. 1  will als o prese nt t he n u m ber a n d perce nta ge of ra n d o mize d s u bjects i n eac h of t he 
defi ne d  a n al ysis  p o p ulati o ns  (as  defi ne d  i n  Secti o n  4. 1. 3 )  b y st u d y  pr o d uct a n d  o verall.  
Perce nta g es will be base d o n t he n u m ber of s u bjects ra n d o mize d . 
S u bject dis p ositi o n i ncl u di n g de m o gra p hic data (a ge, se x, race a n d et h nicit y), scree ni n g d ate, 
st u d y  pr o d uct start  dat e/ti me,  s u bject  stat us  (c o m pleter,  Yes/ N o),  st u d y  c o m pleti o n  or  
wit h dra wal  date , d urati o n (i n da ys) i n t he st u d y ( defi ne d as [( date of c o m pleti o n or wit h dra wal 
– st u d y pr o d uct start d ate) + 1], a n d t he pri mar y reas o n f or wit h dra w al a n d f urt her det ails f or 
wit h dra wal will be liste d ( Listi n g 1 6. 2. 1. 1) b y st u d y pr o d uct. 
S u bject dis p ositi o n i nf or mati o n will be liste d f or n o n -ra n d o mize d s u bjects (Listi n g 1 6. 2. 1. 2 ), 
i ncl u di n g de m o gra p hic i nf or mati o n (a ge, se x race a n d et h nicit y), e nr olle d ( Yes/ N o), scree ni n g 
date, reas o n f or scree n fail ure a n d a n y f urt her d etails of reas o n f or s cree n fail ure. 
4. 1. 2  Pr ot o c ol D e vi ati o n s  
Pr ot oc ol de viati o ns will be trac k e d b y t he st u d y tea m t hr o u g h o ut t he c o n d uct of t he st u d y. Dat a 
will  be  re vie we d  pri or  t o  u n bli n di n g  a n d  cl os ure  of  t he  data base  t o  e ns ure  all  i m p orta nt  
de viati o ns are ca pt ure d a n d cate g orize d. S u bjects wit h i m p orta nt pr ot oc ol de viati o ns lia ble t o 
i nfl ue nce t h e efficac y o ut c o mes will be e xcl u d e d fr o m t he P P p o p ulati o n. S u bjects ma y als o b e 
i de ntifie d  as  ha vi n g  i m p orta nt  pr ot oc ol  de viati o ns  n ot  lea di n g  t o  e xcl usi o n  fr o m  t he  P P  
p o p ulati o n.  
I m p ort a nt de viati o ns of t he pr ot oc ol pr oce d ures m a y i ncl u de, b ut will n ot n ecessaril y be li mite d 
t o t he f oll o wi n g:  
•  C o nse nt pr oce d ur es 
•  I n cl usi o n or e xcl usi o n criteria 
•  C o nc o mita nt me dicati o n/t hera p y  
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Pa ge 1 5  of 4 5  
•  St u d y pr oce d ures 
•  Ra n d o mizati o n pr oce d ur es 
•  St u d y dr u g d osi n g/st u d y pr o d uct a d mi nistrati o n/st u d y pr o d uct c o m plia nce  
•  V isit sc he d ule/i nter val 
•  Ot her  
T he s pecific det ails of t he i m p orta nt pr ot oc ol de viati o ns will be liste d i n t he Pr ot oc ol De viati o n 
Ma na ge me nt Pla n, a n d t he assess me nt pr ocess will be s pecifie d i n t he Bli n d Data Re vie w Pla n . 
S u bjects wit h i m p orta nt pr ot oc ol de viati o ns will be i de ntifie d at t he B D R M.   
T he n u m ber a n d per ce nta ge of s u bjects wit h at least o ne i m p orta nt pr ot oc ol de viati o n, s u bjects 
wit h i m p orta nt pr ot oc ol de viati o ns n ot lea di n g t o e xcl usi o n fr o m P P p o p ulati o n wit h reas o ns 
f or de viati o ns a n d s u bjects wit h i m p orta nt pr ot oc ol de viati o ns lea di n g t o e xcl usi o n fr o m t he P P 
p o p ulati o n wit h reas o ns f or de viati o ns will be prese nte d b y  st u d y pr o d uct a n d o verall, f or all 
ra n d o mize d s u bjects ( Ta ble 1 4. 1. 2) a n d liste d i n Listi n g 1 6. 2. 2. 1. 
All pr ot oc ol de viati o ns c ollecte d o n t he pr ot oc ol d e viati o n case re p ort f or m  ( C R F) will be liste d 
i n Listi n g 1 6. 2. 2. 2 . T he listi n g will prese nt date of de viati o n, t y pe of de vi ati o n a n d de viati o n 
descri pti o n.  
4. 1. 3  A n al y si s P o p ul ati o n s  
Fi ve  a n al ysis p o p ulati o ns are defi ne d. 
   
P o p ul ati o n  
D efi niti o n / Crit eri a  
A n al y s es Ev al uat e d  
S af et y  
C o m pri s e of all r a n d o mi z e d s u bj e ct s w h o r e c ei v e 
at l e a st o n e d o s e  of t h e st u d y pr o d u ct.  
T hi s p o p ul ati o n will b e b a s e d o n t h e pr o d u ct t h e 
s u bj e ct a ct u all y r e c ei v e d. 
•  D e m o gr a p hi c s  
•  S af et y  
 
M o difi e d 
I nt e nt-T o -Tr e at 
( mI T T) 
C o m pri s e of all r a n d o mi z e d s u bj e ct s  w h o 
c o m pl et e at l e a st o n e u s e of st u d y p r o d u ct a n d 
h a v e at l e a st o n e p o st b a s eli n e cli ni c al  
p erf or m a n c e a s s e s s m e nt.  
T hi s p o p ul ati o n will b e b a s e d o n t h e st u d y pr o d u ct 
t o w hi c h t h e s u bj e ct w a s r a n d o mi z e d.  
A n y s u bj e ct w h o r e c ei v e s a r a n d o mi z ati o n 
n u m b er will b e  c o n si d er e d t o h a v e b e e n 
r a n d o mi z e d. 
•  D e m o gr a p hi c s  
•  C o m pli a n c e  
•  Effi c a c y  
 
P er -Pr ot o c ol ( P P ) 
C o m pri s e of all r a n d o mi z e d s u bj e ct s w h o d o n ot 
h a v e a n y  pr ot o c ol d e vi ati o n s  t h at c o ul d c o nf o u n d 
t h e i nt er pr et ati o n of a na l y s e s c o n d u ct e d o n t h e 
mI T T .  
T hi s p o p ul ati o n will b e b a s e d o n t h e st u d y pr o d u ct 
t o w hi c h t h e s u bj e ct w a s r a n d o mi z e d. 
•  Effi c a c y  
 
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Pa ge 1 6  of 4 5  
P o p ul ati o n  
D efi niti o n / Crit eri a  
A n al y s es Ev al uat e d  
Pr ot o c ol d e vi ati o n s t h at m a y e x cl u d e s u bj e ct s 
fr o m t h e P P p o p ul ati o n ar e d efi n e d i n S e cti o n 
4. 1. 2  ( Pr ot o c ol D e vi ati o n s) 
M GI R e p e at a bilit y  
C o m pri s e of all s u bj e ct s w h o h a v e at l e a st o n e 
r e p e at M GI cli ni c al a s s e s s m e nt at a n y vi sit. 
•  R e p e at a bilit y f or M GI  
T PI R e p e at a bilit y  
C o m pri s e of all s u bj e ct s w h o h a v e at l e a st o n e 
r e p e at T PI cli ni c al a s s e s s m e nt at a n y vi sit. 
•  R e p e at a bilit y f or T PI  
N O T E S:  
Pl e a s e r ef er t o  A p p e n di x 1 : Li st of D at a Di s pl a y s, w hi c h d et ail s t h e p o p ul ati o n t o b e u s e d f or e a c h 
di s pl a y b ei n g g e n er at e d.  
T he n u m bers of s u bjects i ncl u de d i n eac h of t he a nal ysis p o p ulati o ns  will be  prese nte d ( Ta bl e 
1 4. 1. 1 ). S u bjects e xcl u de d fr o m a n y of t he a nal ysis p o p ulati o ns will be liste d i n Listi n g 1 6. 2. 3. 1 , 
wit h t he reas o n f or e xcl usi o n.   
T he pri mar y p o p ulati o n f or assess me nt of efficac y will be t he mI T T p o p ulati o n.   A P P a nal ysis 
will be perf or me d o n t h e pri mar y e n d p oi nt o nl y if m ore t ha n  1 0 % of mI T T s u bjects are e x cl u de d 
fr o m t he P P p o p ulati o n. A decisi o n o n w het h er a P P a nal ysis will be perf or me d will be ma de 
pri or t o st u d y u n bli n di n g (release of t he ra n d o mizati o n c o des).  
A n y re peat cli nical dat a c ollecte d f or t he re peat a bilit y assess me nt will o nl y be use d t o assess 
re peat a bilit y. T he mai n assess me nt of effi cac y will be base d o n t he i nitial assess me nt. 
4. 2   
S u bj e ct D e m o gr a p hi c s a n d O t h er Ba s eli n e C h ar a ct eri sti c s  
4. 2. 1  D e m o gr a p hi c C h ar a ct eri sti c s  
Descri pti ve statistics [ n u m ber of s u bjects ( n), mea n, S D, me dia n, mi ni m u m a n d ma xi m u m f or 
c o nti n u o us  varia bles,  fr e q ue nc y  c o u nt  ( n)  a n d  perce nt a ge  ( %)  of  s u bjects  f or  cat e g orical  
varia bles] will be pr ese nt e d f or de m o gra p hic c h aracteristics b y st u d y pr o d uct a n d o verall. T hese 
varia bles i ncl u de a g e ( y ears) , se x, race, et h nicit y a n d baseli ne M GI s u b gr o u p, a n d will be 
prese nte d f or t he Safet y p o p ulati o n ( Ta ble 1 4. 1. 3. 1 ) a n d t he mI T T p o p ulati o n (Ta ble 1 4. 1. 3. 2 ) . 
De m o gra p hic i nf or mati o n will be liste d f or all ra n d o mize d s u bjects i n Listi n g 1 6. 2. 4. 1. 
4. 2. 2  G e n er al M e di c al H i st or y 
Me dical a n d s ur gical hist or y (i n t he last y ear) i n cl u di n g aller gies or dr u g  se nsiti vit y will be 
liste d i n Listi n g 1 6. 2. 4. 2, wit h start date a n d e n d d ate or o n g oi n g at t he start of st u d y pr o d uct. 
4. 3   
Tr e at m e nt s ( St u d y Pr o d u ct, Re s c u e M e di c ati o n, ot h er C o n c o mit a nt 
T h er a pi e s, C o m pli a n c e) 
Ra n d o mizati o n details will be liste d, i ncl u di n g t he ra n d o mizati o n n u m ber, stratificati o n gr o u p, 
t he pla n ne d st u d y pr o d u ct, t he act ual st u d y pr o d uct t he s u bject w as ra n d o mize d t o a n d t he 
ra n d o mizati o n date ( Listi n g 1 6. 1. 7. 1). 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 1 7  of 4 5  
T he st u d y pr o d uct kit all ocati o ns will be liste d ( Listi n g 1 6. 1. 7. 2), i ncl u di n g kit n u m ber a n d 
st u d y pr o d uct i nf or mati o n.  
4. 3. 1  St u d y Pr o d u ct  C o m pli a n c e  a n d E x p o s ur e  
C o m plia nce data will be s u m marize d f or t he mI T T p o p ulati o n a n d will be assesse d b y n u m ber 
of br us hi n gs. 
N u m ber of br us hi n gs, br us hi n g c o m plia nce ( %), n u m ber of misse d br us hi n gs a n d n u m ber of 
a d diti o nal br us hi n gs will be s u m marize d usi n g descri pti ve statistics b y c u m ulati ve visit a n d b y 
st u d y pr o d uct. T he n u m ber a n d per ce nta g e of s u bjects < 8 0 %, bet w ee n 8 0 % - 1 2 0 % a n d > 1 2 0 % 
c o m plia nt i n eac h st u d y pr o d uct will als o be prese nte d b y c u m ulati ve visit a n d b y st u d y pr o d uct 
( Ta ble 1 4. 2. 1). 
N u m ber of br us hi n gs is d efi ne d as: [( date of Visit x – date of Visit 2) m ulti plie d b y 2 – n u m ber 
of misse d br us hi n gs + n u m ber of a d diti o nal br us hi n gs], w here x = 3, 4 a n d 5, res pecti vel y. 
Br us hi n g c o m plia nce ( %) is defi ne d as: [ 1 0 0 x ( Act ual n u m ber of br us hi n gs / E x pecte d n u m ber 
of br us hi n gs)], w here e x pecte d n u m ber of br us hi n gs is defi ne d as: [( date of Visit x – date of 
Visit 2) m ulti plie d b y 2].  
St u d y pr o d uct c o m plia nce ( n u m ber of br us hi n gs, br us hi n g c o m plia nce [ %], n u m ber of misse d 
br us hi n gs  a n d  n u m ber  of  a d diti o nal  br us hi n gs)  will  be  liste d  i n  Listi n g  1 6. 2. 5. 1  f or  all  
ra n d o mize d s u bjects b y st u d y pr o d uct. 
S u per vise d st u d y pr o d uct a p plicati o n (s u bject n u m ber, visit, date,  a n d ti me of t he s u per vise d 
pr oce d ur e) will be liste d ( Listi n g 1 6. 2. 5. 2) f or all ra n d o mize d s u bjects.  
4. 3. 2  Pri or a n d C o n c o mit a nt M e di c ati o n  
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 b al r e me dies, ta ke n i n t he l ast 3 0 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. T he pri or a n d c o nc o mita nt me dicati o ns will be 
c o de d usi n g a vali date d me dicati o n dicti o nar y, W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y 
( W H O D D). 
Pri or me dicati o n s a n d pri or n o n -dr u g t hera pies will be liste d b y s u bject, wit h dr u g na me, 
W H O D D dr u g  s y n o n y m , reas o n f or me dicati o n, r o ute, d ose, fre q u e nc y, start date, st art  da y 
relati ve t o t he st u d y pr o d uct start date, a n d e n d date a n d e n d da y relati ve t o t he st u d y pr o d uct 
start date (Listi n g  1 6. 2. 4. 3) f or all ra n d o mize d s u bjects. Pri or me dicati o ns are defi ne d as t h ose 
w hic h  st o p pe d bef ore t he  st u d y pr o d uct start date .  
C o nc o mita nt me dicati o ns a n d c o n c o mita nt n o n -dr u g t hera pies ta k e n d uri n g treat me nt will be 
liste d si milarl y (Listi n g  1 6. 2. 4. 4) f or all ra n d o mi ze d s u bjects wit h eit her o n g oi n g or e n d dat e 
dis pla ye d. C o nc o mita nt me dicati o ns are defi ne d as me dicati o ns t hat starte d or st o p pe d o n or 
after t he st u d y pr o d u ct start date or are o n g oi n g.  
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 1 8  of 4 5  
U n k n o w n dates will n ot be i m p ute d . Ho we v er , if t he start or st o p date is u n k n o w n, t he n it will 
be ass u me d t o be c o n c o mita nt me dicati o n u nless t he p artial start date or st o p date i n dicates 
differe ntl y.  
4. 4   
A n al y si s of Effi c a c y  
T he pri mar y p o p ulati o n f or assess me nt of effi cac y will be t he m I T T p o p ulati o n. N o re peat 
assess me nt data is t o be use d i n a n y efficac y a nal yses.  
Statistical a nal yses of t he e n d p oi nts will be perf or me d usi n g t he c ha n ge fr o m baseli ne, i n or der  
t o easil y prese nt direct esti mates f or t he wit hi n-treat me nt mea n c ha n ges fr o m baseli ne (e. g. t he 
pri mar y e n d p oi nt).  
Descri pti ve s u m mar y statistics will be prese nte d f or t he act ual a n d c ha n ge fr o m baseli ne v al ues  
at eac h ti me p oi nt.  
All p -val ues prese nt e d will be t w o -si de d a n d assess e d at t h e 5 % si g nifica nce le vel. A s e q ue ntial 
testi n g strate g y will be use d t o a dj ust f or m ulti plicit y f or t he c o m paris o n bet wee n test a n d 
refere nce pr o d u cts i n t he n u m ber of blee di n g sites at W ee k 1 2. T his will o nl y be assesse d f or  
c o nfir mat or y e vi d e nce if t he pri mar y e n d p oi nt (c h a n ge fr o m b aseli ne wit hi n t he test pr o d uct at 
W ee k 1 2) ac hi e ves a statisticall y si g nifica n t re d ucti o n. T here will be n o f urt her a dj ust me nts f or 
m ulti plicit y f or a n y ot her sec o n dar y e n d p oi nts.  
4. 4. 1  Pri m ar y E ffi c a c y E n d p oi nt  
4. 4. 1. 1  
Pri m ar y E ffi c a c y E n d p oi nt D efi niti o n  
T he pri mar y e n d p oi nt  f or t he st u d y is t he c ha n ge fr o m baseli ne N B S at Wee k 1 2 i n t he Test 
Pr o d uct gr o u p i n t he mI T T p o p ulati o n. 
T he BI will be assesse d o n t he facial a n d li n g ual gi n gi val s urfaces of eac h sc ora ble t o ot h ( 7-7 
i n eac h arc h). T hree sc ores (acc or di n g t o t he s cale i n Ta ble 4 - 1 bel o w) s h o ul d be rec or de d 
b uccall y/la biall y ( distal, b o d y a n d mesial sites) a n d t hree sc ores li n g uall y  ( distal, b o d y a n d 
mesial sites). At eac h visit, eac h s u bject t heref ore has u p t o 1 6 8 e val ua bl e t o ot h sites (i.e. 6 
meas ure me nts o n u p t o 2 8 sc ora ble teet h).  
T a bl e 4- 1 
Bl e e di n g I n d e x S c ori n g S y st e m  
S c or e D e s cri pti o n  
0  
N o bl e e di n g aft er 3 0 s e c o n d s  
1  
Bl e e di n g o b s er v e d wit hi n 3 0 s e c o n d s of pr o bi n g  
2  
Bl e e di n g o b s er v e d i m m e di at el y o n pr o bi n g  
9  
Mi s si n g t o ot h or n ot q u alifi e d t o ot h  
 
 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 1 9  of 4 5  
T he n u m ber of blee di n g sites f or eac h s u bject at eac h visit is calc ulat e d as t he n u m ber of 
e val ua ble t o ot h sites wit h a BI s c ore of eit her 1 or 2, t o gi ve a c o u nt bet wee n 0 a n d 1 6 8 sites. 
Descri pti ve statistics ( n, mea n , S D, sta n dar d err or [ S E], me dia n, mi ni m u m , a n d ma xi m u m) will 
be prese nte d f or t he n u m ber of blee di n g sites at eac h ti me p oi nt (a bs ol ute val ue , c ha n g e fr o m 
baseli ne   a n d perce nt c h a n ge fr o m baseli ne) i n Ta ble 1 4. 2. 2. 1. 1 f or all s u bjects i n t he m I T T 
p o p ulati o n b y st u d y pr o d uct. Ra w mea ns ( ± S E) of t he n u m ber of blee di n g sites at eac h ti m e 
p oi nt  will  be  pl otte d  b y  st u d y  pr o d uct  i n  Fi g ure  1 4. 2. 2. 1. 5  f or  all  s u bjects  i n  t he  m I T T 
p o p ulati o n. 
A d diti o nall y, t he n u m ber a n d p erce nta ge  of s u bjects w h ose n u m b er of blee di n g sites  has  
re d uce d (i m pr o ve d), r e mai ne d t he sa m e or i n crease d (w ors e ne d ), res p ecti vel y c o m pare d t o 
baseli ne, will be prese nte d b y st u d y pr o d uct at eac h ti me p oi nt i n Ta ble 1 4. 2. 2. 1. 3 f or t he m I T T 
p o p ulati o n. 
I n di vi d ual d ata f or t he n u m ber of blee di n g sites will be liste d f or eac h s u bject b y st u d y pr o d uct 
gr o u p a n d visit i n Listi n g 1 6. 2. 6. 1 f or all ra n d o mize d s u bjects.  
4. 4. 1. 2  
St ati sti c al H y p ot h e si s, M o d el, a n d M et h o d of A n al y si s  
T he f oll o wi n g n ull a n d alter nati ve h y p ot heses will be e val uat e d: 
•  H 0: T here is n o differ e nce i n t he n u m ber of blee di n g sites fr o m baseli ne t o Wee k 1 2 i n t he 
Test Pr o d uct gr o u p. 
•  H 1: T here is a differe nce i n  t he n u m ber of blee di n g sites at Wee k 1 2, c o m pare d t o bas eli ne 
i n t he Test Pr o d uct gr o u p. 
A Mi xe d M o del f or Re peate d Meas ures ( M M R M) will be use d, wit h c ha n ge fr o m baseli ne i n 
n u m ber of blee di n g sites as t he de pe n d e nt varia ble, t he cate g ori cal ti me p oi nt ( Wee k 3, Wee k 
6, or Wee k 1 2), treat me nt gr o u p ( Test Pr o d uct or Refere n ce Pr o d u ct) a n d treat me nt gr o u p b y 
ti me p oi nt i nteracti o n as fi xe d effects, a n d baseli ne n u m ber of blee di n g sites as a c o v ariate. 
S u bject will be i ncl u de d as a re peate d meas ure wit h a n u nstr uct ure d c o v aria nce matri x. T h e 
Ke n war d R o ger de gr ees of fr ee d o m a p pr oac h will be a p plie d. If u nstr uct ure d c o vari a nce matri x 
d oes  n ot  c o n ver g e,  t he  f oll o wi n g  c o varia n ce  str uct ures  will  be  a p pli e d  i n  or der  u ntil  
c o n ver ge n ce is ac hie ve d: 1) T oe plitz, 2) c o m p o u n d s y m metr y ( C S). 
Usi n g t he a b o ve m o del, t he least s q uare (L S ) mea n  c ha n ge fr o m bas eli ne i n n u m ber of blee di n g 
sites will be prese nte d  f or t he Test Pr o d uct at Wee k 1 2, al o n g wit h 9 5 % CI a n d p -val ue, testi n g 
f or a n o n-zer o c ha n g e fr o m baseli ne  ( Ta ble 1 4. 2. 2. 2. 1).  
T he ass u m pti o n of n or malit y a n d h o m o ge neit y of varia nce i n t he M M R M will be i n vesti gate d. 
I n  cas e of vi olati o n of t hese ass u m pti o ns, a Wilc o x o n Si g ne d Ra n k T est  ( wit hi n pr o d uct  
c o m paris o ns wit h baseli n e) will be perf or me d t o s u p p ort t he M M R M res ults.  
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2 0  of 4 5  
4. 4. 1. 3  
S u p p orti v e A n al y s e s  
A P P a nal ysis will be p erf or me d o n t he n u m b er of blee di n g sites if t here is m ore t ha n a 1 0 % 
differe n ce i n t he n u m ber of s u bjects bet wee n t he P P a n d m I T T p o p ulati o ns. A decisi o n o n 
w het her a P P a nal ysis will be perf or me d will be ma de pri or t o st u d y u n bli n di n g (release of 
ra n d o mizati o n c o des). 
A s u m mar y of t h e mea n n u m ber of blee di n g sites at eac h ti me p oi nt will b e pres e nte d f or t he 
P P p o p ulati o n i n Ta ble 1 4. 2. 2. 1. 2. A s u m mar y of t he n u m ber a n d perce nta g e of s u bjects at eac h 
ti me  p oi nt  w h ose  n u m ber  of  blee di n g  sites  has  i m pr o ve d/re mai ne d  t he  same/ w orse n e d 
c o m pare d t o baseli ne will be prese nte d f or t he P P p o p ulati o n i n Ta ble 1 4. 2. 2. 1. 4. Statistical 
a nal ysis of t he mea n n u m ber of blee di n g sites will be prese nte d f or t he P P p o p ulati o n i n Ta ble 
1 4. 2. 2. 2. 2. I n a d diti o n, t he mea n n u m ber of blee di n g si tes at eac h ti me p oi nt will be pl otte d b y 
st u d y pr o d uct f or all s u bjects i n t he P P p o p ulati o n ( Fi g ure 1 4. 2. 2. 1. 6). 
I n or der t o e x pl or e t he s e nsiti vit y of res ults t o t he effect of missi n g data, t he M M R M m o del 
descri be d i n  S e cti o n 4. 4. 1. 2  will be re p eate d usi n g t h e Last O bser v ati o n Carrie d F or war d ( L O C F )  
a p pr oac h f or t he mI T T p o p ulati o n ( Ta ble 1 4. 2. 2. 2. 3) a n d t he P P p o p ulati o n ( Ta ble 1 4. 2. 2. 2. 4).  
4. 4. 2  
S e c o n d ar y E ffi c a c y E n d p oi nt s  
All sec o n dar y e n d p oi nt a nal yses will be perf or me d o n t he m I T T p o p ulati o n. Ot her t ha n t he 
se q ue ntial testi n g strate g y f or c o m pari n g t he c h a n ge fr o m bas eli ne i n t he n u m ber of blee di n g 
sites bet wee n pr o d ucts (s ee Secti o n 4. 4 ), there will be n o a dj ust me nt f or m ulti plicit y perf or me d 
f or a n y ot her s ec o n d ar y e n d p oi nts detaile d i n t his secti o n. 
4. 4. 2. 1  
C h a n g e fr o m B a s eli n e i n N u m b er of Bl e e di n g Sit e s  
T he n u m ber of blee di n g sites f or eac h s u bject at eac h visit is calc ulat e d usi n g t he BI sc ore, a n d 
descri pti ve statistics a n d fre q ue nc y c o u nts will be prese nte d f or t h e m I T T p o p ulati o n as detaile d 
i n Secti o n 4. 4. 1. 1 . 
4. 4. 2. 1. 1  St ati sti c al H y p ot h e si s, M o d el a n d M et h o d of A n al y si s  
F or c o m paris o ns t o baseli ne wit hi n eac h treat me nt gr o u p, t he f oll o wi n g n ull a n d alter nati ve 
h y p ot heses will be e val u ate d f or p ost -bas eli ne ti me p oi nts at Wee k 3 a n d Wee k 6 (f or t he Test 
Pr o d uct gr o u p a n d t he Refer e nce Pr o d uct gr o u p), a n d at Wee k 1 2 (f or t he Refere nce Pr o d uct 
gr o u p) res p ecti vel y: 
•  H 0: T here is n o differ e nce i n t he n u m ber of blee di n g sites fr o m baseli ne. 
•  H 1: T here is a differe nce i n t he n u m ber of blee di n g sites c o m pare d t o bas eli ne. 
F or c o m paris o ns t o ne g ati ve c o ntr ol, t he f oll o wi n g n ull a n d alter nati ve h y p ot heses will be 
e val uate d f or p ost- baseli ne ti me p oi nts at Wee k 3 , Wee k 6 , a n d Wee k 1 2, res pecti vel y: 
•  H 0: T here is n o differ e nce i n c ha n ge fr o m baseli n e i n t he n u m ber of blee di n g sites i n t he 
Test Pr o d uct gr o u p c o m p are d t o t he Refere nce Pr o d uct gr o u p. 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2 1  of 4 5  
•  H 1: T here is a differe nce i n c ha n ge fr o m baseli ne i n t he n u m ber of blee di n g sites i n t he 
Test Pr o d uct gr o u p c o m p are d t o t he Refere nce Pr o d uct gr o u p. 
T he res ults  fr o m  t he M M R M  descri be d i n Secti o n 4. 4. 1. 2  will  be use d t o test  t he a b o ve 
h y p ot heses. 
T he L S mea n c h a n ge fr o m baseli ne i n n u m ber of blee di n g sites will be prese nte d f or eac h st u d y 
pr o d uct at eac h p ost- bas eli ne ti me p oi nt wit h c orres p o n di n g 9 5 % CIs a n d p- val ues t o test f or a 
n o n- zer o c ha n g e fr o m baseli ne.  
T he differ e nce i n L S mea n c ha n g e fr o m bas eli ne n u m ber of blee di n g sites ( Test Pr o d uct – 
Refere n ce Pr o d u ct) will als o be pres e nte d at eac h p ost -baseli ne ti me p oi nt wit h c orres p o n di n g 
9 5 % CIs a n d p -val ues t o t est f or a n o n -zer o differe nce ( T a ble 1 4. 2. 2. 2. 1) . T he % a dj uste d mea n 
differe n ce will als o be pr ese nte d .  
T he ass u m pti o n of n or malit y a n d h o m o ge neit y of varia nce i n t he M M R M will be i n vesti gate d. 
I n  case  of  vi olati o n  of  t hese  ass u m pti o ns,  a  Wilc o x o n  Ra n k  S u m  test  ( bet wee n  pr o d ucts  
c o m paris o ns) a n d Wilc o x o n Si g ne d Ra n k Test ( wit hi n pr o d uct c o m paris o ns wit h base li ne) will 
be perf or me d t o s u p p ort t he M M R M res ults. 
T he M M R M m o del will be re peate d usi n g t he L O C F a p pr oac h f or t he mI T T p o p ulati o n ( Ta ble 
1 4. 2. 2. 2. 3) a n d t he P P p o p ulati o n ( Ta ble 1 4. 2. 2. 2. 4). 
4. 4. 2. 2  
C h a n g e fr o m B a s eli n e i n Bl e e di n g I n d e x ( BI)  
T he BI will be assesse d at eac h e v al ua ble t o ot h site f or eac h s u bject at eac h visit as descri be d 
i n Secti o n 4. 4. 1. 1 , acc or di n g t o t he sc ori n g s yste m i n Ta ble 4 - 1. T he BI sc ore f or eac h s u bject 
at eac h visit is calc ulate d as t he s u m of i n de x v al ues o ver all e val ua ble t o ot h sites, di vi de d b y 
t he n u m ber of e v al ua ble t o ot h sites. E val ua ble t o ot h sites are t h ose sc ore d as 0, 1 or 2, s o the 
BI sc ore has a ra n g e of 0 t o 2.  
Descri pti ve statistics ( n, mea n, S D, S E, me dia n, mi ni m u m , a n d ma xi m u m) will be prese nt e d 
f or t he BI sc ore at eac h ti me p oi nt (a bs ol ute val ue, c ha n ge fr o m baseli ne a n d perce nt c ha n ge 
fr o m baseli ne) i n T a ble 1 4. 2. 3. 1. 1 f or t h e mI T T p o p ulati o n . Ra w mea ns ( ± S E) of t h e BI s c ore 
at eac h ti me p oi nt will be pl otte d b y st u d y pr o d uct i n Fi g ure 1 4. 2. 3. 1. 3 f or all s u bjects i n t he 
mI T T p o p ulati o n. 
A d diti o nall y, t he n u m ber a n d p erce nta ge of s u bjects w h ose BI sc ore h as re d uce d (i m pr o ve d), 
re mai ne d  t he  sa me  a n d  i ncreas e d  ( w orse n e d),  res pecti vel y  c o m pare d  t o  baseli ne,  will  be  
prese nte d b y st u d y pr o d u ct at eac h ti me p oi nt i n Ta ble 1 4. 2. 3. 1. 2 f or t he mI T T p o p ulati o n. 
I n di vi d ual data f or t he BI assess me nt at eac h e val u a ble t o ot h site will be list e d f or eac h s u bject 
i n Listi n g 1 6. 2. 6. 2. 1, a n d i n di vi d ual data f or t he d eri ve d BI sc ore will be liste d f or eac h s u bject 
i n Listi n g 1 6. 2. 6. 2. 2, b y st u d y pr o d uct gr o u p a n d visit f or all ra n d o mize d s u bjects. 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2 2  of 4 5  
4. 4. 2. 2. 1  St ati sti c al H y p ot h e si s, M o d el a n d M et h o d of A n al y si s  
F or c o m paris o ns t o baseli ne wit hi n eac h treat me nt gr o u p, t he f oll o wi n g n ull a n d alter nati ve 
h y p ot heses will be e val uate d f or p ost -baseli ne ti me p oi nts at Wee k 3, Wee k 6 a n d Wee k 1 2, 
res pecti vel y: 
•  H 0: T here is n o differ e nce i n t he BI s c ore fr o m baseli ne. 
•  H 1: T here is a differe nce i n  t he BI sc ore  c o m p are d t o baseli ne . 
F or c o m paris o ns t o ne g ati ve c o ntr ol, t he f oll o wi n g n ull a n d alter nati ve h y p ot heses will be 
e val uate d f or p ost- baseli ne ti me p oi nts at Wee k 3, Wee k 6 , a n d Wee k 1 2, res pecti vel y: 
•  H 0: T here is n o differ e nce i n c ha n ge fr o m baseli n e i n t he BI s c ore i n t he T est Pr o d uct 
gr o u p c o m par e d t o t he Refer e nce Pr o d uct gr o u p. 
•  H 1: T here is a differe nce  i n c ha n ge fr o m baseli ne i n t he BI s c ore i n t he T est Pr o d uct gr o u p 
c o m pare d t o t he Refer e n ce Pr o d uct gr o u p. 
A M M R M will be use d as descri be d i n  Secti o n 4. 4. 1. 2 , wit h c ha n ge fr o m baseli ne i n BI sc ore  
as t he d e pe n de nt vari a ble  a n d baseli ne BI sc ore as a c o variate i nstea d of baseli ne n u m ber of 
blee di n g sites. 
Usi n g t he a b o v e m o del, t he L S mea n c ha n g e fr o m baseli ne BI sc ore  will be prese nt e d f or eac h 
st u d y pr o d uct at eac h p ost-baseli ne ti me p oi nt wit h c orres p o n di n g 9 5 % CIs a n d p -val ues t o test 
f or a n o n-zer o c ha n g e fr o m baseli ne.  
T he differe n ce i n L S mea n c ha n g e fr o m baseli ne  BI sc ore  ( Test Pr o d uct – Refere n ce Pr o d u ct) 
will als o be pres e nte d at eac h p ost -bas eli ne ti me p oi nt wit h c orres p o n di n g 9 5 % CIs a n d p -val ues 
t o test f or a n o n-zer o differe n ce ( T a ble 1 4. 2. 3. 2. 1 ). T he % a dj uste d mea n differe n ce will als o 
be prese nt e d.  
T he ass u m pti o n of n or malit y a n d h o m o ge neit y of varia nce i n t he M M R M will be i n vesti gate d. 
I n  case  of  vi olati o n  of  t hese  ass u m pti o ns,  a  Wilc o x o n  Ra n k  S u m  test ( bet wee n  pr o d ucts  
c o m paris o ns ) a n d Wilc o x o n Si g ne d Ra n k Test ( wit hi n pr o d uct c o m paris o ns wit h baseli ne) will 
be perf or me d  t o s u p p ort t he M M R M res ults. 
T he M M R M m o del will be re peate d usi n g t he L O C F a p pr oac h f or t he mI T T p o p ulati o n ( Ta ble 
1 4. 2. 3. 2. 2).  
4. 4. 2. 3  
C h a n g e fr o m B a s eli n e i n M o difi e d Gi n gi v al I n d e x ( M GI)  
T he M GI will be assesse d o n t he facial a n d li n g ual s urfaces of eac h sc ora bl e t o ot h ( 7 7 i n eac h 
arc h).  T w o  sc ores  (acc or di n g  t o  t he  scale  i n  Ta ble  4 - 2 bel o w)  s h o ul d  be  rec or de d  
b uccall y/la biall y  ( pa pilla  a n d  mar gi n)  a n d  t w o  sc ores  li n g uall y  ( pa pilla  a n d  mar gi n).  T he 
e xce pti o n t o t his is f or T o ot h 1 5 ( U ni vers al) a n d T o ot h 1 8 ( U ni versal) , w here t he p a pillae 
assess me nts ( b ot h b u ccal a n d li n g ual) are n ot sc orea ble a n d n ot c ollecte d. At eac h visit, eac h 
s u bject t heref or e has u p t o 1 0 8 e val ua ble t o ot h sites (i.e. 4 meas ure me nts o n u p t o 2 8 sc ora ble 
teet h). 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2 3  of 4 5  
T a bl e 4- 2 
M o difi e d Gi n gi v al I n d e x S c ori n g S y st e m  
S c or e D e s cri pti o n  
0  
A b s e n c e of i nfl a m m ati o n  
1 
Mil d i nfl a m m ati o n; sli g ht c h a n g e i n c ol o ur, littl e c h a n g e i n c ol o ur; littl e c h a n g e i n t e xt ur e of a n y 
p orti o n of t h e m ar gi n al or p a pill ar y gi n gi v al u nit  
2  
Mil d i nfl a m m ati o n; crit eri a a s a b o v e b ut i n v ol vi n g t h e e ntir e m ar gi n al or p a pill ar y gi n gi v al u nit 
3 
M o d er at e i nfl a m m ati o n; gl a zi n g, r e d n e s s, e d e m a, a n d/ or h y p ertr o p h y of t h e m ar gi n al or 
p a pill ar y gi n gi v al u nit  
4 
S e v er e i nfl a m m ati o n; m ar k e d r e d n e s s, e d e m a a n d/ or h y p ertr o p h y of t h e m ar gi n al or  p a pill ar y 
gi n gi v al u nit, s p o nt a n e o u s bl e e di n g, c o n g e sti o n, or ul c er ati o n  
9  
Mi s si n g t o ot h or n ot q u alifi e d t o ot h  
T he M GI sc or e f or eac h s u bject at eac h visit is calc ulate d as t he s u m of i n de x val ues o ver all 
e val ua ble t o ot h sites, di vi de d b y t he n u m ber of e val ua ble t o ot h sites. E val ua ble t o ot h sites are 
t h ose sc ore d as 0, 1, 2, 3 or 4 s o t he M GI sc ore has a ra n ge of 0 t o 4. 
Descri pti ve statistics ( n, mea n, S D, S E, me dia n, mi ni m u m , a n d ma xi m u m) will be prese nt e d 
f or t he M G I sc or e at eac h ti me p oi nt (a bs ol ute val u e, c h a n ge fr o m b aseli ne a n d perce nt c ha n ge 
fr o m baseli ne) i n Ta ble 1 4. 2. 4. 1. 1 f or t he m I T T p o p ulati o n. Ra w mea ns ( ± S E) of t he M G I 
sc ore at eac h ti me p oi nt will be pl otte d b y st u d y pr o d uct i n Fi g ure 1 4. 2. 4. 1. 3 f or all s u bjects i n 
t he mI T T p o p ul ati o n. 
A d diti o nall y, t he n u m ber a n d perce nt a ge of s u bjects w h ose M G I sc ore has re d uce d (i m pr o ve d), 
re mai ne d  t he  sa me  a n d  i ncreas e d  ( w orse n e d),  res pecti vel y  c o m pare d  t o  baseli ne,  will  be  
prese nte d b y st u d y pr o d u ct at eac h ti me p oi nt i n Ta ble 1 4. 2. 4. 1. 2 f or t he mI T T p o p ulati o n. 
I n di vi d ual data f or t he M G I assess me nt at eac h e val ua ble t o ot h site will be liste d f or eac h 
s u bject i n Listi n g 1 6. 2. 6.3 . 1, a n d i n di vi d ual d ata f or t he deri v e d M G I sc ore will b e liste d f or 
eac h s u bject i n Listi n g 1 6. 2. 6. 3 . 2, b y st u d y pr o d uct gr o u p a n d visit f or all ra n d o mize d s u bjects. 
4. 4. 2. 3. 1  St ati sti c al H y p ot h e si s, M o d el a n d M et h o d of A n al y si s  
F or c o m paris o ns t o baseli ne wit hi n eac h treat me nt gr o u p, t he f oll o wi n g n ull a n d alter nati ve 
h y p ot heses will be e val u ate d f or p ost -b aseli ne ti me p oi nts at Wee k 3, Wee k 6, a n d Wee k 1 2, 
res pecti vel y: 
•  H 0: T here is n o differ e nce i n t he M GI sc ore fr o m baseli ne. 
•  H 1: T here is a differe nce i n  t he M GI s c ore  c o m pare d t o baseli ne. 
F or c o m paris o ns t o ne g ati ve c o ntr ol, t he f oll o wi n g n ull a n d alter nati ve h y p ot heses will be 
e val uate d f or p ost- baseli ne ti me p oi nts at Wee k 3, Wee k 6 , a n d Wee k 1 2, res pecti vel y: 
•  H 0: T here is n o differ e nce i n c ha n ge fr o m baseli n e i n t he M G I sc ore i n t he Test Pr o d uct 
gr o u p c o m par e d t o t he Refer e nce Pr o d uct gr o u p. 
•  H 1: T here is a differe nce i n c ha n ge fr o m baseli ne i n t he M G I sc ore i n t he T est Pr o d uct 
gr o u p c o m par e d t o t he Refer e nce Pr o d uct gr o u p. 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2 4  of 4 5  
A M M R M will be use d as descri be d i n  Secti o n 4. 4. 1. 2 , wit h c ha n ge fr o m b aseli ne i n M GI s c ore 
as t he de pe n de nt vari a ble a n d baseli ne M GI sc ore as a c o v ariate i nstea d of baseli ne n u m ber of 
blee di n g sites. 
Usi n g t he a b o ve m o del, t he L S mea n c ha n ge fr o m baseli ne M G I sc ore will be prese nte d f or 
eac h st u d y pr o d uct at eac h p ost -baseli ne ti me p oi nt wit h c orres p o n di n g 9 5 % CIs a n d p -val ues 
t o test f or a n o n-zer o c h a n ge fr o m baseli ne.  
T he diff ere n ce i n L S mea n c ha n g e fr o m bas eli ne M G I sc ore ( Test Pr o d u ct – Refere nce Pr o d uct) 
will als o be pres e nte d at eac h p ost -bas eli ne ti me p oi nt wit h c orres p o n di n g 9 5 % CIs a n d p -val ues 
t o test f or a n o n-zer o differe n ce ( Ta bl e 1 4. 2. 4. 2. 1 f or t he m I T T p o p ulati o n). T he % a dj uste d 
mea n differe nce will als o be prese nt e d.  
T he ass u m pti o n of n or malit y a n d h o m o ge neit y of varia nce i n t he M M R M will be i n vesti gate d. 
I n  case  of  vi olati o n  of  t hese  ass u m pti o ns,  a  Wilc o x o n  Ra n k  S u m  test ( bet wee n  pr o d ucts  
c o m paris o ns ) a n d Wilc o x o n Si g ne d Ra n k Test ( wit hi n pr o d uct c o m paris o ns wit h baseli ne) will 
be perf or me d  t o s u p p ort t he M M R M res ults. 
T he M M R M  m o del will be re peate d usi n g t he L O C F a p pr oac h f or t he m I T T p o p ulati o n ( Ta ble 
1 4. 2. 4. 2. 2 ). 
4. 4. 2. 4  
C h a n g e fr o m B a s eli n e i n T ur e s k y Pl a q u e I n d e x ( T PI)  
T he T PI will be us e d t o assess pl a q ue o n all gra da ble teet h meeti n g t h e i ncl usi o n/e xcl usi o n 
criteria ( nat ur al teet h o nl y). T he T PI will be assesse d o n t he facial a n d li n g ual s urfaces of eac h 
sc ora ble t o ot h ( 7-7 i n eac h ar c h). T hree sc ores (acc or di n g t o t he  s cale i n Ta ble 4 - 3 b el o w) 
s h o ul d be rec or de d b uccall y/la biall y ( distal, b o d y a n d mesial sites) a n d t hree sc ores li n g uall y  
( distal, b o d y a n d mesial sites). At eac h visit, eac h s u bject t heref ore h as u p t o 1 6 8 e v al ua bl e 
t o ot h sites (i.e. 6 meas ure me nts o n u p t o 2 8 sc ora ble teet h). 
T a bl e 4- 3 
T ur e s k y  Pl a q u e I n d e x S c ori n g S y st e m  
S c or e D e s cri pti o n  
0  
N o pl a q u e  
1  
S e p ar at e fl e c k s of pl a q u e at t h e c er vi c al m ar gi n  
2  
T hi n c o nti n u o u s b a n d of pl a q u e ( u p t o 1 m m) at t h e c er vi c al m ar gi n  
3  
B a n d of pl a q u e wi d er t h a n 1 m m b ut c o v eri n g < 1/ 3 of t h e t o ot h s urf a c e  
4  
Pl a q u e c o v eri n g ≥ 1/ 3 b ut < 2/ 3 of t h e t o ot h s urf a c e  
5  
Pl a q u e c o v eri n g ≥ 2/ 3 of t h e t o ot h s urf a c e  
9  
Mi s si n g t o ot h or n ot q u alifi e d t o ot h  
T he o ver all T PI s c ore f or eac h s u bject at eac h visit is calc ulate d as t he s u m of i n de x val ues o v er 
all e val ua ble t o ot h sites, di vi de d b y t he n u m ber of e val ua bl e t o ot h sites. E val ua ble t o ot h sites 
are t h ose sc ore d as 0, 1, 2, 3, 4 or 5 s o t he o verall T PI sc ore has a ra n g e of 0 t o 5. 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2 5  of 4 5  
T he i nter pr o xi mal T PI sc ore f or eac h s u bject at eac h visit is calc ulate d as t he s u m of i n de x 
val ues o ver all e val u a ble distal a n d mesial t o ot h sites, di vi de d b y t he n u m ber of e val ua ble distal 
a n d mesial t o ot h sites. Si milar t o t he o verall T PI s c ore, t he i n ter pr o xi mal T PI sc ore h as a ra n ge 
of 0 t o 5. 
Descri pti ve statistics ( n, mea n, S D, S E, me dia n, mi ni m u m, a n d ma xi m u m) will be pres e nte d at 
eac h ti me p oi nt (a bs ol ute val ue, c ha n ge fr o m baseli ne a n d perce nt c h a n g e fr o m baseli ne) i n 
Ta ble  1 4. 2. 5. 1. 1 f or o ver all T PI sc ore a n d i n Ta ble 1 4. 2. 5. 1. 3 f or i nter pr o xi mal T PI sc ore  f or 
t he mI T T p o p ul ati o n . Ra w mea ns (± S E) at eac h ti me p oi nt will be pl otte d b y st u d y pr o d uct i n 
Fi g ure 1 4. 2. 5. 1. 5 f or o verall T PI s c ore a n d i n Fi g ure 1 4. 2. 5. 1. 6 f or i nter pr o xi mal T PI sc or e, f or 
t he mI T T p o p ul ati o n. 
A d diti o nall y, t he n u m ber a n d perce nt a ge of s u bjects w h ose sc ore h as re d uce d (i m pr o ve d), 
re mai ne d  t he  sa me  a n d  i ncreas e d  ( w orse n e d),  res pecti vel y  c o m pare d  t o  baseli ne,  will  be  
prese nte d b y st u d y pr o d u ct at eac h ti me p oi nt i n Ta ble 1 4. 2. 5. 1. 2 ( o verall T PI sc ore) a n d T a ble 
1 4. 2. 5. 1. 4 (i nter pr o xi mal T PI sc ore) f or t he mI T T p o p ulati o n. 
I n di vi d ual d ata f or t he T PI assess me nt at eac h e val ua ble t o ot h site will be liste d f or eac h s u bject 
i n Listi n g 1 6. 2. 6. 4. 1, a n d i n di vi d ual data f or t he deri ve d T PI sc ore ( o verall a n d i nter pr o xi mal, 
res pecti vel y), will be liste d f or eac h s u bject i n Listi n g 16. 2. 6. 4. 2, b y st u d y pr o d uct gr o u p a n d 
visit f or all ra n d o mize d s u bjects.  
4. 4. 2. 4. 1  St ati sti c al H y p ot h e si s, M o d el a n d M et h o d of A n al y si s  
F or c o m paris o ns t o baseli ne wit hi n eac h treat me nt gr o u p, t he f oll o wi n g n ull a n d alter nati ve 
h y p ot heses will be e val u ate d f or p ost -b aseli ne ti me p oi nts at Wee k 3, Wee k 6, a n d Wee k 1 2, 
f or t he o ver all T PI s c ore a n d i nter pr o xi mal T PI sc ore, res p ecti vel y: 
•  H 0: T here is n o differ e nce i n t he T PI s c ore fr o m b aseli ne. 
•  H 1: T here is a differe nce i n  t he T PI sc ore  c o m p are d t o baseli ne. 
F or c o m paris o ns t o ne g ati ve c o ntr ol, t he f oll o wi n g n ull a n d alter nati ve h y p ot heses will be 
e val uate d f or p ost -baseli ne ti me p oi nts at Wee k 3, Wee k 6 a n d Wee k 1 2, f or t h e o verall T PI 
sc ore a n d i nter pr o xi mal T PI sc ore, res pecti vel y: 
•  H 0: T here is n o differe n ce i n c ha n ge fr o m baseli n e  t he T P I s c ore i n t he T est Pr o d uct gr o u p 
c o m pare d t o t he Refer e n ce Pr o d uct gr o u p. 
•  H 1: T here is a diff ere n ce i n c ha n ge fr o m baseli ne i n t he T P I s c ore i n t he Test Pr o d uct gr o u p 
Se parate M M R Ms will be use d as descri be d i n  Secti o n 4. 4. 1. 2 , wit h c ha n ge fr o m baseli ne i n 
T PI sc or e ( o verall a n d i nter pr o xi mal, res pecti vel y) as t he de pe n d e nt varia ble a n d baseli ne T PI 
sc ore ( o v erall a n d i nter pr o xi mal, res pecti vel y) as a c o vari ate i nstea d of b aseli ne n u m ber of 
blee di n g sites. 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2 6  of 4 5  
Usi n g t he a b o ve m o del, t he L S mea n c ha n ge fr o m baseli ne T PI sc ore will be pres e nte d f or eac h 
st u d y pr o d uct at eac h p ost-baseli ne ti me p oi nt wit h c orres p o n di n g 9 5 % CIs a n d p -val ues t o test 
f or a n o n-zer o c ha n g e fr o m baseli ne.  
T he differ e nce i n L S mea n c ha n ge fr o m baseli ne T PI sc ore ( Test Pr o d uct – Refere n ce Pr o d uct) 
will als o be pres e nte d at eac h p ost -bas eli ne ti me p oi nt wit h c orres p o n di n g 9 5 % CIs a n d p -val ues 
t o test f or a n o n-zer o differ e nce  ( Ta ble 1 4. 2. 5. 2. 1 f or o verall T PI, a n d T a ble 1 4. 2. 5. 2. 3 f or 
i nter pr o xi mal T PI). T he % a dj uste d mea n differe nce will als o be prese nte d.  
T he ass u m pti o n of n or malit y a n d h o m o ge neit y of varia nce i n t he M M R M will be i n vesti gate d. 
I n  case  of  vi olati o n  of  t hese  ass u m pti o ns,  a  Wilc o x o n  Ra n k  S u m  test  ( bet wee n  pr o d ucts  
c o m paris o ns) a n d Wilc o x o n Si g ne d Ra n k Test ( wit hi n pr o d uct c o m paris o ns wit h base li ne) will 
be perf or me d t o s u p p ort t he M M R M res ults. 
T he M M R M  m o del will be re peate d usi n g t he L O C F a p pr oac h f or t he m I T T p o p ulati o n ( Ta ble 
1 4. 2. 5. 2. 2 f or o ver all T PI, a n d Ta ble 1 4. 2. 5. 2. 4 f or i nter pr o xi mal T PI ). 
4. 4. 3  E x pl or at or y Effi c a c y V ari a bl e s  
Res ults bet wee n st u d y pr o d ucts ( mea n  c ha n g e fr o m baseli ne f or Test Pr o d uct v ers us mea n 
c ha n ge fr o m baseli ne f or R efer e nce  Pr o d u ct) at eac h ti me p oi nt will als o be  o btai ne d a n d 
prese nte d  i n a si milar m a n ner as i n t he pri mar y o bjecti ve f or t h e l o w a n d hi g h baseli ne M GI 
s u b gr o u ps i n t he mI T T p o p ulati o n: 
•  L o w: M GI  ≤ 2 
•  Hi g h: M GI >  2 
4. 4. 3. 1  
C h a n g e fr o m B a s eli n e i n N B S  
Descri pti ve statistics ( n, mea n, S D, S E, me dia n, mi ni m u m , a n d ma xi m u m) f or t he N B S will be 
prese nte d as d escri b e d  i n Secti o n 4. 4. 1. 1  f or eac h baseli ne M GI s u b gr o u p i n Ta ble 1 4. 2. 6. 1. 1. 
Ra w mea ns ( ± S E) at eac h ti me p oi nt will be pl otte d b y st u d y pr o d uct f or eac h baseli ne M GI 
s u b gr o u p se par atel y i n Fi g ure 1 4. 2. 6. 1. 2. 
T he c ha n g e fr o m b aseli n e i n N B S will be a nal yze d at Wee k 3, Wee k 6 a n d Wee k 1 2 f or eac h 
M GI s u b gr o u p se paratel y usi n g t he sa me M M R M as descri be d i n Secti o n 4. 4. 2. 1. 1   (Ta ble 
1 4. 2. 6. 2. 1). 
4. 4. 3. 2  
C h a n g e fr o m B a s eli n e i n BI  
Descri pti ve statistics ( n, mea n, S D, S E, me di a n, mi ni m u m, a n d ma xi m u m) f or t he BI sc ore will 
be prese nte d as descri b e d i n Secti o n 4. 4. 2. 2  f or eac h baseli ne M GI s u b gr o u p i n Ta ble 1 4. 2.7. 1. 1. 
Ra w mea ns ( ± S E) at eac h ti me p oi nt will be pl otte d b y st u d y pr o d uct f or eac h baseli ne M GI 
s u b gr o u p se par atel y i n Fi g ure 1 4. 2. 7. 1. 2. 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 2 7  of 4 5  
T he c ha n ge fr o m baseli n e i n BI sc ore will  be a nal yze d at Wee k 3, Wee k 6 a n d Wee k 1 2 f or 
eac h M GI s u b gr o u p s e paratel y usi n g t he sa me M M R M as descri be d i n Secti o n 4. 4. 2. 2. 1  ( Ta ble 
1 4. 2. 7. 2. 1 ). 
4. 4. 3. 3  
C h a n g e fr o m B a s eli n e i n M GI  
Descri pti ve statistics ( n, mea n, S D, S E, me dia n, mi ni m u m, a n d ma xi m u m) f or t he M GI sc ore 
will be prese nte d as des cri be d i n Secti o n 4. 4. 2. 3  f or eac h bas eli ne M GI s u b gr o u p i n Ta ble 
1 4. 2. 8. 1. 1 . Ra w mea ns (± S E) at eac h ti me p oi nt will be pl otte d b y st u d y pr o d uct f or eac h 
baseli ne M GI s u b gr o u p s e parat el y i n Fi g ure 1 4. 2. 8. 1. 2. 
T he c ha n ge fr o m baseli n e i n M GI sc ore will  be a nal yze d at Wee k 3, Wee k 6 a n d Wee k 1 2 f or 
eac h M GI s u b gr o u p s e paratel y usi n g t he sa me M M R M as descri be d i n Secti o n 4. 4. 2. 3. 1  ( Ta ble 
1 4. 2. 8. 2. 1 ). 
4. 4. 3. 4  
C h a n g e fr o m B a s eli n e i n T PI  
Descri pti ve statistics ( n, mea n, S D, S E, me dia n, mi ni m u m, a n d ma xi m u m) will be prese nte d as 
descri be d i n  Secti o n 4. 4. 2. 4  f or eac h b aseli ne M GI s u b gr o u p i n Ta ble 1 4. 2.9. 1. 1 f or t he o verall 
T PI sc or e a n d i n Ta ble 1 4. 2. 9. 1. 2 f or t he i nter pr o xi mal T PI sc ore. Ra w mea ns (± S E) at eac h 
ti me p oi nt will be pl otte d b y st u d y pr o d uct f or eac h baseli ne M GI s u b gr o u p s e parat el y i n Fi g ure 
1 4. 2. 9. 1. 3 f or o ver all T PI sc ore a n d i n Fi g ure 1 4. 2. 9. 1. 4 f or i nter pr o xi mal T PI sc ore. 
T he c ha n g e fr o m b aseli ne i n T PI s c ore will be a n al yze d at Wee k 3, Wee k 6 a n d Wee k 1 2 f or 
eac h M GI s u b gr o u p usi n g t he sa me M M R M as descri be d i n Secti o n 4. 4. 2. 4. 1  ( Ta ble 1 4. 2.9. 2. 1 
f or o ver all T PI, a n d Ta bl e 1 4. 2. 9. 2. 2 f or i nter pr o xi mal T PI). 
4. 4. 4  
H a n dli n g of M i s si n g V al u e s/ C e n s ori n g/ D i s c o nti n u ati o n s 
F or t he pri mar y a nal yses, m issi n g data will n ot be re place d or i m p ute d. S u bjects w h o wit h dra w 
fr o m  t he st u d y pre mat urel y will  be i ncl u de d i n t he statistical  a nal yses u p t o t he p oi nt  of 
disc o nti n uati o n. S u bjects w h o wit h dra w will n ot b e re pl ace d. I n t h e e v e nt t hat a s u bject has n o 
i n di vi d ual BI, M GI or T PI assess me nts a v aila ble at a gi ve n visit, t he n u m ber of blee di n g sites, 
BI sc ore, M GI s c ore or T PI sc ore will als o be c o nsi dere d as missi n g f or t hat visit.  
E x perie nce i n pre vi o us, si milar st u dies s u g gest missi n g data will n ot be pre vale nt.  T he S A S 
Pr oc Mi xe d i m ple me ntati o n of t he re peate d meas ures  a nal ysis of c o varia n ce ( A N C O V A ) t hat 
will  be  use d  i n  al m ost  all  a nal yses,  i m plicitl y  i m p utes  a n y  missi n g  data  base d  o n  t he  
n o n- missi n g o bser vati o ns. T he basic t he or y o n w hic h Pr oc Mi xe d is base d h ol ds e ve n  wit h 
missi n g data as l o n g as t he missi n g data are missi n g at ra n d o m. 
A n a d diti o nal a nal ysis will e x pl ore t he se nsiti vit y of res ults t o t he effect of missi n g data o n t he  
pri mar y a n d sec o n dar y efficac y e n d p oi nts. T he se nsiti vit y a nal ysis will use t he sa me M M R M  
m o del, b ut wit h L O C F f or missi n g data. O nl y p ost- baseli ne res ults ma y be carri e d f or w ar d.   
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4. 5   
A n al y si s of S af et y  
T he safet y pr ofile of t he st u d y pr o d ucts will be assesse d wit h res pect t o a d verse e v e nts ( A Es), 
i nci de nts a n d O S T/ O H T a b n or malities i n t his oral healt h st u d y. 
4. 5. 1  
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  
All A Es will be re vie we d b y t he Cli nical Researc h Scie ntist or Desi g nee pri or t o data base l oc k 
a n d u n bli n di n g, a n d will be c o de d t o a s yste m or g a n class ( S O C) a n d preferre d ter m ( P T) usi n g 
t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A). 
A Es will be classifie d as oral a n d n o n - oral o n t he A E pa ge of e C R F. 
Treat me nt e mer ge nt a d v erse e ve nts ( T E A Es) are d efi ne d as n e w A Es t hat o cc ur o n or after t he 
first st u d y pr o d uct use (if t his date is missi n g, a s uita ble alter nati ve will be use d e. g. date of 
ra n d o mizati o n). A Es wit h a n o nset date/ti me pri or t o t he first stu d y pr o d uct use at baseli ne visit 
will be c o nsi dere d as n o n- treat me nt e mer ge nt. 
T he f oll o wi n g s u m mar y ta bles a n d listi n gs will be prese nte d b y st u d y pr o d u ct gr o u p. 
•  Ta ble of T E A Es b y S O C a n d P T ( Ta ble 1 4. 3. 1. 1) 
•  Ta ble of T E A Es b y Oral/ N o n- Oral a n d P T ( Ta ble 1 4. 3. 1. 2) 
•  Ta ble of treat me nt relat e d T E A Es b y S O C a n d P T ( Ta ble 1 4. 3. 1. 3) 
•  Ta ble of treat me nt relat e d T E A Es b y Oral/ N o n - Oral a n d P T ( Ta bl e 1 4. 3. 1. 4) 
•  Ta ble of n o n-s eri o us T E A Es b y S O C a n d P T ( Ta ble 1 4. 3. 1. 5) [ o nl y pr o d u ce d if t here are 
m ore t ha n 5 A Es] 
•  Ta ble of seri o us T E A Es b y S O C a n d P T ( Ta ble 1 4. 3. 1. 6) [ o nl y pr o d uce d if t here are m ore 
t ha n 5 seri o us T E A Es] 
•  Listi n g of all A Es ( Listi n g 1 6. 2. 7. 1 f or all ra n d o mize d s u bjects; Listi n g 1 6. 2. 7. 2 f or 
n o n-ra n d o mize d s u bjects) 
•  Listi n g of deat hs ( Listi n g 1 4. 3. 2. 1) 
•  Listi n g of n o n-fatal S A Es ( Listi n g 1 4. 3. 2. 2) 
•  Listi n g of T E A Es lea di n g t o st u d y or pr o d uct disc o nti n uati o n ( Listi n g 1 4. 3. 2. 3) 
•  Listi n g of T E A Es classifie d as Oral ( Listi n g 1 4. 3. 2. 4) 
All i nci de nts will be liste d i n Listi n g 1 6. 2. 7. 3. 
I n t he e ve nt t hat t here is n ot hi n g t o re p ort, a n ull ta ble or listi n g will be pr o d uce d. 
4. 5. 2  
Ot h er S af et y V ari a bl e s  
Ot her saf et y varia bl es ar e liste d bel o w:  
•  O S T e xa mi nati o n  
•  O H T e xa mi nati o n  
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4. 5. 2. 1  
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 n ce 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 direct 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 g eal area,  
t o n g ue, s u bli n g ual area, s u b ma n di b ular area a n d s ali var y gla n ds.  
 
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 as eit her n or m al or a b n or m al, wit h 
details of a n y  a b n or m alities. T he r es ults of t he O S T e xa mi nati o n perf or m e d at scree ni n g will 
be  use d  t o  deter mi ne  s u bject  eli gi bilit y.  A n y  ne w  O S T  a b n or malit y  or  w ors e 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 h e 
scree ni n g e xa mi nati o n will be rec or d e 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. 
O S T will be s u m marize d ( n u m ber of s u bjects a n d perce nta ges wit h a b n or malities, wit h o ut 
a b n or malities, or O S T n ot e xa mi ne d) b y visit a n d st u d y pr o d uct i n Ta ble 1 4. 3. 4. 1 f or all s u bjects 
i n t he Saf et y P o p ulati o n. O S T e x a mi nati o n will be liste d ( Listi n g 1 6. 2. 8. 1) f or all ra n d o mize d 
s u bjects. 
4. 5. 2. 2   
O HT E x a mi n ati o n  
T his pr oce d ur e s h o ul d b e c o n d uct e d b y a q ualifi e d, e x perie nce d cli nical e xa mi ner. T h e 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 deca 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 v ati o ns  
will be liste d as eit her 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 ha 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 h e res ults of t he O H 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 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. 
O H T e xa mi nati o n will be liste d ( Listi n g 1 6. 2. 8. 2) f or all ra n d o mize d s u bjects. 
4. 6   
A n al y si s of Ot h er V ari a bl e s 
4. 6. 1  
R e p e at a bilit y of t h e E x a mi n er  
Re peat M GI a n d T PI ass ess me nts will be perf or me d b y t he cli nical e xa mi n er at D a y 0 ( Visit 2; 
Baseli ne),  Wee k  3  ( Visit  3),  Wee k  6  ( Visit  4)  a n d  Wee k  1 2  ( Visit  5).  At  least  1  re peat  
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assess me nt s h o ul d b e perf or me d f or eac h i n de x o n eac h cli nical ass ess me nt da y, t hat is, at least 
o ne M GI a n d o n e T PI r e peat ass ess me nt o n eac h assess me nt da y. ‘ Re p eat’ s u bjects will be 
selecte d at r a n d o m fr o m t h ose i n atte n da nce. Differe nt s u bjects ca n b e use d f or re p eat M GI a n d 
T PI assess me nts. If t he sa me s u bject is s electe d at ra n d o m f or re peata bilit y assess me nts at 
m ulti ple visits, t he pairs of o bser vati o ns will be c o nsi dere d as i n de p e n de nt f or t he p ur p oses of 
re peat a bilit y a nal ysis; t hat is, a n y p ote ntial wit hi n s u bject c orrelati o n will be i g n ore d. 
T here s h o ul d be a dela y of at least 1 0 mi n utes bet wee n ori gi nal a n d re p eat assess me nts f or a  
gi ve n s u bject a n d i deall y se parat e d b y a n ot her s u bj ect. N o ot her pr oce d ure o n t he s u bject s h o ul d  
be carrie d o ut bet w ee n t h e first a n d t he re peat assess me nt.  
Sc ores fr o m t he first ass ess me nt m ust n ot be visi ble t o t he e xa mi ner/scri be w he n t he re p eat  
assess me nt is carrie d o ut.  
T he r e peat M GI a n d T PI assess me nts will be c o m pare d t o t he res pecti ve ori gi nal assess me nts  
(e xcl u di n g a n y t o ot h s urfaces assess e d as missi n g or n ot q ualifie d) . T he re p eat assess me nts will  
n ot be use d i n a n y efficac y a nal ysis. 
T he first a n d s ec o n d assess me nts of eac h i n de x will be a nal yze d wit h a Fleiss - C o he n wei g hte d 
ka p pa c o effi cie nt ( κ), al o n g wit h t he 9 5 % CI, t o assess t he i ntra -e xa mi ner relia bilit y. Relia bilit y 
will be dee me d:  
•  E xcelle nt if κ  > 0. 7 5  
•  Fair t o g o o d if 0. 4 ≤ κ  ≤ 0. 7 5 
•  P o or if κ  < 0. 4 
4. 6. 1. 1  
M GI R e p e at a bilit y  
T he first a n d re peat val ues of t he M GI f or eac h t o ot h site will be c o m bi ne d a n d cr oss -t a b ulate d 
f or t he M GI Re peata bilit y p o p ulati o n ( Ta ble 1 4. 2. 1 0. 1 ). O nl y s u bjects wit h b ot h first a n d re peat 
M GI ass ess me nts a vaila ble f or a gi ve n t o ot h site at t he sa me visit will be prese nte d a n d a nal yze d.  
4. 6. 1. 2  
T PI R e p e at a bilit y  
T he first a n d re p eat val u es of t he T PI f or eac h t o ot h site will be c o m bi ne d a n d cr oss -ta b ulat e d 
f or t he T PI Re p eata bilit y p o p ulati o n ( Ta ble 1 4. 2. 1 0. 2 ). O nl y s u bjects wit h b ot h first a n d re p eat 
T PI assess me nts a v aila ble f or a gi ve n t o ot h site at t he sa me visit will be prese nte d a n d a nal y ze d.  
5 
C h a n g e s t o t h e Pr ot o c ol D efi n e d St ati sti c al A n al y si s Pl a n  
C ha n ges fr o m t he ori gi nall y pla n ne d statistical a nal ysis s pecifie d i n t he pr ot oc ol are o utli ne d i n  
Ta ble 5 - 1 bel o w.  
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T a bl e 5- 1 
C h a n g e s t o t h e Pr ot o c ol D efi n e d St ati sti c al A n al y si s Pl a n  
Pr ot o c ol  
St ati sti c al A n al y si s Pl a n  
St ati sti c al A n al y si s S e cti o n  
St ati sti c al A n al y si s Pl a n  
R ati o n al e f or C h a n g e s  
S e cti o n  6. 8: M e di c ati o n/tr e at m e nt s 
t a k e n wit hi n 2 8 d a y s of si g ni n g t h e 
i nf or m e d c o n s e nt f or m will b e 
d o c u m e nt e d a s a pri or 
m e di c ati o n/tr e at m e nt.  
 
S e cti o n 8. 1. 3: Pri or 
m e di c ati o n s/tr e at m e nt s, i n cl u di n g 
pr e s cri pti o n a n d n o n -pr e s cri pti o n 
dr u g s, di et ar y  s u p pl e m e nt s a n d 
h er b al r e m e di e s, t a k e n i n t h e l a st 
3 0 d a y s a n d pri or t o si g ni n g t h e 
i nf or m e d c o n s e nt f or m, will b e 
d o c u m e nt e d i n t h e e C R F.  
S e cti o n 4. 3. 2: Pri or 
m e di c ati o n s/tr e at m e nt s, 
i n cl u di n g pr e s cri pti o n a n d 
n o n -pr e s cri pti o n dr u g s, 
di et ar y s u p pl e m e nt s a n d 
h er b al r e m e di e s, t a k e n i n 
t h e l a st 3 0 d a y s a n d pri or 
t o si g ni n g t h e i nf or m e d 
c o n s e nt f or m, will b e 
d o c u m e nt e d i n t h e C R F.  
T h er e i s a di s cr e p a n c y 
b et w e e n S e cti o n s 6. 8 ( 2 8 d a y s) 
a n d 8. 1. 3 ( 3 0 d a y s) of t h e 
Pr ot o c ol , r e g ar di n g t h e ti m e 
fr a m e f or c oll e cti o n of 
m e di c ati o n s/tr e at m e nt s pri or t o 
si g ni n g of i nf or m e d c o n s e nt.  
 
T h e i nt e n d e d ti m e fr a m e i s 3 0 
d a y s, c o n si st e nt wit h Pr ot o c ol 
S e cti o n 8. 1. 3.  
S e cti o n 1 2. 1:  T h e pri m ar y e n d p oi nt 
f or t hi s st u d y i s “C h a n g e fr o m 
B a s eli n e i n N B S at W e e k 1 2 f or t h e 
t e st pr o d u ct ( c o nt ai ni n g 0. 4 5 4 %  
w/ w S n F 2 )”. T h er e w er e n o pr e vi o u s 
si mil ar st u di e s w h er e t h e s a m e  
a cti v e i n gr e di e nt i n t h e t e st pr o d u ct 
w a s u s e d wit h o ut pr e -pr o p h yl a xi s. 
T h u s, d u e t o t h e  u n c ert ai nt y of w h at 
w o ul d b e e x p e ct e d i n t er m s of 
c h a n g e fr o m b a s eli n e f or t h e t e st 
pr o d u ct  gi v e n t h e af or e m e nti o n e d 
p ar a m et er s, tr e at m e nt effi c a c y 
e sti m at e s f or t h e k e y s e c o n d ar y  
o bj e cti v e (t e st d e ntifri c e c o m p ar e d 
t o t h e r ef er e n c e d e ntifri c e) w er e 
u s e d i n st e a d. t h e s a m pl e si z e f or 
t hi s st u d y. 
S e cti o n 1. 4: T h e pri m ar y 
e n d p oi nt f or t hi s st u d y i s 
“ C h a n g e fr o m B a s eli n e i n 
N B S at W e e k 1 2 f or t h e 
t e st pr o d u ct ( c o nt ai ni n g 
0. 4 5 4 % w/ w S n F 2 )”. T h er e 
w er e n o pr e vi o u s si mil ar 
st u di e s w h er e b ot h a 
n o n -pr e -pr o p h yl a xi s w a s 
u s e d i n c o nj u n cti o n wit h 
t h e s a m e or si mil ar a cti v e 
i n gr e di e nt i n t h e t e st 
pr o d u ct. T h u s, d u e t o t h e 
u n c ert ai nt y of w h at w o ul d 
b e e x p e ct e d i n t er m s of 
c h a n g e fr o m b a s eli n e f or 
t h e t e st pr o d u ct gi v e n t h e 
af or e m e nti o n e d 
p ar a m et er s, tr e at m e nt 
effi c a c y e sti m at e s f or t h e 
s e c o n d ar y o bj e cti v e 
( c h a n g e fr o m b a s eli n e i n BI 
f or t e st d e ntifri c e c o m p ar e d 
t o c h a n g e fr o m b a s eli n e i n 
BI f or r ef er e n c e d e ntifri c e) 
w er e u s e d i n st e a d.  
T h er e i s a c o ntr a di cti n g 
st at e m e nt i n t h e S e cti o n  1 2. 1  
of t h e Pr ot o c ol. T h e t e xt st at e s 
t h at t h e s a m pl e si z e i s b a s e d 
o n t h e k e y s e c o n d ar y o bj e cti v e,  
w hi c h i s N B S , b ut t h e s a m pl e 
si z e c al c ul ati o n i s b a s e d o n  BI . 
F or  c orr e ct n e s s , S e cti o n 1. 4 of 
t h e S A P cl arifi e s t h at o nl y BI 
w a s u s e d f or t h e s a m pl e si z e 
c al c ul ati o n.  
S e cti o n 1 2. 2: T h e P er -Pr ot o c ol 
( P P) p o p ul ati o n will i n cl u d e all 
r a n d o mi z e d s u bj e ct s w h o d o n ot 
h a v e a n y pr ot o c ol d e vi ati o n s.  
S e cti o n 4. 1. 3:  T h e P P 
p o p ul ati o n will c o m pri s e of 
all r a n d o mi z e d s u bj e ct s 
w h o d o n ot h a v e a n y 
pr ot o c ol d e vi ati o n s t h at 
F or c o n si st e n c y wit h pr e vi o u s 
st u di e s u si n g si mil ar e n d p oi nt s , 
w h er e t h e P P s p e cifi c all y 
f o c u s e s o n mI T T s u bj e ct s 
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Pr ot o c ol  
St ati sti c al A n al y si s Pl a n  
St ati sti c al A n al y si s S e cti o n  
St ati sti c al A n al y si s Pl a n  
R ati o n al e f or C h a n g e s  
c o ul d c o nf o u n d t h e 
i nt er pr et ati o n of a n al y s e s 
c o n d u ct e d o n t h e mI T T.  
r at h er t h a n j u st r a n d o mi z e d 
s u bj e ct s.  
S e cti o n  1 2. 3. 5 : S e n siti vit y a n al y s e s 
will pr e s e nt r e s ult s fr o m t h e 
s e p ar at e A N C O V A m o d el s u si n g 
o nl y n o n -mi s si n g v al u e s at e a c h 
si n gl e ti m e p oi nt.  
S e cti o n 4. 4. 4: A n a d diti o n al 
a n al y si s will e x pl or e t h e 
s e n siti vit y of r e s ult s t o t h e 
eff e ct of mi s si n g d at a o n 
t h e pri m ar y a n d s e c o n d ar y 
effi c a c y e n d p oi nt s. T h e 
s e n siti vit y a n al y si s will u s e 
t h e s a m e M M R M m o d el, 
b ut wit h L O C F f or mi s si n g 
d at a.  
F or c o n si st e n c y wit h pr e vi o u s 
st u di e s u si n g si mil ar e n d p oi nt s, 
s e n siti vit y a n al y si s will b e 
c o n d u ct e d wit h a n M M R M 
u si n g L O C F i m p ut ati o n, r at h er 
t h a n s e p ar at e A N C O V A 
m o d el s b y ti m e p oi nt u si n g o nl y 
o b s er v e d v al u e s.  
N o m e nti o n of a s uit a bl e 
n o n -p ar a m etri c t e st of t h e pri m ar y 
effi c a c y e n d p oi nt.  
S e cti o n 4. 4. 1. 2: T h e 
a s s u m pti o n of n or m alit y 
a n d h o m o g e n eit y of 
v ari a n c e i n t h e M M R M will 
b e i n v e sti g at e d. I n c a s e of 
vi ol ati o n of t h e s e 
a s s u m pti o n s, a Wil c o x o n 
Si g n e d R a n k T e st ( wit hi n 
pr o d u ct c o m p ari s o n s wit h 
b a s eli n e) will b e p erf or m e d 
t o s u p p ort t h e M M R M 
r e s ult s. 
F or c o n si st e n c y wit h pr e vi o u s 
st u di e s, w h er e Wil c o x o n 
Si g n e d R a n k p -v al u e s w er e 
a d d e d f or i n cl u si o n i n t h e 
Cli ni c al St u d y R e p ort.  
N o m e nti o n of a s uit a bl e 
n o n p ar a m etri c t e st of wit hi n gr o u p  
c o m p ari s o n s t o b a s eli n e f or t h e 
s e c o n d ar y effi c a c y e n d p oi nt s.  
S e cti o n s 4. 4. 2. 1. 1, 
4. 4. 2. 2. 1, 4. 4. 2. 3. 1 a n d 
4. 4. 2. 4. 1: T h e a s s u m pti o n 
of n or m alit y a n d 
h o m o g e n eit y of v ari a n c e i n 
t h e M M R M will b e 
i n v e sti g at e d. I n c a s e of 
vi ol ati o n of t h e s e 
a s s u m pti o n s, a Wil c o x o n 
R a n k S u m t e st ( b et w e e n 
pr o d u ct s c o m p ari s o n s) a n d 
Wil c o x o n Si g n e d R a n k 
T e st ( wit hi n pr o d u ct 
c o m p ari s o n s wit h b a s e li n e) 
will b e p erf or m e d t o 
s u p p ort t h e M M R M r e s ult s.  
F or c o n si st e n c y wit h pr e vi o u s 
st u di e s, w h er e Wil c o x o n 
Si g n e d R a n k p -v al u e s w er e 
a d d e d f or i n cl u si o n i n t h e 
Cli ni c al St u d y R e p ort.  
 
 
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Pa ge 3 3  of 4 5  
A p p e n di x 1: Li st of D at a Di s pl a y s 
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
1 4. 1 D e m o gr a p hi c D at a S u m m ar y T a bl e s a n d Fi g ur e s  
  
T a bl e  
1 4. 1. 1  
S u bj e ct Di s p o siti o n  
All S cr e e n e d 
S u bj e ct s  
1 4. 1. 1  
Y e s  
 
T a bl e  
1 4. 1. 2  
I n ci d e n c e of I m p ort a nt Pr ot o c ol D e vi ati o n s 
All R a n d o mi z e d 
S u bj e ct s  
1 4. 1. 2  
 
 
T a bl e  
1 4. 1. 3. 1  
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  
S af et y 
P o p ul ati o n  
1 4. 1. 3. 1  
 
 
T a bl e  
1 4. 1. 3. 2  
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  
mI T T P o p ul ati o n  
1 4. 1. 3. 1  
Y e s  
1 4. 2 Effi c a c y D at a S u m m ar y T a bl e s a n d Fi g ur e s  
  
T a bl e  
1 4. 2. 1  
S u m m ar y of Br u s hi n g C o m pli a n c e  
mI T T P o p ul ati o n  
1 4. 2. 1  
  
  
T a bl e  
1 4. 2. 2. 1. 1  
S u m m ar y of N u m b er of Bl e e di n g Sit e s  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 1  
Y e s  
  
T a bl e  
1 4. 2. 2. 1. 2  
S u m m ar y of N u m b er of Bl e e di n g Sit e s  
P P P o p ul ati o n  
1 4. 2. 2. 1. 1  
 
 
T a bl e  
1 4. 2. 2. 1. 3  
S u m m ar y of C h a n g e i n N u m b er of Bl e e di n g 
Sit e s  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 3  
 
 
T a bl e  
1 4. 2. 2. 1. 4  
S u m m ar y of C h a n g e i n N u m b er of Bl e e di n g 
Sit e s  
P P P o p ul ati o n  
1 4. 2. 2. 1. 3  
 
 
Fi g ur e  
1 4. 2. 2. 1. 5  
N u m b er of Bl e e di n g Sit e s ( ± S E) Pl ot O v er 
Ti m e b y St u d y Pr o d u ct  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 5  
 
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Pa ge 3 4  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
Fi g ur e  
1 4. 2. 2. 1. 6  
N u m b er of Bl e e di n g Sit e s ( ± S E) Pl ot O v er 
Ti m e b y St u d y Pr o d u ct  
P P P o p ul ati o n  
1 4. 2. 2. 1. 5  
 
 
T a bl e  
1 4. 2. 2. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s  
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
Y e s  
 
T a bl e  
1 4. 2. 2. 2. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s  
P P P o p ul ati o n  
1 4. 2. 2. 2. 1  
 
 
T a bl e  
1 4. 2. 2. 2. 3  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s ( L O C F)  
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
 
 
T a bl e  
1 4. 2. 2. 2. 4  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s ( L O C F)  
P P P o p ul ati o n  
1 4. 2. 2. 2. 1  
 
 
T a bl e  
1 4. 2. 3. 1. 1  
S u m m ar y of Bl e e di n g I n d e x ( BI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 1  
Y e s  
 
T a bl e  
1 4. 2. 3. 1. 2  
S u m m ar y of C h a n g e i n Bl e e di n g I n d e x ( BI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 3  
 
 
Fi g ur e  
1 4. 2. 3. 1. 3  
Bl e e di n g I n d e x ( BI) ( ± S E) Pl ot O v er Ti m e b y 
St u d y Pr o d u ct  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 5  
 
 
T a bl e  
1 4. 2. 3. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
Bl e e di n g I n d e x ( BI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
Y e s  
 
T a bl e  
1 4. 2. 3. 2. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
Bl e e di n g I n d e x ( BI) ( L O C F)  
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
 
 
T a bl e  
1 4. 2. 4. 1. 1  
S u m m ar y of M o difi e d Gi n gi v al I n d e x ( M GI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 1  
Y e s  
 
T a bl e  
1 4. 2. 4. 1. 2  
S u m m ar y of C h a n g e i n M o difi e d Gi n gi v al 
I n d e x ( M GI) 
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 3  
 
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Pa ge 3 5  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
Fi g ur e  
1 4. 2. 4. 1. 3  
M o difi e d Gi n gi v al I n d e x ( M GI) ( ± S E) Pl ot O v er 
Ti m e b y St u d y Pr o d u ct  
m I T T P o p ul ati o n  
1 4. 2. 2. 1. 5  
 
 
T a bl e  
1 4. 2. 4. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
M o difi e d Gi n gi v al I n d e x ( M GI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
Y e s  
 
T a bl e  
1 4. 2. 4. 2. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
M o difi e d Gi n gi v al I n d e x ( M GI)  ( L O C F) 
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
 
 
T a bl e  
1 4. 2. 5. 1. 1  
S u m m ar y of O v er all T ur e s k y Pl a q u e I n d e x 
( T PI) 
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 1  
Y e s  
 
T a bl e  
1 4. 2. 5. 1. 2  
S u m m ar y of C h a n g e i n O v er all T ur e s k y 
Pl a q u e I n d e x ( T PI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 3  
 
 
T a bl e  
1 4. 2. 5. 1. 3  
S u m m ar y of I nt er pr o xi m al T ur e s k y Pl a q u e 
I n d e x ( T PI) 
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 1  
 
 
T a bl e  
1 4. 2. 5. 1. 4  
S u m m ar y of C h a n g e i n I nt er pr o xi m al T ur e s k y 
Pl a q u e I n d e x ( T PI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 3  
 
 
Fi g ur e  
1 4. 2. 5. 1. 5  
O v er all T ur e s k y  Pl a q u e I n d e x ( T PI) ( ± S E) Pl ot 
O v er Ti m e b y St u d y Pr o d u ct  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 5  
 
 
Fi g ur e  
1 4. 2. 5. 1. 6  
I nt er pr o xi m al T ur e s k y Pl a q u e I n d e x ( T PI) ( ± 
S E) Pl ot O v er Ti m e b y St u d y Pr o d u ct  
m I T T P o p ul ati o n 
1 4. 2. 2. 1. 5  
 
 
T a bl e  
1 4. 2. 5. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
O v er all T ur e s k y Pl a q u e I n d e x ( T PI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
Y e s  
 
T a bl e  
1 4. 2. 5. 2. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
O v er all T ur e s k y Pl a q u e I n d e x ( T PI)  ( L O C F) 
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
 
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 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 3 6  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
T a bl e  
1 4. 2. 5. 2. 3  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
I nt er pr o xi m al T ur e s k y Pl a q u e I n d e x ( T PI)  
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
 
 
T a bl e  
1 4. 2. 5. 2. 4  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
I nt er pr o xi m al T ur e s k y Pl a q u e I n d e x ( T PI)  
( L O C F) 
m I T T P o p ul ati o n 
1 4. 2. 2. 2. 1  
 
 
T a bl e  
1 4. 2. 6. 1. 1  
S u m m ar y of N u m b er of Bl e e di n g Sit e s  b y M GI 
S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 1  
 
 
Fi g ur e  
1 4. 2. 6. 1. 2  
N u m b er of Bl e e di n g Sit e s ( ± S E) Pl ot O v er 
Ti m e b y St u d y Pr o d u ct  a n d M GI S u b gr o u p  
m I T T P o p ul ati o n  
1 4. 2. 6. 1. 2  
 
 
T a bl e  
1 4. 2. 6. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s  b y M GI S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 2. 1  
 
 
T a bl e  
1 4. 2. 7. 1. 1  
S u m m ar y of Bl e e di n g I n d e x ( BI)  b y M GI 
S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 1  
 
 
Fi g ur e  
1 4. 2. 7. 1. 2  
Bl e e di n g I n d e x ( BI) ( ± S E) Pl ot O v er Ti m e b y 
St u d y Pr o d u ct a n d M GI S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 2  
 
 
T a bl e  
1 4. 2. 7. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
Bl e e di n g I n d e x ( BI)  b y M GI S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 2. 1  
 
 
T a bl e  
1 4. 2. 8. 1. 1  
S u m m ar y of M o difi e d Gi n gi v al I n d e x ( M GI)  b y 
M GI S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 1  
 
 
Fi g ur e  
1 4. 2. 8. 1. 2  
M o difi e d Gi n gi v al I n d e x ( M GI) ( ± S E) Pl ot O v er 
Ti m e b y St u d y Pr o d u ct  a n d M GI S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 2  
 
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Pa ge 3 7  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
T a bl e  
1 4. 2. 8. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
M o difi e d Gi n gi v al I n d e x ( M GI)  b y M GI 
S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 2. 1  
 
 
T a bl e  
1 4. 2. 9. 1. 1  
S u m m ar y of O v er all T ur e s k y Pl a q u e I n d e x 
( T PI) b y M GI S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 1  
 
 
T a bl e  
1 4. 2. 9. 1. 2  
S u m m ar y of I nt er pr o xi m al T ur e s k y Pl a q u e 
I n d e x ( T PI) b y M GI S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 1  
 
 
Fi g ur e  
1 4. 2. 9. 1. 3  
O v er all T ur e s k y Pl a q u e I n d e x ( T PI) ( ± S E) Pl ot 
O v er Ti m e b y St u d y Pr o d u ct  a n d M GI 
S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 2  
 
 
Fi g ur e  
1 4. 2. 9. 1. 4  
I nt er pr o xi m al T ur e s k y Pl a q u e I n d e x ( T PI) ( ± 
S E) Pl ot O v er Ti m e b y St u d y Pr o d u ct  a n d M GI 
S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 1. 2  
 
 
T a bl e  
1 4. 2. 9. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
O v er all T ur e s k y Pl a q u e I n d e x ( T PI)  b y M GI 
S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 2. 1  
 
 
T a bl e  
1 4. 2. 9. 2. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
I nt er pr o xi m al T ur e s k y Pl a q u e I n d e x ( T PI)  b y 
M GI S u b gr o u p  
m I T T P o p ul ati o n 
1 4. 2. 6. 2. 1  
 
 
T a bl e  
1 4. 2. 1 0. 1  
I ntr a-E x a mi n er R e p e at a bilit y A n al y si s of 
M o difi e d Gi n gi v al I n d e x ( M GI) 
M GI 
R e p e at a bilit y 
P o p ul ati o n  
1 4. 2. 1 0. 1  
 
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 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 3 8  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
T a bl e  
1 4. 2. 1 0. 2  
I ntr a-E x a mi n er R e p e at a bilit y A n al y si s of 
T ur e s k y Pl a q u e I n d e x ( T PI)  
T PI R e p e at a bilit y 
P o p ul ati o n  
1 4. 2. 1 0. 2  
 
1 4. 3 S af et y D at a S u m m ar y T a bl e s a n d Fi g ur e s  
1 4. 3. 1 Di s pl a y s of A d v er s e E v e nt s  
  
T a bl e  
1 4. 3. 1. 1  
Tr e at m e nt E m er g e nt A d v er s e E v e nt s b y 
S y st e m Or g a n Cl a s s a n d Pr ef err e d T er m  
S af et y 
P o p ul ati o n  
1 4. 3. 1. 1  
 Y e s  
  
T a bl e  
1 4. 3. 1. 2  
Tr e at m e nt E m er g e nt A d v er s e E v e nt s b y 
Or al/ N o n -Or al a n d Pr ef err e d T er m  
S af et y 
P o p ul ati o n  
1 4. 3. 1. 2  
 
 
T a bl e  
1 4. 3. 1. 3  
Tr e at m e nt R el at e d Tr e at m e nt E m er g e nt 
A d v er s e E v e nt s b y S y st e m Or g a n Cl a s s a n d 
Pr ef err e d T er m  
S af et y 
P o p ul ati o n  
1 4. 3. 1. 1  
 
 
T a bl e  
1 4. 3. 1. 4  
Tr e at m e nt R el at e d Tr e at m e nt E m er g e nt 
A d v er s e E v e nt s b y Or al/ N o n -Or al a n d 
Pr ef err e d T er m  
S af et y 
P o p ul ati o n  
1 4. 3. 1. 2  
 
 
T a bl e  
1 4. 3. 1. 5  
N o n -S eri o u s Tr e at m e nt E m er g e nt A d v er s e 
E v e nt s b y S y st e m Or g a n Cl a s s a n d Pr ef err e d 
T er m  
S af et y 
P o p ul ati o n  
1 4. 3. 1. 1  
 
 
T a bl e  
1 4. 3. 1. 6  
S eri o u s Tr e at m e nt E m er g e nt A d v er s e E v e nt s 
b y S y st e m Or g a n Cl a s s a n d Pr ef err e d T er m  
S af et y 
P o p ul ati o n  
1 4. 3. 1. 1  
 
1 4. 3. 2 Li sti n g s of D e at h s, Ot h er S eri o u s a n d Si g nifi c a nt A d v er s e E v e nt s  
  
Li sti n g  
1 4. 3. 2. 1  
D e at h s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 7. 1  
 
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Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 3 9  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
Li sti n g  
1 4. 3. 2. 2  
N o n -F at al S eri o u s A d v er s e E v e nt s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 7. 1  
 
 
Li sti n g  
1 4. 3. 2. 3  
Tr e at m e nt E m er g e nt A d v er s e E v e nt s L e a di n g 
t o St u d y or Pr o d u ct Di s c o nti n u ati o n 
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 7. 1  
 
 
Li sti n g  
1 4. 3. 2. 4  
Tr e at m e nt E m er g e nt A d v er s e E v e nt s 
Cl a s sifi e d a s Or al  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 7. 1  
 
1 4. 3. 3 N arr ati v e s of D e at h s, Ot h er S eri o u s a n d C ert ai n Ot h er Si g nifi c a nt A d v er s e E v e nt s  
  
N A  
 
 
 
 
 
1 4. 3. 4 Ot h er O b s er v ati o n s R el at e d t o S af et y a n d A b n or m al L a b or at or y V al u e s  
  
T a bl e  
1 4. 3. 4. 1  
S u m m ar y of Or al S oft Ti s s u e E x a mi n ati o n  
S af et y 
P o p ul ati o n  
1 4. 3. 4. 1  
 
A P P E N DI X  
1 6. 1. 6 Li sti n g of S u bj e ct s R e c ei vi n g T e st Dr u g( s)/I n v e sti g ati o n al Pr o d u ct( s) fr o m S p e cifi c B at c h e s, w h er e m or e t h a n o n e b at c h w a s u s e d  
  
N A  
  
  
  
  
  
1 6. 1. 7 R a n d o mi z ati o n S c h e m e a n d C o d e s ( S u bj e ct i d e ntifi c ati o n a n d tr e at m e nt a s si g n e d)  
 
  
Li sti n g  
1 6. 1. 7. 1  
R a n d o mi z ati o n I nf or m ati o n  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 1. 7. 1  
  
  
Li sti n g  
1 6. 1. 7. 2  
Kit Li st All o c ati o n  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 1. 7. 2  
 
1 6. 1. 9 D o c u m e nt ati o n of St ati sti c al M et h o d s  
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Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 4 0  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
R a w 
o ut p ut  
1 6. 1. 9. 1. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s  ( R ef er e n c e: T a bl e 
1 4. 2. 2. 2. 1)  
m I T T P o p ul ati o n 
S A S O ut p ut  
Y e s  
 
R a w 
o ut p ut  
1 6. 1. 9. 1. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s  ( R ef er e n c e: T a bl e 
1 4. 2. 2. 2. 2)  
P P P o p ul ati o n  
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 1. 3  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s  ( L O C F) ( R ef er e n c e: 
T a bl e 1 4. 2. 2. 2. 3)  
m I T T P o p ul ati o n 
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 1. 4  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s  ( L O C F) ( R ef er e n c e: 
T a bl e 1 4. 2. 2. 2. 4)  
P P P o p ul ati o n  
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 2. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
Bl e e di n g I n d e x ( BI)  ( R ef er e n c e: T a bl e 
1 4. 2. 3. 2. 1)  
mI T T P o p ul ati o n  
S A S O ut p ut  
Y e s  
 
R a w 
o ut p ut  
1 6. 1. 9. 2. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
Bl e e di n g I n d e x ( BI) ( L O C F)  ( R ef er e n c e: T a bl e 
1 4. 2. 3. 2. 2)  
mI T T P o p ul ati o n  
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 3. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
M o difi e d Gi n gi v al I n d e x ( M GI)  ( R ef er e n c e: 
T a bl e 1 4. 2. 4. 2. 1)  
mI T T P o p ul ati o n  
S A S O ut p ut  
Y e s  
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 4 1  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
R a w 
o ut p ut  
1 6. 1. 9. 3. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
M o difi e d Gi n gi v al I n d e x ( M GI)  ( L O C F) 
( R ef er e n c e: T a bl e 1 4. 2. 4. 2. 2) 
m I T T P o p ul ati o n 
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 4. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
O v er all T ur e s k y Pl a q u e I n d e x ( T PI)  
( R ef er e n c e: T a bl e 1 4. 2. 5. 2. 1) 
mI T T P o p ul ati o n  
S A S O ut p ut  
Y e s  
 
R a w 
o ut p ut  
1 6. 1. 9. 4. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
O v er all T ur e s k y Pl a q u e I n d e x ( T PI)  ( L O C F) 
( R ef er e n c e: T a bl e 1 4. 2. 5. 2. 2) 
mI T T P o p ul ati o n  
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 4. 3  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
O v er all T ur e s k y Pl a q u e I n d e x ( T PI)  b y M GI 
S u b gr o u p  ( R ef er e n c e: T a bl e 1 4. 2.2 .4 .5 ) 
mI T T P o p ul ati o n  
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 4. 4 
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
I nt er pr o xi m al T ur e s k y Pl a q u e I n d e x ( T PI)  
( R ef er e n c e: T a bl e 1 4. 2. 5. 2. 3) 
mI T T P o p ul ati o n  
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 5  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
N u m b er of Bl e e di n g Sit e s  b y M GI S u b gr o u p 
( R ef er e n c e: T a bl e 1 4. 2. 6. 2. 1 ) 
m I T T P o p ul ati o n 
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 6  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
Bl e e di n g I n d e x ( BI) b y M GI S u b gr o u p 
( R ef er e n c e: T a bl e 1 4. 2. 7. 2. 1 ) 
mI T T P o p ul ati o n  
S A S O ut p ut  
 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 4 2  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
R a w 
o ut p ut  
1 6. 1. 9. 7  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
M o difi e d Gi n gi v al I n d e x ( M GI)  b y M GI 
S u b gr o u p ( R ef er e n c e: T a bl e 1 4. 2. 8. 2. 1 ) 
m I T T P o p ul ati o n 
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 8. 1  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
I nt er pr o xi m al T ur e s k y Pl a q u e I n d e x ( T PI)  
( R ef er e n c e: T a bl e 1 4. 2. 9. 2. 1 ) 
mI T T P o p ul ati o n  
S A S O ut p ut  
 
 
R a w 
o ut p ut  
1 6. 1. 9. 8. 2  
St ati sti c al A n al y si s of C h a n g e fr o m B a s eli n e i n 
I nt er pr o xi m al T ur e s k y Pl a q u e I n d e x ( T PI)  b y 
M GI S u b gr o u p ( R ef er e n c e: T a bl e 1 4. 2. 9. 2. 2 ) 
mI T T P o p ul ati o n  
S A S O ut p ut  
 
1 6. 2 S u bj e ct D at a Li sti n g s  
1 6. 2. 1 Di s c o nti n u e d S u bj e ct s  
  
Li sti n g  
1 6. 2. 1. 1  
S u bj e ct Di s p o siti o n  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 1. 1  
 
 
Li sti n g  
1 6. 2. 1. 2  
S u bj e ct Di s p o siti o n  
N o n -
R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 1. 2  
 
1 6. 2. 2 Pr ot o c ol D e vi ati o n s  
  
Li sti n g  
1 6. 2. 2. 1  
I m p ort a nt Pr ot o c ol D e vi ati o n s 
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 2. 1  
 
 
Li sti n g  
1 6. 2. 2. 2  
All Pr ot o c ol D e vi ati o n s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 2. 2  
 
1 6. 2. 3 P ati e nt s E x cl u d e d fr o m t h e Effi c a c y A n al y si s  
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 4 3  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
  
Li sti n g  
1 6. 2. 3. 1  
E x cl u si o n s fr o m A n al y si s P o p ul ati o n s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 3. 1  
 
1 6. 2. 4 D e m o gr a p hi c D at a  
  
Li sti n g  
1 6. 2. 4. 1  
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  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 4. 1  
 
 
Li sti n g  
1 6. 2. 4. 2  
M e di c al Hi st or y a n d C urr e nt M e di c al 
C o n diti o n s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 4. 2  
 
 
Li sti n g  
1 6. 2. 4. 3  
Pri or M e di c ati o n s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 4. 3  
 
 
Li sti n g  
1 6. 2. 4. 4  
C o n c o mit a nt M e di c ati o n s a n d C o n c o mit a nt  
N o n -Dr u g T h er a pi e s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 4. 4  
 
1 6. 2. 5 C o m pli a n c e a n d/ or Dr u g C o n c e ntr ati o n D at a (if a v ail a bl e)  
  
Li sti n g  
1 6. 2. 5. 1  
Br u s hi n g C o m pli a n c e  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 5. 1  
 
 
Li sti n g  
1 6. 2. 5. 2  
S u p er vi s e d Br u s hi n g  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 5. 2  
 
1 6. 2. 6 I n di vi d u al Effi c a c y R e s p o n s e D at a  
  
Li sti n g  
1 6. 2. 6. 1  
N u m b er of Bl e e di n g Sit e s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 6. 1  
 
 
Li sti n g  
1 6. 2. 6. 2. 1  
Bl e e di n g I n d e x ( BI) I n di vi d u al S c or e s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 6. 2. 1  
 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 4 4  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
Li sti n g  
1 6. 2. 6. 2. 2  
Bl e e di n g I n d e x ( BI) D eri v e d S c or e s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 6. 2. 2  
 
 
Li sti n g  
1 6. 2. 6. 3. 1  
M o difi e d Gi n gi v al I n d e x ( M GI) I n di vi d u al 
S c or e s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 6. 3. 1  
 
 
Li sti n g  
1 6. 2. 6. 3. 2  
M o difi e d Gi n gi v al I n d e x ( M GI) D eri v e d S c or e s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 6. 3. 2  
 
 
Li sti n g  
1 6. 2. 6. 4. 1  
T ur e s k y Pl a q u e I n d e x ( T PI) I n di vi d u al S c or e s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 6. 4. 1  
 
 
Li sti n g  
1 6. 2. 6. 4. 2  
T ur e s k y  Pl a q u e I n d e x ( T PI) D eri v e d S c or e s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 6. 4. 2  
 
1 6. 2. 7 A d v er s e E v e nt Li sti n g s  
  
Li sti n g  
1 6. 2. 7. 1  
All A d v er s e E v e nt s  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 7. 1  
 
 
Li sti n g  
1 6. 2. 7. 2  
All A d v er s e E v e nt s  
N o n -
R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 7. 1  
 
 
Li sti n g  
1 6. 2. 7. 3  
I n ci d e nt s 
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 7. 3 
 
1 6. 2. 8 Ot h er Li sti n g s a n d Li sti n g of L a b or at or y M e a s ur e m e nt s, w h e n r e q uir e d b y r e g ul at or y a ut h oriti e s (if a p pli c a bl e)  
  
Li sti n g  
1 6. 2. 8. 1  
Or al S oft Ti s s u e E x a mi n ati o n  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 8. 1  
 
C CI


0. 4 5 4 % w/ w Sta n n o us Fl u ori de ( S n F 2) 
3 0 0 1 0 7  
 
 
 
 
Hale o n  C o nfi de ntial  
 Statistical A nal ysis Pla n  Te m plate v 7 . 0 
Pa ge 4 5  of 4 5  
C S R 
S e cti o n  
T L F  
N u m b er  
Titl e  
P o p ul ati o n  
T e m pl at e  
T o pli n e  
 
Li sti n g  
1 6. 2. 8. 2  
Or al H ar d Ti s s u e E x a mi n ati o n  
All R a n d o mi z e d 
S u bj e ct s  
1 6. 2. 8. 2  
 
1 6. 4 I n di vi d u al S u bj e ct D at a Li sti n g s  
  
N A  
  
  
  
  
  
 
C CI