Clinical trial NCT04239872
Conditions: Hyposalivation
Sponsor: University of Michigan
Start date: 2020-03-11; Completion date: 2021-04-05
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Individuals with dry mouth (a reduction in the production of saliva) suffer from high rates of oral diseases. Dry mouth is a common problem among older individuals, because many medications to control chronic conditions (such as blood pressure, bladder-control problems and depression) reduce the flow of saliva. For these individuals, fluoride is used to maintain a good oral health. Usually, higher fluoride concentration products, such as prescription toothpastes, are recommended. In this project, the ability to increase fluoride retention in the mouth by using calcium before a conventional fluoride rinse will be tested in older adults with a range of salivary flow rates. This approach was never tested in patients with dry mouth, for whom the treatment with calcium may also be beneficial. A crossover, clinical study with two experimental phases will be conducted, in which patients with a range of saliva flows (from normal to dry mouth) will rinse with a fluoride rinse only (used at over the counter concentration), or a fluoride rinse preceded by a calcium rinse. The concentration of fluoride and calcium in the saliva and dental plaque residues will be determined up to two hours after the rinse(s), to test the effect of the approach to optimize fluoride retention in the mouth of patients with dry mouth.

Detailed description:

Arms: arm 1: Participants with normal to dry mouth will first test a Fluoride mouthwash containing 226 ppm of fluoride, and fluoride concentration in saliva and dental biofilm will be assessed overtime for up to 2 hours. After a washout period of at least 3 days, they will then test a Calcium mouthwash (150 milimolars of calcium) immediately before the Fluoride mouthwash, and fluoride concentration in saliva and dental biofilm will be assessed overtime for up to 2 hours. arm 2: Participants with normal to dry mouth will first test a Calcium mouthwash (150 milimolars of calcium) immediately before a Fluoride mouthwash containing 226 ppm of fluoride, and fluoride concentration in saliva and dental biofilm will be assessed overtime for up to 2 hours. After a washout period of at least 3 days, they will then test the Fluoride mouthwash alone, and fluoride concentration in saliva and dental biofilm will be assessed overtime for up to 2 hours.
Interventions: intervention 1: Fluoride mouthwash intervention 2: Calcium and fluoride mouthwash
Intervention descriptions: intervention 1: Sodium fluoride, at a concentration of 0.05% (226 parts per million (ppm) of fluoride), will be used to rinse the mouth for 1 minute and expectorated. intervention 2: Calcium lactate, at a concentration of 150 milimolar, will be used to rinse the mouth for 1 minute and expectorated; immediately after, a sodium fluoride rinse, at a concentration of 0.05% (226 ppm of fluoride), will be used to rinse the mouth for 1 minute, and expectorated.

Protocol documents:
Prot_SAP_000.pdf: 
O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er 
a d ults wit h disti nct s ali v ar y fl o w r at es  
 
Pr ot oc ol N u m b er: 0 1  
N ati o n al Cli nic al Tri al ( N C T) I d e ntifi e d N u m b er:  N C T 0 4 2 3 9 8 7 2  
Pri nci p al I n v esti g at or:  Li vi a M. A. T e n ut a  
F u n d e d b y : MI C H R  
V ersi o n N u m b er:  v . 1.3  
2 0 A u g ust 2 0 2 0  
 
 


  
 
ii 
Ta bl e of C o nt e nts  
S T A T E M E N T O F C O M P LI A N C E  ............................................................................................................................ 1  
1  
P R O T O C O L S U M M A R Y  .............................................................................................................................. 1  
1. 1  
S y n o p si s  ............................................................................................................................................... 1  
1. 2  
S c h e m a  ................................................................................................................................................ 2  
1. 3  
S c h e d ul e of A cti viti e s ( S o A)  .............................................................................................................. 3  
2  
I N T R O D U C TI O N ........................................................................................................................................... 3  
2. 1  
St u d y R ati o n al e  ................................................................................................................................... 3  
2. 2  
B a c k gr o u n d  .......................................................................................................................................... 4  
2. 3  
Ri s k/ B e n efit A s s e s s m e nt  ................................................................................................................... 4  
2. 3. 1  
K n o w n P ot e nti al Ri s k s  .................................................................................................... 4  
2. 3. 2  
K n o w n P ot e nti al B e n efit s  ............................................................................................... 5  
2. 3. 3  
A s s e s s m e nt of P ot e nti al Ri s k s a n d B e n efit s  ............................................................... 5  
3  
O B J E C TI V E S A N D E N D P OI N T S  ............................................................................................................... 5  
4  
S T U D Y D E SI G N  ............................................................................................................................................ 6  
4. 1  
O v er all D e si g n  ..................................................................................................................................... 6  
4. 2  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  ............................................................................................... 7  
4. 3  
J u stifi c ati o n f or D o s e  .......................................................................................................................... 7  
4. 4  
E n d of St u d y D efi niti o n  ....................................................................................................................... 7  
5  
S T U D Y P O P U L A TI O N  .................................................................................................................................. 7  
5. 1  
I n cl u si o n Crit eri a ................................................................................................................................. 7  
5. 2  
E x cl u si o n Crit eri a  ................................................................................................................................ 8  
Lif e st yl e C o n si d er ati o n s  ........................................................................................................................................ 8  
5. 3  
S cr e e n F ail ur e s  ................................................................................................................................... 8  
5. 4  
Str at e gi e s f or R e cr uit m e nt a n d R et e nti o n  ....................................................................................... 8  
6  
S T U D Y I N T E R V E N TI O N  .............................................................................................................................. 9  
6. 1  
St u d y I nt er v e nti o n( s) A d mi ni str ati o n  ................................................................................................ 9  
6. 1. 1  
St u d y I nt er v e nti o n D e s cri pti o n  ...................................................................................... 9  
6. 1. 2  
D o si n g a n d A d mi ni str ati o n  ............................................................................................. 9  
6. 2  
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y  ................................................................................. 9  
6. 2. 1  
A c q ui siti o n a n d a c c o u nt a bilit y  ....................................................................................... 9  
6. 2. 2  
F or m ul ati o n, A p p e ar a n c e, P a c k a gi n g, a n d L a b eli n g  ............................................... 1 0  
6. 2. 3  
Pr o d u ct St or a g e a n d St a bilit y  ...................................................................................... 1 0  
6. 2. 4  
Pr e p ar ati o n  ..................................................................................................................... 1 0  
6. 3  
M e a s ur e s t o Mi ni mi z e Bi a s: R a n d o mi z ati o n a n d Bli n di n g  .......................................................... 1 1  
6. 4  
St u d y I nt er v e nti o n C o m pli a n c e  ....................................................................................................... 1 1  
7  
S T U D Y I N T E R V E N TI O N DI S C O N TI N U A TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ................................................................................................................... 1 1  
7. 1  
Di s c o nti n u ati o n of St u d y I nt er v e nti o n  ............................................................................................ 1 1  
7. 2  
P arti ci p a nt Di s c o nti n u ati o n/ Wit h dr a w al fr o m t h e St u d y  .............................................................. 1 1  
7. 3  
L o st t o F oll o w -U p  .............................................................................................................................. 1 2  
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................................................................... 1 2  
8. 1  
Effi c a c y A s s e s s m e nt s  ...................................................................................................................... 1 2  
8. 2  
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  .............................................................................. 1 5  
8. 3  
U n a nti ci p at e d Pr o bl e m s  ................................................................................................................... 1 5  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  .......................................................................................................... 1 5  
9. 1  
St ati s ti c al H y p ot h e s e s ...................................................................................................................... 1 5  


  
 
iii 
9. 2  
S a m pl e Si z e D et er mi n ati o n  ............................................................................................................. 1 6  
9. 3  
P o p ul ati o n s f or A n al y s e s  ................................................................................................................. 1 6  
9. 4  
St ati s ti c al A n al y s e s ........................................................................................................................... 1 6  
9. 4. 1  
G e n er al A p pr o a c h  ......................................................................................................... 1 6  
9. 4. 2  
A n al y si s of t h e Pri m ar y Effi c a c y E n d p oi nt( s)  ............................................................ 1 7  
9. 4. 3  
A n al y si s of t h e S e c o n d ar y E n d p oi nt( s)  ...................................................................... 1 7  
1 0  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L C O N SI D E R A TI O N S  .............................. 1 8  
1 0. 1  
R e g ul at or y, Et hi c al, a n d St u d y O v er si g ht C o n si d er ati o n s  .......................................................... 1 8  
1 0. 1. 1  
I nf or m e d C o n s e nt Pr o c e s s .......................................................................................... 1 8  
1 0. 1. 2  
St u d y Di s c o nti n u ati o n a n d Cl o s ur e  ............................................................................. 1 8  
1 0. 1. 3  
C o nfi d e nti alit y a n d Pri v a c y  ........................................................................................... 1 9  
1 0. 1. 4  
K e y R ol e s a n d St u d y G o v er n a n c e  .............................................................................. 1 9  
1 0. 1. 5  
D at a H a n dli n g a n d R e c or d K e e pi n g  ........................................................................... 1 9  
1 0. 1. 6  
Pr ot o c ol D e vi ati o n s  ....................................................................................................... 2 0  
1 0. 1. 7  
P u bli c ati o n a n d D at a S h ari n g P oli c y  .......................................................................... 2 0  
1 0. 1. 8  
C o nfli ct of I nt er e st P oli c y .............................................................................................. 2 0  
1 0. 2  
A b br e vi ati o n s  ..................................................................................................................................... 2 1  
1 1  
R E F E R E N C E S  ............................................................................................................................................. 2 2  
 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1  
S T A T E M E N T O F C O M P LI A N C E  
T h e pr ot oc ol, i nf or m e d c o ns e nt f or m(s), r ecr uit m e nt m at eri als, a n d all p artici p a nt m at eri als will b e 
s u b mitt e d t o t h e I R B f or r evi e w a n d a p pr o v al.  A p pr o v al of b ot h t h e pr ot oc ol a n d t h e c o ns e nt f or m m ust 
b e o bt ai n e d b ef or e a n y p artici p a nt is e nr oll e d.  A n y a m e n d m e nt t o t h e pr ot oc ol will r e q uir e r evi e w a n d 
a p pr ov al by t h e I R B b ef or e t h e c h a n g es ar e i m pl e m e nt e d t o t h e st u d y.  All c h a n g es t o t h e c o ns e nt f or m 
will b e I R B a p pr ov e d; a d et er mi n ati o n will b e m a d e r e g ar di n g w h et h er  a n e w c o ns e nt n e e ds t o b e 
o bt ai n e d fr o m p artici p a nts w h o pr ovi d e d c o ns e nt, usi n g a pr evi o usl y  a p pr ov e d c o ns e nt f or m. 
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  
Titl e:  
O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct 
s ali v ar y fl o w r at es 
 
St u d y D es cri pti o n: 
 
T his st u d y will ass ess t h e eff ect of a n i m pr ov e d fl u ori d e m o ut h r i ns e 
(c o m bi n e d wit h a c alci u m pr e ri ns e) o n e n h a nci n g t h e r et e nti o n of fl u ori d e 
i n t h e m o ut h of ol d er a d ults wit h s ali v a fl o w r a n gi n g fr o m n or m al t o 
h y p os ali v ati o n . T h e st u d y h y p ot h esis is t h at t h e c alci u m pr eri ns e  will 
i ncr e as e t h e r et e nti o n of fl u ori d e i n t h e m o ut h of ol d er a d ults, w h e n 
c o m p ar e d wit h t h e fl u ori d e ri ns e al o n e.  
  
O bj ecti v es:  
Pri m ar y O bj ecti v e: D et er mi n e t h e b e n efit of usi n g a c alci u m m o ut h ri ns e, 
b ef or e a fl u ori d e m o ut h ri ns e, t o e n h a nc e fl u ori d e r et e nti o n i n t h e m o ut h 
of i n di vi d u als wit h h y p os ali v ati o n.   
 
S ec o n d ar y O bj ecti v es: T o d et er mi n e t h e r ol e of h y p os ali v ati o n o n t h e 
r et e nti o n of fl u ori d e i n t h e m o ut h aft er a fl u ori d e ri ns e.   
 
E n d p oi nts:  
 
Pri m ar y E n d p oi nt: Fl u ori d e c o nc e ntr ati o n i n d e nt al pl a q u e ( bi ofil m) u p t o 2 
h aft er a m o ut h ri ns e  
S ec o n d ar y E n d p oi nts: Fl u ori d e c o nc e ntr ati o n i n s ali v a u p t o 2 h aft er a 
m o ut h ri ns e; C alci u m c o nc e ntr ati o n i n d e nt al pl a q u e a n d s ali v a u p t o 2 h 
aft er a m o ut h ri ns e  
 
St u d y P o p ul ati o n:  
 
T w e nt y i n di vi d u als , wit h 6 5 y e ars of a g e  or m or e , fr o m b ot h g e n d ers, wit h 
g o o d g e n er al h e alt h, i n d e p e n d e nt, wit h g o o d or al h e alt h, fr o m t h e A n n 
Ar b or, MI ar e a. At l e ast 1 0 i n di vi d u als s h o ul d h av e si g ns of h y p os ali v ati o n 
( dr y m o ut h). 
 
P h as e:  
 
1  
 
D escri pti o n of 
Sit es/ F aciliti es E nr olli n g 
P artici p a nts:  
 
P artici p a nts will b e r ecr uit e d a m o n g p ati e nts fr o m t h e Sc h o ol of D e ntistr y, 
U ni v ersit y of Mic hi g a n, i n A n n Ar b or, MI.  
 
 
D escri pti o n of St u d y 
I nt er v e nti o n: 
 
T h e st u d y will h av e 2 i nt erv e nti o ns (cr oss ov er d esi g n): a. a s o di u m fl u ori d e 
m o ut h ri ns e at a n ov er-t h e-c o u nt er c o nc e ntrati o n of 0. 0 5 % ( 2 2 6 p p m of 
fl u ori d e), us e d f or 1 mi n; b. a c alci u m m o ut h ri ns e (c alci u m l act at e at a 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
2  
c o nc e ntr ati o n of 1 5 0 m M) us e d f or 1 mi n, f oll o w e d b y t h e s o di u m fl u ori d e 
m o ut h ri ns e d escri b e d i n a. 
 
 
St u d y D ur ati o n:  
 
3 6 m o nt hs  
 
P artici p a nt D ur ati o n:  
 
1 m o nt h  
 
 
1. 2  
S C H E M A  
    
Fl o w di a gr a m  of t h e st u d y  
Pri or t o  
E nr oll m e nt  
 
 
Visit 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 2  
 
 
W as h -o ut  
( at l e ast o n e w e e k) 
 
 
Visit 3  
 
 
 
 
 
N = 2 0 + p artici p a nts:  R ecr uit m e nt of  i n di vi d u als wit h  6 5 y e ars of a g e or m or e, 
wit h at l e ast 2 0 t e et h i n t h e m o ut h ( 4 i n e ac h q u a dr a nt).  
O bt ai n i nf or m e d c o ns e nt. I ntr a or al ex a m t o c h ec k f or a d diti o n al i ncl usi o n a n d 
excl usi o n crit eri a. P erf or m ass ess m e nt of u nsti m ul at e d a n d sti m ul at e d s ali v ar y 
fl o w r at e.  
Eli gi bl e i n di vi d u als will r ec ei v e st a n d ar diz e d t o ot h p ast e a n d t o ot h br us h a n d 
c o nti n u e t o f oll o wi n g visits.  
A p plic ati o n of t h e ot h er tr e at m e nt, n ot t est e d b ef or e (cr oss o v er d esi g n). 
C oll ecti o n of s ali v a a n d bi ofil m s a m pl es b ef or e a n d u p t o 2 h aft er t h e ri ns e.  
 
Tr e at m e nt B  
F ri ns e pr ec e d e d b y C a ri ns e  
N = 1 0  
Tr e at m e nt A  
F ri ns e o nl y  
N = 1 0  
A p plic ati o n of t h e tr e at m e nt assi g n e d b y r a n d o miz ati o n. C oll ecti o n of s ali v a a n d 
bi ofil m s a m pl es b ef or e a n d u p t o 2 h aft er t h e ri ns e.  
R a n d o miz e  


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
3  
1. 3  
S C H E D U L E O F A C TI VI TI E S ( S O A)  
 
Pr oc e d ur es  
B as eli n e, Visit 1  
D ay 0  
St u dy Visit 2  
D ay 7   
( + 1 m o nt h) 
St u dy Visit 3  
D ay 1 4   
( + 1 m o nt h)  
I nf or m e d c o ns e nt 
X  
 
 
D e m o gr a p hics  
X  
 
 
M e dic al hist ory  
X  
 
 
I ntr a-or al ex a m  
X  
 
 
S aliv a fl o w r at e ass ess m e nt  
X  
 
 
R a n d o miz ati o n  
X  
 
 
A d mi nist er st u dy i nt erv e nti o n  
 
X  
X  
S aliv a s a m pl es c oll ecti o n  
 
X  
X  
D e nt al bi ofil m s a m pl es c oll ecti o n  
 
X  
X  
A dv ers e ev e nts r e p orti n g 
 
X  
X  
 
 
2  
 
I N T R O D U C TI O N 
 
2. 1  
S T U D Y R A TI O N A L E   
S ali v a pl ays a m aj or r ol e i n m ai nt ai ni n g or al h e alt h. A r e d ucti o n i n s ali v a fl o w ( h y p os ali v ati o n) dr astic all y 
i ncr e as es t h e ris k f or or al dis e as es, i ncl u di n g  c aviti es. H y p os ali v ati o n ( dr y m o ut h) is a s p eci al c o nc er n f or 
ol d er i n divi d u als : a b o ut 8 0 % of A m eric a n p e o pl e o v er 6 5 y e ars of a g e h a v e at l e ast o n e c hr o nic 
c o n diti o n a n d 6 8 % h av e at l e ast t w o [ N ati o n al C o u ncil o n A gi n g, 2 0 1 5]. M a n y of t h e m e dic ati o ns us e d t o 
c o ntr ol t h es e c o n diti o ns c a us e h y p os ali v ati o n [ W olff et al., 2 0 1 7]. Als o, w it h a gi n g t h er e is a n at ur al 
ex p os ur e of t h e t e et h r o ots t o t h e or al c a vit y, a n d t h es e ar e m or e s usc e pti bl e t o c aviti es d u e t o t h e 
hi g h er s ol u bilit y of t h eir c e m e nt u m/ d e nti n w h e n c o m p ar e d wit h t h e e n a m el c ov eri n g t h e t e et h cr o w ns. 
T h er ef or e, m ai nt ai ni n g or al h e alt h i n ol d er i n di vi d u als wit h dr y m o ut h is c h all e n gi n g ; t h e r es ulti n g p ai n, 
p o or n utriti o n a n d i m p air e d s oci al f u ncti o ns a d d t o t h e ov er all r e d ucti o n i n q u alit y of lif e i n t h es e ol d er 
a d ults alr e a d y s uff eri n g fr o m dr y m o ut h.  
Fl u ori d e h as b e e n s ucc ess f ull y us e d t o m ai nt ai n or al h e alt h, es p eci all y i n dr y m o ut h p ati e nts. Y et, t h e 
ki n etics of fl u ori d e i n t h e m o ut h of ol d er a d ults, i ncl u di n g t h os e wit h h y p os ali v ati o n, is p o orl y 
u n d erst o o d. Alt h o u g h t h ey n e e d t o us e fl u ori d e i n hi g h er c o nc e ntr ati o ns, s uc h as pr escri pti o n 
t o ot h p ast es c o nt ai ni n g 5, 0 0 0 p p m of fl u ori d e ( F), t h e ext e nt of t h e eff ecti v e n ess of usi n g hi g h er fl u ori d e 
c o nc e ntr ati o ns i n h y p os ali v ati o n p ati e nts  h as sc arc el y b e e n ex pl or e d. Ev e n i n i n di vi d u als wit h n or m al 
s ali v ar y fl o w, t h e us e of a 5, 0 0 0 p p m F ri ns e d o es n ot r es ult i n t h e ex p ect e d i ncr e as e d r et e nti o n of 
fl u ori d e i n t h e m o ut h [ St a u n L ars e n et al., 2 0 1 8], s u g g esti n g t h at t h er e is a li mit f or i ncr e asi n g i ntr a or al 
fl u ori d e c o nc e ntr ati o n fr o m or al h y gi e n e pr o d ucts w h e n ai mi n g at i ncr e asi ng t h eir r et e nti o n. T his m a y 
b e d u e t o t h e li mit e d s u p pl y of p ositi v el y c h ar g e d c ati o ns, s uc h as c alci u m, t o w hic h fl u ori d e c o ul d b e 
b o u n d, t o b e r et ai n e d f or l o n g er p eri o ds i n t h e m o ut h [ V o g el 2 0 1 1]. Alt er n ati v e a p pr o ac h es ai mi n g t o 
o pti miz e t h e fl u ori d e r et e nti o n b y pr evi o usl y s u p pl yi n g a c alci u m s o urc e h a v e b e e n d ev el o p e d [ V o g el et 
al., 2 0 0 6 a, 2 0 0 6 b, 2 0 0 8 a, 2 0 0 8 b], b ut n ev er t est e d i n h y p os ali v ati o n p ati e nts. F or i nst a nc e, t h e us e of a 
c alci u m ri ns e b ef or e a fl u ori d e ri ns e ( C a →F) s ucc essf ull y e n h a nc es fl u ori d e r et e nti o n i n t h e m o ut h 
[ S o uz a et al., 2 0 1 6], u n d er n or m al s ali v ar y fl o w c o n diti o ns. T his a p pr o ac h c o ul d b e p artic ul arl y h el pf ul 
f or hy p os ali v ati o n p ati e nts, b y als o pr ovi di n g a s u p pl y of c alci u m i o ns, w hic h ar e li mit e d d u e t o t h e l o w 
s ali v a pr o d ucti on.  


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
4  
I n t h e pr es e nt tri al, t h e eff ect of s ali v ar y fl o w r at e (fr o m n or m al t o h y p os ali v ati o n) o n t h e r et e nti o n of 
fl u ori d e i n t h e m o ut h  of ol d er a d ults aft er a fl u ori d e ri ns e will b e st u di e d. W e h y p ot h esiz e t h at alt h o u g h 
a r e d ucti o n i n s ali v ar y fl o w r e d uc es t h e r at e of cl e ar a nc e of fl u ori d e fr o m t h e m o ut h, t h e l o w er 
av ail a bility of c alci u m i o ns d u e t o t h e l ac k of s ali v a als o r e d uc es fl u ori d e r et e nti o n.  Als o, t h e eff ect usi n g 
a c alci u m ri ns e b ef or e t h e fl u ori d e ri ns e t o i ncr e as e fl u ori d e r et e nti o n i n t h e m o ut h will b e t est e d i n 
ol d er i n divi d u als wit h a r a n g e of s ali v ar y  fl o w r at es. W e h y p ot h esiz e t h at t h e i ncr e as e d r et e nti o n of 
fl u ori d e o bs erv e d aft er a c alci u m pr eri ns e will b e e n h a nc e d i n i n di vi d u als wit h l o w s ali v a fl o w. 
 
2. 2  
B A C K G R O U N D   
Dry m o ut h is a s eri o us a n d pr ev al e nt pr o bl e m i n ol d er a d ults [ F ur n ess et al., 2 0 1 1] a n d is ass oci at e d wit h 
i ncr e as e d ris k f or or al dis e as es, s uc h as c ari es [N av az es h, 2 0 1 2].  T h e l ac k of s ali v a r e d uc es t h e cl e ar a nc e 
of c ari o g e nic s u g ars a n d aci ds fr o m t h e d e nt al bi ofil m, i m p airs t h e acti o n of s ali v ar y b uff eri n g a g e nts a n d 
r e d uc es t h e s u p pl y of c alci u m a n d p h os p h at e i o ns, w hic h ar e n at ur al r e mi n er alizi n g a g e nts [ E d g ar et al., 
2 0 1 2]. B as e d o n li mit e d evi d e nc e, hi g h er fl u ori d e c o nc e ntr ati o n pr o d ucts ar e us u all y r ec o m m e n d e d f o r 
ol d er a d ults wit h h y p os ali v ati o n [ Z er o et al., 2 0 1 6].  
N ev ert h el ess, p r evi o us st u di es h av e s h o w n t h at a c alci u m ( C a) pr eri ns e c a n b o ost t h e r et e nti o n of F i n t h e 
m o ut h [ V o g el et al., 2 0 0 6 a; 2 0 0 6 b; 2 0 0 8 a; 2 0 0 8 b; S o uz a et al., 2 0 1 6], e n h a nci n g its eff ect . Alt h o u g h t h e 
eff ect of t h e C a pr eri ns e o n F a v ail a bilit y i n h y p os ali v ati o n p ati e nts h as n ev er b e e n st u di e d, pr eli mi n ar y 
d at a giv e s u p p ort t o t h e e n h a nc e d eff ect ex p ect e d f or t his pr oc e d ur e. U si n g a n i n sit u m o d el, it w as s h o w n 
t h at a C a pr eri ns e us e d b ef or e a F ri ns e f or 1 4 d a ys i ncr e as e d ~ 2 2 a n d 4 -f ol d t h e F a n d C a c o nc e ntr ati o ns 
i n d e nt al bi ofil m, r es p ecti v el y [ S o uz a et al., 2 0 1 6]. T his c orr o b or at es t h e h y p ot h esis t h at t h e r et e nti o n of 
F i n t h e m o ut h c a n be e n h a nc e d, wit h o ut t h e n e e d t o i ncr e as e t h e F c o nc e ntr ati o n i n t h e m. T h e i ncr e as e d 
F a n d C a r et e nti o n m a y b e  p artic ul arl y us ef ul f or h y p os ali v ati o n p ati e nts.  
I n t h e c urr e nt pr oj ect w e ai m t o ass ess t h e eff ect of t his a p pr o ac h i n m ai nt ai ni n g i ncr e as e d a n d s ust ai n e d 
l ev els of C a a n d F i n t h e or al fl ui ds of p ati e nts wit h a r a n g e of s ali v ar y fl o w r at es, v ar yi n g fr o m n or m al t o 
hy p os aliv ati o n. T h er e ar e n o k n o w n ris ks ass oci at e d wit h t h e us e of t h es e ri ns es. 
 
 
2. 3  
RI S K / B E N E FI T A S S E S S M E N T   
  
2. 3. 1  K N O W N  P O T E N TI A L RI S K S  
N o m or e t h a n mi ni m al ris ks ar e ex p ect e d t o p artici p a nts e nr oll e d i n t his tri al. T h e disc o mf orts/ris ks ar e 
list e d b el o w: 
 
I m m e di at e disc o mf orts/ris ks: 
1. Disc o mf ort r el at e d t o r efr ai ni n g fr o m t o ot h br us hi n g fr o m t h e pr evi o us ni g ht u ntil t h e m or ni n g o f 
ri ns es a n d s a m pli n g c oll ecti o n. T his is ex p ect e d t o b e a c o m m o n disc o mf ort (i nci d e nc e > 2 5 %). T h e 
s u bj ect m a y f e el m al o d or i n t h e m or ni n g of t h e t est d u e t o t h e s us p e nsi o n of or al h y gi e n e. Aft er t h e 
s a m pli n g is c o m pl et e d, t h e s u bj ect will r ec ei v e a pr of essi o n al cl e a ni n g or s u p er vis e d t o ot h br us hi n g t o 
r e m ov e r e m n a nts of d e nt al pl a q u e. 
2. Disc o mf ort r el at e d t o c oll ecti n g s ali v a s a m pl es. T his is ex p ect e d t o b e a li k el y disc o mf ort ( 1 0 -2 5 %), as 
s o m e i n di vi d u als d o n ot f e el c o mf ort a bl e i n s pitti n g s ali v a i nt o a t u b e. T his disc o mf ort will b e mi ni miz e d 
by m ai nt ai ni n g t h e s u bj ect e d i n a pri v at e d e nt al c h air, wit h o nl y t h e tr ai n e d st u d y st aff off eri n g 
i nstr ucti o ns o n t h e pr oc e d ur e. 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
5  
3. Disc o mf ort r el at e d t o ri nsi n g wit h u nfl av or e d ri ns es. T his is ex p ect e d t o b e a li k el y disc o mf ort ( 1 0 -
2 5 %), as t h e ri ns es will b e pr e p ar e d fr o m r e a g e nt gr a d e c h e mic als, wit h n o fl av ori n g a g e nts.  
4. Disc o mf ort r el at e d t o r efr ai ni n g fr o m e ati n g or dri n ki n g f or u p t o 2 h o urs d uri n g t h e c oll ecti o n of 
s a m pl es. T his is ex p ect e d t o b e a li k el y disc o mf ort ( 1 0-2 5 %). T his m a y b e m or e dist ur bi n g f or i n di vi d u als 
wit h r e d uc e d s ali v a fl o w, if t h e y ar e us e d t o si p w at er c o nst a ntl y. If t h e s u bj ect ( es p eci all y t h os e wit h  dr y 
m o ut h) f e el t h e n e e d of dri n k w at er d uri n g t h e t w o -h o ur p eri o d aft er t h e ri ns e, h e/s h e will b e all o w e d 
t o d o s o, a n d n ot es t a k e n as pr ot oc ol d evi ati o n i n or d er t o l at er ass ess t h eir eff ect o n t h e st u d y 
o utc o m es.  
 
L o n g-r a n g e ris ks: 
1 . L oss of c o nfi d e nti alit y of t h e st u d y r ec or ds. T his ris k is ex p ect e d t o b e r ar e. T o mi ni miz e t h e ris k of 
c o nfi d e nti alit y br e ac h, d at a will b e st or e d i n p ass w or d -pr ot ect e d el ectr o nic fil es or l oc k e d st or a g e 
c a bi n ets acc essi bl e o nl y t o t h e st u d y p ers o n n el. St a n d ar ds f or d at a c oll ecti o n, m a n a g e m e nt a n d a n al ysis 
will b e f oll o w e d.  
 
2. 3. 2  K N O W N P O T E N TI A L B E N E FI T S  
T h e s u bj ects will r ec ei v e or al h y gi e n e a n d c ar e i nstr ucti o ns pr ovi d e d b y t h e st u d y p ers o n n el. Als o, i n 
c as e t h ey h av e h y p os ali v ati o n, t h ey will b e i nf or m e d a b o ut t his, b ec a us e  t his c o n diti o n is n ot n ec ess aril y 
p erc eiv e d by t h e p ati e nts a n d it i ncr e as es t h e ris k f or or al dis e as es .  
 
T h e s u bj ects m a y als o b e n efit fr o m t h e u n d erst a n di n g of t h e st u d y o bj ecti v es, m a ki n g t h e m b ett er 
a w ar e of t h e i m p ort a nc e t a ki n g c ar e of t h eir or al h e alt h. 
 
2. 3. 3  A S S E S S M E N T O F P O T E N TI A L R I S KS  A N D B E N E FI T S  
T h e ris ks/ disc o mf ort ass oci at e d wit h t his st u d y ar e n o m or e t h a n mi ni m al. T h e s u bj ects will b e i nf or m e d 
a b o ut t h e m a n d s h o ul d a gr e e t o p artici p at e b ef or e b ei n g e nr oll e d. T h ey will b e n efit fr o m l e ar ni n g a b o ut 
t h eir or al h e alt h a n d g o o d or al h y gi e n e pr actic es .  
 
By i nv esti g ati n g a n e as y a n d i n ex p e nsi v e pr oc e d ur e t o e n h a nc e t h e eff ect of fl u ori d e, t his r es e arc h will 
h el p d ev el o p a m or e eff ecti v e a n d c ost -b e n efit w a y f or fl u ori d e us e , wit h o ut t h e n e e d t o i ncr e as e t h e 
fl u ori d e c o nc e ntr ati o n. T his p ot e nti al b e n efit, es p eci all y f or v ul n er a bl e  gr o u ps li k e el d ers wit h 
hy p os aliv ati o n, o ut w ei g h  t h e mi ni m al ris ks ass oci at e d wit h t h e tri al. N o ris ks ass oci at e d wit h t h e us e of 
t h e m o ut h  ri ns es ar e ex p ect e d. 
 
3  
O BJ E C TI V E S A N D E N D P OI N T S  
 
O BJ E C TI V E S  
E N D P OI N T S  
J U S TI FI C A TI O N F O R E N D P OI N TS  
Pri m ar y  
 
 
D et er mi n e t h e b e n efit of 
usi n g a c alci u m ri ns e, b ef or e 
a fl u ori d e ri ns e, t o e n h a nc e 
fl u ori d e r et e nti o n i n d e nt al 
bi ofil m  of  i n di vi d u als wit h 
hy p os aliv ati o n.  
 
Fl u ori d e c o nc e ntr ati o n i n d e nt al 
bi ofil m (fl ui d a n d s oli d p h as e) u p 
t o 2 h aft er ri nsi n g wit h fl u ori d e. 
 
D e nt al bi ofil m c a n t a k e u p 
fl u ori d e a n d r el e as e it f or 
pr ol o n g e d p eri o ds of ti m e, li k e 
t h e h o urs i n b et w e e n or al 
h y gi e n e pr oc e d ur es.  
S ec o n d ar y  
 
 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
6  
O BJ E C TI V E S  
E N D P OI N T S  
J U S TI FI C A TI O N F O R E N D P OI N TS  
D et er mi n e t h e b e n efit of 
usi n g a c alci u m ri ns e, b ef or e 
a fl u ori d e ri ns e, t o e n h a nc e 
fl u ori d e r et e nti o n i n s ali v a of  
i n di vi d u als wit h 
hy p os aliv ati o n.  
 
1.  Fl u ori d e c o nc e ntr ati o n i n 
s ali v a u p t o 2 h aft er ri nsi n g 
wit h fl u ori d e.  
 
2.  C alci u m c o nc e ntr ati o n i n 
d e nt al bi ofil m (fl ui d a n d s oli d 
p h as e) u p t o 2 h aft er ri nsi n g 
wit h fl u ori d e.  
 
3.  C alci u m c o nc e ntr ati o n i n 
s ali v a u p t o 2 h aft er ri nsi n g 
wit h fl u ori d e.   
 
1.  S ali v ar y fl u ori d e c a n b e 
c o nsi d er e d as a s urr o g at e 
m e as ur e of fl u ori d e av ail a bilit y i n 
t h e m o ut h, b ec a us e fr o m s ali v a 
fl u ori d e fr o m ri ns es g ets t o 
d e nt al bi ofil m.  
 
2. Si nc e a c alci u m ri ns e will b e 
us e d i n o n e of t h e tr e at m e nts i n 
t his st u d y, d et er mi n ati o n of 
c alci u m c o nc e ntr ati o n i n d e nt al 
bi ofil m will b e m a d e t o i d e ntif y 
p ot e nti al s o urc es of fl u ori d e 
r et e nti o n (e. g. fl u ori d e b o u n d t o 
c alci u m i o ns, c alci u m fl u ori d e 
pr eci pit ati o n).  
 
3. S ali v ar y c alci u m c a n b e 
c o nsi d er e d as a s urr o g at e 
m e as ur e of c alci u m av ail a bilit y i n 
t h e m o ut h; si nc e a c alci u m ri ns e 
will b e us e d i n o n e of t h e st u d y 
tr e at m e nts, s ali v ar y c alci u m will 
b e d et er mi n e d.  
 
T erti ary/ Ex pl or at or y  
 
 
D et er mi n e t h e r ol e of 
hy p os aliv ati o n o n t h e 
r et e nti o n of fl u ori d e i n t h e 
m o ut h aft er a fl u ori d e ri ns e  
1.  C orr el ati o n b et w e e n s ali v ar y 
fl o w r at e a n d fl u ori d e 
c o nc e ntr ati o n i n d e nt al bi ofil m 
u p t o 2 h aft er a ri ns e.  
2.  C orr el ati o n b et w e e n s ali v ar y 
fl o w r at e a n d fl u ori d e 
c o nc e ntr ati o n i n s ali v a u p t o 2 
h aft er a ri ns e.  
 
T h e c orr el ati o n b et w e e n s ali v ar y 
fl o w r at e a n d fl u ori d e i n d e nt al 
bi ofil m a n d s ali v a  will b e 
i n v esti g at e d t o esti m at e h o w t h e 
fl o w r at e aff ect t h es e v ari abl es.  
 
 
4  
S T U D Y D E SI G N  
 
4. 1  
O V E R A L L  D E SI G N  
T h e ov er all hy p ot h esis of t his st u d y is t h at a c alci u m pr eri ns e us e d b ef or e a fl u ori d e ri ns e e n h a nc es t h e 
r et e nti o n of fl u ori d e i n t h e m o ut h. A d diti o n al h y p ot h esis t o b e t est e d is t h at t h e r e d ucti o n i n s ali v a fl o w 
( hy p os ali v ati o n) r e d uc es t h e cl e ar a nc e a n d t h er ef or e i ncr e as es t h e r et e nti o n of fl u ori d e i n t h e m o ut h.  
 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
7  
T h e st u dy will b e a si n gl e -sit e, p h as e 1 cli nic al tri al, wit h a r a n d o miz e d, bli n d e d (r e g ar di n g t h e 
i nv esti g at ors a n d l a b or at or y a n al ysts) a n d cr oss ov er d esi g n. T w o i nt erv e nti o n gr o u ps will b e t est e d: 1. 
Ri nsi n g wit h a fl u ori d e m o ut h ri ns e o nl y, b as e d o n s o di u m fl u ori d e at a n ov er -t h e-c o u nt er 
c o nc e ntr ati o n; 2. Ri nsi n g wit h t h e s a m e fl u ori d e m o ut h ri ns e as i n 1, b ut aft er a m o ut h ri ns e wit h 
c alci u m l act at e ( a f o o d a d diti v e, pr evi o usl y us e d t o e n h a nc e t h e i ntr a or al fl u ori d e r et e nti o n [ V o g el et al., 
2 0 0 6 a; 2 0 0 6 b; 2 0 0 8 a; 2 0 0 8 b; S o uz a et al., 2 0 1 6]) .  
 
F or e ac h v ol u nt e er, r a n d o miz at i o n will b e us e d t o d et er mi n e w hic h of t h e t w o i nt er v e nti o n gr o u ps t o b e 
t est e d first. V ol u nt e ers r a n d o miz e d t o st art t h e tri al i n gr o u p 1, will t est gr o u p 2 i n t h e f oll o wi n g p h as e, 
a n d vic e v ers a. D e nt al pl a q u e ( pri m ar y e n d p oi nt) a n d s ali v a (s ec o n d ar y e n d p oi nt) will b e c oll ect e d f or 
fl u ori d e a n al ysis. C alci u m c o nc e ntr ati o n i n b ot h s a m pl es will als o b e d et er mi n e d (s ec o n d ar y e n d p oi nts).  
 
4. 2  
S CI E N TI FI C R A TI O N A L E F O R S T U D Y D E SI G N  
T h e us e of a r a n d o miz e d d esi g n is j ustifi e d t o r e d uc e a n y p ot e nti al bi as i n all oc at i n g t h e tr e at m e nt t o 
t h e s u bj ects. I n a d diti o n, b y usi n g a cr oss o v er d esi g n ( all s u bj ects ex p os e d t o b ot h i nt er v e nti o ns) it is 
p ossi bl e t o i ncr e as e t h e st u d y p o w er a n d r e d uc e t h e v ari a bilit y c a us e d b y t h e v ol u nt e er. T his is 
es p eci all y i m p ort a nt i n t his tri al as p e o pl e wit h a r a n g e of s ali v ar y fl o w r at es (fr o m n or m al t o 
hy p os aliv ati o n) will b e p artici p ati n g. Si nc e ev er y s u bj ect will s erv e as its o w n c o ntr ol, t h e v ari a bilit y d u e 
t o k n o w n (s uc h as s ali v ar y fl o w) a n d u n k n o w n f act ors c a n b e mi ni miz e d. 
  
T h e i nv e sti g at or/ a n al yst will b e bli n d wit h r es p ect t o t h e all oc ati o n of tr e at m e nts w h e n a n al yzi n g t h e 
s a m pl es f or fl u ori d e a n d c alci u m c o nc e ntr ati o n. T his is t o miti g at e  i n v esti g at or/ a n al yst bi as d uri n g t h e 
a n al ysis of s a m pl es.  
 
4. 3  
J U S TI FI C A TI O N F O R D OS E  
B ot h i nt erv e nti o ns will b e us e d as m o ut h ri ns es, p erf or m e d f or 1 mi n , w hic h is t h e t y pic all y 
r ec o m m e n d e d ri nsi n g ti m e f or or al pr o d ucts. T h e c o nc e ntr ati o ns t o b e us e d ar e als o s u p p ort e d b y t h e 
cli nic al r ec o m m e n d ati o ns a n d t h e lit er at ur e: 1. T h e fl u ori d e ri ns e will b e us e d at o v er-t h e-c o u nt er 
c o nc e ntr ati o ns of 2 2 6 p p m of fl u ori d e  ( 0. 0 5 % N a F); 2. T h e c alci u m l act at e ri ns e will b e t est e d at 15 0 m M 
c o nc e ntr ati o n, w hic h h as pr evi o usl y s h o w n t h e b est p erf or m a nc e w h e n c o m bi n e d wit h fl u ori d e i n 
c o m p aris o n t o l o w er ( 3 0 m M) or hi g h er ( 3 0 0 m M) c o nc e ntr ati o ns [ V o g el et al., 2 0 0 6 a ].  
 
4. 4  
E N D O F S T U D Y D E FI NI TI O N  
A p artici p a nt is c o nsi d er e d t o h av e c o m pl et e d t h e st u d y if h e or s h e h as c o m pl et e d all p h as es of t h e 
st u d y i ncl u di n g t h e l ast visit or t h e l ast sc h e d ul e d pr oc e d ur e s h o w n i n t h e Sc h e d ul e of Acti viti es ( S o A), 
S ecti o n 1. 3 . 
 
T h e e n d of t h e st u d y is d efi n e d as c o m pl eti o n of t h e l ast visit or pr oc e d ur e s h o w n i n t h e S o A i n t h e tri al 
gl o b all y . 
 
5  
S T U D Y P O P U L A TI O N  
 
5. 1  
I N C L U SI O N C RI T E RI A 
 I n or d er t o b e eli gi bl e t o p artici p at e i n t his st u d y, a n i n di vi d u al m ust m e et all of t h e f oll o wi n g crit eri a: 
1.  Pr ovisi o n of si g n e d a n d d at e d i nf or m e d c o ns e nt f or m 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
8  
2.  St at e d willi n g n ess t o c o m pl y wit h all st u d y pr oc e d ur es a n d av ail a b ilit y f or t h e d ur ati o n of t h e 
st u d y  
3.  M al e or f e m al e, a g e d 6 5 or ol d er  
4.  I n g o o d g e n er al h e alt h as evi d e nc e d b y m e dic al hist or y  
5.  I n g o o d or al h e alt h as evi d e nc e d b y a cli nic al or al ex a m  
6.  H avi n g at l e ast 2 0 t e et h i n t h e m o ut h, b ei n g at l e a st 4 ( n at ur al or cr o w n e d) t e et h i n all f o ur 
q u a dr a nts of t h e m o ut h  
7.  H avi n g s ali v ar y fl o w r at e r a n gi n g fr o m n or m al t o h y p os ali v ati o n acc or di n g t o dir ect fl o w r at e 
d et er mi n ati o n m et h o ds  
8.  A gr e e m e nt t o a d h er e t o Lif est yl e C o nsi d er ati o n s (s e e b el o w ) t hr o u g h o ut stu d y d ur ati o n  
 
5. 2  
E X C L U SI O N C RI T E RI A  
 A n i n divi d u al w h o m e ets a n y of t h e f oll o wi n g crit eri a will b e excl u d e d fr o m p artici p ati o n i n t his st u d y:  
1.  U n a bl e t o u n d erst a n d a n d/ or f oll o w st u d y i nstr ucti o ns  
2.  Activ e p eri o d o ntitis  
3.  Or al p ai n  
4.  I n ne e d o f ur g e nt d e nt al c ar e  
  
LI F E S T Y L E C O N SI D E R A TI O N S  
D uri n g t his st u d y , p artici p a nts ar e as k e d t o:  
•  
Us e a st a n d ar diz e d t o ot h p ast e a n d t o ot h br us h, pr ovi d e d b y t h e st u d y t e a m  at t h e first visit , t o 
l ev el t h e b ac k gr o u n d ex p os ur e t o fl u ori d e, 7 d a ys pri or t o e ac h ex p eri m e nt al p h as e  
•  
R efr ai n fr o m usi n g a n y ot h er m o ut h ri ns e or pr of essi o n al pr o d ucts d uri n g t h e st u d y p eri o d  
•  
R efr ai n fr o m dri n ki n g gr e e n or bl ac k t e a ( w hic h h av e hi g h fl u ori d e c o nc e ntr ati o n) o n t h e ni g ht 
b ef or e or t h e d a y of t h eir visits 
•  
R efr ai n fr o m br us hi n g t h eir t e et h o n t h e ni g ht b ef or e a n d t h e m or ni n g of t ests/s a m pli n g  
•  
R efr ai n fr o m e ati n g or dri n ki n g f or 2 h o urs aft er t h e ri ns es, d uri n g w hic h s ali v a a n d d e nt al 
pl a q u e will b e s a m pl e d  
 
5. 3  
S C R E E N F AI L U R E S  
Scr e e n f ail ur es ar e d efi n e d as p art ici p a nts w h o c o ns e nt t o p artici p at e i n t h e cli nic al tri al b ut ar e n ot 
s u bs e q u e ntl y r a n d o ml y assi g n e d t o t h e st u d y i nt er v e nti o n or e nt er e d i n t h e st u d y. A mi ni m al s et of 
scr e e n f ail ur e i nf or m ati o n is r e q uir e d t o e ns ur e tr a ns p ar e nt r e p orti n g of scr e e n f ail ure p artici p a nts , t o 
m e et t h e C o ns oli d at e d St a n d ar ds of R e p orti n g Tri als ( C O N S O R T) p u blis hi n g r e q uir e m e nts a n d t o 
r es p o n d t o q u eri es fr o m r e g ul at or y a ut h oriti es. Mi ni m al i nf or m ati o n i ncl u d es d e m o gr a p h y, scr e e n 
f ail ur e d et ails, eli gi bilit y crit eri a, a n d a n y s eri o us a dv ers e ev e nt ( S A E).  
 
I n di vi d u als w h o d o n ot m e et t h e crit eri a f or p artici p ati o n i n t his tri al (scr e e n f ail ur e) b ec a us e of acti v e 
p eri o d o ntitis, or al p ai n or n e e d o f ur g e nt d e nt al c ar e  m a y b e r escr e e n e d  if t h e y h a v e t h e excl usi o n 
f act or tr e at e d. R escr e e n e d p artici p a nts s h o ul d b e assi g n e d t h e s a m e p artici p a nt n u m b er as f or t h e i niti al 
scr e e ni n g. 
 
5. 4  
S T R A T E GI E S F O R R E C R UI T M E N T A N D R E T E N TI O N  
P artici p a nts will b e r ecr uit e d fr o m t h e cli nics of t h e Sc h o ol of D e nt istr y, U ni v ersit y of Mic hi g a n. Pri m ar y 
crit eri a t o b e i ncl u d e d i n t h e st u d y ( h avi n g 6 5 y e ars of a g e  or m or e, at l e ast 2 0 t e et h, at l e ast 4 t e et h i n 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
9  
e ac h q u a dr a nt) will b e a n n o u nc e d t o d e nt al pr o vi d ers i n t h e cli nics of t h e Sc h o ol of D e ntistr y. If 
i d e ntifi ed s u bj ects i n dic at e t h at t h ey ar e i nt er est e d i n p artici p ati n g, t h e pr ovi d er c a n r ef er t h eir 
n a m e/ p h o n e n u m b er t o t h e st u d y t e a m f or c o nt act a n d sc h e d ul e of t h e first visit.  It is ex p ect e d t h at a 
si mil ar n u m b er of m e n a n d w o m e n, a n d a di v ers e p o p ul ati o n i n t er ms of r ac es/ et h niciti es is r ecr uit e d. 
 
P artici p a nts will b e c o m p e ns at e d f or t h eir p artici p ati o n i n t h e st u d y usi n g a r e -c h ar g e a bl e c ar d. T h ey will 
b e c o m p e ns at e d wit h $ 1 8. 0 0 f or t h e first visit (c h ec ki n g of i ncl usi o n a n d excl usi o n crit eri a), $ 1 8. 0 0 f or 
t h e s ec o n d visit (t est of first i nt er v e ntio n gr o u p) a n d $ 4 8. 0 0 f or t h e t hir d visit (t est of s ec o n d 
i nt erv e nti o n gr o u p). T h es e a m o u nts will b e tr a nsf err e d t o t h e r e-c h ar g e a bl e c ar d wit hi n 2 -5  b usi n ess 
d ay s of t h e visit b ei n g c o m pl et e d.   
 
6  
S T U D Y I N T E R V E N TI O N 
 
6. 1  
S T U D Y I N T E R V E N TI O N( S) A D MI NI S T R A TI O N  
 
6. 1. 1  S T U D Y IN T E R V E N TI O N  D E S C RI P TI O N  
Fl u ori d e -o nl y ri ns e: T his i nt erv e nti o n is a 1 -mi n m o ut h ri ns e  wit h 1 5 mL of a 0. 0 5 % s o di u m fl u ori d e ri ns e 
(2 2 6 p p m F). T his is t h e s a m e fl u ori d e c o m p o u n d a n d c o nc e ntr ati o n f o u n d i n ov er -t h e-c o u nt er fl u ori d e 
ri ns es.  
 
Fl u ori d e ri ns e f oll o wi n g a c alci u m pr eri ns e: T his i nt er v e nti o n c o nsists of t w o 1 -mi n m o ut h ri ns es  of 1 5 
mL e ac h ; t h e first will b e p erf or m e d wit h a c alci u m l act at e s ol uti o n, pr e p ar e d at t h e c o nc e ntr ati o n of 
1 5 0 m M [ V o g el et al., 2 0 0 6a ]. C alci u m l act at e is a f o o d a d diti v e a n d s af e f or h u m a n c o ns u m pti o n, 
alt h o u g h i n t h e c urr e nt st u d y it will n ot b e i n g est e d, b ut ex p ect or at e d ( us e d as a ri ns e). T h e s ec o n d 
ri ns e, t o b e p erf or m e d wit hi n 3 0 s  aft er t h e first ri ns e, will b e t h e s o di u m fl u ori d e ri ns e at 2 2 6 p p m F, as 
d escri b e d a b ov e.  
6. 1. 2  D O SI N G A N D A D MI NI S T R A TI O N  
All p artici p a nts will t est b ot h i nt er v e nti o n gr o u ps; h alf of t h e m will t est t h e gr o u ps i n o n e or d er ( 1-> 2) , 
t h e ot h er h alf i n t h e ot h er or d er ( 2-> 1) . T h e or d er will b e d et er mi n e d r a n d o ml y usi n g a c o m p ut er -
g e n er at e d r a n d o miz ati o n list i n M S Exc el.  
 
E ac h i nt erv e nti o n gr o u p will b e t est e d i n o n e ex p eri m e nt al p h as e, s p ac e d at l e ast 7 d a ys fr o m t h e 
f oll o wi n g p h as e t o av oi d a n y i nt erf er e nc e wit h t h e pr evi o us tr e at m e nt [ F er ná n d ez et al., 2 0 1 5].  
 
N o tr e at m e nt will b e p erf or m e d b y t h e p ati e nt at h o m e; b ot h i nt erv e nti o ns will b e d eli v er e d b y t h e 
st u d y t e a m at t h e st u d y visits. 
 
6. 2  
P R E P A R A TI O N / H A N D LI N G / S T O R A G E / A C C O U N T A BI LI T Y  
 
6. 2. 1  A C Q UI SI TI O N A N D A C C O U N T A BI LI T Y  
B ot h ri ns es t o b e us e d i n t h e st u d y will b e pr e p ar e d at t h e r es e arc h l a b or at or y of t h e pri nci p al 
i nv esti g at or, f oll o wi n g g ui d eli n es us e d at t h e U ni v ersit y of Mic hi g a n R es e arc h P h ar m ac y. T h e us e of 
pl ai n m o ut h ri ns es ( n o n -c o m m erci al, wit h o ut fl av ori n g a g e nts, s urf act a nts, c ol ori n g a g e nts) is r e q uir e d 
t o t est t h e r e al eff ect of t h e c h e mic als u n d er ev al u ati o n (s o di u m fl u ori d e a n d c alci u m l act at e), wit h o ut 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 0  
i nt erf er e nc e of i n gr e di e nts t h at ma y aff ect t h e s ali v ar y fl o w r at e (fl av ori n g a g e nts) or t h e i nt er acti o n 
b et w e e n c alci u m a n d fl u ori d e i nt e n d e d t o b e t est e d h er e  ( d et er g e nts) [ B ar kv oll et al., 1 9 8 8]. 
 
C alci u m l act at e , C at # C 8 3 5 6, Si g m a , a n d s o di u m fl u ori d e , C at # 2 0 1 1 5 4, Si g m a , will b e us e d f or pr e p ari n g 
t h e ri ns es.  
 
T h e r es e arc h l a b or at or y of t h e pri nci p al i nv esti g at or, l oc at e d at t h e U ni v ersit y of Mic hi g a n Sc h o ol of 
D e ntistry, 1 0 1 1 N U ni v ersit y Av e, r o o m 2 3 1 0i, 4 8 1 0 9 -1 0 7 8, A n n Ar b or, MI , will pr e p ar e t h e ri ns es. A n 
ex p eri e nc e d p h ar m acist fr o m R es e arc h P h ar m ac y visit e d t h e l a b or at or y a n d r ec o m m e n d e d t h e 
pr e p ar ati o n of t h e ri ns es t h er e. . T h e s o urc e of e ac h pr e p ar e d a n d dis p e ns e d ri ns e ( dr u gs l ot #) will b e 
n ot e d i n a dis p e nsi n g l o g. Als o, t h e fi n al us e (if us e d f or a m o ut h ri ns e, or disc ar d e d d u e t o a c a nc el ati o n 
i n t h e p artici p a nt ’s a p p oi nt m e nt) will b e r ec or d e d. A n al ys es of t h e c alci u m a n d fl u ori d e c o nc e ntr ati o n i n 
e ac h b atc h of pr e p ar e d ri ns es will b e m a d e a n d r ec or d e d.   
 
6. 2. 2  F O R M U L A TI O N, A P P E A R A N C E, P A C K A GI N G, A N D L A B E LI N G  
T h e ri ns es will b e pr e p ar e d t o c o nt ai n 1 5 0 m M of c alci u m l act at e a n d 0. 0 5 % of s o di u m fl u ori d e, 
r es p ectiv el y.  
 
T h e 0. 0 5 % s o di u m fl u ori d e ri ns e will b e pr e p ar e d  i n o n e, 1-L b atc h, t o b e st or e d i n a pl astic fl as k, wit h a n 
ex pir ati o n d at e of 6 m o nt hs. Fr o m t h e t ot al v ol u m e pr e p ar e d, 1 5 -mL ali q u ots t o b e us e d b y e ac h p ati e nt 
will b e dis p e ns e d b y t h e PI,  acc or di n g t o t h e p ati e nt’s sc h e d ul e.   
 
T h e 1 5 0 m M c alci u m l act at e will b e pr e p ar e d  i n b atc h es  of 1 0 0 mL , t o b e us e d b y p ati e nts sc h e d ul e d i n 
t h e f oll o wi n g 7 d a ys . If n ot us e d, t h e ri ns es will b e disc ar d e d. Fift e e n mL b atc h es t o b e us e d b y e ac h 
p artici p a nt  will b e dis p e ns e d b y PI, acc or di n g t o t h e p ati e nt’s sc h e d ul e.  
 
Fr o m pr e p ar ati o n u ntil us e, dis p e ns e d ri ns es will b e st or e d at t h e PI’s l a b, i n t h e r efri g er at or (c alci u m 
l act at e ri ns e) or i n a l oc k e d c a bi n et. All fl as ks will b e l a b el e d acc or di n gl y. 
 
6. 2. 3  P R O D U C T S T O R A G E A N D S T A BI LI T Y  
A 1 -L b atc h of t h e s o di u m flu ori d e s ol uti o n will b e pr e p ar e d a n d st or e d i n a pl astic fl as k at r o o m 
t e m p er at ur e f or 6 m o nt hs ( U S P 7 9 5) . T h e s o di u m fl u ori d e s ol uti o n s h o ul d b e st a bl e f or t his p eri o d of 
ti m e a n d n o c o nt a mi n ati o n is ex p ect e d c o nsi d eri n g t h e a nti b act eri al acti o n of fl u ori d e [v a n L ov er e n, 
1 9 9 0] . T h e fl u ori d e c o nc e ntr ati o n i n t his s ol uti o n will b e c o nfir m e d usi n g a fl u ori d e el ectr o d e, a g ai nst 
st a n d ar ds wit h k n o w n fl u ori d e c o nc e ntr ati o n [ N ó br e g a et al., 2 0 1 9]. Fift e e n mL b atc h es f or i n di vi d u al 
p ati e nt us e will b e dis p e ns e d o n e d a y pri or t o t h e a p p oi nt m e nt. Aft er 6 m o nt hs, if t h e ex p eri m e nt al 
p h as e is n ot c o m pl et e d, a n e w b atc h will b e pr e p ar e d ( a m o u nt t o b e d et er mi n e d b y t h e n u m b er of visits 
t o b e c o m pl et e d), f oll o wi n g t h e s a m e pr oc e d ur es d escri b e d a b ov e.   
 
F or t h e c alci u m l act at e s ol uti o n, 1 0 0 -mL b atc h es will b e pr e p ar e d e ac h w e e k p artici p a nts ar e sc h e d ul e d. 
T his is t o e ns ur e t h at t his s ol uti o n is fr es hl y -us e d ( 1-4 d a ys) aft er pr e p ar ati o n. O nc e pr e p ar e d, t h e 
b atc h es will b e st or e d i n t h e r efri g er at or, b ut will b e br o u g ht t o r o o m t e m p er at ur e t o b e us e d f or m o ut h 
ri nsi n g. T h e c alci u m c o nc e ntr ati o n i n all b atc h es will b e c h ec k e d usi n g t h e Ars e n az o III m et h o d f or 
d et ecti o n of c alci u m, i n a micr o pl at e r e a d er , a g ai nst st a n d ar ds wit h k n o w n c alci u m c o nc e ntr ati o n 
[ N ó br e g a et al., 2 0 1 9].  
 
6. 2. 4  P R E P A R A TI O N  


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 1  
T h e ri ns es will b e d eli v er e d dir ectl y t o t h e s u bj ects f or m o ut h ri nsi n g. N o ot h er mixi n g will b e p erf or m e d 
by t h e s u bj ects.  
 
6. 3  
M E A S U R E S T O MI NI MI Z E BI A S: R A N D O MI Z A TI O N  A N D B LI N DI N G  
Bli n di n g of t h e v ol u nt e ers or cli nic al st aff will n ot b e p ossi bl e b ec a us e o n e of t h e tr e at m e nts i nv ol v es 
o n e ri ns e, t h e ot h er i nv ol v es t w o ri ns es. N ev ert h el ess, t h e l a b or at or y a n al yst will b e bli n d wit h r es p ect 
wit h t h e s a m pl es t o b e a n al yz e d; f or t his, t h e s a m pl es will b e c o d e d wit h t h e p artici p a nt I D a n d 
tr e at m e nt p h as e ( 1st or 2 n d, n ot t o b e c o nf o u n d e d wit h tr e at m e nt A or B; t h e tr e at m e nt t o b e us e d i n 
e ac h p h as e will b e d et er mi n e d r a n d o ml y f or e ac h v ol u nt e er ).  
 
T h e or d er i n w hic h t h e t w o i nt erv e nti o n gr o u ps will b e t est e d will b e r a n d o miz e d usi n g t h e M S Exc el , 
usi n g a r a n d o miz ati o n t a bl e c o nt ai ni n g 3 c ol u m ns wit h 2 0 r o ws:  
1.  F irst c ol u m n: p artici p a nt I D n u m b er, fr o m 1 t o 2 0 
2.  S ec o n d c ol u m n: l ett ers A or B (t o r e pr es e nt t h e 2 i nt er v e nti o n gr o u ps; 1 0 of e ac h l ett er)  
3.  T hir d c ol u m n: r a n d o m n u m b ers cr e at e d usi n g Exc el f u ncti o n “r a n d ” 
 
T h e t hir d a n d s ec o n d c ol u m n will b e s el ect e d a n d s ort e d b y t h e t hir d c ol u m n; t his will r a n d o miz e t h e 
tr e at m e nt t o b e us e d i n t h e first p h as e, acc or di n g t o t h e p artici p a nt I D. T h e ot h er i nt erv e nti o n gr o u p will 
b e t est e d i n t h e f oll o wi n g p h as e.  
 
6. 4  
S T U D Y IN T E R V E N TI O N  C O M P LI A N C E  
T h er e will b e n o st u d y c o m pli a nc e c h ec ks i n t h e st u d y as all pr oc e d ur es will b e p erf or m e d i n t h e cli nic, 
w h e n  t h e s u bj ect will b e f oll o w e d b y  a  st u d y t e a m m e m b er. D evi ati o ns fr o m t h e pr ot oc ol d uri n g t h e 
ex p eri m e nt al p h as es ( e. g. i nt a k e of w at er i n b et w e e n s a m pl e c oll ecti o n) will b e n ot e d i n t h e pr ot oc ol. 
 
7  
S T U D Y I N T E R V E N TI O N DI S C O N TI N U A TI O N  A N D P A R TI CI P A N T  
DI S C O N TI N U A TI O N / WI T H D R A W A L  
 
7. 1  
DI S C O N TI N U A TI O N  O F S T U D Y I N T E R V E N TI O N  
D u e t o t h e s h ort -t er m ex p os ur e t o t h e i nt er v e nti o ns t o b e t est e d h er e (o n e or t w o 1 -mi n ri ns es wit h t h e 
pr o d ucts u n d er t est), n o disc o nti n u ati o n of t h e st u d y i nt erv e nti o n is ex p ect e d.  
 
7. 2  
P A R TI CI P A N T  D I S C O N TI N U A TI O N/ W I T H D R A W A L F R O M T H E S T U D Y  
P artici p a nts ar e fr e e t o wit h dr a w fr o m p artici p ati o n i n t h e st u d y at a n y ti m e u p o n r e q u est.  
A n i nv esti g at or m a y disc o nti n u e or wit h dr a w a p artici p a nt fr o m  t h e st u d y f or t h e f oll o wi n g r e as o ns: 
•  
Si g nific a nt st u d y i nt er v e nti o n n o n -c o m pli a nc e  
•  
If any cli nic al  u n a ntici p at e d  a dv ers e ev e nt ( A E)  occ urs s uc h t h at c o nti n u e d p artici p ati o n i n t h e 
st u d y w o ul d n ot b e i n t h e b est i nt er est of t h e p artici p a nt  
•  
Dis e as e pr o gr essi o n  ( or al or g e n er al) w hic h r e q uir es disc o nti n u ati o n of t h e st u d y i nt er v e nti o n 
•  
If th e p artici p a nt m e ets a n excl usi o n crit eri o n ( eit h er n e wl y d ev el o p e d or n ot pr evi o usl y 
r ec o g niz e d) t h at pr ecl u des f urt h er st u d y p artici p ati o n  
T h e r e as o n f or p artici p a nt disc o nti n u ati o n or wit h dr a w al fr o m t h e st u d y will b e r ec or d e d o n t h e 
Disc o nti n u ati o n  C as e R e p ort F or m ( C R F ). S u bj ects w h o si g n t h e i nf or m e d c o ns e nt f or m a n d ar e 
r a n d o miz e d b ut d o n ot r ec ei v e t h e st u d y i nt er v e nti o n m a y b e r e pl ac e d.  S u bj ects w h o si g n t h e i nf or m e d 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 2  
c o ns e nt f or m, a n d ar e r a n d o miz e d a n d r ec ei v e t h e st u d y i nt er v e nti o n, a n d s u bs e q u e ntl y wit h dr a w, or 
ar e  wit h dr a w n or disc o nti n u e d fr o m t h e st u d y will n ot b e r e pl ac e d.  
7. 3  
L O S T T O F O L L O W -U P  
 A p artici p a nt will b e c o nsi d er e d l ost t o f oll o w -u p if h e or s h e f ails t o r et ur n f or t h e t hir d st u d y visit 
(s ec o n d i nt erv e nti o n visit) a n d is u n a bl e t o b e c o nt act e d b y t h e st u d y sit e st aff.  
 
T h e f oll o wi n g acti o ns m ust b e t a k e n if a p artici p a nt f ails t o r et ur n t o t h e cli nic f or a r e q uir e d st u d y visit:  
•  
T h e sit e will att e m pt t o c o nt act t h e p artici p a nt a n d r esc h e d ul e t h e miss e d visit a n d c o u ns el t h e 
p artici p a nt o n t h e i m p ort a nc e of m ai nt ai ni n g t h e assi g n e d visit sc h e d ul e a n d asc ert ai n if t h e 
p artici p a nt wis h es t o a n d/ or s h o ul d c o nti n u e i n t h e st u d y.  
•  
B ef or e a p artici p a nt is d e e m e d l ost t o f oll o w -u p, t h e i nv esti g at or or d esi g n e e will m a k e ev er y 
eff ort t o r e g ai n c o nt act wit h t h e p artici p a nt ( w h er e p ossi bl e, 3 t el e p h o n e c alls a n d, if n ec ess ar y, 
a c ertifi e d l ett er t o t h e p artici p a nt’s l ast k n o w n m aili n g a d dr ess or l oc al e q ui v al e nt m et h o ds). 
T h es e c o nt act att e m pts s h o ul d b e d oc u m e nt e d i n t h e p a rtici p a nt’s m e dic al r ec or d or st u d y fil e.  
•  
S h o ul d t h e p artici p a nt  c o nti n u e t o b e u nr e ac h a bl e, h e or s h e will b e c o nsi d er e d t o h a v e 
wit h dr a w n fr o m t h e st u d y wit h a pri m ar y r e as o n o f l ost t o f oll o w-u p.  
 
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
 
8. 1  
E F FI C A C Y A S S E S S M E N T S  
T h e f oll o wi n g ass ess m e nts a n d pr oc e d ur es will b e c o n d uct e d d uri n g t h e st u d y:  
 
1.  I niti al i ntr a or al ex a mi n ati o n: R ecr uit e d s u bj ects will c o m e t o a first visit i n w hic h t h e st u d y 
d et ails will b e r evis e d a n d t h ey will si g n t h e i nf or m e d c o ns e nt. S u bj ects w h o si g n e d t h e 
i nf or m e d c o ns e nt will t h en  g o t hr o u g h a n i ntr a or al ex a mi n ati o n. T h e n u m b er of t e et h i n t h e 
m o ut h ( mi ni m u m of 2 0) a n d p er q u a dr a nt ( mi ni m u m of 4) will b e c h ec k e d. T h e  pr es e nc e of 
activ e p eri o d o ntit is or a n y ot h er t o ot h-r el at e d pr o bl e m n e e di n g ur g e nt c ar e will b e us e d as 
excl usi o n crit eri a. I n t his c as e, t h e p artici p a nt will b e dis e nr oll e d fr o m t h e tri al a n d  c o nsi d er e d a 
scr e e n f ail ur e. 
 
2.  D et er mi n ati o n of s ali v ar y fl o w r at e: All s u bj ects will h av e t h eir u nsti m ul at e d a n d sti m ul at e d 
s ali v ar y fl o w r at es d et er mi n e d i n t h e first visit. T his will b e d o n e usi n g t h e dr ai ni n g a n d t h e g u m -
sti m ul at e d m et h o ds f or u nsti m ul at e d a n d sti m ul at e d s ali v ar y fl o w d et er mi n ati o n, r es p ecti v el y 
[ N av az es h & K u m ar, 2 0 0 8]. F or u nsti m ul at e d s ali v ar y fl o w , t h e s u bj ects will sit wit h t h e h e a d 
tilti n g f or w ar d, a n d all s ali v a acc u m ul ati n g i n t h eir m o ut h will b e p assi v el y dr o ol e d i nt o a pr e-
w ei g ht e d, 1 5 mL -t u b e, vi a a dis p os a bl e f u n n el. Aft er 5 mi n of c oll ecti o n, t h e v ol u m e of s ali v a will 
b e d et er mi n e d b y w ei g ht, a n d t h e fl o w r at e esti m at e d i n mL/ mi n. A v al u e l o w er t h a n 0. 1 mL  
u nsti m ul at e d s ali v a / mi n will b e c o nsi d er e d as h y p os ali v ati o n. F or sti m ul at e d s ali v ar y fl o w , a n 
i n ert g u m or p ar affi n b as e will b e us e d as a m astic at or y sti m ul us f or s ali v a pr o d ucti o n. S u bj ects 
will b e as k e d t o c h e w t h e g u m ( 0. 5 g) a n d s pit t h e s ali v a pr o d uc e d i nt o 1 5 mL t u b es, f or 5 mi n. A 
sti m ul at e d s ali v ar y fl o w r at e of less t h a n 0. 5 mL  sti m ul at e d s ali v a/ mi n will b e c o nsi d er e d 
hy p os ali v ati o n.  B ot h i n di vi d u als wit h n or m al s ali v ar y fl o w r at e a n d h y p os ali v ati o n will b e 
e nr oll e d i n t h e st u d y, b ut at l e ast h alf of t h e i n di vi d u als s h o ul d h a v e s o m e si g n of h y p os ali v ati o n 
(s e e e nroll m e nt acc or di n g t o s ali v ar y fl o w r at e).  
 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 3  
3.  E nr oll m e nt of p artici p a nts acc or di n g t o s ali v ar y fl o w r at e: A m axi m u m of 1 0 s u bj ects wit h 
n or m al s ali v ar y fl o w c a n b e e nr oll e d  i n t h e st u d y ( at l e ast 1 0 of t h e e nr oll e d s u bj ects s h o ul d 
h av e h y p os ali v ati o n) . T h e f oll o wi n g t a bl e ex e m plif y t h e scr e e ni n g crit eri a will b e us e d t o 
c o nsi d er a s u bj ect eli gi bl e f or t h e tri al  acc or di n g t o s ali v ar y fl o w r at e: 
 
T a bl e: Ex a m pl e of scr e e ni n g t a bl e.  O nc e 1 0 i n di vi d u als wit h n or m al s ali v ar y fl o w r at e ar e 
e nr oll e d, t h e f oll o wi n g i n di vi d u als n e e d t o h a v e b el o w n or m al s ali v ar y fl o w t o b e  eli gi bl e.  
# scr e e n e d  
s u bj ect 
S ali v ar y fl o w r at e (sti m ul at e d 
a n d / or u nsti m ul at e d)  
Eli gi b l e 
S u m of i n di vi d u als wit h n or m al 
fl o w r at e (s h o ul d n ot exc e e d 1 0) 
1  
N or m al  
Y es  
1  
2  
B e l o w n or m al 
Y es  
1  
3  
B el o w n or m al  
Y es  
1  
4  
N or m al  
Y es  
2  
5  
N or m al  
Y es  
3  
6  
B el o w n or m al  
Y es  
3  
7  
N or m al  
Y es  
4  
8  
N or m al  
Y es  
5  
9  
N or m al  
Y es  
6  
1 0  
B el o w n or m al  
Y es  
6  
1 1  
B el o w n or m al  
Y es  
6  
1 2  
N or m al  
Y es  
7  
1 3  
B el o w n or m al  
Y es  
7  
1 4  
N or m al  
Y es  
8  
1 5  
N or m al  
Y es  
9  
1 6  
N or m al  
Y es  
1 0  
 
 
 
S u bj ects e nr oll e d fr o m t his p oi nt o n 
m ust h av e h y p os ali v ati o n  
1 7  
B el o w n or m al  
Y es  
1 0  
1 8  
N or m al  
N o  
1 0  
1 9  
B el o w n or m al  
Y es  
1 0  
2 0  
N or m al  
N o  
1 0  
2 1  
B el o w n or m al  
Y es  
1 0  
2 2  
B el o w n or m al  
Y es  
1 0  
T ot al n u m b er of s u bj ects scr e e n e d: 2 2  
T ot al n u m b er of s u bj ects e nr oll e d: 2 0  
N u m b er of scr e e n f ail ur es: 2  
C o nsi d eri n g t h e p o p ul ati o n wit h 6 5 y e ars of a g e  or m or e att e n di n g t h e Sc h o ol of D e ntistr y, it  is 
ex p ect e d t h at a l o w s ali v ar y fl o w is f o u n d i n m or e t h a n h alf of t h e e nr oll e d s u bj ects  ( d u e t o t h e 
fr e q u e nt us e of m e dic ati o ns t h at c a us e h y p os ali v ati o n). T h er ef or e, t h e r ecr uit m e nt acc or di n g t o 
s ali v ar y fl o w r at e is n ot ex p ect e d t o r es ult i n m or e t h a n 5 scr e e n f ail ur es.  
 
It s h o ul d b e n ot e d t h at th e crit eri u m  of h avi n g “at l e ast  1 0 i n di vi d u als wit h h y p os ali v ati o n ” 
e nr oll e d  all o ws f or t h e r ecr uit m e nt of  2 0 i n di vi d u als wit h  h y p os ali v ati o n.  
 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 4  
T h e e nr oll m e nt t a bl e will b e c h ec k e d w e e kl y. If t h e n u m b er of e nr oll e d i n di vi d u als wit h n or m al 
s ali v ar y fl o w is r e ac hi n g 1 0, e m p h asis o n t h e r ecr uiti n g of i n di vi d u als wit h h y p os ali v ati o n ( as 
o bs erv e d b y t h e ir Sc h o ol of D e ntistr y pr o vi d ers) will b e e m p h asiz e d.  
 
4.  C oll ecti o n of d e nt al pl a q u e ( bi ofil m) s a m pl es: O n t h e 2 n d a n d 3 r d visits, p artici p a nts will h av e 
d e nt al pl a q u e s a m pl es c oll ect e d f or t h e a n al ysis of fl u ori d e a n d c alci u m i n t h e bi ofil m fl ui d a n d 
s oli d p h as es. T h e c oll ecti o ns will b e m a d e at t h e f oll o wi n g ti m e p oi nts:  
• 
At t h e b e gi n ni n g of t h e s essi o n  
• 
1 5 mi n ±  5 mi n  aft er ri nsi n g wit h t h e i nt erv e nti o n gr o u p  
• 
6 0 mi n ±  5 mi n aft er ri nsi n g wit h t h e i nt er v e nti o n gr o u p 
• 
1 2 0 mi n ±  5 mi n aft er ri nsi n g wit h t h e i nt erv e nti o n gr o u p  
T h e pl a q u e s a m pl es will b e c oll ect e d b y a lic e ns e d pr of essi o n al ( d e ntist). E ac h s a m pl e will b e 
c oll ect e d fr o m a diff er e nt q u a dr a nt of t h e m o ut h. A r a n d o miz e d t a bl e will b e us e d t o  d et er mi n e 
t h e or d er of c oll ecti o n fr o m e ac h q u a dr a nt.  
T h e p artici p a nt will b e as k e d t o s uc k a n d s w all o w a n y exc essi v e s ali v a i n his/ h er m o ut h a n d a 
pl astic s p at ul a will b e us e d t o scr a p e t h e b ucc al s urf ac es (f aci n g t h e c h e e k) of t h e t e et h i n t h at 
q u a dr a nt of t h e m o ut h, c oll ecti n g a n y d e nt al pl a q u e acc u m ul at e d  t h er e. T his c oll ecti o n is 
ex p ect e d t o t a k e a b o ut 1 mi n. T h e p o ol e d pl a q u e s a m pl e will b e i m m e di at el y i m m ers e d i n  
mi n er al oil t o av oi d d esicc ati o n. T h e pl a q u e s a m pl es will t h e n b e c e ntrif u g e d t o s e p ar at e t h e 
fl ui d a n d s oli d p h as es. T h e fl ui d will b e c oll ect e d usi n g a micr o pi p ett e, u n d er micr osc o p e. B ot h 
s a m pl es –  t h e fl ui d a n d t h e s oli ds –  will b e a n al yz e d f or c alci u m a n d fl u ori d e c o nc e ntr ati o n usi n g 
a c ol ori m etric m et h o d ( Ars e n az o III r e a g e nt) a n d a n i o n -s el ecti v e el ectr o d e, r es p ecti v el y. 
 
5.  C oll ecti o n of s a li v a s a m ples: O n t h e 2 n d a n d 3 r d visits, p artici p a nts will h av e u nsti m ul at e d s ali v a 
s a m pl es c oll ect e d f or t h e a n al ysis of fl u ori d e a n d c alci u m. T h e c oll ecti o ns will st art at t h e 
f oll o wi n g ti m e p oi nts: 
• 
At t h e b e gi n ni n g of t h e s essi o n, i m m e di at el y aft er bi ofi l m c oll ecti o n 
• 
1 6 mi n ±  5 mi n aft er ri nsi n g wit h t h e i nt er v e nti o n gr o u p, i m m e di at el y aft er bi ofil m 
c oll ecti o n 
• 
3 0 mi n ±  5 mi n aft er ri nsi n g wit h t h e i nt erv e nti o n gr o u p  
• 
6 1 mi n ±  5 mi n aft er ri nsi n g wit h t h e i nt erv e nti o n gr o u p , i m m e di at el y aft er bi ofil m 
c oll ecti o n 
• 
9 0 mi n ±  5 mi n aft er ri nsi n g wit h t h e i nt erv e nti o n gr o u p  
• 
1 2 1 mi n ±  5 mi n aft er ri nsi n g wit h t h e i nt erv e nti o n gr o u p, i m m e di at el y aft er bi ofil m 
c oll ecti o n 
F or s ali v a c oll ecti o n, p artici p a nts will dr o ol a n y pr o d uc e d s ali v a i nt o a f u n n el att ac h e d t o a t u b e, 
f or 5 mi n.  T h e c oll ect e d s a m pl e will b e a n al yz e d f or fl u ori d e a n d c alci u m c o nc e ntr ati o n b ef or e 
a n d aft er b ei n g c e ntrif u g e d. A n i o n -s el ecti v e el ectr o d e a n d t h e Ars e n az o III r e a g e nt will b e us e d 
i n t h e d et er mi n ati o n of fl u ori d e a n d c alci u m c o nc e ntr ati o ns, r es p ecti v el y. 
 
6.  Ri nsi n g wit h t h e i nt erv e nti o n gr o u ps: O n t h e 2 n d a n d 3 r d visits, p artici p a nts will ri ns e wit h t h e 
assi g n e d m o ut h ri ns e ( fl u ori d e o nl y or a c alci u m f oll o w e d b y a fl u ori d e ri ns e) f or 1 mi n e ac h. T h e 
ri ns es will b e p erf or m e d wit h 1 5 mL of t h e assi g n e d pr o d ucts, as a n or m al m o ut h ri ns e. All ri ns es 
will b e ex p ect or a t e d. At t h e e n d of t h e 1-mi n ri nsi n g wit h t h e fl u ori d e ri ns e , a c hr o n o gr a p h will 
b e s et u p t o d et er mi n e t h e f oll o wi n g c oll ecti o ns, st arti n g 1 5 mi n aft er t h e ri ns e a n d e n di n g at 
l e ast 2 h l at er. 
 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 5  
7.  D et er mi n ati o n of fl u ori d e ( F) a n d c alci u m ( C a) c o nc e ntr ati o ns i n d e nt al bi ofil m a n d s ali v a 
s a m pl es: Bi ofil m fl ui d a n d s ali v a s a m pl es will b e ass ess e d f or F a n d C a c o nc e ntr ati o ns dir ectl y. I n 
t h e s oli d p h as e of d e nt al bi ofil m, F a n d C a will b e pr evi o usl y extr act e d fr o m t h e bi ofil m wit h 0. 5 
M H Cl f or 3 h at r o o m t e m p e r at ur e [ C ur y et al., 1 9 9 7; T e n ut a et al., 2 0 0 6] b ef or e d et er mi n ati o n 
of c o nc e ntr ati o ns i n t h e aci d extr act. F c o nc e ntr ati o ns will b e d et er mi n e d usi n g a F el ectr o d e s et 
u p f or micr o a n al ysis [ V o g el et al., 1 9 9 7; T e n ut a et al., 2 0 0 6] usi n g a p pr o pri at e fl u ori d e st a n d ar ds 
a n d TI S A B III as t h e b uff er. C a c o nc e ntr ati o n i n t h e bi ofil m fl ui d a n d s ali v a s a m pl es will b e 
d et er mi n e d usi n g a c alci u m micr o el ectr o d e [ V o g el et al., 2 0 0 0; T e n ut a et al., 2 0 1 0]. I n t h e aci d 
extr act of t h e bi ofil m s oli d p h as e, t ot al c alci u m c o n c e ntr ati o n will b e d et er mi n e d usi n g a 
c ol ori m etric r e acti o n ( Ars e n az o III), i n a micr o pl at e r e a d er [L eit ã o et al., 2 0 1 8].  
N o st u d y r es ults will b e c o m m u nic at e d t o t h e p ati e nts, exc e pt f or t h eir s ali v ar y fl o w r at e, w hic h 
c a n si g nific a ntl y i ncr e as e t h eir ris k f or c ari es dis e as es i n c as e it is l o w.  
 
8. 2  
A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S  
I R B M e d’s g ui d eli n es o n a dv ers e ev e nts ( A E) a n d s eri o us a dv ers e ev e nts ( S A E) r e p orti n g will b e f oll o w e d. 
T h es e g ui d eli n es i ncl u d e t h e d efi niti o ns of A E/ S A E a n d w h e n t o r e p ort it.  
 
8. 3  
U N A N TI CI P A T E D P R O B L E M S  
I R B M e d’s g ui d eli n es o n u n a ntici p at e d pr o bl e ms ( U a P) r e p orti n g will b e f oll o w e d. T h es e g ui d eli n es 
i ncl u d e t h e d efi niti o n of U a P a n d w h e n t o r e p ort it. 
 
9  
S T A TI S TI C A L C O N SI D E R A TI O N S   
 
9. 1  
St ati sti c al H y p ot h e s e s  
•  
Pri m ar y Effic ac y E n d p oi nt:  
•  
Fl u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m  
o  N ull h y p ot h esis: A fl u ori d e ri ns e pr ec e d e d b y a c alci u m ri ns e is n ot s u p eri or t h a n a 
fl u ori d e-o nl y ri ns e i n e n h a nci n g f l u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m (fl ui d a n d s oli d 
p h as e s) u p t o 2 h aft er m o ut h ri nsi n g . 
o  Alt er n ati v e h y p ot h esis: A fl u ori d e ri ns e pr ec e d e d b y a c alci u m ri ns e is s u p eri or t h a n a 
fl u ori d e-o nl y ri ns e i n e n h a nci n g fl u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m (fl ui d a n d s oli d 
p h as es) u p t o 2 h aft er m o ut h ri nsi n g.  
 
•  
S ec o n d ar y Effic ac y E n d p oi nts:  
•  
Fl u ori d e c o nc e ntr ati o n i n s ali v a  
o  N ull h y p ot h esis : A fl u ori d e ri ns e pr ec e d e d b y a c alci u m ri ns e is n ot s u p eri or t h a n a 
fl u ori d e-o nl y ri ns e i n e n h a nci n g fl u ori d e c o nc e ntr ati o ns i n s ali v a u p t o 2 h aft er m o ut h 
ri nsi n g. 
o  Alt er n ati v e h y p ot h esis: A fl u ori d e ri ns e pr ec e d e d b y a c alci u m ri ns e is s u p eri or t h a n a 
fl u ori d e-o nl y ri ns e i n e n h a nci n g fl u ori d e c o nc e ntr ati o ns i n s ali v a (fl ui d a n d s oli d p h as es) 
u p t o 2 h aft er m o ut h ri nsi n g.  
•  
C alci u m c o nc e ntr ati o n i n d e nt al bi ofil m  
o  N ull h y p ot h esis: A fl u ori d e ri ns e pr ec e d e d b y a c alci u m ri ns e is n ot s u p eri or t h a n a 
fl u ori d e-o nl y ri ns e i n e n h a nci n g c alci u m c o nc e ntr ati o n i n d e nt al bi ofil m (f l ui d a n d s oli d 
p h as es) u p t o 2 h aft er m o ut h ri nsi n g.  


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 6  
o  Alt er n ati v e h y p ot h esis: A fl u ori d e ri ns e pr ec e d e d b y a c alci u m ri ns e is s u p eri or t h a n a 
fl u ori d e-o nl y ri ns e i n e n h a nci n g c alci u m c o nc e ntr ati o n i n d e nt al bi ofil m (fl ui d a n d s oli d 
p h as es) u p t o 2 h aft er m o ut h ri nsi n g.  
•  
C alci u m c o nc e ntr ati o n i n s ali v a  
o  N ull h y p ot h esis: A fl u ori d e ri ns e pr ec e d e d b y a c alci u m ri ns e is n ot s u p eri or t h a n a 
fl u ori d e-o nl y ri ns e i n e n h a nci n g c alci u m c o nc e ntr ati o n i n s ali v a u p t o 2 h aft er m o ut h 
ri nsi n g. 
o  Alt er n ati v e h y p ot h esis: A fl u ori d e ri ns e pr ec e d e d b y a c alci u m ri ns e is s u p eri or t h a n a 
fl u ori d e-o nl y ri ns e i n e n h a nci n g c alci u m c o nc e ntr ati o n i n s ali v a u p t o 2 h aft er m o ut h 
ri nsi n g. 
 
•  
T erti ar y / ex pl or at or y E n d p oi nts:  
•  
C orr el ati o n b et w e e n s ali v ar y fl o w r at e a n d fl u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m  
o  N ull h y p ot h esis: T h er e is n o c orr el ati o n ( b et a = 0) b et w e e n s ali v ar y fl o w r at e a n d 
fl u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m aft er ri nsi n g wit h a fl u ori d e m o ut h ri ns e. 
o  Alt er n ati v e h y p ot h esis: T h er e is a c orr el ati o n ( b et a ¹  0) b et w e e n s ali v ar y fl o w r at e a n d 
fl u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m aft er ri nsi n g wit h a fl u ori d e m o ut h ri ns e. 
•  
C orr el ati o n b et w e e n s ali v ar y fl o w r at e a n d fl u ori d e c o nc e ntr ati o n i n s ali v a  
o  N ull h y p ot h esis: T h er e is n o c orr el ati o n ( b et a = 0) b et w e e n s ali v ar y fl o w r at e a n d 
fl u ori d e c o nc e ntr ati o n i n s ali v a aft er ri nsi n g wit h a fl u ori d e m o ut h ri ns e. 
o  Alt er n ati v e h y p ot h esis: T h er e is a c orr el ati o n ( b et a ¹  0) b et w e e n s ali v ar y fl o w r at e a n d 
fl u ori d e c o nc e ntr ati o n i n s ali v a aft er ri nsi n g wit h a fl u ori d e m o ut h ri ns e. 
 
9. 2  
S A M P L E SI Z E  D E T E R MI N A TI O N  
D at a fr o m S o uz a et al., 2 0 1 6, usi n g ri ns es si mil ar t o b e us e d i n t his st u d y, w er e us e d i n s a m pl e siz e 
c alc ul ati o n. I n t h at st u d y, a n al ysis of fl u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m 1 0 h aft er usi n g t h e ri ns es 
w as av ail a b l e. ( N ot e t h at t h e ex p ect e d diff er e nc es b et w e e n t h e gr o u ps u p t o 2 h aft er t h e m o ut h ri nsi n g 
ar e ex p ect e d t o b e bi g g er, as s ali v a pr o d ucti o n ov erti m e t e n ds t o cl e ar all s u bst a nc es fr o m t h e m o ut h).  
 
C o nsi d eri n g a n  8 0 % p o w er t o d et ect diff er e nc es at t h e 5 % si g nific a nc e l ev el, a n esti m at e d s a m pl e siz e of 
1 5 w as d et er mi n e d ( St at a/ S E 1 5. 1 f or M ac). T h e s a m pl e siz e w as i ncr e as e d t o 2 0 s u bj ects c o nsi d eri n g a n 
attriti o n of 3 0 % . 
 
9. 3  
P O P U L A TI O N S F O R A N A L Y S E S  
F or t h e pri m ar y a n d s ec o n d ar y o utc o m es, o nl y p artici p a nts c o m pl eti n g t h e w h ol e st u d y will pr ovi d e 
d at a f or t h e a n al ys es ( p er -pr ot oc ol a n al ysis).  
 
F or t h e t erti ar y o utc o m es, a m o difi e d i nt e nti o n -t o-tr e at a n al ysis will b e us e d; all v ol u nt e ers c o m pl eti n g 
t h e fl u ori d e-o nl y m o ut h ri ns e tr e at m e nt will pr ovi d e d at a f or t h e c orr el ati o n a n al ys es, ev e n if t h ey di d 
n ot c o m pl et e t h e ot h er st u d y tr e at m e nt.  
 
9. 4  
S T A TI S TI C A L A N A L Y S E S  
 
9. 4. 1  G E N E R A L A P P R O A C H  
D escri pti v e st atistics:  D at a of fl u ori d e c o nc e ntr ati o n i n s ali v a a n d d e nt al bi ofil m t e n d t o h av e a n ot -
n or m al distri b uti o n. If t h at is t h e c as e i n t his st u d y, t h es e d at a will b e pr es e nt e d as t h e g e o m etric m e a n 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 7  
( of l o g tr a nsf or m e d d at a) a n d c o nfi d e nc e i nt erv al (c alc ul at e d fr o m l og tr a nsf or m e d d at a). D at a of 
c alci u m, if fitti n g n or m al distri b uti o n, will b e pr es e nt e d as m e a ns a n d st a n d ar d d evi ati o ns. If n ot fitti n g 
n or m al distri b uti o n, t h e s a m e a p pr o ac h f or fl u ori d e will b e us e d.  
 
I nf er e nti al t ests: T h e c o m p aris o ns b et w e e n gr o u ps wi ll b e m a d e usi n g an al ysis of v ari a nc e, h avi n g t h e 
v ol u nt e ers as st atistic al bl oc ks (s o urc e of v ari ati o n). T his is o nl y t o r e d uc e k n o w n v ari a bilit y fr o m t h e 
err or c alc ul ati o n. O n e -t ail e d t ests will b e us e d t o t est f or s u p eri orit y of o n e tr e at m e nt v ers us t h e ot h er. 
T h e p -v al u e will b e s et at 5 %.  
B ef or e t h e a n al ysis of v ari a nc e, t h e n or m alit y of err ors will b e t est e d. It is ex p ect e d t h at fl u ori d e d at a is 
n ot n or m all y distri b ut e d, a n d t h er ef or e a l o g tr a nsf or m ati o n of d at a will b e p erf or m e d ( w hic h us u all y is 
a d e q u at e t o n or m aliz e t h e d at a). T h e s a m e a p pr o ac h will b e us e d f or t h e c alci u m d at a.  
 
B esi d es t h e gr o u ps c o m p aris o ns , t h e s ali v ar y fl o w r at e will b e c orr el at e d wit h t h e fl u ori d e c o nc e ntr ati o n 
i n d e nt al bi ofil m a n d s ali v a, t o h el p u n d erst a n d t h e eff ect of fl o w r at e o n fl u ori d e s ali v ar y cl e ar a nc e. F or 
t h at, a r e gr essi o n a n al ysis will b e us e d t o c orr el at e t h e d at a of s ali v ar y fl o w wit h fl u ori d e c o nc e ntr ati o n 
( ar e a u n d er t h e c urv e of fl u ori d e c o nc e ntr ati o n ov er ti m e) i n s ali v a a n d d e nt al bi ofil m. A si g nific a nc e 
l ev el of 5 % will b e us e d i n t his a n al ysis.  
 
9. 4. 2  A N A L Y SI S O F T H E P RI M A R Y E F FI C A C Y E N D P OI N T( S)  
Fl u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m ( pri m ar y effic ac y e n d p oi nt) will b e d et er mi n e d fr o m t h e 
s a m pl es c oll ect e d at b as eli n e a n d 1 5 mi n, 6 0 mi n a n d 1 2 0 mi n (±  5 mi n) aft er ri nsi n g wit h t h e assi g n e d 
m o ut h ri ns e(s). T h e c o nc e ntr ati o n at e ac h i n di vi d u al ti m e p oi nt will b e c o m p ar e d b et w e e n t h e t w o 
i nt erv e nti o n gr o u ps. Als o, t h e ar e a u n d er t h e c ur v e of fl u ori d e c o nc e ntr ati o n i n d e nt al bi ofil m v ers us 
ti m e will b e c alc ul at e d. T his si n gl e m e as ur e m e nt of fl u ori d e bi o a v ail a bilit y o v erti m e aft er t h e m o ut h 
ri ns e(s) will b e c o m p ar e d b et w e e n t h e t w o i nt erv e nti o n gr o u ps. 
 
E ac h s et of d at a will b e c h ec k e d f or n or m alit y of err ors. If t h e d at a is n ot n or m al, it will b e l o g -
tr a nsf orm e d. A n a n al ysis of v ari a nc e will b e c o n d uct e d, c o nsi d eri n g as f act ors t h e p artici p a nt 
( ex p eri m e nt al bl oc k) a n d t h e tr e at m e nt. T h e us e of t h e p artici p a nt as a s o urc e of v ari ati o n ai ms s ol el y t o 
r e d uc e u n k n o w n v ari a bilit y i n t h e err or. A n al p h a l ev el of 5 % will b e us e d t o d et er mi n e si g nific a nt 
diff er e nc es b et w e e n t h e t w o gr o u ps.  
 
I n c as e d at a w er e l o g-tr a nsf or m e d t o fit t h e st atistic al a n al ysis, t h eir g e o m etric m e a ns a n d c o nfi d e nc e 
i nt erv als (c alc ul at e d fr o m t h e l o g-tr a nsf or m e d d at a) will b e pr es e nt e d. 
 
If dat a is missi n g fr o m o n e of t h e i nt erv e nti o n gr o u ps, t h e r est of t h e p artici p a nt d at a (fr o m t h e ot h er 
i nt erv e nti o n) will b e excl u d e d fr o m t h e a n al ysis. 
 
9. 4. 3  A N A L Y SI S O F T H E S E C O N D A R Y E N D P OI N T( S)  
Fl u ori d e a n d c alci u m c o nc e ntr ati o ns i n s ali v a (s ec o n d ar y e n d p oi nts ) will b e d et er mi n e d fr o m t h e 
s a m pl es c oll ect e d at b as eli n e a n d 1 6 mi n, 3 0 mi n, 6 1 mi n, 9 0 a n d 1 2 1  mi n ( ±  5 mi n) aft er ri nsi n g wit h t h e 
assi g n e d m o ut h ri ns e(s). T h e c o nc e ntr ati o n at e ac h i n di vi d u al ti m e p oi nt will b e c o m p ar e d b et w e e n t h e 
t w o i nt erv e nti o n gr ou ps. Als o, t h e ar e a u n d er t h e c urv e of fl u ori d e  a n d c alci u m  c o nc e ntr ati o n i n s ali v a 
v ers us ti m e will b e c alc ul at e d  a n d  c o m p ar e d b et w e e n t h e t w o i nt erv e nti o n gr o u ps.  
 
C alci u m c o nc e ntr ati o n i n d e nt al bi ofil m ( pri m ar y effic ac y e n d p oi nt) will b e d et er mi n e d fr o m t h e s a m pl es 
c oll ect e d at b as eli n e a n d 1 5 mi n, 6 0 mi n a n d 1 2 0 mi n ( ±  5 mi n) aft er ri nsi n g wit h t h e assi g n e d m o ut h 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 8  
ri ns e(s). T h e c o nc e ntr ati o n at e ac h i n di vi d u al ti m e p oi nt will b e c o m p ar e d b et w e e n t h e t w o i nt erv e nti o n 
gr o u ps. Als o, t h e ar e a u n d er t h e c urv e of c alci u m c o nc e ntr ati o n i n d e nt al bi ofil m v ers us ti m e will b e 
c alc ul at e d a n d c o m p ar e d b et w e e n t h e t w o i nt erv e nti o n gr o u ps.  
 
E ac h s et of d at a will b e c h ec k e d f or n or m alit y of err ors. If t h e d at a is n ot n or m al, it will b e l o g -
tr a nsf or m e d. A n a n al ysis of v ari a nc e will b e c o n d uct e d, c o nsi d eri n g as f act ors t h e p artici p a nt 
( ex p eri m e nt al bl oc k) a n d t h e tr e at m e nt. T h e us e of t h e p artici p a nt as a s o urc e of v ari ati o n ai ms s ol el y t o 
r e d uc e u n k n o w n v ari a bilit y i n t h e err or. A n al p h a l ev el of 5 % will b e us e d t o d et er mi n e si g nific a nt 
diff er e nc es b et w e e n t h e t w o gr o u ps.  
 
I n c as e d at a w er e l o g-tr a nsf or m e d t o fit t h e st atistic al a n al ysis, t h eir g e o m etric m e a ns a n d c o nfi d e nc e 
i nt erv als (c alc ul at e d fr o m t h e l o g-tr a nsf or m e d d at a) will b e pr es e nt e d. 
 
If d at a is missi n g fr o m o n e of t h e i nt er v e nti o n gr o u ps, t h e r est of t h e p artici p a nt d at a (fr o m t h e ot h er 
i nt erv e nti o n) will b e excl u d e d fr o m t h e a n al ysis. 
 
 
1 0  S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L C O N SI D E R A TI O N S  
1 0. 1  R E G U L A T O R Y, E T HI C A L , A N D S T U D Y O V E R SI G H T C O N SI D E R A TI O N S  
 
1 0. 1. 1  I N F O R M E D C O N S E N T P R O C E S S 
A n i nf or m e d c o ns e nt  d escri bi n g i n d et ail t h e st u d y i nt erv e nti o n, st u d y pr oc e d ur es, a n d ris ks ar e gi v e n t o 
t h e p artici p a nt a n d writt e n d oc u m e nt ati o n of i nf or m e d c o ns e nt is r e q uir e d pri or t o st arti n g 
i nt erv e nti o n/ a d mi nist eri n g st u d y i nt er v e nti o n.  
 
1 0. 1. 1. 1  C O N S E N T P R O C E D U R E S A N D D O C U M E N T A TI O N  
I nf or m e d c o ns e nt is a pr oc ess t h at is i niti at e d pri or t o t h e i n di vi d u al’s a gr e ei n g t o p artici p at e i n t h e 
st u d y a n d c o nti n u es t hr o u g h o ut t h e i n di vi d u al’s st u d y p artici p ati o n. C o ns e nt f or ms will b e I nstit uti o n al 
R evi e w B o ar d ( I R B)-a p pr ov e d a n d t h e p artici p a nt will b e as k e d t o r e a d a n d r evi e w t h e d oc u m e nt. T h e 
i nv esti g at or will ex pl ai n t h e r es e arc h st u d y t o t h e p artici p a nt a n d a ns w er a n y q u esti o ns t h at m a y aris e. 
A v er b al ex pl a n ati o n will b e pr o vi d e d i n t er ms s uit e d t o t h e p artici p a nt’s c o m pr e h e nsi o n of t h e 
p ur p os es, pr oc e d ur es, a n d p ot e nti al ris ks of t h e st u d y a n d of t h eir ri g hts as r es e arc h p artici p a nts.  
P artici p a nts will h a v e t h e o p p ort u nit y t o c ar ef ull y r evi e w t h e writ t e n c o ns e nt f or m a n d as k q u esti o ns 
pri or t o si g ni n g.  T h e p artici p a nts s h o ul d h av e t h e o p p ort u nit y t o disc uss t h e st u d y wit h t h eir f a mil y or 
s urr o g at es or t hi n k a b o ut it pri or t o a gr e ei n g t o p artici p at e. T h e p artici p a nt will si g n t h e i nf or m e d 
c o ns e nt d oc u m ent pri or t o a n y pr oc e d ur es b ei n g d o n e s p ecific all y f or t h e st u d y. P artici p a nts m ust b e 
i nf or m e d t h at p artici p ati o n is v ol u nt ar y a n d t h at t h e y m a y wit h dr a w fr o m t h e st u d y at a n y ti m e, wit h o ut 
pr ej u dic e. A c o p y of t h e i nf or m e d c o ns e nt d oc u m e nt will b e gi v e n t o t h e p artici p a nts f or t h eir r ec or ds. 
T h e i nf or m e d c o ns e nt pr oc ess will b e c o n d uct e d a n d t h e f or m si g n e d, b ef or e t h e p artici p a nt u n d er g o es 
a ny st u dy -s p ecific pr oc e d ur es. T h e ri g hts a n d w elf ar e of t h e p artici p a nts will b e pr ot ect e d b y 
e m p h asizi n g t o t h e m t h at t h e q u alit y of t h eir m e dic al c ar e will n ot b e a dv ers el y aff ect e d if t h ey d ecli n e 
t o p artici p at e i n t his st u d y. 
 
1 0. 1. 2  S T U D Y DI S C O N TI N U A TI O N A N D C L O S U R E  
T his st u dy m a y b e t e m p or aril y s us p e n d e d or pr e m at ur el y t er mi n at e d if t h er e is s uffici e nt r e as o n a bl e 
c a us e.  Writt e n n otific ati o n, d oc u m e nti n g t h e r e as o n f or st u d y s us p e nsi o n or t er mi n ati o n, will b e 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
1 9  
pr ovi d e d by t h e s us p e n di n g or t er mi n ati n g p art y t o st u d y p artici p a nts.  If t h e st u d y is pr e m at ur el y 
t er mi n at e d or s us p e n d e d, t h e P ri nci p al Inv esti g at or ( PI ) will pr o m ptl y i nf or m st u d y p artici p a nts, t h e 
I nstit utio n al R evi e w B o ar d ( I R B), a n d s p o ns or a n d will pr o vi d e t h e r e as o n(s) f or t h e t er mi n ati o n or 
s us p e nsi o n.  St u d y p artici p a nts will b e c o nt act e d, as a p plic a bl e, a n d b e i nf or m e d of c h a n g es t o st u d y 
visit sc h e d ul e.  
  
Circ u mst a nc es t h at m a y w arr a nt t er mi n ati o n or s us p e nsi o n i ncl u d e, b ut ar e n ot li mit e d t o:  
•  
D et er mi n ati o n of u n ex p ect e d, si g nific a nt, or u n acc e pt a bl e ris k t o p artici p a nts  
•  
D e m o nstr ati o n of effic ac y t h at w o ul d w arr a nt st o p pi n g    
•  
I ns uffici e nt c o m pli a nc e t o pr ot oc ol r e q uir e m e nts 
•  
D at a t h at ar e n ot s uffici e ntl y c o m pl et e a n d/ or ev al u a bl e  
•  
D et er mi n ati o n t h at t h e pri m ar y e n d p oi nt h as b e e n m et  
•  
D et er mi n ati o n of f utilit y  
 
1 0. 1. 3  C O N FI D E N TI A LI T Y A N D P RI V A C Y  
P artici p a nt c o nfi d e nti alit y a n d pri v ac y is strictl y h el d i n tr ust b y t h e p artici p ati n g i n v esti g at ors, t h eir 
st aff, a n d t h e s p o ns or a n d t h eir i nt er v e nti o ns. T his c o nfi d e nti alit y is ext e n d e d t o c o v er t esti n g of 
bi ol o gic al s a m pl es i n a d diti o n t o t h e cli nic al i nf or m ati o n r el ati n g t o p artici p a nts.  T h er ef or e, t h e st u d y 
pr ot oc ol, d oc u m e nt ati o n, d at a, a n d all ot h er i nf or m ati o n g e n er at e d will b e h el d i n strict c o nfi d e nc e. N o 
i nf or m ati o n c o nc er ni n g t h e st u d y or t h e d at a will b e r el e as e d t o a n y u n a ut h oriz e d t hir d p art y wit h o ut 
pri or writt e n a p pr ov al of t h e s p o ns or.  
 
All r es e arc h acti v iti es will b e c o n d uct e d i n as pri v at e a s etti n g as p ossi bl e. 
 
T h e st u dy p artici p a nt’s c o nt act i nf or m ati o n will b e s ec ur el y st or e d at e ac h cli nic al sit e f or i nt er n al us e 
d uri n g t h e st u d y. At t h e e n d of t h e st u d y, all r ec or ds will c o nti n u e t o b e k e pt i n a s e c ur e l oc ati o n f or as 
l o n g a p eri o d as dict at e d b y t h e r evi e wi n g I R B, I nstit uti o n al p olici es, or s p o ns or r e q uir e m e nts. 
 
1 0. 1. 4  K E Y R O L E S  A N D S T U D Y G O V E R N A N C E  
 
Pri nci p al I n v esti g at or  
Li vi a M. A. T e n ut a, D D S, M Sc, P h D, Ass oci at e Pr of ess or 
U niv ersity of Mic hi g a n, Sc h o ol of D e ntistr y  
1 0 1 1 N. U ni v ersit y Av e, r o o m 2 2 1 7, A n n Ar b or, MI  
7 3 4 -7 6 3 -3 7 0 3  
lit e n ut a @ u mic h. e d u 
 
1 0. 1. 5  D A T A  H A N D LI N G  A N D R E C O R D  K E E PI N G   
 
1 0. 1. 5. 1  D A T A C O L L E C TI O N A N D  M A N A G E M E N T R E S P O N SI BI LI TI E S  
D at a c oll ecti o n is t h e r es p o nsi bilit y of t h e cli nic al tri al st aff, u n d er t h e s u p ervisi o n of t h e pri nci p al 
inv esti g at or . T h e i nv esti g at or is r es p o nsi bl e f or e ns uri n g t h e acc ur ac y, c o m pl et e n ess, l e gi bilit y, a n d 
ti m eli n ess of t h e d at a r e p ort e d. 
 
All s o urc e d oc u m e nts s h o ul d b e c o m pl et e d i n a n e at, l e gi bl e m a n n er t o e ns ur e acc ur at e i nt er pr et ati o n 
of d at a.   


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
2 0  
 
H ar dc o pi es of t h e st u d y visit w or ks h e ets will b e pr ovi d e d f or us e as s o urc e d oc u m e nt  w or ks h e ets f or 
r ec or di n g d at a f or e ac h p artici p a nt e nr oll e d i n t h e st u d y.   
 
1 0. 1. 5. 2  S T U D Y R E C O R D S R E T E N TI O N  
 
1 0. 1. 6  P R O T O C O L D E VI A TI O N S  
A pr ot oc ol d evi ati o n is a n y n o nc o m pli a nc e wit h t h e cli nic al tri al pr ot oc ol. T h e n o nc o m pli a nc e m a y b e 
eit h er o n t h e p art of t h e p artici p a nt, t h e i n v esti g at or, or t h e st u d y sit e st aff. As a r es ult of d evi ati o ns, 
c orr ectiv e acti o ns ar e t o b e d ev el o p e d b y t h e sit e a n d i m pl e m e nt e d pr o m ptl y.  
 
It is t h e r es p o nsi bilit y of t h e pri nci p al  i n v esti g at or t o us e c o nti n u o us vi gil a nc e t o i d e ntif y pr ot oc ol 
d evi ati o n s. All d evi ati o ns m ust b e a d dr ess e d i n st u d y s o urc e d oc u m e nts .  Pr ot oc ol d evi ati o ns m ust b e 
s e nt t o t h e r evi e wi n g Instit uti o n al R evi e w B o ar d (I R B)  p er t h eir p olici es . T h e pri nci p al i n v esti g at or is 
r es p o nsi bl e f or k n o wi n g a n d a d h eri n g t o t h e r evi e wi n g I R B r e q uir e m e nts.  
 
1 0. 1. 7  P U B LI C A TI O N A N D D A T A S H A RI N G P O LI C Y  
T his tri al will b e  r e gist er e d at Cli nic al Tri als. g ov, a n d r es ults i nf or m ati o n fr o m t his tri al will  b e s u b mitt e d 
t o Cli nic al Tri als. g o v. I n a d diti o n, ev er y att e m pt will b e m a d e t o p u blis h r es ults i n p e er-r evi e w e d j o ur n als.  
D at a fr o m t his st u d y m a y b e r e q u est e d  fr o m ot h er r es earc h ers 3  y e ars aft er t h e c o m pl eti o n of t h e 
pri m ary e n d p oi nt b y c o nt acti n g Li vi a M. A. T e n ut a.  
 
1 0. 1. 8  C O N F LI C T O F  IN T E R E S T  P O LI C Y  
T h e i n d e p e n d e nc e of t his st u d y fr o m a n y act u al or p erc ei v e d i nfl u e nc e, s uc h as b y t h e p h ar m ac e utic al 
i n d ustr y, is critic al.  T h er efor e , a n y act u al c o nflict of i nt er est of p ers o ns w h o h av e a r ol e i n t h e d esi g n, 
c o n d uct, a n al ysis, p u blic ati o n, or a n y as p ect of t his tri al will b e discl os e d a n d m a n a g e d. F urt h er m or e, 
p ers o ns w h o h av e a p erc ei v e d c o nflict of i nt er est will b e r e q uir e d t o h av e s u c h c o nflicts m a n a g e d i n a 
w ay t h at is a p pr o pri at e t o t h eir p artici p ati o n i n t h e d es ig n a n d c o n d uct of t his tri al.  
 
 
 
 


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
2 1  
1 0. 2  A b br e vi ati o n s  
A E  
A d v ers e E v e nt  
C a  
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C O N S O R T  C o ns oli d at e d St a n d ar ds of R e p orti n g Tri als  
C R F  
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F  
Fl u ori d e  
F D A  
F o o d a n d Dr u g A d mi nistr ati o n  
GL P  
G o o d L a b or at or y Pr actic es  
I R B 
I nstit uti o n al R e vi e w B o ar d  
N a F  
S o di u m fl u ori d e  
N C T  
N ati o n al Cli nic al Tri al  
PI  
Pri nci p al I n v esti g at or  
S A E  
S eri o us A d v ers e E v e nt  
S O A  
Sc h e d ul e of Acti viti es  
U a P  
U n a ntici p at e d Pr o bl e m  
U S P  
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O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
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2 0 A u g ust 2 0 2 0  
 
 
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1 1  R E F E R E N C E S  
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fl u ori d e o n e n a m el i n vitr o. C ari es R es. 1 9 8 8; 2 2( 3): 1 3 9-4 4.  
C ury  J A,  R e b ell o  M A,  D el  B el  C ur y  A A.  I n  sit u  r el ati o ns hi p  b et w e e n  s ucr os e  ex p os ur e  a n d  t h e 
c o m p ositi o n of d e nt al pl a q u e. C ari es R es. 1 9 9 7; 3 1( 5): 3 5 6 -6 0.  
E d g ar M, D a w es C, O' M ull a n e D. S ali v a a n d or al h e alt h. 4. e d. St e p h e n H a nc oc ks Li mit e d, 2 0 1 2.  
F er n á n d ez C E, T e n ut a L M A, C ur y J A. W as h -o ut p eri o d f or cr oss ov er d esi g n ex p eri m e nts usi n g hi g h 
fl u ori d e c o nc e ntr ati o n d e ntifric e. R ev Cli n P eri o d I m p R e h a bil Or al. 2 0 1 5; 8( 1): 1 -6.  
F ur n ess S, W ort hi n gt o n H V, Br y a n G, Birc h e n o u g h S, Mc Mill a n R. I nt er v e nti o ns f or t h e m a n a g e m e nt 
of  dry  m o ut h:  t o pic al  t h er a pi es.  C oc hr a n e  D at a b as e  S yst  R ev.  2 0 1 1  D ec  7;( 1 2): C D 0 0 8 9 3 4.  d oi: 
1 0. 1 0 0 2/ 1 4 6 5 1 8 5 8. C D 0 0 8 9 3 4. p u b 2.  
L eit ã o TJ, C ur y J A, T e n ut a L M A. Ki n etics of c alci u m bi n di n g t o d e nt al bi ofil m b act eri a. PL o S O n e. 2 0 1 8 
J a n 3 1; 1 3( 1): e 0 1 9 1 2 8 4. d oi: 1 0. 1 3 7 1/j o ur n al. p o n e. 0 1 9 1 2 8 4. 
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htt ps:// w w w. nc o a. or g/ n e ws/r es o urc es -f or-r e p ort ers/ g et-t h e-f acts/ h e alt h y-a gi n g -f acts/.  
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o n M ar 2 0 t h, 2 0 1 9. 
N av az es h M, K u m ar S K; U ni v ersit y of S o ut h e r n C alif or ni a Sc h o ol of D e ntistr y. M e as uri n g s ali v ar y fl o w: 
c h all e n g es a n d o p p ort u niti es. J A m D e nt Ass oc. 2 0 0 8 M a y; 1 3 9 S u p pl: 3 5 S -4 0 S.  
N av az es h, M. X er ost o mi a a n d s ali v ar y gl a n d h y p of u ncti o n; a eti ol o g y , di a g n osis, cli nic al i m plic ati o ns 
a n d  m a n a g e m e nt.  I n:  E d g ar  M,  D a w es  C,  O' M ull a n e  D,  e ds.  S ali v a  a n d  or al  h e alt h.  4. e d.  St e p h e n 
H a nc oc ks Li mit e d, 2 0 1 2. C h. 4.  
N ó br e g a D F, L eit ã o TJ, C ur y J A, T e n ut a L M A. Fl u ori d e bi n di n g t o d e nt al bi ofil m b act éri a : s y n er gistic 
eff ect wit h c alci u m q u esti o n e d. C ari es R es. 2 0 1 9; 5 3: 1 0 -5.  
S o uz a  J G,  T e n ut a  L M,  D el  B el  C ur y  A A,  N ó br e g a  D F,  B u di n  R R,  d e  Q u eir oz  M X,  V o g el  GL,  C ur y  J A. 
C alci u m pr eri ns e b ef or e fl u ori d e ri ns e r e d uc es e n a m el d e mi n er aliz ati o n: a n i n sit u C ari es St u d y. C ari es 
R es. 2 0 1 6; 5 0( 4): 3 7 2 -7. d oi: 1 0. 1 1 5 9/ 0 0 0 4 4 6 4 0 7.  
St a u n L ars e n L, B a el u m V, T e n ut a L M A, Ric h ar ds A, Nyv a d B. Fl u ori d e i n s ali v a a n d d e nt al bi ofil m aft er 
1 5 0 0  a n d  5 0 0 0 
p p m  fl u ori d e  ex p os ur e.  Cli n  Or al  I nv esti g.  2 0 1 8  A pr; 2 2( 3): 1 1 2 3 -1 1 2 9. 
d oi: 1 0. 1 0 0 7/s 0 0 7 8 4 -0 1 7 -2 1 9 5 -y.  
T e n ut a L M, D el B el C ur y A A, B ort oli n M C, V o g el GL, C ur y J A. C a, Pi, a n d F i n t h e fl ui d of bi ofil m f or m e d 
u n d er s ucr os e. J D e nt R es. 2 0 0 6; 8 5( 9): 8 3 4 -8.  
T e n ut a  L M,  D el  B el  C ur y  A A,  T a bc h o ur y  C P,  M oi  G P,  Sil v a  WJ,  C ur y  J A.  Ki n etics  of 
m o n ofl u or o p h os p h at e h y dr ol ysis i n a b act eri al t est pl a q u e i n sit u. C ari es R es.  2 0 1 0; 4 4( 1): 5 5 -9. d oi: 
1 0. 1 1 5 9/ 0 0 0 2 7 9 4 6 6.  
v a n L ov er e n C. T h e a nti micr o bi al acti o n of fl u ori d e a n d its r ol e i n c ari es i n hi biti o n. J D e nt R es. 1 9 9 0; 6 9 
S p ec N o: 6 7 6 -8 1.  
V o g el  GL,  C h o w  L C,  C ar e y  C M,  Sc h u m ac h er  G E,  T a k a gi  S.  Eff ect  of  a  c alci u m  pr eri ns e  o n  s ali v ar y 
fl u ori d e aft er a 2 2 8-p p m fl u ori d e ri ns e. C ari es R es 2 0 0 6 a; 4 0: 1 7 8 -8 0.  
V o g el GL, C h o w L C, C ar ey C M. C alci u m pr e -ri ns e gr e atl y i ncr e as es o v er ni g ht s ali v ar y fl u ori d e aft er a 
2 2 8 p p m fl u ori d e ri ns e. C ari es R es. 2 0 0 8 a; 4 2( 5): 4 0 1 -4. d oi: 1 0. 1 1 5 9/ 0 0 0 1 5 4 7 8 6.  


O pti mizi n g fl u ori d e r et e nti o n i n t h e m o ut h of ol d er a d ults wit h disti nct s aliv ary fl o w r at es 
V ersi o n 1. 3  
Pr ot oc ol 0 1  
2 0 A u g ust 2 0 2 0  
 
 
2 3  
V o g el GL, M a o Y, C ar ey C M, C h o w L C. I ncr e as e d ov er ni g ht fl u ori d e c o nc e ntr ati o ns i n s ali v a, pl a q u e, 
a n d pl a q u e fl ui d aft er a n ov el t w o -s ol uti o n ri ns e. J D e nt R es. 1 9 9 7; 7 6( 3): 7 6 1-7.  
V o g el GL, Sc h u m ac h er G E, C h o w L C, T a k a gi S, C ar ey C M. C a pr e -ri ns e gr e atl y i ncr e as es pl a q u e a n d 
pl a q u e fl ui d F. J D e nt R es. 2 0 0 8 b; 8 7( 5): 4 6 6 -9.  
V o g el  GL,  S hi m  D,  Sc h u m ac h er  G E,  C ar ey  C M,  C h o w  L C,  T a k a gi  S.  S ali v ar y  fl u ori d e  fr o m  fl u ori d e 
d e ntifric es or ri ns e s aft er us e of a c alci u m pr e-ri ns e or c alci u m d e ntifric e. C ari es R es. 2 0 0 6 b; 4 0( 5): 4 4 9-
5 4.  
V o g el GL, Z h a n g Z, C h o w L C, C ar ey C M, Sc h u m ac h er G E, B a nti n g D W. Eff ect i n  vitr o aci dific ati o n o n 
pl a q u e fl ui d c o m p ositi o n wit h a n d wit h o ut a N a F or a  c o ntr oll e d-r el e as e fl u ori d e ri ns e. J D e nt R es. 
2 0 0 0 A pr; 7 9( 4): 9 8 3 -9 0.  
V o g el GL. Or al fl u ori d e r es erv oirs a n d t h e pr ev e nti o n of d e nt al c ari es. M o n o gr Or al Sci. 2 0 1 1; 2 2: 1 4 6 -
5 7. d oi: 1 0. 1 1 5 9/ 0 0 0 3 2 5 1 6 6.  
W olff A, J os hi R K, E kstr ö m J, Afr a mi a n D, P e d ers e n A M, Pr oct or G, N ar a y a n a N, Vill a A, Si a Y W, Ali k o 
A, Mc G o w a n R, K err A R, J e ns e n S B, Vissi n k A, D a w es C. A g ui d e t o m e dic ati o ns i n d uci n g s ali v ar y gl a n d 
dysf u ncti o n,  x er ost o mi a,  a n d  s u bj ec ti v e  si al orr h e a:  A  s yst e m atic  r evi e w  s p o ns or e d  b y  t h e  W orl d 
W or ks h o p o n Or al M e dici n e VI. Dr u gs R D. 2 0 1 7 M ar; 1 7( 1): 1 -2 8. d oi: 1 0. 1 0 0 7/s 4 0 2 6 8 -0 1 6 -0 1 5 3 -9.  
Z er o D T, Br e n n a n M T, D a ni els T E, P a p as A, St e w art C, Pi nt o A, Al -H as hi mi I, N a v az es h M, R h o d us N, 
Sci u b b a J, Si n g h M, W u AJ, Fr a ntsv e -H a wl e y J, Tr ac y S, F ox P C, F or d TL, C o h e n S, Vi vi n o F B, H a m mitt 
K M;  Sj ö gr e n’s  S y n dr o m e  F o u n d ati o n  Cli nic al  Pr actic e  G ui d eli n es  C o m mitt e e.  Cli nic al  pr actic e 
g ui d eli n es  f or  or al  m a n a g e m e nt  of  Sj ö gr e n  dis e as e:  D e nt al  c ari es  pr e v e nti o n.  J  A m  D e nt  Ass oc. 
2 0 1 6; 1 4 7( 4): 2 9 5 -3 0 5. d oi: 1 0. 1 0 1 6/j. a d aj. 2 0 1 5. 1 1. 0 0 8.  

ICF_001.pdf: 
 
 
 
 
 
 
 
 
Official Title: Optimizing Fluoride Retention in the Mouth of Older Adults With 
Distinct Salivary Flow Rates 
 
NCT Number: NCT04239872 
 
Document Date: 8/24/2022 
 


Page 1 of 10
Consent Version: 02/05/2020
UNIVERSITY OF MICHIGAN
CONSENT TO BE PART OF A RESEARCH STUDY
 
1.  KEY INFORMATION ABOUT THE RESEARCHERS AND THIS STUDY  
Study title: Optimizing fluoride retention in the mouth of older adults with distinct salivary flow rates
Company or agency sponsoring the study: MICHR
Principal Investigator: Livia M. A. Tenuta, DDS, MSc, PhD, Department of Cariology, Restorative Sciences 
and Endodontics, University of Michigan School of Dentistry
Study coordinator: Taylor M. Cezon, RDH, BSDH, University of Michigan School of Dentistry
1.1 Key Study Information
You may be eligible to take part in a research study.  This form contains important information that will 
help you decide whether to join the study.  Take the time to carefully review this information.  You 
should talk to the researchers about the study and ask them any questions you have.  You may also wish 
to talk to others such as your family, friends, or other doctors about joining this study.  If you decide to 
join the study, you will be asked to sign this form before you can start study-related activities.  Before 
you do, be sure you understand what the research study is about.
A research study is different from the regular medical care you receive from your doctor.  Research 
studies hope to make discoveries and learn new information about diseases and how to treat them.  You 
should consider the reasons why you might want to join a research study or why it is not the best 
decision for you at this time.  
Research studies do not always offer the possibility of treating your disease or condition.  Research 
studies also have different kinds of risks and risk levels, depending on the type of the study.  You may 
also need to think about other requirements for being in the study.  For example, some studies require 
you to travel to scheduled visits at the study site in Ann Arbor or elsewhere. This may require you to 
arrange travel, change work schedules, find child care, or make other plans.  In your decision to 
participate in this study, consider all of these matters carefully.  
This research is studying a new type of fluoride mouth rinse in small numbers of people to learn about 
its safety and its effect on your body.  This study will assess if rinsing with calcium before rinsing with a 
fluoride mouth rinse can increase the retention of fluoride in the mouth. In the first research visit, we 
will check your oral health and measure how much saliva you have in your mouth. In the second 
research visit, you will be asked to rinse with one of the mouth rinses under test in the study (fluoride 
only of a calcium rinse followed by a fluoride rinse).  Finally, in the third visit, you will be asked to rinse 
your mouth with the other rinse (not tested before). Your saliva and dental plaque samples will be 
collected after you do the rinses in visits 2 and 3, for analysis of fluoride concentration.
This study involves a process called randomization. This means that the mouth rinse you will use in the 
second visit is not chosen by you or the researcher.  The study design divides study participants into 
separate groups, based on chance (like the flip of a coin), to start the study in different treatments. In 
the third visit, you will use the other treatment. You will know in which group you are in because one of 
Study ID: HUM00159624   IRB: IRBMED   Date Approved: 8/24/2022   Expiration Date: 8/23/2023


Page 2 of 10
Consent Version: 02/05/2020
the treatments involves one mouth rinse, the other involves two mouth rinses. But you will not be able 
to choose in which treatment to start.
There can be risks associated with joining any research study.  The type of risk may impact whether you 
decide to join the study.  For this study, some of these risks may include the discomfort in the collection 
of saliva or rinsing with the mouth rinses, or discomfort to be asked to come to the School of Dentistry 
without having brushed your teeth in the morning. More detailed information will be provided later in 
this document.
This study may offer some benefit to you now or others in the future by developing an improved 
fluoride rinse to keep fluoride longer in the mouth. More information will be provided later in this 
document.
We expect the amount of time you will participate in the study will be one month.
You can decide not to be in this study.  Even if you decide to join the study now, you are free to leave at 
any time if you change your mind.
More information about this study continues in Section 2 of this document.
2. PURPOSE OF THIS STUDY
2.1 Study purpose: 
People with dry mouth tend to have more oral diseases. We know that using fluoride is helpful, but the 
effect of fluoride has a limit, especially in people with dry mouth. However, a new type of fluoride 
treatment, associated with calcium, is showing better results than fluoride alone in order to retain 
fluoride in the mouth. In this study we will test how well this treatment (a mouth rinse with calcium and 
fluoride) works in older individuals with different rates of production of saliva.
3. WHO MAY PARTICIPATE IN THE STUDY
Taking part in this study is completely voluntary.  You do not have to participate if you don't want to.  
You may also leave the study at any time.  If you leave the study before it is finished, there will be no 
penalty to you, and you will not lose any benefits to which you are otherwise entitled. 
3.1 Who can take part in this study?
Individuals with at least 65 years of age, who are able to follow the study instructions, who have at least 
20 teeth in the mouth, and at least 4 teeth in each side of the upper and lower parts of the mouth. 
If you have dental pain or need urgent dental care, you are not eligible to participate.
3.2 How many people are expected to take part in this study?
20 subjects are expected to participate.
Study ID: HUM00159624   IRB: IRBMED   Date Approved: 8/24/2022   Expiration Date: 8/23/2023


Page 3 of 10
Consent Version: 02/05/2020
4.  INFORMATION ABOUT STUDY PARTICIPATION
4.1 What will happen to me in this study?  
You will have to follow the following instructions during the study:

Use a standardized toothpaste and toothbrush, provided to you by the study team at your first 
visit, starting 7 days before your scheduled return for visits 2 and 3. This is to make sure every 
participant is using the same type of fluoride in the toothpaste.

Do not rinse your mouth with any other oral product during the study period

Do not drink green or black tea on the night before or the day of their visits. These teas have a 
high fluoride content.

Do not brush your teeth on the night before and the morning of the study visits 2 and 3

Do not eat or drink for 2 hours after the rinses during visits 2 and 3. Your saliva and plaque will 
be collected during this period.
You can find details about what will happen during each visit below:
Visit 1 – about an hour
You will be scheduled for a first visit to the School of Dentistry to check your eligibility to participate in 
this study. In this visit, you will have your teeth examined, and will be asked to collect two samples of 
saliva, one without stimulation (just drooling into a tube) and the other while chewing gum. The amount 
of saliva you produce will be used as one of the eligibility criteria. During this visit, we will also ask you to 
report the list of medications that you regularly take. If you are eligible, you will also receive a 
standardized toothpaste and toothbrush, which you will have to use for one week before visits 2 and 3.
Visit 2 & 3 – about 3 hours for each
If you are eligible, you will be scheduled to come to the School of Dentistry 2 more times within the next 
2 to 4 weeks. These visits will be at least 7 days apart. In Visit 2, you will be randomly assigned to one of 
two treatments (like flipping a coin). One of the treatments is a mouth rinse with fluoride (one rinse 
only), the other is a mouth rinse with calcium followed by a mouth rinse with fluoride (2 rinses). If you 
are assigned to use the one-rinse treatment in visit 2, you will use the 2-rinse treatment in visit 3, and 
vice versa.
For each visit, you will have to come to the School of Dentistry in the morning, without having brushed 
your teeth. When you arrive, the study team will ask you to drool saliva into a tube; they will also collect 
a sample of dental plaque from your teeth. You will then do a mouth rinse with the assigned treatment 
(only 1 rinse or 2 rinses). Each rinse is done for 1 minute, and then spit out. After rinsing, we will collect 
3 more dental plaque samples from your teeth (at 15, 60 and 120 min after the rinse(s)); each collection 
should be done in one minute. We will also ask you to drool saliva into a tube immediately after 
collecting the dental plaque sample (at 16, 61 and 121 min after the rinse(s)) and also at time points 30 
min and 90 min after the rinse. 
As a subject participating in this research study, you have certain responsibilities that may apply to this 
study, such as ensuring that you arrive in time for all of your scheduled appointments, do your rinse and 
collect saliva samples as directed, and report any adverse reactions (e.g. feeling your mouth different 
after the rinses, feeling the taste of food different) you may have during the study.
Study ID: HUM00159624   IRB: IRBMED   Date Approved: 8/24/2022   Expiration Date: 8/23/2023


Page 4 of 10
Consent Version: 02/05/2020
4.2 How much of my time will be needed to take part in this study?  
You will participate in a first visit that will last about 1 hour. The following visits (2 and 3) will last about 
3 hours each. At least 7 days will be allowed between visits 2 and 3. Therefore, your total participation in 
the study is expected to be about one month.
4.3 When will my participation in the study be over? 
At the end of visit 3 your participation in the study will be over. 
4.4 What will happen with my information and/or biospecimens used in this study?
Your biospecimens and collected information may be shared with MICHR (Michigan Institute for Clinical 
and Health Research). 
With appropriate permissions, your biospecimens and collected information may also be shared with 
other researchers, here, around the world, and with companies.
Your identifiable private information or identifiable biospecimens may be stripped of identifiers and 
used for future research studies or distributed to another researcher for future research studies without 
additional informed consent. 
5.  INFORMATION ABOUT STUDY RISKS AND BENEFITS
5.1 What risks will I face by taking part in the study?  What will the researchers do to protect me 
against these risks?
The known or expected risks are:
The most common discomfort (occurring in more than 25% of patients) is related to not brushing 
your teeth the night before and in the morning of visits 2 and 3. You may feel bad breath in the 
morning of the test due to not brushing. The researchers will try to minimize this discomfort by 
having you brush your teeth under supervision or performing a professional cleaning at the end of 
the visit to remove dental plaque.
Less common discomforts (10% - 25% of patients) are:
o
Discomfort related to collecting saliva samples, as some individuals may not feel 
comfortable to drool into a tube. This discomfort will be minimized by keeping you 
seated in a private dental chair, with only the trained study staff offering instructions on 
the procedure.
o
Discomfort related to rinsing with unflavored rinses. This discomfort will be minimized 
by having you only rinse for about 1 minute with each rinse. 
o
Discomfort related to refraining from eating or drinking for up to 2 hours during the 
collection of samples. This may be harder if you have dry mouth and sip water 
constantly. In order to minimize this discomfort, if required, you will be allowed to drink 
a small amount of water.
Additionally, there may be a risk of loss to confidentiality or privacy.  See Section 9 of this document for 
more information on how the study team will protect your confidentiality and privacy.
As with any research study, there may be additional risks that are unknown or unexpected.
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5.2 What happens if I get hurt, become sick, or have other problems as a result of this research?
The researchers have taken steps to minimize the risks of this study.  Even so, you may still have 
problems or side effects, even when the researchers are careful to avoid them. Please tell the 
researchers listed in Section 10 about any injuries, side effects, or other problems that you have during 
this study.  You should also tell your regular doctors.
5.3 If I take part in this study, can I also participate in other studies?
Being in more than one research study at the same time, or even at different times, may increase the 
risks to you.  It may also affect the results of the studies.  You should not take part in more than one 
study without approval from the researchers involved in each study.  
5.4 How could I benefit if I take part in this study?  How could others benefit?  
You may not receive any personal benefits from being in this study. However, you will receive oral 
hygiene and care instructions provided by the study personnel. Also, in case we find out that you have 
low production of saliva, you will be informed about this, because this condition increases the risk for 
oral diseases. You may also benefit from the understanding of the study objectives, and by being more 
motivated for taking care of your oral health.
Even if you do not benefit directly, others may benefit from the knowledge gained from this study.
5.5 Will the researchers tell me if they learn of new information that could change my willingness to 
stay in this study?
Yes, the researchers will tell you if they learn of important new information that may change your 
willingness to stay in this study. If new information is provided to you after you have joined the study, it 
is possible that you may be asked to sign a new consent form that includes the new information.
6.  ALTERNATIVES TO PARTICIPATING IN THE STUDY
6.1 If I decide not to take part in this study, what other options do I have?
This study is not meant to treat any condition or disease. Even if you have dry mouth, the mouth rinses 
to be tested are not considered standard of care for the prevention of any oral disease, including tooth 
decay. You will be provided with all information available about your oral health and where you can find 
treatment available, shall we find any treatment needs during the study procedures.
7.  ENDING THE STUDY
7.1 If I want to stop participating in the study, what should I do?
You are free to leave the study at any time.  If you leave the study before it is finished, there will be no 
penalty to you. You will not lose any benefits to which you may otherwise be entitled.  If you choose to 
tell the researchers why you are leaving the study, your reasons for leaving may be kept as part of the 
study record. If you decide to leave the study before it is finished, please tell one of the persons listed in 
Section 10 “Contact Information”.
7.2 Could there be any harm to me if I decide to leave the study before it is finished?
No, we do not anticipate any harm to you if you leave the study before the end. 
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7.3 Could the researchers take me out of the study even if I want to continue to participate?
Yes. There are many reasons why the researchers may need to end your participation in the study.  
Some examples are:

The researcher believes that it is not in your best interest to stay in the study.

You become ineligible to participate.

Your condition changes and you need treatment that is not allowed while you are taking part in 
the study.

You do not follow instructions from the researchers.

The study is suspended or canceled.
8.  FINANCIAL INFORMATION
8.1 Who will pay for the costs of the study?  Will I or my health plan be billed for any costs of the 
study?  
There are not costs or billing for this study. If you get a bill you think is wrong, call the researcher’s 
telephone number listed in Section 10.1.
By signing this form, you do not give up your right to seek payment if you are harmed as a result of 
being in this study.
8.2 Will I be paid or given anything for taking part in this study?
Yes, you will receive gift cards that amount to $84 for completing the study. This payment will be 
prorated; you will receive $18 for completing visit 1, $18 for completing visit 2 and $48 for completing 
visit 3. If you withdraw from the study you will only be paid up to the point when you withdraw.
The gift cards will be reloaded with the next payment so it is very important that you keep your gift card 
the whole study.
8.3 Who could profit or financially benefit from the study results?
The American Dental Association Foundation is an owner and Dr. Gerald L. Vogel is a named inventor on 
patents or patent applications on the use of calcium before a fluoride rinse. This means, the American 
Dental Association Foundation and Dr. Gerald L. Vogel could gain financially from this study.
Research can lead to new discoveries, such as new tests, drugs, or devices. Researchers, their 
organizations, and other entities, including companies, may potentially benefit from the use of the data 
or discoveries. You will not have rights to these discoveries or any proceeds from them.
9. CONFIDENTIALITY OF SUBJECT RECORDS AND AUTHORIZATION TO RELEASE YOUR PROTECTED 
HEALTH INFORMATION
The information below describes how the confidentiality of your research records will be protected in 
this study, and any sub-studies described in this document.  
9.1 How will the researchers protect my information? 
Your research information will be stored in password-protected electronic files or locked storage 
cabinets accessible only to the study personnel. Standards for data collection, management and analysis 
will be followed.
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A description of this clinical trial will be available on http://www.clinicaltrials.gov/, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time.
9.2 What protected health information (PHI) about me could be seen by the researchers or by other 
people?  Why?  Who might see it?
Signing this form gives the researchers your permission to obtain, use, and share information about you 
for this study, and is required in order for you to take part in the study.  
Medical information and billing records are protected by the privacy regulations of the federal Health 
Insurance Portability and Accountability Act of 1996 (HIPAA).  This type of information is called 
protected health information (PHI).  PHI about you may be obtained from any hospital, doctor, and 
other health care provider involved in your care, including:

Hospital/doctor's office records, including test results and dental records

All records relating to your condition, the treatment you have received, and your response to 
the treatment

Demographic information

Personal identifiers
There are many reasons why information about you may be used or seen by the researchers or others 
during or after this study.  Examples include:

The researchers may need the information to make sure you can take part in the study.  

University, Food and Drug Administration (FDA) and/or other government officials, auditors, 
and/or the IRB may need the information to make sure that the study is done in a safe and 
proper manner.   

Study sponsors or funders, or safety monitors or committees, may need the information to: 
o
Make sure the study is done safely and properly
o
Learn more about side effects 
o
Analyze the results of the study 

The researchers may need to use the information to create a databank of information about 
your condition or its treatment.

If you receive any payments for taking part in this study, the University of Michigan accounting 
department may need your name, address, Social Security number, payment amount, and 
related information for tax reporting purposes.

Federal or State law may require the study team to give information to government agencies. 
For example, to prevent harm to you or others, or for public health reasons. 
The results of this study could be published in an article, but would not include any information that 
would let others know who you are. 
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9.3 What happens to information about me after the study is over or if I cancel my permission to use 
my PHI?
As a rule, the researchers will not continue to use or disclose information about you, but will keep it 
secure until it is destroyed.  Sometimes, it may be necessary for information about you to continue to be 
used or disclosed, even after you have canceled your permission or the study is over.  
Examples of reasons for this include:

To avoid losing study results that have already included your information 

To provide limited information for research, education, or other activities. (This information 
would not include your name, social security number, or anything else that could let others 
know who you are.) 

To help University and government officials make sure that the study was conducted properly
As long as your information is kept within the University of Michigan Health System, it is protected by 
the Health System’s privacy policies.  For more information about these policies, ask for a copy of the 
University of Michigan “Notice of Privacy Practices”.  This information is also available on the web at 
http://www.uofmhealth.org/patient+and+visitor+guide/hipaa.  Note that once your information has 
been shared with others as described under Question 9.2, it may no longer be protected by the privacy 
regulations of the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
9.4 When does my permission to use my PHI expire?  
Your permission expires at the end of the study, unless you cancel it sooner. You may cancel your 
permission at any time by writing to the researchers listed in Section 10 "Contact Information" (below).  
If you withdraw your permission, you may no longer be eligible to participate in this study.
10. CONTACT INFORMATION
10.1 Who can I contact about this study?
Please contact the researchers listed below to:

Obtain more information about the study

Ask a question about the study procedures or treatments

Talk about study-related costs to you or your health plan 

Report an illness, injury, or other problem (you may also need to tell your regular doctors)

Leave the study before it is finished

Express a concern about the study
Principal Investigator: Livia M. A. Tenuta
Mailing Address: 1011 N University Ave, room 2217, 48109, Ann Arbor, MI
Telephone: 734-763-3703
Study Coordinator: Taylor M. Cezon
Mailing Address: 1011 N University Ave, room 3323c, 48109, Ann Arbor, MI 
e-mail: thouseho@umich.edu
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You may also express a question or concern about a study by contacting the Institutional Review 
Board listed below:
University of Michigan Medical School Institutional Review Board (IRBMED)
2800 Plymouth Road
Building 520, Room 3214
Ann Arbor, MI 48109-2800
Telephone: 734-763-4768  (For International Studies, include the appropriate calling codes.)
Fax: 734-763-1234
e-mail: irbmed@umich.edu 
If you are concerned about a possible violation of your privacy or concerned about a study you may 
contact the University of Michigan Health System Compliance Help Line at 1-866-990-0111.
When you call or write about a concern, please provide as much information as possible, including the 
name of the researcher, the IRBMED number (at the top of this form), and details about the problem.  
This will help University officials to look into your concern.  When reporting a concern, you do not have to 
give your name unless you want to.
11.  RECORD OF INFORMATION PROVIDED
11.1 What documents will be given to me?
Your signature in the next section means that you have received copies of all of the following 
documents:

This "Consent to be Part of a Research Study" document, signed and dated (Note: In addition to 
the copy you receive, copies of this document will be stored in a separate confidential research 
file and may be entered into your regular University of Michigan medical record.)
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12.  SIGNATURES
Sig-A
Consent to Participate in the Research Study
I understand the information printed on this form.  I have discussed this study, its risks and potential 
benefits, and my other choices with _________________________________________.  My 
questions so far have been answered.  I understand that if I have more questions or concerns about 
the study or my participation as a research subject, I may contact one of the people listed in Section 
10 (above).  I understand that I will receive a copy of this form at the time I sign it and later upon 
request.  I understand that if my ability to consent or assent for myself changes, either I or my legal 
representative may be asked to re-consent prior to my continued participation in this study.
Print Legal Name: ___________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Sig-G
Principal Investigator or Designee
I have provided this participant and/or his/her legally authorized representative(s) with information 
about this study that I believe to be accurate and complete.  The participant and/or his/her legally 
authorized representative(s) indicated that he or she understands the nature of the study, including 
risks and benefits of participating.
Printed Legal Name: __________________________________________________________________
Title: ______________________________________________________________________________
Signature: _________________________________________________________________________
Date of Signature (mm/dd/yy): ________________________
Study ID: HUM00159624   IRB: IRBMED   Date Approved: 8/24/2022   Expiration Date: 8/23/2023