A Randomized, Controlled, Examiner-Blind Clinical Study Investigating the Effects of a Dentifrice Containing 0.454% w/w Stannous Fluoride on Gingivitis Treatment and Plaque Reduction When Used Twice Daily for 12 Weeks
Phase: NA
Conditions: Gingivitis
Sponsor: HALEON

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  of 7 0  
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  
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
T his d oc u me nt c o ntai ns c o nfi de ntialit y state me nts t hat are n ot rele va nt 
f or t his p u blicl y a vaila ble versi o n
C CI

Hale o n  
 
Cli nical Pr ot oc ol  
 
 
Pr ot oc ol N u m ber : 3 0 0 1 0 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  of 7 0  
 
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)  
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  of 7 0  
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.   
 
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  of 7 0  
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  
 
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
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  of 7 0  
T a bl e of C o nt e nt s  
S p o ns or I nf or mati o n  ............................................................................................................ 2  
D oc u me nt Hist or y  ............................................................................................................... 3  
Pri nci pal I n v esti gat or Pr ot oc ol A gree me nt Pa ge  ................................................................ 4  
Ta ble of C o nte nts  ................................................................................................................ 5  
1  
P R O T O C O L S U M M A R Y  ................................................................................................ 1 0  
1. 1  
S y n o psis  ................................................................................................................. 1 0  
1. 2  
Sc he d ule of A cti vities  ............................................................................................ 1 4  
2  
I N T R O D U C TI O N ............................................................................................................. 1 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  
5. 5. 6  
C O VI D -1 9  ............................................................................................. 2 8  
5. 6  
Scree n Fail ures ....................................................................................................... 2 8  
5. 7  
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  
6  
I N V E S TI G A TI O N A L/ S T U D Y P R O D U C T S................................................................... 2 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  
6. 2  
A d mi nistrati o n  ....................................................................................................... 3 2  
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  of 7 0  
6. 2. 1  
Me dicati o n/ D osi n g Err ors  ..................................................................... 3 2  
6. 2. 2  
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  
7  
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  
9  
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  
9. 2. 2  
BI Assess me nt ( Sa xt o n a n d va n der O u d eraa, 1 9 8 9)  ............................ 4 3  
9. 2. 3  
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  
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  of 7 0  
9. 3. 1  
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  
1 0. 3  
Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A E a n d S A E I nf or mati o n  .................. 4 8  
1 0. 4  
Re p orti n g Pr oce d ures ............................................................................................. 4 9  
1 0. 4. 1  
Re p orti n g of a n A d verse E ve nt  ............................................................. 4 9  
1 0. 4. 2  
Re p orti n g of a Seri o us A d verse E ve nt  .................................................. 5 0  
1 0. 5  
E val uati n g A d v erse E ve nts  .................................................................................... 5 0  
1 0. 5. 1  
Assess me nt of I nte nsit y  ........................................................................ 5 0  
1 0. 5. 2  
Assess me nt of Ca usalit y  ....................................................................... 5 1  
1 0. 6  
F oll o w -u p of A Es a n d S A Es .................................................................................. 5 1  
1 0. 7  
Wit h dra wal D ue t o a n A d verse E ve nt  ................................................................... 5 2  
1 0. 8  
Re g ulat or y Re p orti n g Re q uire me nts f or S A Es ...................................................... 5 2  
1 0. 9  
Pre g n a nc y  .............................................................................................................. 5 2  
1 0. 9. 1  
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  
1 0. 1 0. 1  
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  
1 2. 2  
P o p ulati o ns f or A nal ysis  ........................................................................................ 5 7  
1 2. 3  
Statistical A nal yses  ................................................................................................ 5 7  
1 2. 3. 1  
Pri mar y A n al ysis(es)  ............................................................................. 5 8  
1 2. 3. 2  
Sec o n dar y A nal ysis(es)  ......................................................................... 5 8  
1 2. 3. 3  
E x pl orat or y A nal ysis(es)  ....................................................................... 5 9  
1 2. 3. 4  
Safet y A nal ysis(es) ................................................................................ 5 9  
1 2. 3. 5  
Ot her A nal ysis(es)  ................................................................................. 5 9  
1 2. 3. 6  
De m o gra p hic a n d Baseli ne C haracteristics  ........................................... 6 0  
1 2. 3. 7  
St u d y Dr u g/ Pr o d uct C o m plia nce  .......................................................... 6 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 8  of 7 0  
1 2. 3. 8  
Ha n dli n g of Dr o p o uts a n d Missi n g Data  .............................................. 6 1  
1 2. 3. 9  
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  
1 3. 1  
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  
1 3. 3. 3  
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  
1 3. 3. 5  
Re p orti n g of Safet y Iss ues a n d Seri o us Breac hes of t he Pr ot oc ol or 
I C H G C P ............................................................................................... 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  
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 9  of 7 0  
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 
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 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