Evaluating Intermittent Dosing of Aspirin for Colorectal Cancer Chemoprevention
Phase: PHASE2
Conditions: Colorectal Adenoma, Colorectal Carcinoma
Sponsor: National Cancer Institute (NCI)

 
 
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Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
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C O V E R P A G E  
  
  
  
  
 
D C P Pr ot oc ol #:   
N W U 2 0 1 5- 0 6- 0 1 
 
L oc al Pr ot oc ol #:   N CI 2 0 1 5- 0 6- 0 1 
 
E v al u ati n g I nter mitte nt D osi n g of As piri n f or C ol orect al C a ncer C he m o pre ve nti o n 
  
 
C o ns orti u m N a me:  
  
 
N ort h wester n Ca ncer Pre ve nti o n C o ns orti u m  
 
Or g a niz ati o n N a me *:  
N ort h wester n U ni versit y  
N a me of C o ns orti u m Pri nci p al  
See ma A. K ha n, M D  
I n vesti g at or:    
  
 
3 0 3 E. S u peri or, S uite 4- 1 1 1  
 
 
C hica g o, I L 6 0 6 1 1 
 
  
P h o ne: ( 3 1 2) 5 0 3- 4 2 3 6   
 
 
Fa x: ( 3 1 2) 5 0 3- 2 5 5 5 
 
  
E-mail: s k ha n @ n m. or g  
 
  
  
 
Or g a niz ati o n N a me:    
 
Va n der bilt U ni versit y   
Pr ot oc ol Pri nci p al I n vesti g at or:   Qi Dai , M D, P h. D. 
  
  
  
  
  
2 5 2 5 West E n d A ve n ue 
  
  
  
  
  
S uite 8 0 0, 8t h Fl o or 
  
  
  
  
  
Nas h ville, T N 3 7 2 0 3 
  
  
  
  
  
P h o ne: ( 6 1 5) 9 3 6- 0 7 0 7 
  
  
  
  
 
Fa x : ( 6 1 5) 3 4 3- 5 9 3 8 
  
  
  
  
  
E-mail : Qi. dai @ v u mc. or g  
 
 
Or g a niz ati o n N a me:  
N ort h wester n U ni versit y 
Pr ot oc ol C o -PI:  
Lifa n g H o u, M D, P h. D. 
6 8 0 N La ke S h ore Dri ve, S uite 1 4 0 0 
C hica g o, I L 6 0 6 1 1 
P h o ne: ( 3 1 2) 5 0 3 - 4 7 9 8  
Fa x: ( 3 1 2) 9 0 8 - 9 5 8 8 
  
  
  
  
  
E-mail: l- h o u @ n ort h wester n.e d u 
 
 
Or g a niz ati o n:     
  
 
Va n der bilt U ni versit y   
I n vesti g at or ( St u d y C h air ):  
 
Rei d Ness, M D, M P H  
  
  
  
  
 
Gastr oe nter ol o gist  
  
  
  
  
 
6t h Fl o or Me dical Ce nter East  
  
  
  
  
  
Nas h ville, T N 3 7 2 3 2 
  
  
  
  
  
P h o ne: ( 6 1 5) 3 2 2- 0 1 2 8 
  
  
  
  
 
Fa x : ( 6 1 5) 3 4 3- 8 1 7 4 
  
  
  
  
  
E-mail: rei d. ness @ v u mc. or g   
 
 
Or g a niz ati o n:     
  
  
Va n der bilt U ni versit y  
I n vesti g at or ( St u d y P h ysici a n): 
Ris hi Nai k,  M D , M S CI 

 
 
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– 2 – 
  
  
  
  
 
Gastr oe nter ol o gist  
  
  
  
  
 
1 3 0 1 Me dical Ce nter Dri ve 
  
  
  
  
  
1 6 6 0 T V C 
  
  
  
  
  
Nas h ville, T N 3 7 2 3 2 
  
  
  
  
  
P h o ne: ( 6 1 5) 3 4 3- 0 1 0 9 
  
  
  
  
 
Fa x: ( 6 1 5)  3 4 3- 8 1 7 4 
  
  
  
  
  
E-mail: ris hi. d. nai k @ v u mc. or g  
 
 
 
Or g a niz ati o n:  
  
N ort h wester n U ni versit y 
St atistici a n:  
 
Mas ha K oc her gi ns k y, P h D  
 
 
6 8 0 N. La ke S h ore Dr., S uite 1 4 0 0 
 
  
C hica g o, I L 6 0 6 1 1  
 
 
Tel: ( 3 1 2) 5 0 3 - 4 2 2 4 
    
 
Fa x: ( 3 1 2) 9 0 8 - 9 5 8 8 
 
 
E mail: m k oc her g @ n ort h wester n.e d u   
  
 
 
 
I N D S p o ns or:   
N CI/ Di visi o n of Ca ncer Pre ve nti o n  
I N D #    
 
( E xe m pt) 
A ge nt(s)/ S u p plier : 
As p iri n / N CI D C P  
N CI C o ntr act #  
H H S N 2 6 1 2 2 0 1 2 0 0 0 3 5I  
Pr ot oc ol Versi o n D ate:  A u g ust 1 1, 2 0 2 2 
 
Pr ot oc ol Versi o n  
Versi o n 2. 1 9  
 
 
 
 
 
* N o partici pa nt accr ual occ urs at t his site 
 
 

 
 
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– 4 – 
Ta ble of C o nte nts  
C O V E R P A G E .............................................................................................................................................. 1 
S C H E M A  ...................................................................................................................................................... 3 
Ta ble of C o nte nts  .......................................................................................................................................... 4 
1.  
O BJ E C TI V E S  ..................................................................................................................................... 6 
1. 1  
Pri mar y O bje cti ves ...................................................................................................................................... 6 
1. 2  
Sec o n dar y O bjecti ves  .................................................................................................................................. 6 
1. 3  
E x pl orat or y O bjecti ves  ................................................................................................................................ 6 
2.  
B A C K G R O U N D ................................................................................................................................. 6 
2. 1  
St u d y Disease: C ol orectal Ca n cer  ................................................................................................................ 6 
2. 2  
St u d y A ge nt: As piri n  ................................................................................................................................... 7 
2. 3  
Rati o nale  ...................................................................................................................................................... 7 
3.  
S U M M A R Y O F S T U D Y P L A N  ........................................................................................................ 9 
4.  
P A R TI CI P A N T S E L E C TI O N  .......................................................................................................... 1 0 
4. 1  
I ncl usi o n Criteria ....................................................................................................................................... 1 0  
4. 2  
E xcl usi o n Criteria  ...................................................................................................................................... 1 0  
4. 3  
I ncl usi o n of W o me n a n d Mi n orities .......................................................................................................... 1 1  
4. 4  
Recr uit me nt a n d Rete nti o n Pla n  ................................................................................................................ 1 1  
5.  
A G E N T A D MI NI S T R A TI O N  .......................................................................................................... 1 2 
5. 1  
D ose Re gi me n a n d D ose Gr o u ps  ............................................................................................................... 1 2  
5. 2  
As piri n  A d mi nistrati o n  .............................................................................................................................. 1 2  
5. 3  
R u n -i n Pr oce d ures ..................................................................................................................................... 1 3  
5. 4  
C o ntrai n dicati o ns  ....................................................................................................................................... 1 3  
5. 5  
C o nc o mita nt Me dicati o ns  .......................................................................................................................... 1 3  
5. 6  
D ose M o dificati o n  ..................................................................................................................................... 1 3  
5. 7  
A d here nce/ C o m plia nce  .............................................................................................................................. 1 4  
6.  
P H A R M A C E U TI C A L I N F O R M A TI O N  ......................................................................................... 1 4 
6. 1  
As piri n (I N D:  
E xe m pt, I N D S p o ns or: N CI/ Di visi o n of Ca ncer Pre ve nti o n)  ............................... 1 4  
6. 2  
Re p orte d A d verse E ve nts a n d P ote ntial Ris ks  ........................................................................................... 1 4  
6. 3  
A vaila bilit y  ................................................................................................................................................ 1 4  
6. 4  
A ge nt Distri b uti o n  ..................................................................................................................................... 1 5  
6. 5  
A ge nt Acc o u nta bilit y  ................................................................................................................................. 1 5  
6. 6  
Pac ka gi n g a n d La beli n g  ............................................................................................................................. 1 5  
6. 7  
St ora ge  ....................................................................................................................................................... 1 5  
6. 8  
Re gistrati o n/ Ra n d o mizati o n  ...................................................................................................................... 1 6  
6. 9  
Bli n di n g a n d U n bli n di n g Met h o ds  ............................................................................................................. 1 6  
6. 1 0  A ge nt Destr ucti o n/ Dis p osal  ....................................................................................................................... 1 7  
7.  
C LI NI C A L E V A L U A TI O N S A N D P R O C E D U R E S  ...................................................................... 1 7 
7. 1  
Sc he d ule of E ve nts  .................................................................................................................................... 1 7  
7. 2  
Pre -st u d y E val uati o n .................................................................................................................................. 1 8  
7. 3  
E val uati o n D uri n g St u d y I nter ve nti o n  ....................................................................................................... 1 9  
7. 4  
E val uati o n at C o m pleti o n of St u d y I nter ve nti o n  ....................................................................................... 2 0  
7. 5  
P ost -i nter ve nti o n F oll o w-u p Peri o d  ........................................................................................................... 2 0  
7. 6  
Met h o ds f or Cli nical Pr oce d ures  ............................................................................................................... 2 0  
8.  
C RI T E RI A F O R E V A L U A TI O N A N D E N D P OI N T D E FI NI TI O N ............................................... 2 1 
8. 1  
Pri mar y E n d p oi nt  ....................................................................................................................................... 2 1  
8. 2  
Sec o n dar y a n d E x pl orat or y E n d p oi nts  ....................................................................................................... 2 2  
8. 3  
Off -A ge nt Criteria  ..................................................................................................................................... 2 2  
8. 4  
Of f-St u d y Criteria  ...................................................................................................................................... 2 3  
8. 5  
St u d y Ter mi nati o n  ..................................................................................................................................... 2 3  
9.  
C O R R E L A TI V E/ S P E CI A L S T U DI E S  ............................................................................................ 2 3 
1 0.  
S P E CI M E N M A N A G E M E N T  ......................................................................................................... 2 3 
1 0. 1  La b orat ories  ............................................................................................................................................... 2 3  
1 0. 2  C ollecti o n a n d Ha n dli n g Pr oce d ures  ......................................................................................................... 2 3  

 
 
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1 0. 3  S hi p pi n g I nstr ucti o ns  ................................................................................................................................. 2 7  
1 0 . 4 Tiss ue Ba n ki n g  .......................................................................................................................................... 2 8  
1 1.  
R E P O R TI N G A D V E R S E E V E N T S  ................................................................................................. 2 8 
1 1. 1  A d verse E ve nts  .......................................................................................................................................... 2 8  
1 1. 2  Ser i o us A d verse E ve nts ............................................................................................................................. 2 9  
1 2.  
S T U D Y M O NI T O RI N G  ................................................................................................................... 3 1 
1 2. 1  Data Ma na ge me nt  ...................................................................................................................................... 3 1  
1 2. 2  Case Re p ort F or ms  .................................................................................................................................... 3 1  
1 2. 3  S o urce D oc u me nts  ..................................................................................................................................... 3 1  
1 2. 4  Data a n d Safet y M o nit ori n g Pla n  ............................................................................................................... 3 1  
1 2. 5  S p o ns or or F D A M o nit ori n g  ...................................................................................................................... 3 1  
1 2. 6  Rec or d Rete nti o n  ....................................................................................................................................... 3 1  
1 2. 7  C o o perati ve Researc h a n d De vel o p me nt A gree me nt ( C R A D A)/ Cli nical Trials A gree me nt ( C T A)  ......... 3 2  
1 3.  
S T A TI S TI C A L C O N SI D E R A TI O N S  .............................................................................................. 3 2 
1 3. 1  St u d y Desi g n/ Descri pti o n  .......................................................................................................................... 3 2  
1 3. 2  Ra n d o mizati o n/ Stratificati o n  ..................................................................................................................... 3 2  
1 3. 3  Accr ual a n d Feasi bilit y  .............................................................................................................................. 3 2  
1 3. 4  Pri mar y O bjecti ve, E n d p oi nt(s), A nal ysis Pla n  ......................................................................................... 3 2  
1 3. 5  Sec o n dar y a n d E x pl orat or y O bjecti ves, E n d p oi nts, A nal ysis Pla ns  .......................................................... 3 4  
1 3. 6  Re p orti n g  a n d E xcl usi o ns .......................................................................................................................... 3 5  
1 3. 7  E val uati o n of T o xicit y  ............................................................................................................................... 3 5  
1 3. 8  E val uati o n of Res p o nse  ............................................................................................................................. 3 5  
1 3. 9  I nteri m A nal ysis......................................................................................................................................... 3 6  
1 3. 1 0  A ncillar y St u dies  ....................................................................................................................................... 3 6  
1 4.  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ................................................................ 3 6 
1 4. 1  F or m F D A 1 5 7 2  ......................................................................................................................................... 3 6  
1 4. 2  Ot her Re q uire d D oc u me nts  ....................................................................................................................... 3 6  
1 4. 3  I nstit uti o nal Re vie w B oar d A p pr o val ........................................................................................................ 3 7  
1 4. 4  I nf or me d C o nse nt ...................................................................................................................................... 3 7  
1 4. 5  S u b missi o n of Re g ulat or y D oc u me nts  ....................................................................................................... 3 7  
1 4. 6  Ot her  .......................................................................................................................................................... 3 8  
1 5.  
FI N A N CI N G, E X P E N S E S, A N D/ O R I N S U R A N C E  ...................................................................... 3 8 
R E F E R E N C E S  ........................................................................................................................................... 3 9 
C O N S E N T F O R M  ...................................................................................................................................... 4 3 
A p pe n di x A – Cli nic Visit I nstr ucti o ns  ....................................................................................................... 5 3 
A p pe n di x B – At - H o me St o ol C ollecti o n I nstr ucti o ns ............................................................................... 5 4 
A p pe n di x C – Baseli ne Cli nic Visit Q uesti o n n aire..................................................................................... 5 6 
A p pe n di x D – Partici pa nt Diar y .................................................................................................................. 6 4 
A p pe n di x E – S u g geste d State me nts f or Partici pa nt C o m m u nicati o ns  ...................................................... 6 4 
 
 

 
 
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1. 
O B J E C TI V E S  
 
1. 1 
Pri m ar y O bjecti ves   
  
T he pri mar y o bjecti ve of t he st u d y is t o test f or t he e q ui vale nc y of t he t w o as piri n sc he d ules. We are 
g oi n g t o  e val uate t he effects of a 3 - m o nt h i nter ve nti o n of c o nti n u o us vers us i nter mitte nt as piri n d osi n g 
(i.e. 3 2 5 m g dail y a n d 3 2 5 m g 3 wee ks o n/ 3 wee ks off) o n t he rati o of cell pr oliferati o n  ( Ki- 6 7) /a p o pt osis 
(B A X ) i n rectal bi o psies.  
 
1. 2 
Sec o n d ar y O bjecti ves   
 
T o e val uate t he effects of as piri n treat me nts o n:  
1) t he rati o of cell pr oliferati o n ( Ki-6 7)/a p o pt osis ( T U N E L) i n rectal bi o psies  
2) t he rati o of cell pr oliferati o n ( Ki-6 7)/ necr o pt osis ( p M L K L) i n rectal bi o psies  
3 ) fecal occ ult bl o o d test ( meas ures of a d verse e ve nts) as meas ure d b y st o ol sa m ples  
 
1. 3  
E x pl or at or y  O bjecti ves   
 
T o e val uate t he effects of as piri n treat me nts o n:  
 
1) C O X -2 i n rectal bi o psies  
             2) BA X  i n rectal bi o psies 
  
3) T R P M 7 i n rectal bi os pies 
4 ) j oi nt i n de x of C O X-2 wit h T R P M 7 e x pressi o n i n rectal bi o psies;  
  
5) j oi nt i n de x of T R P M 7 wit h B A X i n rectal bi o psies; 
  
6) met h ylati o n assa ys usi n g t he Met h ylati o n E PI C Bea d C hi p t o i de ntif y met h ylati o n bi o mar kers  
  
     i n ge nes (i.e. C D K N 2 A (cell c ycle re g ulati o n), M G M T ( D N A re pair), D A P K 1(a p o pt osis),   
   
                  C D H 1(cell i n vasi o n), W N T 1 6 ( W nt pat h wa y) a n d R A S S F 1 ( R A S si g nali n g)) i n v ol ve d i n   
 
                  c ol orectal carci n o ge nesis, a n d ot her e pi ge n o me- wi de met h ylati o n bi o mar kers as meas ure d i n    
                  rectal bi o psies; 
  
7) meta ge n o mics a nal ysis t o meas ure a b u n da nce of E. c oli a n d F us o bacteri u m a n d ot her     
 
  
     micr o bi ota i n rectal s wa bs 
 
2. 
B A C K G R O U N D 
 
2. 1 
St u d y Dise ase : C ol orect al C a ncer 
 
A p pr o xi matel y 1 i n 1 8 i n di vi d uals will de vel o p C R C o ver t heir lifeti me a n d 4 0 %  will die  wit hi n 5 years 
of dia g n osis, mai nl y d ue t o dia g n osis at a late sta ge 1; 2. Re m o val of c ol orectal a de n o ma via c ol o n osc o p y 
has bee n c o nsi dere d t he m ost effecti ve strate g y t o re d uce b ot h  i nci de nce a n d m ortalit y of C R C.  H o we ver, 
rece nt re p orts f o u n d t hat s uc h a n a p pr oac h is m ore si g nifica ntl y li n ke d t o re d uce d deat hs fr o m t u m ors i n 
t he dist al si de of t he c ol o n t h a n fr o m t he pr oxi m al si de 3; 4. I n as ma n y as 2 4 % of cases, s nare p ol y pect o m y 
of e x o p h ytic lesi o ns di d n ot i n hi bit pr o gressi o n t o carci n o ma 5. F urt her m ore, a n n ual rec urre nce rates i n 
patie nts wit h s mall a n d a d va nce d a de n o mas were as hi g h as 1 9. 3 % a n d 2 2. 9 %, res pecti vel y 6. M ost 
i m p orta ntl y, C R C still re mai ns t he 4t h m ost c o m m o n i nci de nt ca ncer a n d t he 2 n d m ost c o m m o n ca use of 
ca ncer deat h i n t he U nite d States 7; 8. T h us, i n a d diti o n  t o c ol o n osc o py, it is critic al t o devel o p n ovel 
pri m ary a n d/ or sec o n d ary preve ntive str ate gies f or C R C , p artic ul arly pr oxi m al c ol o n c a ncer.  
A n u m ber of lar ge i nitiati ves o ver t he past deca de ha ve ge nerate d disa p p oi nti n g res ults f or t he pre ve nti o n 
of c ol o rectal ca ncer usi n g ve geta bles, fi ber9, car ote n oi ds9, vita mi ns E a n d C1 0, folic aci d 1 1- 1 3, a n d calci u m 
a n d/ or vita mi n D 1 4; 1 5.  
 

 
 
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2. 2 
St u d y A ge nt : As piri n 
 
E pi de mi ol o gic st u dies a n d ra n d o mize d trials ha ve relati vel y c o nsiste ntl y s h o w n t hat l o n g- ter m use of 
n o nster oi dal a nti-i nfla m mat or y dr u gs ( N S AI Ds), i ncl u di n g as piri n a n d n o n- as piri n N S AI Ds, a n d C O X - 2 
i n hi bit ors, is ass ociate d wit h a re d uce d ris k of c ol orectal ca ncer a n d a de n o ma rec urre nce 1 6- 2 1.  Selecti ve 
C O X - 2 i n hi bit ors were de vel o pe d t o a v oi d t he p ote ntial a d verse e ve nts of C O X-1 i n hi biti o n 2 2. H o we ver, 
l o n g-ter m use of C O X- 2 i n hi bit ors was s h o w n t o ha ve se vere si de effects of car di o vasc ular disease 
(C V D )2 2.  I n a d diti o n t o C O X-2 i n hi bit ors, l o n g -ter m use of n o n-as piri n N S AI D S ca uses se vere si de 
effects.  O n J ul y 9 t h 2 0 1 5, t he U. S. F o o d a n d Dr u g a d mi nistrati o n ( F D A) has stre n gt he ne d a n e xisti n g 
la bel war ni n g t hat n o n-as piri n N S AI Ds i ncrease t he ris k of C V D e ve nts 
htt p:// w w w.f da. g o v/ Dr u gs/ Dr u g Safet y/ uc m 4 5 1 8 0 0. ht m .    
 
2. 3  
R ati o n ale 
 
Effic ac y:  U nl ike C O X - 2 i n hi bit ors a n d n o n-as piri n N S AI Ds w hic h ma y lea d t o a d verse C V D e ve nts, 
as piri n has bee n c o m m o nl y use d f or t he pre ve nti o n of c hr o nic C V diseases 2 3. I n 1 9 8 8, use of as piri n was 
first f o u n d t o be li n ke d t o a re d uce d ris k of C R C 2 4. S u bse q ue ntl y, ma n y e pi de mi ol o gic st u dies ha ve 
li n ke d as piri n use t o a l o wer ris k of C R C a n d c ol orectal a de n o ma2 5; 2 6. I n a p o ole d a nal ysis of 5 
ra n d o mize d trials f or t he pri mar y pre ve nti o n of C V diseases, dail y use of as piri n at d oses of 7 5 t o 1 2 0 0  
m g f or at least 5 years si g nifica ntl y re d uce d m ortalit y d ue t o C R C b y 5 9 %, partic ularl y f or pr o xi mal 
c ol o n ca nc er 2 7. F urt her m ore, cli nical trials f o u n d use of as piri n at d oses of 8 1 t o 3 2 5  m g per da y re d uce d 
a de n o ma rec urre nce b y 1 7 % 2 8; 2 9. I n a d diti o n, use of as piri n at 6 0 0 m g per da y re d uce d ris k of C R C 
a m o n g patie nts wit h here ditar y c ol orectal ne o plasia 2 3. H o we ver, t w o ra n d o mize d trials (i.e. t he P h ysicia n 
Healt h St u d y ( P H S) 3 0, usi n g 3 2 5 m g as piri n e ver y ot her da y, a n d W o me n’s Healt h St u d y ( W HS) 3 1, usi n g 
1 0 0 m g as piri n e ver y ot her d a y ) di d n ot fi n d a be neficial effect. I ns ufficie nt d ose a n d s h ort f oll o w-u p i n 
t he t w o trials ma y be t he pri mar y reas o ns2 3; 2 6.  I nterestin gl y, alt h o u g h t he W H S di d n ot s h o w a re d ucti o n 
i n ris k of C R C o ver t he first 1 0- year f oll o w- u p3 1, t he differe nce e mer ge d after 1 0 years3 2. After t he 
e xte n de d 8-year f oll o w - u p, t he ris k of C R C was re d uce d b y 2 0 % i n t he as piri n ar m, particularl y f or 
pr o xi mal c ol o n ca ncer 3 2 ( See m ore details i n t he Ris k- be nefit c o nsi derati o n secti o n).  I n a re vie w b y C ha n 
et al, it is c o ncl u de d after c o m bi ni n g e xte nsi ve data fr o m b ot h o bser vati o nal st u dies a n d ra n d o mize d 
trials, “t here is ver y str o n g e vi de nce t hat as piri n i n d oses as l o w as 3 2 5 m g/ da y re d uces C R C ris k” 2 3.    
 
Ris k -b e nefit c o nsi der ati o n: T h us, as piri n is a ver y pr o misi n g c he m o pre ve nti ve a ge nt f or t he pre ve nti o n 
of C R C, partic ularl y pr o xi mal c ol o n ca ncer, w hic h is less effecti vel y pre ve nte d b y c ol o n osc o p y. F urt her, 
c o m pare d t o C O X- 2 i n hi bit ors a n d ot her N S AI Ds, as piri n d oes n ot ha ve se vere C V D si de effects. I nstea d, 
as piri n was c o m m o nl y use d f or t he pre ve nti o n of C V disease 2 3. H o we ver, as state d b y a rece nt 
c o m me ntar y, bef ore as piri n is rea d y f or pri me ti me, “t he o pti mal d osi n g, fre q ue nc y a n d d urati o n a n d ris k -
be nefit iss ue ha ve n ot bee n yet f ull y a d dresse d” 3 3. T he t y pical dail y d oses of as piri n use d f or t he 
pre ve nti o n of C V D are fr o m 7 5 t o 3 2 5 m g w hic h ha ve bee n s h o w n i n pre vi o us ra n d o mize d trials t o ha ve 
si milar effects f or C R C pre ve nti o n as hi g h d ose as piri n (i.e. 1 2 0 0 m g/ da y) 2 3. H o we ver, l o n g-ter m use of 
eit her e nteric -c oate d or b uffere d as piri n at l o w d oses of fr o m 7 5 t o 3 2 5 m g has bee n li n ke d t o a n 
i ncrease d ris k of u p per a n d l o wer gastr oi ntesti nal c o m plicati o ns (i.e. d u o de nal a n d gastric ulcers a n d 
gastr oi ntesti nal blee di n g) 3 4. D ue t o t he clear be nefit of re d uci n g C V D, it is o b vi o us t hat a m o n g t h ose at 
ris k of C V D, t he be nefit of as piri n s ur passe d t he blee di n g ris k2 3. Use of as piri n is als o j ustifia ble a m o n g 
patie nts wit h here ditar y c ol orectal ne o plasia 2 3. H o we ver, t he U. S. Pre ve nti ve Ser vices tas k f orce 
rec o m me n de d a gai nst t he r o uti ne use of as piri n t o pre ve nt C R C i n i n di vi d uals at a vera ge ris k of C R C3 5. 
A meta -a nal ysis of 2 2 cli nical trials f o u n d t hat l o w d oses of as piri n i ncrease t he ris k of maj or blee di n g b y 
a b o ut 7 0 % wit h n o differe nce bet wee n 7 5- 1 6 2. 5 m g dail y vers us > 1 6 2. 5- 3 2 5 m g dail y 3 6. H o we ver, s o me 
st u dies i n dicate d gastr oi ntesti nal blee di n g was d ose-relate d with d oses bet wee n 3 0 0 a n d 3 2 5 m g/ da y 
ha vi n g hi g her ris k t ha n t h ose bet wee n 7 5 a n d 1 6 2. 5 m g/ da y 2 3; 2 7; 3 7- 3 9.  I n a d diti o n t o dail y use, as we 
me nti o ne d pre vi o usl y, t w o ra n d o mize d trials ( W H S a n d P H S) w hic h use d as piri n e ver y ot her da y di d n ot 

 
 
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fi n d a n y effects i n i nitial re p orts.  After 8- year e xte n de d f oll o w-u p be y o n d t he i nitial 1 0 - year f oll o w- u p, 
pr o misi n g be nefits were f o u n d i n t he W H S ar m usi n g 1 0 0 m g as piri n e ver y ot her da y 3 2.  I n t he W H S, t he 
relati ve ris k was 1. 1 4 ( 9 5 % CI: 1. 0 6 t o 1. 2 2) f or gastr oi ntesti nal blee di n g a n d 1. 1 7 ( 9 5 % CI: 1. 0 9 t o 1. 2 7) 
f or pe ptic ulcers i n t he as piri n ar m 3 2, w hic h were l o wer t ha n t he R Rs o bser ve d f or dail y use of as piri n3 6. 
O n t he ot her ha n d, it is li kel y t hat it ta kes l o n ger t o see a be neficial effect c o m pare d t o 5- year wi n d o w f or 
dail y use of as piri n 2 7.  
 
I n a d diti o n t o usi n g as piri n e ver y ot her da y, as me nti o ne d i n t he N CI T O R F P B B- 2 0 1 5, pre vi o us a ni mal 
st u dies ha ve e xa mi ne d ot her i nter mitte nt d osi n g strate gies i n carci n o ge nesis m o dels 4 0. Ver y rece ntl y, a 
D C P -s p o ns ore d r o de nt st u d y f o u n d as piri n deli vere d o n a n i nter mitte nt sc he d ule (i.e. 3 wee ks o n 
f oll o we d b y 3 wee ks off) ha d a n e q uall y hi g h efficac y i n pre ve nti n g c ol o n ca ncer wit h as piri n deli vere d 
c o nti n u o usl y.  T his is a n o vel strate g y. If c o nfir me d i n h u ma n st u dies, it ma y be a ble t o mi ni mize t he 
a d verse e ve nt a n d si m ulta ne o usl y ma xi mize t he hi g h efficac y.  
 
A p o pt osis  M o u nt in g e vi de nce fr o m i n vitr o, i n viv o a n d h u ma n st u dies i n dicates ac q uire d resista nce t o 
a p o pt osis is o ne hall mar k f or al m ost all ca ncer t y pes 4 1.  T he mai nte na nce of n or mal c ol orectal cr y pt 
arc hitect ure is base d o n t he bala nce bet wee n t he a p o pt osis at t he base of cr y pts a n d t he pr oliferati o n at t he 
t o p 4 2. T he tr a nsf or m ati o n fr o m n or m al c ol orect al e pit heli u m t o c arci n o m a is acc o m p a nie d by a 
pr o gressive resist a nce t o a p o pt osis  4 3. Dr. Sa n dler’s gr o u p f o u n d i n a pr os pecti ve st u d y t hat s u bjects wit h 
t he hi g hest tertile le vel of ap o pt osis i n n or mal rectal m uc osa ha d a 7 0 % re d ucti o n i n ris k of f ut ure 
c ol orectal a de n o ma, c o m pare d t o t he l o west tertile le vel of a p o pt osis 4 4. Ter mi nal de o x yri b o n ucle oti d yl  
tra nsferase– me diate d d U T P nic k e n d la beli n g ( T U N E L) a n d B A X  e x pressi o n 4 5 was use d t o meas ure 
a p o pt osis.  
 
Bi o m ar ker f or pr olifer ati o n  ( Ki-6 7) Cell pr oliferati o n is a n ot her critical fact or i n t u m ori ge nesis 4 6. As 
we me nti o ne d earlier, t he bala nce bet wee n a p o pt osis a n d pr oliferati o n mai ntai ns t he n or mal c ol orectal 
cr y pt arc hitect ure 4 2. Cell pr oliferati o n i n de x has bee n use d i n ma n y pre vi o us i nter ve nti o n trials t o assess 
t he effects of c he m o pre ve nti o n a ge nts 4 7 w hile Ki - 6 7 is o ne of t he m ost fre q ue ntl y use d nat ural pr otei ns 
ass ociate d wit h pr ol iferati o n 4 6. We ha ve i de ntifie d o ne p u blis he d st u d y w hic h f o u n d as piri n treat me nt 
si g nifica ntl y re d uce d cell pr oliferati o n i n y o u n g pe o ple wit h fa milial a de n o mat o us p ol y p osis c o m pare d t o 
place b o ar m 4 8. 
 
T heref ore, we h y p ot hesize  t hat 3 2 5 m g as piri n deli vere d 3 wee ks o n/ 3 wee ks off has t he sa me efficac y i n 
i ncreasi n g c ol orectal a p o pt osis, re d uci n g c ol orectal cell pr oliferati o n a n d, i n t ur n, decreasi n g  cell 
pr oliferati o n/a p o pt osis rati o as as piri n deli vere d 3 2 5 m g dail y, b ut c o nfer s re d uce d si de-effect, i.e. 
gastr oi ntesti nal blee di n g.  
 
B A X  e x pressi o n reflects earlier si g nali n g of a p o pt osis a n d, t h us, it is a m ore se nsiti ve bi o mar ker of 
a p o pt osis t ha n T U N E L. Necr o pt osis is a ne w pat h wa y f or pr o gra m mi n g cell deat h. C ell pr oliferati o n/ 
B A X  rati o will be use d as a pri mar y e n d p oi nt a n d cell pr oliferati o n /T U N E L rati o a n d cell 
pr oliferati o n/ necr o pt osis rati o will be sec o n dar y e n d p oi nts. 
 
I n c o ntrast t o a p o pt osis, w hic h d oes n ot i n d uce i nfla m mati o n4 9, necr o pt osis, a pr o gra m me d necr osis 
pat h wa y disc o vere d o ver t he past deca de 4 9, 5 0, elicits r o b ust a da pti ve i m m u ne res p o nses b y i n d uci n g t he 
i nfla m mat or y res p o nse casca de a n d releasi n g da ma ge-ass ociate d m olec ular patter ns a gai nst bacterial 
i nfecti o n5 1, 5 2. I n a rece nt l o n git u di nal st u d y, we f o u n d necr o pt osis a n d i nfla m mati o n pla ys a ke y r ole i n 
c ol orectal carci n o ge nesis. C o m p osite i n de x sc ores of necr o pt osis (e. g. Tra nsie nt rece pt or p ote ntial 
melastati n 7 ( T R P M 7)) wit h i nfla m mati o n (i.e. C O X - 2) or a p o pt osis (i.e. B A X) ca n i m pr o ve t he 
pre dicti o n of metac hr o n o us p ol y p/a de n o ma ris k. I ncrease d C O X- 2 i nte nsit y i n t he e pit heli u m was see n 
d uri n g carci n o ge nesis ( Ptre n d = 0. 0 2) a n d was si g nifica ntl y ass ociate d wit h a n i ncrease d ris k of 
metac hr o n o us p ol y p ( O R = 5. 1 2, 9 5 % CI: 1. 5 0- 1 7. 4 5, Ptre n d = 0. 0 0 8), a n d f or b ot h metac hr o n o us 
a de n o ma/serrate d p ol y p. Hi g her e x pressi o n of T R P M 7 was mar gi nall y ass ociate d wit h ris k of 

 
 
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metac hr o n o us a de n o ma/serrate d p ol y p i n a d ose -res p o nse ma n ner. C o m bi ne d c o m p osite i n de x sc ores of 
necr o pt osis wit h i nfla m mati o n or a p o pt osis usi n g pri nci pal c o m p o ne nt a nal ysis were str o n gl y ass ociate d 
wit h a 4 - t o 1 7-f ol d i ncrease d ris k of metac hr o n o us a de n o ma/serrate d p ol y p. We ha ve prese nte d t he 
res ults i n 2 0 2 2 A A C R A n n ual Meeti n g. T he ma n uscri pt will be s u b mitte d f or p u blicati o n s h ortl y. 
T heref ore, we pr o p ose t o a d d 1) C O X -2 e x pressi o n i n rectal bi o ps y ; 2) B A X i n rectal bi o psies; 3 ) 
T R P M 7 i n rectal bi o psies; 4 ) j oi nt i n de x of C O X- 2 wit h T R P M 7 e x pressi o n i n rectal bi o psies; a n d 5) 
j oi nt i n de x of T R P M 7 wit h B A X i n rectal bi o psies as e x pl orat or y e n d p oi nts.  
 
 
3. 
S U M M A R Y O F S T U D Y P L A N  
 
Desi g n  
Eli gi ble partici pa nts f or t his i nter ve nti o n st u d y will be c ol orectal a de n o ma patie nts dia g n ose d at Va n der bilt 
U ni versit y Me dical Ce nter , wit h a t hree-ar m P hase IIa ra n d o mize d place b o -c o ntr olle d trial desi g n.  T he 
t hree ar ms i ncl u de t w o treat me nt ar ms a n d one place b o ar m. Treat me nt 1 will be 3 2 5 m g as piri n orall y 
per da y f or 1 2 wee ks.  Treat me nt 2 will be 3 2 5 m g as piri n orall y o n a n i nter mitte nt, “ 3- wee k s acti ve/ 3-
wee k s place b o” sc he d ule f or 3 m o nt hs. We will ra n d o mize a t otal of 9 0 partici pa nts i nt o t w o treat me nt 
ar ms wit h 4 0 partici pa nts per ar m a n d place b o ar m wit h 1 0 partici pa nts. We a ntici pate at least 7 2 
p arti ci p a nts will c o m pl et e t h e st u d y ( wit h a 2 0 % dr o p -o ut r at e d u e t o b ot h n o n -c o m pli a n c e a n d 
a d v ers e e v e nt s); we ar e b uil di n g i n a hi g h er attriti o n r at e t h a n o ur P P C C T tri al of m a g n esi u m 
s u p pl e m e nt ati o n b e c a us e we e x p e ct t h er e will b e m or e a d v ers e e v e nts r el at e d t o as piri n us e t h a n wit h 
m a g n esi u m s u p pl e m e nt ati o n .  
 
Re c r uit m e nt a n d S c r e e ni n g  
Partici pa nts will be recr uite d fr o m t he Va n der bilt electr o nic me dical rec or ds, a n d fr o m t he P P C C T 
recr uit me nt p o ol.  St u d y gastr oe nter ol o gists will perf or m a me dica l c hart re vie w, a n d partici pa nts w h o are 
p ote ntiall y eli gi ble will be i n vite d f or Cli nic Vis it 1 (scree ni n g).   
 
Cli nic Visits  
 
Cli nic Visit 1: After t he c o nse nt is si g ne d, scree ni n g pr oce d ures are perf or me d t o deter mi ne eli gi bilit y, 
i ncl u di n g bl o o d, st o ol, a n d pre g na nc y tests.  A me dical hist or y, c o nc o mita nt me dicati o ns re vie w, a n d 
p h ysical i nclu di n g vital si g ns a n d E C O G perf or ma nce stat us  will als o be perf or me d.  A n o pti o nal uri ne 
sa m ple is c ollecte d f or f ut ure researc h.  U p o n fi nal deter mi nati o n of eli gi bilit y, t he st u d y tea m will s u b mit 
t he re gistrati o n i nf or mati o n t hr o u g h t he st u d y e C R F data base. Partici pa nt will be ra n d o mize d acc or di n g t o 
Secti o n 6. 8 pr oce d ures. 
 
Cli nic Visit 2 ( wit hi n 6 wee ks of Cli nic Visit 1 ): Baseli ne tests are perf or me d, i ncl u di n g t he F o o d 
Fre q ue nc y Q uesti o n naire a n d Baseli ne Cli nic Visit Q uesti o n naire, c o nc o mita nt me dicati o ns re vie w, a n d 
vital si g ns .  A bl o o d a n d st o ol sa m ple are c ollecte d f or cli nical m o nit ori n g.  Baseli ne s peci me ns c ollecte d 
i ncl u de rectal s wa bs, a n d bi o psies.  A n ot her o pti o nal uri ne sa m ple is c ollecte d.  T hree b ottles of st u d y 
me dicati o n are dis pe nse d .   
 
Cli nic Visit 3 ( 9 wee ks after starti n g st u d y a ge nt): C o nc o mita nt me dicati o ns are re vie we d a n d vital si g ns 
are perf or me d.  A bl o o d a n d st o ol sa m ple are c ollecte d f or cli nical m o nit ori n g.  Mi d -st u d y s peci me ns 
c ollecte d i ncl u de rectal s wa bs, a n d bi o psies.  A n o pti o nal uri ne sa m ple is c ollecte d.  U n use d pills are 
c ollecte d a n d c o u nte d.  T he f o urt h b ottle of st u d y me diati o n is dispe nse d.   
 
Cli nic Visit 4 ( 1 2 wee ks after starti n g st u d y a ge nt): C o nc o mita nt me dicati o ns are re vie we d a n d vital si g ns 
are perf or me d.  A bl o o d a n d st o ol sa m ple are c ollecte d f or cli nical m o nit ori n g.  P ost -st u d y s peci me ns 
c ollecte d i ncl u de rectal s wa bs, a n d bi o psies.  A n o pti o nal uri ne sa m ple is c ollecte d.  U n use d pills are 

 
 
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c ollecte d a n d c o u nte d.   
 
 
4. 
P A R TI CI P A N T S E L E C TI O N  
 
4. 1 
I ncl usi o n Criteri a 
 
4. 1. 1  
Dia g n osis of c ol orectal a de n o ma  of a n y gra de . 
 
4. 1. 2  
A ge ≥1 8 years. Beca use n o d osi n g or a d verse e ve nt ( A E) data are c urre ntl y a vaila ble o n t he use 
of a s piri n i n partici pa nts < 1 8 years of a ge, c hil dre n are e xcl u de d fr o m t his st u d y b ut will be eli gi ble f or 
f ut ure pe diatric trials, if a p plica ble. 
 
4. 1. 3  
E C O G perf or ma nce stat us ≤1 ( Kar n ofs k y ≥7 0 %) 
 
4. 1. 4   
Partici pa nts m ust ha ve n or mal or ga n a n d marr o w f u ncti o n as defi ne d bel o w: 
  
Le u k oc ytes  
 
≥3, 0 0 0/ micr oliter  
 
A bs ol ute ne utr o p hil c o u nt  
≥1, 5 0 0/ micr oliter  
 
Platelets   
 
≥1 5 0, 0 0 0 / micr oliter 
 
T otal bilir u bi n    
≤1. 5 x i nstit uti o nal U L N  
 
A S T ( S G O T)/ A L T ( S G P T)  
≤1. 5 x i nstit uti o nal U L N 
 
Creati ni ne   
 
≤1. 5 x i nstit uti o nal U L N  
  
Bl o o d he m o gl o bi n 
≥1 2. 0 g/ d L 
 
Al kali ne p h os p hatase  
≤1. 5 x i nstit uti o nal U L N 
  
Bl o o d urea nitr o ge n ( B U N) 
≤4 0 m g/ d L 
 
e G F R    
 
≥4 5 m L/ mi n  
 
4. 1. 5 
Ne gati ve fecal occ ult bl o o d test.  
 
4. 1. 6 
T he effects of as piri n o n t he de vel o pi n g h u ma n fet us at t he rec o m me n de d t hera pe utic d ose are 
u n k n o w n. F or t his reas o n, w o me n of c hil d- beari n g p ote ntial a n d me n m ust a gree t o use a de q uate 
c o ntrace pti o n ( h or m o nal or barrier met h o d of birt h c o ntr ol; a bsti ne nce) pri or t o st u d y e ntr y a n d f or t he 
d urati o n of st u d y partici pati o n. S h o ul d a w o ma n bec o me pre g na nt or s us pect s he is pre g na nt w hile 
partici pati n g i n t his st u d y, s he s h o ul d i nf or m her st u d y p h ysicia n i m me diatel y. 
 
4. 1. 7 A bilit y t o u n dersta n d a n d t he willi n g ness t o si g n a writte n i nf or me d c o nse nt d oc u me nt. 
 
4. 2 
E xcl usi o n Criteri a  
 
4. 2. 1  
C urre nt ( wit hi n t hree wee ks of ra n d o mizati o n) or pla n ne d use d uri n g t he st u d y i nter ve nti o n of t he 
f oll o wi n g: 
1.  As piri n, ot her N S AI Ds, or C O X- 2 i n hi bit ors;  
2.  A ntic oa g ula nts, a nti platelet a ge nts,  or  c ortic oster oi ds;  
3.  Gi n g k o 
4.  Et ha n ol c o ns u m pti o n > 1 sta n dar d dri n ks/ da y f or w o me n, or > 2 sta n dar d dri n ks/ da y f or me n.  
5.  M et h otre xate ( M T X); 
St u d y partici pa nts will be i nstr ucte d t o use T yle n ol or s o me ot her n o n- e xcl u de d a ge nt t o treat c o m m o n 
ail me nts (i.e. hea dac he/ mi n or ac hes a n d pai ns).   
 

 
 
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4. 2. 2 
Hist or y of  
1.  A n y i n vasi ve mali g na nc y wit hi n t he past 2 years, wit h t he e xce pti o n of n o n- mela n o ma s ki n 
ca ncer.  
2.  C hr o nic re nal diseases o r li ver cirr h osis;  
3.  Diseases s uc h as a ne mia, pe ptic ulcer, gastr oi ntesti nal blee di n g, acti ve c olitis a n d i nfla m mat or y 
b o wel disease;  
4.  H e m orr ha gic str o ke or u nc o ntr olle d h y perte nsi o n. 
 
4. 2. 3  
Partici pa nts ma y n ot be recei vi n g a n y ot her i n vesti gati o nal a ge nts. 
 
4. 2. 4 
Hist or y of aller gic reacti o ns or i nt olera nce attri b ute d t o as piri n or c o m p o u n ds of si milar c he mical 
or bi ol o gic c o m p ositi o n . 
 
4. 2. 5  
U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, o n g oi n g or acti ve i nfecti o n, 
s y m pt o matic c o n gesti ve heart fail ure, u nsta ble a n gi na pect oris, car diac arr h yt h mia, or ps yc hiatric ill ness 
t hat w o ul d li mit c o m plia nce wit h st u d y re q uire me nts. 
 
4. 2. 6  
W o me n w h o are pre g na nt or breastfee di n g.  Pre g na nt w o me n are e xcl u de d fr o m t hi s st u d y 
beca use as piri n has t he p ote ntial f or a b ortifacie nt effects. Beca use t here is a n u n k n o w n b ut p ote ntial ris k 
f or A Es i n n ursi n g i nfa nts sec o n dar y t o treat me nt of t he m ot her wit h as piri n, breastfee di n g s h o ul d be 
disc o nti n ue d if t he m ot her is treate d wit h as piri n. 
 
4. 3 
I ncl usi o n of W o me n a n d Mi n orities 
 
B ot h me n a n d w o me n a n d me m bers of all races a n d et h nic gr o u ps are eli gi ble f or t his trial.  
 
4. 4 
Recr uit m e nt a n d Rete nti o n Pl a n  
 
Recr uit me nt P o ol  of n o n -Afric a n A meric a ns  
P P C C T ( Pers o n alize d Pre ve nti o n of C ol orect al C a ncer Tri al) is a n o n g oi n g R 0 1 ra n d o mize d trial 
f u n de d b y NCI ( R 0 1 C A 1 4 9 6 3 3; Dai & Y u, PI). T he trial was c o n d ucte d a m o n g 2 4 0 c ol orectal a de n o ma 
p ol y p patie nts wit h calci u m/ ma g nesi u m ( Ca/ M g) i nta ke rati o ≥2. 6 0 . We teste d 1)  if re d uci n g t he Ca/ M g 
rati o t o a b o ut 2. 2 t hr o u g h M g s u p ple me ntati o n affects carci n o ge nesis bi o mar kers i n rectal bi o psies; a n d 
2)  if t he effects differ b y T R P M 7 ge n ot y pe. T he P P C C T has e nr olle d 2 5 0 partici pa nts, wit h t he ori gi nal 
e nr oll me nt g oal of 2 4 0.  2 3 9 of t he m c o m plete d t he st u d y  ( dr o p o ut rate 4. 4 %). 
O ver t he past fi ve years, we ha ve s uccessf ull y esta blis he d a ca n di date p o ol of patie nts dia g n ose d wit h 
c ol or ectal a de n o ma d uri n g t he recr uit me nt pr ocess f or t he P P C C T. A n electr o nic me dical rec or d ( E M R) -
b ase d a p pr oac h was use d f or i nitial scree ni n g. Base d o n o ver 1 0, 0 0 0 scree ne d c ol orectal p ol y p patie nts 
dia g n ose d at Va n der bilt U ni versit y Me dical Ce nter  b y usi n g t he Va n der bilt Cli nical a n d Tra nslati o nal 
Scie nce A war ds ( C T S A) researc h data base, we ha ve i de n tifie d a p pr o xi matel y 1, 0 3 3 c ol orectal p ol y p 
patie nts w h o d o nate d a D N A sa m ple a n d are willi n g t o partici pate i n f ut ure st u dies ; of t hese, 7 3 9 ha ve a 
d oc u me nte d c ol orectal a de n o ma.  T he o n g oi n g N CI-f u n de d R 0 1 ra n d o mize d trial “ Fatt y aci d desat urase 
acti vit y, fis h oil a n d c ol orectal ca ncer c he m o pre ve nti o n” ( R 0 1: C A 1 6 0 9 3 8; PI: M urff) has use d t he 
P P C C T recr uit me nt t o ol t o s uccessf ull y c o m plete t he e nr oll me nt of 1 5 0 c ol orectal a de n o ma patie nts.  
 
T h us t h e recr uit me nt p o ol esta blis he d base d o n t he P P C C T has laid a s oli d i nfrastr uct ure f or t he pr o p ose d 
st u d y.  Dr. S hr u bs ole has directe d t he S ur ve y Researc h S hare d Res o urce ( S R S R ), w hic h has c o n d ucte d 
recr uit me nt a n d data c ollecti o n a n d ma na ge d t he data f or t he P P C C T. T h us, Dr. S hr u bs ole a n d S R S R are 
ver y fa mili ar wit h t he st u d y p o p ulati o n a n d rele va nt data. I n t he pr o p ose d st u d y, Dr Dai, t he st u d y PI, a n d 
t he st u d y c o or di nat or will cl osel y w or k wit h Dr. S hr u bs ole a n d t he S R S R  f or partici pa nt recr uit me nt, all 
c o m m u nicati o ns wit h p ote ntial partici pa nts, q uesti o n na ire a d mi nistrati o n, a n d data base mai nte na nce. 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 1 2 – 
 
Recr uit me nt P o ol of Afric a n A meric a ns  
T here are n o Af rica n A merica ns i n o ur S R S R data base.  T he P P C C T recr uit me nt p o ol was f u n de d t o 
e xcl u de Africa n A merica ns beca use Africa n A merica ns are n ot p ol y m or p hic at t he ge netic l oc us t hat is a 
maj or ai m of t he pare nt st u d y.  T heref ore, t o a d d A A s u bjects t o t he p o ol, t he S R S R staff will scree n at 
least 6 0 0 Africa n A merica n patie nts dia g n ose d wit h a c ol orectal a de n o ma at Va n der bilt U ni versit y, as 
t he y di d pre vi o usl y f or t he P P C C T.  
 
Prescree ni n g  
Va n der bilt h os pital’s electr o nic me dical rec or d ( E M R) ma y n ot ha ve t he i nf or mati o n f or t he o ver -t he-
co u nter use of as piri n or ot her N S AI D use or ma y n ot ha ve t he m ost rece ntl y u p date d i nf or mati o n. Als o, 
we pre dict a  fair n u m ber of i n di vi d uals ma y ref use t o partici pate or ha ve m o ve d. I n or der t o e xcl u de t h ose 
w h o are re g ularl y ta ki n g N S AI Ds (see t he e xcl usi o n criteria), t he S R S R  will c o n d uct tele p h o ne 
scree ni n gs. We esti mate o ver 5 0 % of t he st u d y p o p ulati o n is re g ularl y ta ki n g N S AI Ds. Pote ntial 
partici pa nts will be maile d a n i ntr o d uct or y letter f oll o we d b y a tele p h o ne call a b o ut 1 wee k later. T he 
S R S R staff will place calls d uri n g da yti me, a n d o n e ve ni n gs a n d wee ke n ds. F or i n di vi d uals w h o re mai n 
eli gi ble after t he tele p h o ne prescree ni n g, i n scree ni n g 1, o ur researc h n urse will re vie w t heir E M R t o 
f urt her c o nfir m eli gi bilit y. We esti mate t hat a b o ut 2 2 2, i ncl u di n g 2 4 Africa n A merica ns, will be willi n g 
a n d eli gi ble f or t he st u d y. Fi nall y, o ur gastr oe nter ol o gists wil l c o n d uct f urt her re vie w, l o o ki n g t hr o u g h 
pre vi o us c ol o n osc o pies t o c o nfir m a dia g n osis of c ol orectal a de n o mas, re vie wi n g i ncl usi o n/e xcl usi o n 
criteria, a n d re vie wi n g  safet y pr ofiles. We esti mate t hat a b o ut 1 8 0 will partici pate i n ne xt p hase, i.e. 
scree ni n g visit 1.   
 
5. 
A G E N T  A D MI NI S T R A TI O N 
 
I nter ve nti o n will be a d mi nistere d o n a n o ut p atie nt basi s. Re p orte d A Es a n d p ote ntial ris ks are descri be d 
i n Secti o n 6. 2.  
 
5. 1 
D ose Re gi m e n a n d D ose Gr o u ps  
 
T he w h ole i nter ve nti o n peri o d lasts f or 1 2 wee ks (ra n ge: 1 1 wee ks – 1 2 wee ks a n d 2 da ys): 
 
C o ntr ol Ar m: Place b o ( n = 1 0) 
E x peri me ntal Ar m 1: As piri n 3 2 5 m g dail y ( n = 4 0) 
E x peri me ntal Ar m 2: As piri n 3 2 5 m g 3 wee k O N/ O F F ( n = 4 0). I n di vi d uals assi g ne d t o 3 2 5 m g as piri n 3-
wee k o n/ 3- wee k off will ta ke place b o d uri n g 3- wee k off peri o d. 
 
5. 2 
As piri n  A d mi nistr ati o n  
 
T he as piri n a n d matc hi n g place b o ca ps ules will be pr o vi de d b y t he Nati o nal Ca ncer I nstit ute ( N CI)  a n d 
pac ka ge d a n d la bele d b y N CI Di visi o n of Ca ncer Pre ve nti o n’s re p osit or y c o ntract or, M RI Gl o bal.  T he 
Va n der bilt I n vesti gati o nal Dr u g Ser vice ( VI D S) will be res p o nsi ble f or t he st ora ge (c o ntr olle d r o o m 
te m perat ure 5 9° F - 8 6° F a n d u n der l o w h u mi dit y), pre parati o n of all i n vesti gati o nal a ge nts, a n d f or 
mai ntai ni n g acc urate dr u g st ora ge a n d dis pe nsi n g l o gs.    
 
Eac h partici pa nt will recei ve f o ur b ottles:  
•  
B ottle 1 la bele d “ Wee ks 1 - 3” 
•  
B ottle 2 la bele d “ Wee ks 4 - 6” 
•  
B ottle 3 la bele d “ Wee ks 7 - 9” 
•  
B ottle 4 la bele d “ Wee ks 1 0 - 1 2” 
 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 1 3 – 
B ottles 1 -3 will be dis pe nse d at Cli nic Visit 2.  B ottle 4 will be dis pe nse d at Cli nic Visit 3.  T he 
prescri pti o n (a n d, f or t he first dis pe nse, t he si g ne d c o nse nt f or m) will be fa xe d t o VI D S.  T he researc h 
staff will tra ns p ort t he ca ps ules fr o m VI D S t o t he partici pa nt at cli nic.  Partici pa nts will be i nstr ucte d t o 
ta ke st u d y me dicati o n wit h f o o d t o decrease t he ris k of GI u pset.   
 
If t he partici pa nt is u na ble t o sta y at t he cli nic t o recei ve t he ca ps ules, the p har macist at VI D S will mail 
t he ca ps ules via Fe de x wit hi n o ne b usi ness da y of t he Cli nic Visit.  Researc h staff will f oll o w- u p wit h a 
p h o ne call t o t he partici pa nt t o e ns ure recei pt of st u d y a ge nt.   
 
5. 3 
R u n -i n Pr oce d ures  
 
N ot a p plica ble.  
 
5. 4  
C o ntr ai n dic ati o ns 
 
Partici pa nts s h o ul d a v oi d e xcessi ve e t ha n ol use ( > 1 sta n dar d dri n ks/ da y f or w o me n, or > 2 sta n dar d 
dri n ks/ da y f or me n).   
 
5. 5  
C o nc o mit a nt Me dic ati o ns 
 
W hile o n t he st u d y a ge nt, partici pa nts s h o ul d a v oi d N S AI Ds a n d C O X- 2 i n hi bit ors.  W hile o n t he st u d y 
a ge nt, t he y s h o ul d a v oi d ta ki n g a ntic oa g ula nts, a nti plate let a ge nts, a n d c ortic oster oi ds.  Partici pa nts 
s h o ul d disc o nti n ue gi n g k o use w hile ta ki n g t he st u d y a ge nt.  Partici pa nts s h o ul d a v oi d ta ki n g 
met h otre xate ( M T X)  w hile ta ki n g t he st u d y a ge nt.     
 
All me dicati o ns ( prescri pti o n a n d o ver -t he-c o u nter), vita mi n a n d mi neral s u p ple me nts, a n d/ or her bs ta ke n 
b y t he partici pa nt will be d oc u me nte d o n t he c o nc o mita nt me dicati o n C R F a n d will i ncl u de: 1) start a n d 
st o p date, d ose a n d r o ute of a d mi nistrati o n, a n d i n dicati o n. Me dicati o ns ta ke n f or a pr oce d ure (e. g., 
bi o ps y) s h o ul d als o be i ncl u de d. 
 
5. 6  
D ose M o dific ati o n 
 
I n di vi d uals w h o re p ort a n y GI s y m pt o m ≥ gra de 3, s uc h as d ys pe psia or heart b ur n, will be i nstr ucte d t o 
disc o nti n ue t he st u d y me dicati o n i m me diatel y.  
 
Partici pa nts re p orti n g mi n or u p per GI s y m pt o ms ( d ys pe psia or heart b ur n ≤ gra de 2) w h o wis h t o re mai n 
o n trial will be i nstr ucte d t o treat s y m pt o ms wit h o ver -t he-c o u nter calci u m car b o nate a n d/ or ma g nesi u m 
h y dr o xi de base d a ntaci ds (i.e. T u ms ®, R olai ds ®, M yla nta ®, etc.) at t he ma n ufact urers rec o m me n de d 
d ose.  If s y m pt o ms persist or w orse n o ver t he ne xt 3 da ys w hile ta ki n g a ntaci ds ( ≤ gra de 2) a n d t he 
s u bject still wis hes t o re mai n o n trial, t he y will be i nstr ucte d t o treat s y m pt o ms wit h a n o ver-t he-c o u nter 
pr ot o n p u m p i n hi bit or ( P PI).  If s y m pt o ms persist or w orse n w hile ta ki n g a P PI f or m ore t ha n 3 da ys t he n 
t he st u d y a ge nt will be disc o nti n ue d a n d t he partici pa nt will be m o nit ore d u ntil s y m pt o ms res ol ve.  T hese 
s y m pt o matic resc ue me dicati o ns will n ot be pr o vi de d t o t he partici pa nts b y t he st u d y.   
 
I n di vi d uals w h o re p ort t he f oll o wi n g seri o us si de effects t hat are p ossi bl y, pr o ba bl y, or defi nitel y relate d 
t o t he st u d y a ge nt will be wit h dra w n fr o m t he st u d y: 
•  
Br uisi n g gra de 2 or a b o ve  
•  
Heari n g i m pair me nt of a n y gra de  
•  
T i n nit us of a n y gra de 
•  
Na usea gra de 2  or w orse, or na usea gra de 1 t hat lasts f or > 5 da y s  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 1 4 – 
•  
V o miti n g gra de 2 or w orse, or v o m iti n g gra de 1 t hat lasts f or > 5 da ys  
•  
Uri ne o ut p ut decrease gra de 1 or a b o ve  
•  
Uri ne disc ol orati o n gra de 1,  
•  
Blac k/tarr y st o ol,  
•  
Bl urre d visi o n gra de 1 or a b o ve  
•  
H ea dac he gra de 3 or a b o ve  
•  
S eri o us aller gic reacti o n t o t he st u d y a ge nt  
 
I n di vi d uals w h o ha ve o ne of t he f oll o wi n g res ults d uri n g t he i nter ve nti o n will ha ve  t he res ult e val uate d 
i m me diatel y ( prefera bl y wit hi n 1 wee k) a n d re peate d if t he treati n g p h ysicia n dee ms necessar y .  If t he 
treati n g p h ysicia n belie ves t he res ult is p ossi bl y, pr o ba bl y, or defi nitel y relate d t o t he st u d y a ge nt, or if t he 
re peate d test res ult re mai ns t he sa me, t he i n di vi d ual will be wit h dra w n fr o m t he st u d y.   
o  Bl o o d he m o gl o bi n < 1 2. 0 g/ d L (a ne mia, gra de 1) 
o  Platelet c o u nt < 1 5 0, 0 0 0/ micr oliter ( platelet c o u nt decrease d, gra de 1) 
o  As partate a mi n otra nsferase ( A S T) or ala ni ne a mi n otra nsferase ( A L T) > 1. 5 ti mes 
u p per li mit of n or mal ( U L N)  ( A S T/ A L T i ncrease d, gra de 1) 
o  Al kali ne p h os p hatase > 1. 5 ti mes U L N  (al kali ne p h os p hatase i ncreased, gra de 1) 
o  Bilir u bi n > 1. 5 ti mes U L N ( bl o o d bilir u bi n i ncrease d, gra de 2) 
o  B U N > 4 0 m g/ d L 
o  e G F R< 4 5 m L/ mi n  (c hr o nic ki d ne y fail ure, gra de 2) 
o  P ositi ve fecal occ ult bl o o d test 
 
5. 7 
A d here nce/ C o m pli a nce  
 
5. 7. 1  
Partici pa nts will be c o nsi dere d e val ua ble if t he y ha ve ta ke n 8 0 % of t he prescri be d d oses.  
 
5. 7. 2 
Partici pa nt c o m plia nce will be m o nit ore d i n a variet y of wa ys.  Patie nts will be re q uire d t o kee p a 
diar y d oc u me nti n g dr u g d osi n g. Ret ur ne d pills will be c o u nte d.   
 
6. 
P H A R M A C E U TI C A L I N F O R M A TI O N  
 
6. 1 
As piri n  (I N D: 1 3 0 6 2 7, E xe m pt, I N D S p o ns or: N CI/ Di visi o n of C a ncer Pre ve nti o n )   
 
As piri n ( 3 2 5 m g ca ps ule s) a n d place b o will be s u p plie d b y N CI, D C P.  As piri n is a n o d orless w hite, 
nee dle-li ke cr ystalli ne or p o w der y s u bsta nce.  W he n e x p ose d t o m oist ure, as piri n h y dr ol yzes i nt o salic ylic 
a n d acetic aci ds, a n d gi ves off a vi ne gar y - o d or.  It is hi g hl y li pi d s ol u ble a n d sli g htl y s ol u ble i n water.  
T he 3 2 5 m g as piri n ca ps ule c o ntai ns 3 2 5 m g as piri n a n d t he f oll o wi n g e xci pie nts: car na u ba wa x, 
cell ul ose, D & C Yell o w # 1 0 Al u mi n u m La ke, F D & C Yell o w # 6 Al u mi n u m La ke, h y pr o mell ose, ir o n 
o xi des, met hacr ylic aci d c o p ol y mer,  p ol ys or bate 8 0, pr o pyle ne gl yc ol, s hellac, s o di u m la ur yl s ulfate, 
starc h, tita ni u m di o xi de, triaceti n. 
 
6. 2 
Re p orte d A d verse E ve nts a n d P ote nti al Ris ks  
 
As piri n has bee n ass ociate d wit h gastr oi ntesti nal ( GI) si de effects.  GI si de effects i ncl u de st o mac h pai n, 
heart b ur n, na usea, v o miti n g, a n d gr oss GI blee di n g.  Mi n or u p per GI s y m pt o ms, s uc h as d ys pe psia, are 
c o m m o n a n d ca n occ ur a n yti me d uri n g t hera p y.  As piri n has als o bee n ass ociate d wit h ele vate d he patic 
e nz y mes, bl o o d urea nitr o ge n a n d ser u m creati ni n e, h y per kale mia, pr otei n uria, a n d pr ol o n ge d blee di n g 
ti me. 
 
6. 3  
A v ail a bilit y  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 1 5 – 
 
As piri n a n d as piri n place b o are i n vesti gati o nal a ge nts s u p plie d t o i n vesti gat ors b y t he Di visi o n of Ca ncer 
Pre ve nti o n ( D C P), N CI .  
 
6. 4 
A ge nt Distri b uti o n  
 
A ge nts will o nl y be release d b y N CI, D C P after d oc u me ntati o n of I R B a p pr o val of t he D C P-a p pr o ve d 
pr ot oc ol a n d c o nse nt is pr o vi de d t o D C P a n d t he c ollecti o n of all Esse ntial D oc u me nts is c o m plete (see 
D C P we bsite f or descri pti o n of Esse ntial D oc u me nts).  
 
N CI, D C P -s u p plie d a ge nts ma y be re q ueste d b y t he I n vesti gat or ( or t heir a ut h orize d desi g nees) at eac h 
O rga nizati o n. D C P g ui deli nes re q uire t hat t he a ge nt be s hi p pe d directl y t o t he i nstit uti o n or site w here t he 
a ge nt will be pre pare d a n d a d mi nistere d. D C P d oes n ot per mit t he tra nsfer of a ge nts bet wee n i nstit uti o ns 
( u nless pri or a p pr o val fr o m D C P is o btai ne d). D C P d oes n ot a ut o maticall y s hi p a ge nts; t he site m ust 
ma ke a re q uest . A ge nts are re q ueste d b y c o m pleti n g t he D C P Cli nical Dr u g Re q uest f or m ( NI H- 9 8 6) (t o 
i ncl u de c o m plete s hi p pi n g c o ntact i nf or mati o n) a n d fa xi n g or maili n g t he f or m t o t he D C P a ge nt 
re p osit or y c o ntract or: 
 
J o h n C o o kin ha m 
M RI Gl o bal 
D C P Re p osit or y 
1 2 2 2 Ozar k Street 
N ort h Ka nsas Cit y, M O 6 4 1 1 6 
P h o ne: ( 8 1 6) 3 6 0 - 3 8 0 5 
F A X: ( 8 1 6) 7 5 3- 5 3 5 9 
E mer ge nc y Tele p h o ne: ( 8 1 6) 3 6 0- 3 8 0 0 
 
6. 5 
A ge nt Acc o u nt a bilit y  
 
T he I n vesti gat or, or a res p o nsi ble part y desi g nate d b y t he I n vesti gat or, m ust mai ntai n a caref ul rec or d of 
t he i n ve nt or y a n d dis p ositi o n of all a ge nts recei ve d fr o m D C P usi n g t he N CI Dr u g Acc o u nta bilit y Rec or d 
F or m ( D A R F). T he I n vesti gat or is re q uire d t o mai ntai n a de q uate rec or ds of recei pt, dis pe nsi n g a n d fi nal 
dis p ositi o n of st u d y a ge nt. T his res p o nsi bilit y has bee n dele gate d t o Va n der bilt I n vesti gati o nal Dr u g 
Ser vi ce p har macists . I ncl u de o n recei pt rec or d fr o m w h o m t he a ge nt was recei ve d a n d t o w h o m st u d y 
a ge nt was s hi p pe d, date, q ua ntit y a n d batc h or l ot n u m ber. O n dis pe nsi n g rec or d, n ote q ua ntities a n d dates 
st u d y a ge nt was dis pe nse d t o a n d ret ur ne d b y eac h partici pa nt.  
 
6. 6 
P ac k a gi n g a n d L a beli n g  
 
As piri n a n d as piri n place b o will be pac ka ge d a n d la bele d b y N CI, D C P’s Re p osit or y C o ntract or 
M RI Gl o bal.   T hree b ottles will be dis pe nse d at Cli nic Visit 2.  O ne b ottle will be dis pe nse d at Cli nic Visit 
3.  T he b ottles will i ncl u de 2 3 ca ps ules.  B ottles will be la bele d “ Wee ks 1 -3,” “ Wee ks 4 -6,” “ Wee ks 7 - 9,” 
a nd Wee ks “ 1 0 - 1 2.”   
 
6. 7  
St or a ge 
 
St u d y dr u g will be st ore d i n a sec ure l ocati o n, at c o ntr olle d r o o m te m perat ure ( 5 9° F - 8 6° F) a n d u n der 
l o w h u mi dit y. T he Va n der bilt I n vesti gati o nal Dr u g Ser vice ( VI D S) will be res p o nsi ble f or t he st ora ge, 
pre parati o n all i n vesti gati o nal a ge nts, a n d f or mai ntai ni n g acc urate dr u g st ora ge a n d dis pe nsi n g l o gs.   
 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 1 6 – 
6. 8  
Re gistr ati o n/ R a n d o miz ati o n 
 
I n c urre nt st u d y, t here are t hree gr o u ps, t w o treat me nt gr o u ps ( 3 2 5 m g as piri n dail y a n d 3 2 5 m g as piri n 3-
wee k o n/ 3- wee k off) a n d o ne c o ntr ol gr o u p. I n di vi d uals assi g ne d t o 3 2 5 m g as piri n 3- wee k o n/ 3- wee k off 
will ta ke place b o d uri n g 3 - wee k off peri o d.  
 
T his st u d y will recr uit 9 0 partici pa nts wit h c ol orectal a de n o ma. A per m ute d -bl oc k ra n d o mizati o n desi g n  
will be use d t o all ocate t he s u bjects i nt o t he treat me nt/ place b o ar m , a n d will be create d b y t he st u d y 
statisticia n. B ot h t he s u bjects a n d t he i nter ve nti o n a d mi nisteri n g staff will be bli n de d t o assi g n me nts.  
 
Pr oce d ures  
1.  A st u d y c o or di nat or m ust u pl oa d i nt o t he N ort h wester n Cli nical Trials Ma na ge me nt S yste m, a 
si g ne d a n d c o m plete i nf or me d c o nse nt al o n g wit h HI P A A a ut h orizati o n a n d a c o m plete d 
eli gi bilit y f or m f or eac h partici pa nt i de ntifie d as eli gi ble t o be e ntere d i nt o t he st u d y.   
2.  All partici pa nts m ust be re gistere d i n t he N ort h wester n U ni versit y R o bert H. L urie 
C o m pre he nsi ve Ca ncer Ce nter Cli nical Trials Ma na ge me nt S yste m ( C T M S).  Partici pa nts m ust 
n ot start pr ot oc ol treat me nt pri or t o re gistrati o n i n t he L urie Ca ncer Ce nter C T M S.  
3.  After re gistrati o n i n t he C T M S, partici pa nts will be assi g ne d a partici pa nt i de ntificati o n n u m ber.  
4.  A n N C P C Q ualit y Ass ura nce M o nit or will s u b mit t he f oll o wi n g i nt o t he R E D Ca p Ra n d o mizati o n 
I nf or mati o n F or m: ( 1) St u d y N u m ber, ( 2) Site, ( 3) P har macist E mail(s), ( 4) Partici pa nt I D [ PI D], 
( 5) Partici pa nt I nitials, a n d ( 6) Ra n d o mizati o n Date.  
5.  A n A ut o matic Treat me nt Assi g n me nt N otificati o n e mail will be se nt t o t he researc h p har macist(s) 
c o ntai ni n g: ( 1) St u d y N u m ber, ( 2) Site, ( 3) Partici pa nt I D [ PI D], ( 4) Partici pa nt I nitials, ( 5) 
Ra n d o mizati o n Date, a n d ( 6) Treat me nt Assi g n me nt.  
6.  T he cli nical researc h c o or di nat or(s) will recei ve a C o nfir mati o n of Re gistrati o n c o ntai ni n g t he 
PI D via e mail.  
T he res earc h p har macist will dis pe nse t he st u d y a ge nt . 
 
T he f oll o wi n g pe o ple will ha ve a c o p y of t he u n- bli n de d ra n d o mizati o n l o g: t he st u d y statisticia n at N U, 
t he Q ualit y Ass ura nce Tea m  at N U, a n d t he I n vesti gati o nal Phar macist  at Va n der bilt. T he f oll o wi n g 
pe o ple will ha ve access t o t he R E D Ca p st u d y pr oject c o ntai ni n g ra n d o mizati o n i nf or mati o n: t he st u d y 
statisticia n at N U a n d t he Q ualit y Ass ura nce Tea m at N U. T he st u d y statisticia n will set u p ra n d o mizati o n 
bl oc ks.  
 
W he n p ossi ble, t he st u d y c o or di nat or will n otif y a n N C P C Q ualit y Ass ura nce M o nit or a n d/ or se n d a n 
e mail t o nc pc @ n ort h wester n.e d u  pri or t o re gisteri n g a partici pa nt. Pri or n otificati o n is re q uire d f or 
partici pa nt ra n d o mizati o ns o utsi de t he n or mal b usi ness h o urs of M o n da y - Fri da y 9: 0 0a m- 5: 0 0 p m C T.   
 
6. 9 
Bli n di n g a n d U n bli n di n g Met h o ds  
 
T he researc h p har macist will ma na ge t he i n vesti gati o nal a ge nt.  T he bli n d will be mai ntai ne d t hr o u g h t he 
eff ort of t he researc h p har macist a n d t he p har mac y.  U n bli n di n g will o nl y occ ur w he n it is dee me d 
me dicall y necessar y, a n d will o nl y ta ke place after c o ns ultati o n wit h t he N CI, D C P Tas k Or der M o nit or.  
If t he N CI Tas k Or der M o nit or ca n n ot be reac he d a n d t he partici pa nt re q uires e mer ge nc y care, t he St u d y 
C hair ma n ma y a ut h orize t he site PI t o brea k t he bli n d.  T he date a n d reas o n f or brea ki n g t he bli n d m ust be 
s u b mitte d b y t he site PI t o t he St u d y C hair ma n a n d t he N CI Tas k Or der M o nit or as s o o n as p ossi ble.   
 
 
Gar y Della’ Za n na, D O, M Sc  
 
Nati o nal Ca ncer I nstit ute  
  
Di visi o n of Ca ncer Pre ve nti o n 
 
Gastr oi ntesti nal a n d Ot her Ca ncers Researc h Gr o u p  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 1 7 – 
  
9 6 0 9 Me dical Ce nter Dri ve, M S C- 9 7 8 2 
  
R oc k ville, M D 2 0 8 5 0 
 
P h o ne: 2 4 0 - 2 7 6- 7 0 4 2 
  
Fa x ( * wit h c o ver s heet, Att n: Dr. G. Della’ Za n na): 2 4 0- 2 7 6- 7 8 4 8 
 
E mail: gar y. dellaza n na @ ni h. g o v  
 
6. 1 0 
A ge nt Dest r u cti o n/ Dis p os al 
 
At  t he c o m pleti o n of i n vesti gati o n, all u n use d st u d y a ge nt will be ret ur ne d t o N CI, D C P Re p osit or y 
acc or di n g t o t he D C P “ G ui deli nes f or A G E N T R E T U R N S” a n d usi n g t he D C P f or m “ Ret ur n Dr u g List”.  
 
7. 
C LI NI C A L E V A L U A TI O N S A N D P R O C E D U R E S  
 
7. 1 
Sc he d ule of E ve nts  
 
 
Cli nic Visit 1 : 
Scr e e ni n g  
Cli nic Visit 2 : 
B as eli n e, wit hi n 
6 w e e ks of Cli nic 
Visit 1  
B et w e e n -Visit 
T el e p h o n e  or 
E m ail  C o nt acts  
Cli nic Visit 3 : 
9 w e e ks aft er 
st art of st u d y 
a g e nt [ 6]  
Cli nic Visit 4 : 
1 2 w e e ks aft er 
st art of st u d y 
a g e nt [ 7];  
or 
Off -A g e nt Visit 
[ 8] 
I nf or m e d C o ns e nt 
X  
 
 
 
 
Eli gi bility  
X  
 
 
 
 
R e gistr ati o n/ R a n d o miz ati o n [ 1]  
X  
 
 
 
 
C oll ect/ R evi e w Q u esti o n n air es [ 2]  
 
X  
 
 
 
M e dic al Hist ory  
X  
 
 
 
 
P hysic al  [ 1 3] 
X  
 
 
 
 
Vit al  Si g n s [ 1 2], B o dy M e as ur e m e nts [ 3] 
X  
X  
 
X  
X  
C o n M e d R evi e w  
X  
X  
 
X  
X  
Ass ess A dv ers e E v e nts  
X  
X  
 
X  
X  
Pr e g n a ncy T est  
X  
 
 
 
 
Bl o o d S a m pl e f or Cli nic al L a bs  [ 1 0] 
X  
X  
 
X  
X  
Bl o o d S a m pl e f or R es e arc h [ 1 1]  
X  
X  
 
X  
X  
Uri n e S a m pl e [ 9 ] 
X  
X  
 
X  
X  
St o ol S a m pl e  
X  
X  
 
X  
X  
R ect al S w a b  
 
X  
 
X  
X  
R ect al Bi o psi es [ 4]  
 
X  
 
X  
X  
Dis p e ns e St u dy A g e nt  
 
X  
 
X  
 
C oll ect/ C o u nt U n us e d Pills  a n d R evi e w 
P artici p a nt Di ary  
 
 
 
X  
X  
T el e p h o n e or E m ail C o nt act [ 5]  
 
 
X  
 
X [ 1 4] 
C o m p e ns ati o n  
X  
 
 
 
X  
[ 1] Re gistrati o n a n d ra n d o mizati o n will occ ur bet wee n Cli nic Visit 1 a n d Cli nic Visit 2  
[ 2] Cli nic Visit 2: F o o d Fre q ue nc y Q uesti o n naire a n d Baseli ne Cli nic Visit Q uesti o n naire   
[ 3] Hei g ht;  wei g ht;  hi p a n d waist circ u mfere nces  
[ 4] Verif y e m pt y rectal va ult pri or t o rectal bi o ps y pr oce d ure  
[ 5] P h o ne  or e mail  c o ntacts will i ncl u de t he f oll o wi n g t o pics: c o m plia nce, a d verse e ve nts, re mi n der t o s witc h 
b ottles , re mi n der t o bri n g u n use d pills bac k t o cli nic. Partici pa nts will be c o ntacte d  wit hi n 3 da ys after eac h bi o ps y 
visit  (after Cli nic Visits 2, 3, a n d 4), a n d at Wee ks 1, 3, a n d 6 (± 3 da ys ).   
[ 6] Ra n ge: 8 wee ks – 9 wee ks  a n d  2 da ys  ( 5 6 – 6 5 da ys) after starti n g t he st u d y a ge nt  
[ 7] Ra n ge: 1 1 wee ks – 1 2 wee ks  a n d  2 da ys  ( 7 7 – 8 6 da ys) after starti n g t he st u d y a ge nt  
[ 8] If a partici pa nt c o mes off-a ge nt (e. g. d ue t o A E or c o nc o mita nt me dicati o n), t he Off -A ge nt  Visit will be 
sc he d ule d f or as s o o n as p ossi ble after t he partici pa nt st o ps t he st u d y a ge nt.   
[ 9] Uri ne sa m ples will be o btai ne d o nl y fr o m partici pa nts w h o a gree t o f ut ure u ns pecifie d researc h i n t he c o nse nt 
f or m. 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 1 8 – 
[ 10 ] Cli nic Visit 1- 4: 1 gree n t o p t u be f or C M P a n d  1 p ur ple t o p  t u be f or C B C wit h differe ntial .  C M P a n d C B C will 
be pr ocesse d o n t he da y of t he visit.  
[ 11 ] 1 E D T A p ur ple t o p t u be f or plas ma, w hite bl o o d cell ( W B C), re d bl o o d cell ( R B C);  1 re d t o p t u be f or ser u m.  
[ 1 2] E C O G perf or ma nce stat us o btai ne d at Scree ni n g Visit o nl y. Vital si g ns i ncl u de p ulse, res pirat or rate, 
te m perat ure, a n d bl o o d press ure. 
[ 1 3] P h ysical e xa m ma y be perf or me d at a n y f oll o w -u p  visit w he n dee me d a p pr o priate b y st u d y tea m d ue t o 
si g nifica nt c ha n ges or me dical e ve nts.  
[ 1 4] F oll o w-u p p h o ne call t o assess a d verse e ve nts 1 m o nt h ±  7 da ys fr o m Cli nic Visit 4.  
 
7. 2 
Pre -st u d y E v al u ati o n 
 
Cli nic V isit 1: Scree ni n g  
•  
Pri or t o t he visit  
o  T he researc h staff will mail t he partici pa nt a st o ol c ollecti o n kit.  T he partici pa nt will 
c ollect st o ol a n d bri n g it t o t he cli nic.  Partici pa nts w h o fail t o bri n g i n t he st o ol sa m ple t o 
t he office visit will be as ke d t o tr y t o pr o d uce a sa m ple d uri n g t he cli nic visit.  If u na ble, 
t he y will be as ke d t o bri n g or mail t he st o ol sa m ple after Cli nic Visit 1 f or t he fecal occ ult 
test.   
•  
D uri n g t he visit  
o  
O btai n writte n i nf or me d c o nse nt (t he st u d y partici pa nt will kee p a c o p y) . 
o  
Re vie w me dical hist or y, p h ysi cal i ncl u di n g vital si g ns, E C O G perf or ma nce stat us, 
c o nc o mita nt me dicati o ns,  a n d s y m pt o ms. 
o  
O btai n t he f oll o wi n g s peci me ns:  
 
O ne t u be of uri ne (f or o pti o nal f ut ure researc h) 
 
O ne t u be of st o ol ( br o u g ht fr o m h o me f or fecal occ ult bl o o d test)  
 
T w o  t u bes of bl o o d (f or cli nical la b orat or y meas ure me nts): 1 gree n t o p f or C M P 
a n d 1 p ur ple t o p f or C B C wit h differe ntial.  
 
T w o t u bes of bl o o d (f or researc h): 1 E D T A p ur ple t o p f or plas ma, w hite bl o o d 
cell ( W B C), re d bl o o d cell ( R B C); 1 re d t o p f or ser u m.  
o  
Perf or m a pre g na nc y test  
•  
After t he visit  
o  
Researc h staff will re vie w fi nal i ncl usi o n/e xcl usi o n criteria base d o n la b orat or y res ults.  
o  
Partici pa nt will be re gistere d i n t he N ort h wester n O nc ol o g y Trial I nf or mati o n S yste m 
( N O TI S).  
o  
Res ults of t he i ncl usi o n/e xcl usi o n criteria re vie w will be c o m m u nicate d t o t he partici pa nt.   
 
Cli nic V isit 2: Baseli ne  
Wit hi n 6 wee ks of Cli nic Visit 1  
•  
Pri or t o t he visit  
o  T he researc h staff will mail or gi ve t he partici pa nt a st o ol c ollecti o n kit.  T he partici pa nt 
will c ollect st o ol a n d bri n g it t o t he cli nic.   
o  T he researc h staff will mail or gi ve t he partici pa nt t he F o o d Fre q ue nc y Q uesti o n naire 
( F F Q) a n d Baseli ne Cli nic Visit Q uesti o n naire .  The partici pa nt will c o m plete t h ese 
q uesti o n naires pri or t o arri vi n g.  
•  
D uri n g t he visit  
o  Re vie w vital si g ns , c o nc o mita nt me dicati o ns, a n d s y m pt o ms. 
o  
P h ysical e xa m ma y be perf or me d w he n  dee me d a p pr o priate b y st u d y tea m  d ue t o 
si g nifica nt c ha n ges or me dical e ve nts. 
o  Re vie w t he F F Q a n d Baseli ne Cli nic Visit Q uesti o n naire.  
o  
O btai n t he f oll o wi n g s peci me ns: 
 
O ne t u be of uri ne (f or o pti o nal f ut ure researc h)  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 1 9 – 
 
O ne t u be of st o ol ( br o u g ht fr o m h o me f or fecal occ ult bl o o d test)  
 
T w o  t u bes of bl o o d (f or cli nical la b orat or y meas ure me nts): 1 gree n t o p f or C M P 
a n d 1 p ur ple t o p f or C B C wit h differe ntial. 
 
T w o t u bes of bl o o d (f or researc h): 1 E D T A t u be f or plas ma, w hite bl o o d cell 
( W B C), re d bl o o d cell ( R B C); 1 re d t o p f or ser u m. 
 
Rectal s wa bs  
 
Rectal bi o psies  
o  
Dis pe nse first t hree b ottles of st u d y a ge nt a n d partici pa nt diar y.  
o  
Gi ve t he partici pa nt a st o ol sa m ple c oll ecti o n kit t o use pri or t o Cli nic Visit 3.  
•  
After t he visit  
o  
Wit hi n 3 da ys after t he visit, t he researc h staff or n urse will tele p h o ne or e mail eac h 
partici pa nt t o m o nit or f or a n y a d verse e ve nts d ue t o bi os peci me n c ollecti o n as well as 
c o m plia nce m o nit ori n g. S u g geste d state me nts f or partici pa nt c o m m u nicati o ns are 
pr o vi de d i n A p pe n di x E.  
 
7. 3 
E v al u ati o n D uri n g St u d y I nter ve nti o n  
 
Bet wee n -Visit Tele p h o ne or E m ail C o nt acts  
Wee ks 1, 3, a n d 6 ( ± 3 d a ys)  
T he researc h staff will tele p h o ne or e mail  eac h partici pa nt t o disc uss t he f oll o wi n g: 
•  
A n y a d verse e ve nts  
•  
C ha n ges i n c o nc o mita nt me dicati o ns  
•  
C o m plia nce m o nit ori n g  
•  
A re mi n der  t hat, at t he be gi n ni n g of wee ks 3 a n d 6, t he partici pa nt nee d s t o s witc h b ottles.   
T he Wee k 6 Tele p h o ne or E mail C o ntact will i ncl u de t he f oll o wi n g re mi n ders:  
•  
T o bri n g u n use d st u d y a ge nt wit h t he m t o t he ne xt Cli nic Visit. 
•  
T o ha ve a b o wel m o ve me nt pri or t o t heir visit, t o pre pare f or t he rectal bi o ps y pr oce d ure. 
S u g geste d state me nts f or partici pa nt c o m m u nicati o ns are  pr o vi de d i n A p pe n di x E. 
 
Cli nic V isit 3: 9 Wee ks 
8 wee ks - 9 wee ks a n d 2 d a ys ( 5 6 – 6 5 d a ys) after st art of st u d y a ge nt   
•  
Pri or t o t he visit  
o  T he partici pa nt will c ollect st o ol usi n g t he c ollecti o n kit gi ve n t o t he m d uri n g Cli nic Visit 
2. 
•  
D uri n g t he visit  
o  Re vie w vital si g ns , c o nc o mita nt me dicati o ns, a n d s y m pt o ms. 
o  
P h ysical e xa m ma y be perf or me d w he n  dee me d a p pr o priate b y st u d y tea m d ue t o 
si g nifica nt c ha n ges or me dical e ve nts. 
o  O btai n t he f oll o wi n g s peci me ns: 
 
O ne t u be of uri ne (f or o pti o nal f ut ure researc h) 
 
O ne t u be of st o ol ( br o u g ht fr o m h o me f or fecal occ ult bl o o d test)  
 
T w o  t u bes of bl o o d (f or cli nical la b orat or y meas ure me nts): 1 gree n t o p f or C M P 
a n d 1 p ur ple t o p f or C B C wit h differe ntial.  
 
T w o t u bes of bl o o d (f or researc h): 1 E D T A t u be f or plas ma, w hite bl o o d cell 
( W B C), re d bl o o d cell ( R B C); 1 re d t o p f or ser u m.  
 
Rectal s wa bs  
 
Rectal bi o psies  
o  C ollect u n use d st u d y a ge nt a n d partici pa nt diar y a n d c o n d uct a pill c o u nt.  
o  Dis pe nse f o urt h b ottle of st u d y a ge nt. 
•  
After t he visit  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 0 – 
o  Wit hi n 3 da ys after t he visit, t he researc h staff or n urse will tele p h o ne or e mail  eac h 
partici pa nt t o m o nit or f or a n y a d verse e ve nts d ue t o bi os peci me n c olle cti o n as well as 
c o m plia nce m o nit ori n g. S u g geste d state me nts f or partici pa nt c o m m u nicati o ns are 
pr o vi de d i n A p pe n di x E. 
 
7. 4  
E v al u ati o n at C o m pleti o n of St u d y I nter ve nti o n 
 
Cli nic V isit 4: 1 2 W ee ks  
1 1 wee ks – 1 2 wee ks a n d 2 d a ys ( 7 7 – 8 6 d a ys) after st art  of st u d y a ge nt  
O R  
Off -A ge nt Visit  
•  
Pri or t o t he visit  
o  
T he partici pa nt will c ollect st o ol usi n g t he c ollecti o n kit gi ve n t o t he m d uri n g Cli nic Visit 
3.  
•  
D uri n g t he visit  
o  Re vie w vital si g ns , c o nc o mita nt me dicati o ns, a n d s y m pt o ms. 
o  
P h ysical e xa m ma y be perf or me d w he n  dee me d a p pr o priate b y st u d y tea m d ue t o 
si g nifica nt c ha n ges or me dical e ve nts. 
o  O btai n t he f oll o wi n g s peci me ns: 
 
O ne t u be of uri ne (f or o pti o nal f ut ure researc h)  
 
O ne t u be of st o ol ( br o u g ht fr o m h o me f or fecal occ ult bl o o d t est) 
 
T w o  t u bes of bl o o d (f or cli nical la b orat or y meas ure me nts): 1 gree n t o p f or C M P 
a n d 1 p ur ple t o p f or C B C wit h differe ntial.  
 
T w o t u bes of bl o o d (f or researc h): 1 E D T A t u be f or plas ma, w hite bl o o d cell 
( W B C), re d bl o o d cell ( R B C); 1 re d t o p f or ser u m. 
 
R ectal s wa bs 
 
Rectal bi o psies  
o  C ollect u n use d st u d y a ge nt a n d partici pa nt diar y a n d c o n d uct a pill c o u nt.  
•  
After t he visit  
o  
Wit hi n 3 da ys after t he visit, t he researc h staff or n urse will tele p h o ne or e mail  eac h 
partici pa nt t o m o nit or f or a n y a d verse e ve nts d u e t o bi os peci me n c ollecti o n as well as 
c o m plia nce m o nit ori n g. S u g geste d state me nts f or partici pa nt c o m m u nicati o ns are 
pr o vi de d i n A p pe n di x E.  
 
7. 5 
P ost -i nter ve nti o n F oll o w-u p Peri o d  
F oll o w -U p Tele p h o ne or E m ail C o nt act  
1 m o nt h after Cli nic Visit 4 or Off -A ge nt Visit ( ± 7  d a ys) 
T he researc h staff will tele p h o ne or e mail  eac h partici pa nt t o disc uss t he f oll o wi n g: 
•  
A n y a d verse e ve nts  
 
7. 6 
Met h o ds f or Cli nic al Pr oce d ures  
 
7. 6. 1 Rect al S w a b a n d Bi o ps y Pr oce d ure  
T he pr oce d ure f or c ollecti n g rectal  s wa bs a n d bi o psies will occ ur at Cli nic Visits 2, 3 a n d 4.  N o 
fasti n g or b o wel clea nsi n g pre parati o ns is re q uire d. Partici pa nts are as ke d t o tr y t o ha ve a b o wel 
m o ve me nt pri or t o arri vi n g at cli nic.   If t he partici pa nt was u na ble t o clear his/ her b o wels, t he 
pr oce d ur e will still pr ocee d.  Partici pa nt is p ositi o ne d i n t he Si ms p ositi o n.  See secti o n 1 0. 2 f or 
s peci me n c ollecti o n i nf or mati o n. 
 
P atie nt m o nit ori n g  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 1 – 
After t he bi o ps y, t he patie nt is m o nit ore d f or t hirt y mi n utes. T he st u d y staff will c hec k bl o o d press ure 
a n d ha ve t he patie nt g o t o t he restr o o m t o c hec k f or blee di n g pri or t o lea vi n g t he cli nic. Patie nt is t ol d 
t hat t he y ca n e x pect s o me bl o o d o n t he tiss ue o n t he da y of t he bi o ps y. Blee di n g hea vier or m ore 
persiste nt t ha n t his s h o ul d be re p orte d. T he y s h o ul d als o re p ort a nal or l o wer a b d o mi nal pai n, fe ver, a 
f o ul a nal disc har ge, or a n yt hi n g else t he y t hi n k c o ul d be relate d t o t he bi o ps y. T he gastr oe nter ol ogists 
a n d t he s u p p orti n g me dical tea m will ha n dle e mer ge ncies.  A n y ot her pr o ble ms disc o vere d b y t he 
st u d y tea m will be disc usse d at a n a p pr o priate le vel wit h t he patie nt s ufficie nt t o affect referral t o t he 
patie nt's gastr oe nter ol o gists or pri mar y care p h ysicia n w h o will als o be i nf or me d if t he partici pa nts 
a gree i n t he i nf or me d c o nse nt f or m (i.e. t he f oll o wi n g q uesti o ns will be a d de d i n t he i nf or me d c o nse nt 
f or m: “If y o u de vel o p a me dical pr o ble m w hile o n st u d y, ma y we i nf or m y o ur p h ysicia n? If yes, 
w h o m w o ul d y o u li ke us t o i nf or m?”) .  
 
A n y p ossi ble c o m plicati o ns t o t he bi o psies will be rec or de d o n a n A d verse E ve nts F or m; i nf or mati o n 
will i ncl u de a descri pti o n of t he c o m plicati o n, a rati n g of t he se verit y, ot her esse ntial i nf or mati o n 
nee de d t o e val uate t he c o m plicati o n, a n assess me nt of t he li keli h o o d t hat t he e ve nt was d ue t o a st u d y 
pr oce d ure, a n d a state me nt of acti o n ta ke n.  Mi n or pr o ble ms after t he pr oce d ure are ha n dle d i n 
c o ns ultati o n wit h t he gastr oe nter ol o gist, a n d rec or de d i n t he s u bjec t's st u d y file.  If u n d ue 
c o m plicati o ns of bi o psies or ot her pr oce d ures arise, t he st u d y will be st o p pe d a hea d of sc he d ule.  I n 
a d diti o n, i n t he e ve nt of a se vere or life- t hreate ni n g c o m plicati o n, t he Va n der bilt Ca ncer Ce nter 
Cli nical pr ot oc ol Re vie w C o m mittee will be i m me diatel y n otifie d , a n d a n S A E s u b mitte d acc or di n g 
t o secti o n 1 1. 2.  Patie nts will c o nti n ue t heir us ual care wit h t he p h ysicia n.  Tele p h o ne n u m bers f or t he 
PI a n d st u d y c o or di nat or will be gi ve n t o t he partici pa nt.  E mer ge ncies will be ha n dl e d b y t he 
gastr oe nter ol o gist a n d s u p p orti n g me dical staff.   
 
7. 6. 2 St o ol C ollecti o n Pr oce d ure  
Bef ore t he cli nic visit, partici pa nts will recei ve a st o ol c ollecti o n kit:  
•  
Sterile st o ol c o ntai ner wit h wi de m o ut h   
•  
Zi p -l oc k ba gs/ bi o hazar d ba gs 
•  
I ns ulate d ba g wit h ice pac ks  
•  
Writte n a n d ver bal i nstr ucti o ns f or c ollecti o n of st o ol sa m ples 
Patie nts will be i nstr ucte d t o c ollect st o ol s peci me n.  C ollect t he st o ol wit hi n 7 da ys pri or t o t he cli nic 
visit da y.  
•  
Place s peci me n i n zi p -l oc k ba g / bi o hazar d ba g. 
•  
Place zi p -l oc ke d ba g i n i ns ulate d ba g wit h ice pac k. 
•  
St ore s peci me n i n t he refri gerat or u ntil rea d y t o lea ve f or cli nic. 
•  
Tra ns p ort t he sa m ple t o t he cli nic  a n d gi ve t o st u d y staff. 
 
7. 6. 3 Rese arc h Bl o o d S a m ple C ollecti o n Pr oce d ure  
Researc h bl o o d sa m ples will be c ollecte d at all Cli nic Visits.  Bl o o d ( 2 5 ml f or eac h pers o n) will be 
dra w n i nt o o ne E D T A  t u be f or plas ma , W B C, R B C a n d o ne re d t o p t u be f or ser u m.   
 
7. 6. 4 Uri ne S a m ple C ollecti o n  
T he uri ne sa m ples will be c ollecte d C li nic Visits 1 - 4.  Eac h uri ne sa m ple will be c ollecte d i n a sterile 
uri ne s peci me n c o ntai ner c o ntai ni n g 1 0 0 m g asc or bic aci d as a preser vati ve.  T his sa m ple will be 
tra nsferre d i nt o 1. 8 ml cr y o vials.   
 
8.  
C RI T E RI A F O R E V A L U A TI O N A N D E N D P OI N T D E FI NI TI O N  
 
8. 1 
Pri m ar y E n d p oi nt  
 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 2 – 
B A X  e x pressi o n reflects earlier si g nali n g of a p o pt osis a n d, t h us, it is a m ore se nsiti ve bi o mar ker of 
a p o pt osis t ha n T U N E L. Necr o pt osis is a ne w l y descri be d pat h wa y f or pr o gra m m e d cell deat h. T o 
e val uate t he effects of a 3 -m o nt h i nter ve nti o n  of c o nti n u o us vers us i nter mitte nt as piri n d osi n g (i.e. 3 2 5 
m g dail y a n d 3 2 5 m g 3 wee ks o n/ 3 wee ks off), we c h ose t he cell pr oliferati o n (i.e. Ki - 6 7)/ BA X  rati o as a 
pri mar y e n d p oi nt. 
 
8. 2 
Sec o n d ar y  a n d E x pl or at or y E n d p oi nts  
 
I m m u n o hist oc he mistr y (I H C) 
C ell pr oliferati o n/T U N E L rati o , a n d cell pr oliferati o n/Necr o pt osis rati o  will be sec o n dar y e n d p oi nts, 
w hereas t he e x pressi o n of C O X - 2, B A X , T R P M 7, j oi nt i n de x of C O X- 2 wit h T R P M 7 a n d j oi nt i n de x of 
T R P M 7 wit h B A X  i n rectal bi o ps y will be e x pl orat or y  e n d p oi nts. 
 
All bi o mar kers ( T U N E L, p M L K L, C O X - 2, BA X , T R P M 7 a n d Ki- 6 7) will be detecte d b y a n esta blis he d 
6- ple x mI H C /I F ( m ulti ple x i m m u n ofl u oresce nt I H C) tec h ni q ue a n d a nal yze d q ua ntitati vel y usi n g a 
s yste m c o m p ose d of a n Ol y m p us B X -6 1 m ot orize d  micr osc o pe, X-Cite X Y LI S Fl u oresce nce Ill u mi nat or 
a n d i ma gi n g s oft ware (Q- Ca pt ure, I ma geJ, Cell Pr ofiler).  T he i ma gi n g q ua ntifi cati o n will be c o n d ucte d b y 
a researc h pat h ol o gist a n d t he detaile d pr oce d ures f or se q ue ntial mI H C/I F stai ni n g pr ot oc ol, q ualit y 
c o ntr ols a n d a ut o mate d i ma ge meas ure me nt pi peli nes are  prese nte d i n t he s u p ple me ntar y file. T he fi nal 
meas ures are ge nerate d a u t o maticall y as ‘‘t otal p ositi ve cell c o u nt / t otal e pit helial n uclei’’  f or n uclear 
stai ni n g mar ker  ( Ki-6 7), or ‘‘t otal p ositi ve area / t otal e pit helial cell area’’ f or c yt o plas mic/ me m bra n o us 
stai ni n g mar kers (i.e. pM L K L, T R P M 7, C O X - 2 a n d BA X ). T he C O X- 2 e x pressi o n i n b ot h e pit heli u m 
a n d str o ma will be se paratel y q ua ntifie d usi n g pa n-C K f or tiss ue se g me ntati o n . Q ua ntitati ve res ults will 
be use d f or e n d p oi nts a n d se mi- q ua ntitati ve res ults will be use d t o vali date q ua ntitati ve res ults.  
 
Fec al occ ult bl o o d tes t 
Fecal occ ult bl o o d test will be use d t o m o nit or t he safet y of t he treat me nt at eac h cli nic visit .  
 
Q u a ntific ati o n of D N A met h yl ati o n   
 
E pi ge netics, partic ularl y a berra nt D N A met h ylati o n i n ge ne pr o m oters (i.e. C p G  met h ylati o n sites), pla y a 
critical r ole d uri n g C R C carci n o ge nesis 5 5; 5 6. H o we ver, a ver y rece nt h u ma n st u d y f o u n d t hat use of 
as piri n re d uce d t he C p G met h ylati o n rates at c ol orectal carci n o ge nic ge nes (i.e. C D K N 2 A (cell c ycle 
re g ulati o n), M G M T ( D N A re pair), D A P K 1(a p o pt osis), C D H 1(cell i n vasi o n), W N T 1 6 ( W nt pat h wa y) 
a n d R A S S F 1 ( R A S si g nali n g)) 5 7.  
 
We will e xtract hi g h m olec ular wei g ht ge n o mic D N A fr o m D B S sa m ples wit h c o m merciall y a vaila ble 
P ure Ge ne Kits ( Ge ntra S yste ms, Mi n nea p olis, M N). We will use t he Met h ylati o n E PI C Bea d C hi p t o 
i de ntif y met h ylati o n bi o mar kers i n ca n di date ge nes (i.e. C D K N 2 A (cell c ycle re g ulati o n), M G M T ( D N A 
re pair), D A P K 1(a p o pt osis), C D H 1(cell i n vasi o n), W N T 1 6 ( W nt pat h wa y) a n d R A S S F 1 ( R A S si g nali n g)) 
i n v ol ve d i n c ol orectal carci n o ge nesis, a n d ot her e pi ge n o me -wi de met h ylati o n bi o mar kers i n rectal 
bi o psies..  
 
G ut micr o bi ot a  
G ut micr o bi ota d ys bi osis 6 1; 6 2, partic ularl y a b u n da nce of E. c oli  or E. c oli- li ke bacteria6 3; 6 4 a n d 
F us o b acteri u m 6 5- 6 8, was li n ke d t o C R C ris k. We will e val uate t he effects of as piri n o n t hese bacteria a n d 
ot her micr o bi ota  i n rectal s wa bs usi n g w h ole-ge n o me s h ot g u n meta ge n o mics ( W G S) D N A se q ue nci n g.   
 
8. 3 
Off -A ge nt C riteri a  
 
Partici pa nts ma y st o p ta ki n g st u d y a ge nt f or t he f oll o wi n g reas o ns:  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 3 – 
( 1) I n di vi d uals w h o re p ort mi n or u p per GI s y m pt o ms s uc h as d ys pe psia, heart b ur n, d ys pe psia, or 
heart b ur n w h o d o n ot wis h t o re mai n o n trial;   
( 2) I na de q uate a ge nt s u p pl y; 
( 3) N o nc o m plia nce ( e. g. f or get ta ki n g st u d y a ge nt);  
( 4) Me dical c o ntrai n dicati o n;  
( 5) C o nc o mita nt me d icati o ns. 
 
Partici pa nts w h o g o off -a ge nt earl y will ha ve a n Off -A ge nt Visit (cli nic visit 4 as liste d i n “ 7. 1 sc he d ule of 
e ve nts”) sc he d ule d as s o o n as p ossi ble.   
 
8. 4 
Off -St u d y Criteri a  
 
Accr ual will be i nterr u pte d if at a n y ti me t o xicit y a m o n g partici pa nts re q uires wit h dra wal of 2 5 % of 
partici pa nts base d o n t he t o xicit y criteria o utli ne d i n Secti o n 5. 6.  T o xicit y will be re vie we d b y t he N CI 
D C P Me dical M o nit or  t o deter mi ne w het her accr ual t o t he st u d y s h o ul d be per ma ne ntl y st o p pe d. 
 
8. 5 
St u d y Ter mi n ati o n  
 
N CI, D C P as t he st u d y s p o ns or has t he ri g ht t o disc o nti n ue t he st u d y at a n y ti me.  
 
9. 
C O R R E L A TI V E/ S P E CI A L S T U DI E S  
N o ne. 
 
1 0. 
S P E CI M E N M A N A G E M E N T  
 
1 0. 1  
L a b or at ories 
 
Dr. Ti m ot h y  S u at Va n der bilt E pi de mi ol o g y Bi os peci me n C ore  (M C N B- 2 1 0 3, Nas h ville, T N 3 7 2 3 2) 
will perf or m  i m m u n o hist oc he mical a nal ysis o n rectal bi o psies .  
Dr. M. A n drea Azcarate -Peril  at U ni versit y of N ort h Car oli na Micr o bi o me C ore Facilit y ( 3 1 2 Isaac 
Ta yl or Hall,  C ha pel Hill, N C 2 7 5 9 9) will c o n d uct micr o bi o me a nal yses o n rectal s wa bs .  
Dr. Lifa n g H o u’s la b orat or y will perf or m D N A met h ylati o n a nal ysis o n rectal bi o psies . T he assa ys will 
be d o ne at U ni versit y of C hica g o Ge n o mics Facilit y ( 9 0 0 E. 5 7 t h Street, C h ica g o, I L 6 0 6 3 7). 
 
1 0. 2 
C ollecti o n a n d H a n dli n g Pr oce d ures  
 
1 0. 2. 1 Rect al Bi o psies  
Rectal bi o psies will be c ollecte d at Cli nic Visits 2, 3, a n d 4.  Bi o mar kers fr o m rectal  bi o psies i ncl u de  
Ki - 6 7 (cell ular pr oliferati o n), BA X  ( pr o-a p o pt osis), T U N E L (a p o pt osis), pM L K L ( necr o pt osis ), 
C O X - 2 (i nfla m mati o n) a n d T R P M 7  ( necr o pt osis) assa ys. T hese bi o mar kers will be a nal yze d usi n g 
i m m u n o hist oc he mical (I H C) tec h ni q ues.  C ell pr oliferati o n/ A p o pt osis rati o will be use d as o ur 
pri mar y e n d p oi nt. 
 
Rect al Bi o ps y C ollecti o n  
N o fasti n g or b o wel clea nsi n g pre parati o ns is re q uire d. Partici pa nts are as ke d t o ha ve a b o wel 
m o ve me nt pri or t o arri vi n g at cli nic.  
•  
Patie nt is p ositi o ne d i n t he Si ms p ositi o n.   
•  
Bi o psies are ta ke n at 1 0 c m a b o ve t he a nal ver ge t hr o u g h a n a n osc o pe usi n g a lar ge c u p C o o k 
fle xi ble 2 3 0 c m bi o ps y f orce ps ( 2. 4 m m c u p dia meter).  Use a sta n dar dize d circ u mfere ntial 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 4 – 
a p pr oac h t o ta ke sa m ples at 1 2 o’cl oc k, 1. 5 o’cl oc k, 3 o’cl oc k, 4. 5 o’cl oc k, 6 o’cl oc k, 7. 5 
o’cl oc k, 9 o’cl oc k, 1 0. 5 o’cl oc k.   
•  
Care is ta ke n t o place t he f ull y o pe n bi o ps y f orce ps at ri g ht a n gles t o a n d a gai nst t he m uc osa i n 
or der t o get a sa m ple of s ufficie nt area a n d de pt h.  
•  
At least ei g ht  a de q uate bi o psies m ust be o btai ne d, a n d s h o ul d be 1-2 m m wi de a n d 1 m m t hic k.  
•  
Re m o ve t he bi o ps y fr o m t he f orce ps wit h a pair of pi ncers, plastic (si n gle use) or metal 
(steriliza ble). D o n ot use a nee dle or ot her i nstr u me nt. If t he bi o ps y ca n not be tease d off usi n g t he 
t o ot h pic k, s ha ke it off i n t he n or mal sali ne, re m o ve usi n g a s mall plastic s p o o n a n d p ut i n 
f or mali n or i n pre pare d gree n ca p pe d cr y o vial.  
•  
St u d y staff will e xa mi ne bi o psies wit h a ma g nif yi n g glass t o deter mi ne a de q uac y of bi o ps y.  If a 
bi o ps y pi nc h is i na de q uate, a n ot her is o btai ne d.   
•  
Pl ace 2  rectal bi o ps y s peci me ns i n la bele d speci me n b ottle wit h 1 0 % n or mal b uffere d f or mali n 
i m me diatel y. 
•  
T he re mai ni n g rectal bi o ps y s peci me ns will be s na p fr oze n f or f ut ure a nal yses re q uiri n g fres h 
( n o n-paraffi n i m be d de d) tiss ue.  
•  
Rec or d  t he f oll o wi n g:  
o  S ite of bi o ps y 
o  N u m ber of bi o psies c ollecte d  
o  N ote a n y blee di n g 
o  E nter t he ti me t he bi o psies w ere dr o p pe d i nt o f or mali n a n d/ or s na p fr oze n  
 
Rect al Bi o ps y Pr ocessi n g  
D uri n g pr ocessi n g, t he bi o psies are di vi de d i nt o f o ur parts: 1. fres h fr oze n, 2. e m be d de d, 3. tiss ue 
bl oc ks, a n d 4. sli des 
1.  Fres h Fr oze n S peci me n  
•  
Rectal bi o ps y i n t he vials s h o ul d be froze n  al m ost i m me diatel y w he n place d i n t he 
li q ui d nitr o ge n or dr y ice. 
•  
Fr oze n s peci me n s h o ul d re mai n i n t he li q ui d nitr o ge n or  dr y ice u ntil t he y ca n be 
place d i n t he - 8 0 ° C freezer  
•  
St u d y staff will t he n tra ns p ort s peci me ns t o E pi de mi ol o g y Bi os peci me n C ore M C N B -
2 1 0 3, e xt # 6- 0 4 6 7 
•  
Date, ti me a n d l ocati o n of sa m ple i n t he freezer will be rec or de d o n t he s peci me n l o g  
•  
Sa m ples will be st ore d at – 8 0 ° C.  
•  
S peci me ns will be st ore d u ntil rea d y f or a nal ysis. 
•  
All sa m ples will be l o g ge d i nt o a l o g s heet f or t hat da y, a n d si g ne d off b y res pecti ve 
pers o n nel al o n g t heir m o ve me nt fr o m t he partici pa nt (retrie val, placi n g i nt o freezi n g 
me di u m, tra ns p ortati o n t o t he la b)  
2.  E m be d de d Bi o ps y S peci me ns  
•  
Deli ver s peci me n t o Dr. Ti m ot h y  S u, E pi de mi ol o g y Bi os peci me n C ore, M C N, B - 2 1 0 3, 
wit hi n o ne h o ur of c ollecti o n 
•  
Bi o psies are a p pr o xi matel y 1 m m t hic k  
•  
C ore la b orat or y staff will orie nt s peci me n tiss ue sa m ples are place d o n a bi o ps y s p o n ge 
a n d vis ualize d u n der t he dissecti n g micr osc o pe.  
•  
T ur n a n d orie nt t he bi o ps y m uc osal si de u p s o t hat t he s peci me n is stretc he d o ut as flat 
as p ossi ble.  
•  
M uc osal si de ca n be i de ntifie d b y its h o ne yc o m b -li ke a p peara nce. Ha n dle t he s peci me n 
as little as p ossi ble.  
•  
D o n ot t o uc h t he m uc osal si de of t he bi o ps y e xce pt at t he ver y e d ge of t he bi o ps y.  
•  
D o n ot w orr y if t he bi o ps y is n ot c o m pletel y flat as l o n g as it is n ot t wiste d  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 5 – 
•  
T he la b orat or y/st u d y staff m ust re orie nt bi o psies wit hi n 3 0 mi n utes of bei n g o btai ne d. 
3.  Tiss ue Bl oc ks  
•  
E m be d di n g Bi o psies (e m be d bi o ps y s peci me ns as s o o n as p ossi ble after bi o ps y) 
o  Bi o psies are fi xe d a n d pr ocesse d f or t we nt y -f o ur h o urs i n a tiss ue pr ocess or.  
o  After 2 4 h fi xati o n i n ne utral b uffere d f or mali n, t he bi o psies are place d i n a 
S ha n d o n H y perce nter Pr ocessi n g Ce nter ( T her m o S ha n d o n, Pitts b ur g h, P A), a 
pr o gra m ma ble, a ut o mate d re a ge nt - m o vi n g s yste m use d t o de h y drate a n d 
i nfiltrate fi xe d tiss ues wit h paraffi n.  
o  Bi o psies will be e m be d de d i n o ne paraffi n bl oc k. Pa y atte nti o n t o e m be d di n g 
orie ntati o n of t he tiss ues s o t hat well - orie nte d l o n git u di nal cr y pts ca n be 
secti o ne d.  
o  T he casse ttes are la bele d wit h a # 3 pe ncil o n t he fr o nt si de of eac h bl oc k wit h 
t he partici pa nts I D # a n d visit date.    
o  I nitial water resi d ues are re m o ve d fr o m tiss ues b y fl us hi n g gra de d alc o h ols ( 7 0, 
8 0, 9 5, a n d 1 0 0 %) se q ue ntiall y i nt o t he reacti o n c ha m ber.  
o  Eac h alc o h ol re mai ns i n t he tiss ue -c o ntai ni n g c ha m ber f or a p pr o xi matel y 4 5 
mi n utes, a n d a 5- mi n ute drai ni n g peri o d is all o we d bet wee n alc o h ol c ha n ges.   
T w o x yle ne e xc ha n ges are f oll o we d b y t w o 6 0 C heate d paraffi n e xc ha n ges, eac h 
o ne h o ur i n d urati o n.   
o  T he p araffi n-i nfiltrate d tiss ues are re m o ve d fr o m t he H y perce nter, e m be d de d i nt o 
paraffi n bl oc ks, a n d pre pare d f or s hi p me nt. 
o  Bl oc ks are t he n st ore d i n t he refri gerat or i n t he c ore la b at 4 de grees C u ntil rea d y 
f or a nal ysis.  
•  
St ora ge: Bl oc ks are st ore d i n t he c ore la b at 4 de grees C. 
4.  Sli de pre p ar ati o n  
•  
Bi o psies will be secti o ne d wit h a micr ot o me s o t hat cr y pts will be l o n git u di nall y 
secti o ne d fr o m base t o l u me n.  
•  
Secti o ns are t he n place d se q ue ntiall y o n p ositi ve c har ge d sli des a n d n u m bere d fr o m 1 
t o 2 6.  
•  
Secti o n le vels are Fi ve micr o ns t hic k, a n d are ta ke n a p pr o xi matel y 5 0 micr o ns a part.  
( Ta ki n g secti o ns 5 0 micr o ns a part t o a v oi d d o u ble c o u nti n g of cr y pts i n bi o ps y 
s peci me ns)  
•  
T he secti o ns n u m bere d 1, 1 1 a n d 2 1 will be use d f or H & E stai ni n g. 
•  
Sli des are pre pare d f or pr ocessi n g eac h of t he a nti b o dies f or a p o pt osis, cell 
pr oliferati o n, a n d necr o p t osis bi o mar kers (e. g. Ki- 6 7, BA X , T U N E L, p M L K L , 
T R P M 7, C O X - 2) assa y. 
•  
M ulti ple bi o psies are c ollecte d a n d m ulti ple secti o ns will be pre pare d. I n case of 
stai ni n g r u n fail ures, o ne bac k u p serial secti o n per sli de f or stai ni n g is pre pare d. 
•  
All bl oc ks a n d sli des will be st ore d i n a vac u u m c ha m ber at 4 de gree C i n a c ol d r o o m 
u ntil a nal ysis.  
 
1 0. 2. 2 Rect al S w a bs  
Rectal S wa bs are c ollecte d at C li nic Visits 2- 4.  Bi o mar kers fr o m rectal  s wa bs i ncl u de t he a b u n da nce 
of E. c oli, F us o bacteri u m , a n d ot her micr o bi ota. 
 
Rect al S w a b C ollecti o n  
Patie nt is p ositi o ne d i n Si ms p ositi o n.  
At least 2 rectal s wa bs will be ta ke n.  
•  
I nsert c ult urette s wa b a b o ut 2 i nc hes i nt o rect u m, rotate s wa b t o c ollect fecal material, a n d 
caref ull y re m o ve s wa b fr o m rec t u m 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 6 – 
•  
I nsert s wa b i nt o t u be ( o ne s wa b t o o ne t u be). Freeze t he t u bes a n d st ore t he sa m ple at -8 0˚ C u ntil 
f ut ure a nal ysis. 
•  
R ec or d t he ti me of c ollecti o n.  
•  
Se n d t he sa m ple t o la b f or i m me di ate st ora ge. 
•  
All sa m ples will be l o g ge d i nt o a l o g s heet f or t hat da y, a n d si g ne d off b y res pecti ve pers o n nel 
al o n g t heir m o ve me nt fr o m t he partici pa nt (retrie val, placi n g i nt o freezi n g me di u m, tra ns p ortati o n 
t o t he la b). 
 
1 0. 2. 3 Bl o o d  
  
Bl o o d is c ollecte d at all Cli nic Visits.  Bl o o d is use d f or cli nical a n d researc h la bs.  T his secti o n 
descri bes t he bl o o d c ollecte d f or researc h la bs.  
 
Bl o o d C ollecti o n 
•  
T w o t u bes of researc h bl o o d are c ollecte d: o ne E D T A f or plas ma, W B C, R B C, a n d o ne re d t o p 
t u be f or ser u m. 
•  
Bl o o d s peci me ns will be st ore d i n C R C or ot her cli nical r o o m refri gerat or u ntil pr ocessi n g. 
 
Bl o o d Pr ocessi n g  
•  
St u d y staff will t he n tra ns p ort s peci me ns t o E pi de mi ol o g y Bi os peci me n C ore M C N B- 2 1 0 3, e xt 
# 6- 0 4 6 7.  
•  
S peci me ns will be pr ocesse d wi t hi n 4-6 h o urs after c ollecti o n . 
•  
All s peci me n’s will be la bele d wit h date, partici pa nt I D #  
•  
Ser u m  w ill be c ollecte d after c oa g ulati o n.  
•  
W h ole bl o o d will be pr ocesse d wit hi n 4- 6 h o urs a n d se parate d i nt o plas ma , b uff y c oats ( w hite 
cells), R B C.  
•  
1- 2 ml ali q u ots of t he ser u m/ plas ma sa m ple will be pi pette d i nt o 3- la bele d cr y o vials. 
•  
Vials will be place d i n s peci me n b o x f or st ora ge  
•  
Date, ti me a n d l ocati o n of sa m ple i n t he freezer will be rec or de d o n t he s peci me n l o g  
•  
Sa m ples will be st ore d at – 8 0 ° C.   
•  
Bl o o d s peci me ns will be st ore d u ntil use i n rele va nt assa ys.  
 
1 0. 2. 4 Uri ne  
Uri ne is c ollecte d at Cli nic Visits 2 - 4.  Uri ne c ollecti o n will be o pti o nal f or partici pa nts.  Pri or t o 
c ollecti o n, t he partici pa nt will nee d t o a gree t o o pti o nal f ut ure researc h o n t he i nf or me d c o nse nt 
f or m.   
 
Uri ne C ollecti o n  
•  
Eac h uri ne sa m ple will be c ollecte d i n a sterile uri ne s peci me n c o ntai ner c o ntai ni n g 1 0 0 m g 
asc or bic aci d as a preser vati ve.   
•  
Uri ne s peci me ns will be st ore d i n C R C or ot her cli nical r o o m freezer u ntil pr ocesse d . 
 
Uri ne Pr ocessi n g  
•  St u d y staff will t he n tra ns p ort s peci me ns t o E pi de mi ol o g y Bi os peci me n C ore M C N B-
2 1 0 3, e xt # 6- 0 4 6 7  
•  S peci me ns will be pr ocesse d wit hi n 4 -6 h o urs after c ollecti o n.  
•  All s peci me n’s will be la bele d wit h date, partici pa nt I D #.  
•  1- 2 ml ali q u ots of t he uri ne sa m ple will be pi pette d i nt o e ac h of 3 -la bele d, 1. 8 ml cr y o vials. 
•  Vials will be place d i n s peci me n b o x f or st ora ge.  
•  Re mai ni n g s peci me n will be discar de d. 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 7 – 
•  Date, ti me a n d l ocati o n of sa m ple i n t he freezer will be rec or de d o n t he s peci me n l o g. 
•  Sa m ples will be st ore d at – 8 0 ° C’  
•  Uri ne s peci me ns will be st ore d u ntil rea d y f or a nal ysis. 
 
1 0. 2. 5 St o ol  
St o ol sa m ples will be c ollecte d f or all Cli nic Visits.  Partici pa nts will c ollect t he st o ol sa m ple at 
h o me wit hi n 7 da ys pri or t o eac h cli nic visit da y , a n d bri n g it t o t he cli nic.  St o ol c ollecti o n kits 
will be maile d t o t he partici pa nt pri or t o Cli nic Vi sit 1.  Partici pa nts will be gi ve n st o ol c ollecti o n 
kits at Cli nic Visits 1 - 3 f or c ollecti o n pri or t o t he s u bse q ue nt Cli nic Visit, acc or di n g t o secti o n 
7. 6.  Bi o mar kers fr o m st o ol sa m ples i ncl u de t he fecal occ ult bl o o d test. 
 
St o ol C ollecti o n 
•  Eac h st o ol sa m ple will be c ollecte d i n a sterile st o ol s peci me n c o ntai ner wit h wi de m o ut h, 
la bele d “ St o ol Sa m ple.”  
•  A b o ut 2 gra ms / 2 ml st o ol will be tra nsferre d i nt o 2 la bele d plastic t u bes wit h s p o o n. 
•  All s peci me n c o ntai n ers will be la bele d wit h c ollecti o n date a n d ti me, sa m ple I D #, a n d 
partici pa nt I D #.  
•  St o ol s peci me ns will be st ore d i n C R C  or ot her cli nical r o o m  freezer. 
 
St o ol Pr ocessi n g 
•  St o ol sa m ple t u bes will be place d i n s peci me n b o x f or st ora ge.  
•  Date, ti me, sa m ple I D #, partici pa nt I D #, a n d l ocati o n of sa m ple i n t he freezer will be 
rec or de d o n t he s peci me n l o g.  
•  Sa m ples will be st ore d at – 8 0 ° C i m me diatel y.  
•  St o ol s peci me ns will be st ore d u ntil rea d y f or a nal ysis.  
 
1 0. 3 
S hi p pi n g I nstr ucti o ns  
 
All sa m ples will be s hi p pe d i n c o m plia nce wit h t he I nter nati o nal Air Tra ns p ort Ass ociati o n (I A T A) 
Da n ger o us G o o ds Re g ulati o ns. All s peci me n s hi p me nts s h o ul d be i nitiate d o n M o n da ys , T ues da ys, or 
We d nes da y s, after c o m m u nicati o n wit h t he recei vi n g site a n d notif yi n g nc pc @ n ort h wester n.e d u  of t he 
trac ki n g n u m ber.   
 
Tiss u e s a m ples f or D N A met h yl ati o n will be s hi p pe d t o Dr. Lifa n g H o u’s la b orat or y o n dr y ice via 
o ver ni g ht Fe d E x. Bel o w is t he s hi p pi n g a d dress:   
 
Dr. Li fa n g H o u/J u n Wa n g 
De part me nt of Pre ve nti ve Me dici ne  
Fei n ber g Sc h o ol of Me dici ne 
N ort h wester n U ni versit y 
6 8 0 N La ke S h ore Dri ve, S uite 1 4 0 0 
C hica g o, I L 6 0 6 1 1 
P h o ne: ( 3 1 2) 5 0 3 - 2 9 6 5 
 
Rect al S w a bs  are s hi p pe d o n dr y ice via o ver ni g ht Fe d E x t o M. A n drea Azcarte-Peril , i n o ne batc he d 
s hi p me nt at t he e n d of t he st u d y.   
M. A n drea Azcarate -Peril  
Direct or, Micr o bi o me C ore Facilit y 
U ni versit y of N ort h Car oli na at C ha pel Hill 
De part me nt of Me dici ne G.I. Di visi o n  

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 8 – 
3 1 2 Isaac Ta yl or Hall  
1 0 9 Mas o n Far m R d 
C ha pel Hill, N C 2 7 5 9 9 
P h o ne: ( 9 1 9) 9 6 6 - 9 8 3 8 
 
 
1 0. 4 
Tiss ue B a n ki n g  
 
After getti n g per missi o n fr o m t he partici pa nts t hat t heir sa m ples ca n be st ore d a n d use d f or f ut ure st u d y, 
t he bi ol o gic s peci me ns c ollecte d d uri n g t he c o n d uct of eac h cli nical trial t hat are n ot use d d uri n g t he 
c o urse of t he st u d y will be c o nsi dere d deli vera bles u n der t he c o ntract a n d t h us t he pr o pert y of t he N CI. At 
st u d y c o m pleti o n, N CI reser ves t he o pti o n t o eit her retai n or reli n q uis h o w ners hi p of t he u n use d bi ol o gic 
s peci me ns. If N CI retai ns o w ners hi p of s peci me ns, t he C o ntract or s hall c ollect, verif y a n d tra nsfer t he 
re q ueste d bi ol o gic s peci me ns fr o m t he site t o a N CI-s pecifie d re p osit or y or la b orat or y at N CI’s e x pe nse.  
 
1 1. 
R E P O R TI N G A D V E R S E E V E N T S  
 
D E FI NI TI O N: A E mea ns a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g i n h u ma ns, 
w het her or n ot c o nsi dere d dr u g relate d. A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n), 
s y m pt o m, or disease te m p orall y ass ociate d wit h partici pati o n i n a st u d y, w het her or n ot relate d t o t hat 
partici pati o n. T his i ncl u des all deat hs t hat occ ur w hile a partici pa nt is o n a st u d y.  
 
Please n ote t hat all a b n or mal cli nical la b orat or y val ues t hat are deter mi ne d t o be of cli nical si g nifica nce 
base d o n a p h ysicia n’s assess me nt are t o be re p orte d as A Es. T h ose la bs deter mi ne d t o be of n o cli nical 
si g nifica nce or of u n k n o w n cli nical si g nifica nce ( per t he p h ysicia n’s assess me nt) s h o ul d n ot be re p orte d 
as A Es. A n y la b val ue of u n k n o w n cli nical si g nifica nce s h o ul d c o nti n ue t o be i n vesti gate d/f oll o we d- u p 
f urt her f or a fi nal deter mi nati o n, if p ossi ble. 
 
A list of A Es t hat ha ve occ urre d or mi g ht occ ur  ca n be f o u n d i n § 6. 2 Re p orte d A d verse E ve nts a n d 
P ote ntial Ris ks , as well as t he I n vesti gat or Br oc h ure or pac ka ge i nsert.  
 
1 1. 1 
A d verse E ve nts  
 
1 1. 1. 1  Re p orta ble A Es 
 
All A Es t hat occ ur after t he i nf or me d c o nse nt is si g ne d a n d baseli ne assess me nts are c o m plete d 
(i ncl u di n g r u n-i n) m ust be rec or de d o n t he A E C R F ( pa per a n d/ or electr o nic) w het her or n ot relate d t o 
st u d y a ge nt. 
 
1 1. 1. 2 A E Data Ele me nts:  
 
T he f oll o wi n g data ele me nts are re q uire d f or A E  re p orti n g. 
•  
A E ver bati m ter m  
•  
N CI C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts versi o n 4. 0 ( C T C A E v 4. 0) A E ter m 
( Me d D R A l o west le vel ter m) 
•  
C T C A E ( Me d D R A) S yste m Or ga n Class ( S O C)  
•  
E ve nt o nset date a n d e ve nt e n de d date 
•  
Treat me nt assi g n me nt c o de ( T A C ) at ti me of A E o nset 
•  
Se verit y gra de 
•  
Attr i b uti o n t o st u d y a ge nt (relate d ness) 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 2 9 – 
•  
W het her or n ot t he e ve nt was re p orte d as a S A E  
•  
W het her or n ot t he s u bject dr o p pe d d ue t o t he e ve nt  
•  
O utc o me of t he e ve nt  
 
1 1. 1. 3  Se verit y of A Es  
  
  
 
1 1. 1. 3. 1 I de ntif y t he A E usi n g t he C T C A E versi o n 4. 0. T he C T C A E pr o vi de s descri pti ve ter mi n ol o g y 
( Me d D R A l o west le vel ter m) a n d a gra di n g scale f or eac h A E  liste d. A c o p y of t he C T C A E ca n be f o u n d 
at htt p://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ctc. ht m  
 
A Es will be assesse d acc or di n g t o t he gra de ass ociate d wit h t he C T C A E  ter m. A Es t hat d o n ot ha ve a 
c orres p o n di n g C T C A E ter m will be assesse d acc or di n g t o t he ge neral g ui deli nes f or gra di n g use d i n t he 
C T C A E v 4. 0. as state d bel o w.  
 
C T C A E v 4. 0 ge ner al se verit y g ui deli nes:  
 
Gr a de  
Se v erit y  
Descri pti o n  
1  
Mil d  
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser v ati o ns o nl y; 
i nter v e nti o n n ot i n dicate d. 
2  
M o d erate  
M o d erate; mi ni mal, l o cal or n o ni n v asi v e i nter v e nti o n i n dicate d;  
li miti n g a g e-a p pr o priate i nstr u me ntal acti vities of d ail y li vi n g ( A D L) *.  
3  
Se v ere  
Se v ere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pitalizati o n or pr ol o n g ati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self -
care A D L * *.  
4  
Life -t hreate ni n g 
Life -t hreate ni n g c o nse q u e n ces; ur g e nt i nter v e nti o n i n dicate d. 
5  
Fatal  
Deat h relate d t o A E.  
   
A D L  
 
*I nstr u me ntal A D L refers t o pre pari n g meals, s h o p pi n g f or gr oceries or cl ot hes, usi n g t he tele p h o ne, 
ma na gi n g m o ne y, etc. 
 
* * Self-care A D L refers t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g 
me dicati o ns, a n d n ot be dri d de n. 
 
1 1. 1. 4 Assess me nt of relati o ns hi p of A E t o treat me nt  
  
 
T he p ossi bilit y t hat t he A E  is relate d t o st u d y a ge nt will be classifie d as o ne of t he f oll o wi n g: n ot relate d, 
u nli kel y, p ossi ble , pr o ba ble, defi nite. 
  
1 1. 1. 5  F oll o w- u p of A Es 
 
All A Es, i ncl u di n g la b a b n or malities t hat i n t he o pi ni o n of t he i n vesti gat or are cli nicall y si g nifica nt, will 
be f oll o we d acc or di n g t o g o o d me dical practices a n d d oc u me nte d as s uc h.  
 
1 1. 2 
Seri o us A d verse E ve nts  
 
1 1. 2. 1 D E FI NI TI O N : Re g ulati o ns at 2 1 C F R § 3 1 2. 3 2 (re vise d A pril 1, 2 0 1 4) defi nes a n S A E as a n y  
u nt o war d me dical occ urre nce t hat at a n y d ose h as o n e or m or e of t h e f oll o wi n g o ut c o m es : 
 
• 
Dea t h 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 3 0 – 
•  
A life-thr eate nin g A E  
•  In patie nt h os pitalizati o n or pr o lo n gati o n of e xisti n g  h os pitalizati o n 
•  
A p ersistent  or si g nificant i n capa cit y or s u bsta ntial disr u pti o n of t he a bilit y t o perf or m n or mal life 
f u ncti o ns 
•  
A c o n ge nital an o m aly or  birt h de fect 
• 
I m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life-t hreate ni n g or res ult i n deat h 
or h os pitalizati o n s h o ul d als o be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate 
me dical j u d g me nt, t he y ma y je o par dize t he patie nt a n d ma y re q uire i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes. 
 
1 1. 2. 2  R ep orti n g S A Es t o D C P 
 
1 1. 2. 2. 1  T he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns will re p ort S A Es o n t he D C P S A E 
Re p ort F or m f o u n d at htt p:// pre ve nti o n.ca ncer. g o v/cli nical- trials/cli nical -trials-ma na ge me nt/ pr ot oc ol -
i nf or mati o n-office/ pi o -i nstr ucti o ns-a n d-t o ols/ 2 0 1 2-c o ns ortia. 
 
1 1. 2. 2. 2  C o ntact t he D C P Me dical M o nit or  b y p h o ne wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt.  
 
Gar y Della’ Za n na, D O, M Sc  
N CI/ Di visi o n of Ca ncer Pre ve nti o n 
Gastr oi ntesti nal a n d Ot her Ca ncers Researc h Gr o u p  
9 6 0 9 Me dical Ce nter Dri ve, M S C- 9 7 8 2 
R oc k ville, M D 2 0 8 5 0 
P h o n e: 2 4 0- 2 7 6- 7 0 4 2 
Fa x ( wit h c o ver s heet, Att n: Dr. G. Della’ Za n na): 2 4 0- 2 7 6- 7 8 4 8 
E mail: gar y. dellaza n na @ ni h. g o v 
 
I ncl u de t he f oll o wi n g i nf or mati o n w he n calli n g t he Me dical M o nit or : 
•  
Date a n d ti me of t he S A E  
•  
Date a n d ti me of t he S A E re p ort  
•  
Na me of re p orter  
•  
Cal l bac k p h o ne n u m ber 
•  
Affiliati o n/I nstit uti o n c o n d ucti n g t he st u d y 
•  
D C P pr ot oc ol n u m ber 
•  
Title of pr ot oc ol  
•  
Descri pti o n of t he S A E, i ncl u di n g attri b uti o n t o dr u g 
 
1 1. 2. 2. 3  T he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns will e mail writte n S A E re p orts t o t he 
D C P Me dical M o nit or at gar y. dellaza n na @ ni h. g o v, t o D C P’s Re g ulat or y C o ntract or C C S Ass ociates, 
I nc. ( C C S A; p h o ne: 6 5 0-6 9 1 - 4 4 0 0) at safet y @ccsai nc.c o m, a n d t o N ort h wester n Ca ncer Pre ve nti o n 
C o ns orti u m ( N C P C, p h o ne 3 1 2- 5 0 3- 7 8 2 1 ) at nc pc @ n ort h wester n.e d u wit h i n 4 8 h o urs of lear ni n g of t he 
e ve nt usi n g t he filla ble P D F S A E Re p ort F or m.  
  
1 1. 2. 2. 4  T he D C P Me dical M o nit or  a n d C C S A re g ulat or y a n d safet y  staff will deter mi ne w hic h S A Es 
re q uire F D A s u b missi o n as I N D safet y re p orts . 
 
1 1. 2. 2. 5  T he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns will c o m pl y wit h a p plica ble re g ulat or y 
re q uire me nts relate d t o re p orti n g S A Es t o t he I R B/I E C.  
 
1 1. 2. 3  F oll o w- u p of S A E 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 3 1 – 
 
We will f oll o w u p after 3 0 da ys of t he i nitial e ve nt. Site staff s h o ul d se n d f oll o w -u p re p orts as 
re q ueste d w he n a d ditio nal i nf or mati o n is a vaila ble. A d diti o nal i nf or mati o n s h o ul d be e ntere d o n t he D C P 
S A E Re p ort F or m i n t he a p pr o priate f or mat. F oll o w- u p i nf or mati o n s h o ul d be se nt t o D C P as s o o n as 
a vaila ble.  
 
1 2. 
S T U D Y M O NI T O RI N G  
 
1 2. 1  
D at a M a n a ge m e nt 
 
Data will be ma na ge d acc or di n g t o sta n dar d o perati n g pr oce d ures, w hic h meet t he g ui deli nes of D C P 
Re q uire me nts f or Data Ma na ge me nt a n d w hic h f oll o w t he Data Ma na ge me nt Pla n t hat N ort h wester n 
U ni versit y has o n file wit h t he Di visi o n of Ca ncer Pre ve nti o n, N C I.  S o urce data verificati o n will be 
perf or me d b y t he De part me nt of Cli nical Researc h Ser vices.   T he C o ns ortia 2 0 1 2 Data Ma na ge me nt Pla n, 
s u b mitte d as part of a c o ntract a gree me nt wit h t he N CI ( H H S N 2 6 1 2 0 1 2 0 0 0 3 5I), was a p pr o ve d.  
 
1 2. 2 
C ase Re p ort F or ms  
 
Partici pa nt data will be c ollecte d usi n g pr ot oc ol- s pecific case re p ort f or ms ( C R Fs) de vel o pe d fr o m t he 
sta n dar d set of D C P C he m o pre ve nti o n C R F Te m plates a n d utilizi n g N CI-a p pr o ve d C o m m o n Data 
Ele me nts ( C D Es). T he a p pr o ve d C R Fs will be use d b y N ort h w ester n U ni versit y t o create t he electr o nic 
C R Fs (e - C R Fs) scree ns i n t he R o bert H. L urie C o m pre he nsi ve Ca ncer Ce nter of N ort h wester n U ni versit y 
( L urie Ca ncer Ce nter) Cli nical Trials Ma na ge me nt S yste m ( C T M S). Site staff will e nter data i nt o t he e-
C R Fs f or tr a ns missi o n t o D C P acc or di n g t o D C P sta n dar ds a n d pr oce d ures. 
 
1 2. 3 
S o urce D oc u m e nts  
 
All s o urce d oc u me nts will be c ollecte d a n d st ore d i n t he Cli nical Researc h Office of t he site w here t he 
partici pa nt was accr ue d.  A n y data rec or de d directl y o n C R Fs t hat c o nstit ute  n o pri or writte n or electr o nic 
rec or d of data, will be s pecificall y i de ntifie d as s o urce data.   Q uesti o n naires c o m plete d i n pers o n ma y be 
c o m plete d directl y o n t he pa per C R F a n d nee d n ot be tra nscri be d fr o m se parate s o urce d oc u me ntati o n.  
 
1 2. 4  
D at a a n d S afet y M o nit o ri n g Pl a n 
 
A c o m pre he nsi ve Data Safet y a n d M o nit ori n g Pla n has bee n s u b mitte d b y N ort h wester n U ni versit y, 
a p pr o ve d b y t he D C P, a n d is o n file t here.  A n y f ut ure c ha n ges will be f or war de d f or re vie w.   
 
1 2. 5  
S p o ns or or F D A M o nit ori n g 
 
T h e N CI, D C P ( or t heir desi g nee), p har mace utical c olla b orat or ( or t heir desi g nee), or F D A ma y 
m o nit or/a u dit vari o us as pects of t he st u d y. T hese m o nit ors will be gi ve n access t o facilities, data bases, 
s u p plies a n d rec or ds t o re vie w a n d verif y data perti ne nt to t he st u d y.  
 
1 2. 6 
Rec or d R ete nti o n  
 
Cli nical rec or ds f or all partici pa nts, i ncl u di n g C R Fs, all s o urce d oc u me ntati o n (c o ntai ni n g e vi de nce t o 
st u d y eli gi bilit y, hist or y a n d p h ysical fi n di n gs, la b orat or y data, res ults of c o ns ultati o ns, etc.), as well as 
I R B rec or ds a n d ot her re g ulat or y d oc u me ntati o n will be retai ne d b y t he I n vesti gat or i n a sec ure st ora ge 
facilit y i n c o m plia nce wit h Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A), Office of 
H u ma n Researc h Pr otecti o ns ( O H R P), F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns a n d g ui da nces, 

 
 
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Pr ot o c ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 3 2 – 
a n d N CI/ D C P re q uire me nts, u nless t he sta n dar d at t he site is m ore stri n ge nt. T he rec or ds f or all st u dies 
perf or me d u n der a n I N D will be mai ntai ne d, at a mi ni m u m, f or t w o years after t he a p pr o val of a Ne w 
Dr u g A p plicati o n ( N D A). F or N CI/ D C P, rec or ds will be retai ne d f or at least t hree years after t he 
c o m pleti o n of t he researc h. N CI will be n otifie d pri or t o t he pla n ne d destr ucti o n of a n y materials. T he 
rec or ds s h o ul d be accessi ble f or i ns pecti o n a n d c o p yi n g b y a ut h orize d pers o ns of t he F o o d a n d Dr u g 
A d mi n istrati o n. If t he st u d y is d o ne o utsi de of t he U nite d States, a p plica ble re g ulat or y re q uire me nts f or 
t he s pecific c o u ntr y partici pati n g i n t he st u d y als o a p pl y. 
 
1 2. 7 
C o o per ati ve R ese arc h a n d De vel o p me nt A gree me nt ( C R A D A)/ Cli nic al Tri als 
A gree m e nt ( C T A) 
 
N ot a p plica ble, si nce a C T A will n ot be re q uire d f or t his st u d y. 
 
1 3. 
S T A TI S TI C A L C O N SI D E R A TI O N S  
 
1 3. 1 
St u d y Desi g n/ Descri pti o n  
 
T his is a P hase IIa, 3 ar m, ra n d o mize d place b o -c o ntr olle d trial (4 0 s u bjects i n eac h of t w o treat me nt ar ms 
a n d 1 0 s u bjec ts i n t he place b o ar m) t o e val uate w het her, use of as piri n at 3 2 5 m g i n a t hree wee ks 
o n/t hree wee ks off re gi me n has si milar/e q ui vale nt efficac y. O ur h y p ot hesis  is t hat i nter mitte nt use gr o u p 
will s h o w e q ui vale nt re d ucti o n i n t he pri mar y e n d p oi nt ( pr olifer ati o n: a p o pt osis  rati o) a n d re d uce d ris k of 
a d verse e ve nts, as t hat usi n g as piri n dail y.  
 
1 3. 2  
R a n d o miz ati o n/ Str atific ati o n  
 
I n c urre nt st u d y, t here are t hree ar ms:  t w o treat me nt ar ms ( 3 2 5 m g as piri n dail y c o nti n u o usl y f or 1 2 
wee ks, a n d 3 2 5 m g as piri n  dail y  3- wee k o n/ 3- wee k off) a n d o ne place b o c o ntr ol ar m . I n di vi d uals 
assi g ne d t o 3 2 5 m g as piri n 3- wee k o n/ 3- wee k off will ta ke place b o d uri n g 3- wee k off peri o d.  
T his st u d y will recr uit 9 0 partici pa nts wit h c ol orectal a de n o ma. A per m ute d -bl oc k ra n d o mizati o n desi g n  
will be use d t o all ocate t he s u bjects i nt o t he treat me nt/ place b o ar m.   
 
1 3. 3  
Accr u al a n d Fe asi bilit y  
 
Base d o n o ur e x perie nce fr o m pre vi o us R 0 1 trials, we e x pect t o e nr oll 3 0- 4 5 partici pa nts i n year 1  a n d 
e nr oll t he re mai ni n g i n Years 2.  
 
1 3. 4  
Pri m ar y O bjecti ve, E n d p oi nt(s), A n al ysis Pl a n 
 
T he pri mar y e n d p oi nt  will be t he rati o of pr oliferati o n  t o a p o pt osis bi o mar kers ( Ki 6 7 i n de x: B A X  i n de x, 
meas ure d c o nti n u o us l y) i n c ol orectal m uc osa.  We a ntici pate t hat t he t w o treat me nt ar ms are “e q ui vale nt” 
wit h re gar d t o t his mai n o utc o me, i n t he ma nner descri be d bel o w, f or w hic h p o wer a nal ysis is pr o vi de d. 
T he statistical a nal ysis will c o nsist of e xa mi ni n g w het her t w o mea ns a re wit hi n prescri be d li mits fr o m 
eac h ot her. Alter nati vel y, t w o o ne si de d tests ca n be perf or me d.  We ha ve n 1 = n 2 = 3 2, w hic h is 4 0 less 
2 0 % dr o p o ut; 4 0 - 8 = 3 2. 
 
P o wer a n al ysis f or t he m ai n o utc o me  
 
T he mai n o utc o me is defi ne d as t he rati o R = P/ A,  w here P f or m eas ure of Pr oliferati o n a n d A sta n ds f or 
meas ure of A p o pt osis. I n pri nci ple, i nter ve nti o n i ncreases t he A p o pt osis a n d decreases Pr oliferati o n, 

 
 
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– 3 4 – 
 
Si z e  
Si z e  
E q ui v.  
E q ui v.  
Tr u e  
St a n d ar d   
  
 
P o w er  
( N 1) 
( N 2) 
Li mit  
Li mit  Diff er e n c e  
D e vi ati o n  
Al p h a  
B et a  
0. 5 2  
3 2  
3 2   
-2. 0 2  
2. 0 2  
0. 0 0  
4. 0 4  
0. 1 0  
0. 4 8  
0. 8 1  
3 2  
3 2   
-3. 0 3  
3. 0 3  
0. 0 0  
4. 0 4  
0. 0 5  
0. 1 9  
0. 9 1  
3 2  
3 2   
-3. 0 3  
3. 0 3  
0. 0 0  
4. 0 4  
0. 1 0  
0. 0 9  
 
T he n or malit y ass u m pti o n f or t he rati o R will be c hec ke d, a n d data will be l o garit h micall y tra nsf or me d if 
t he n or malit y ass u m pti o n d oes n ot h ol d. Ass u mi n g l o g - n or mal distri b uti o n, mea n of 2. 5 4 a n d S D = 4. 0 4 o n 
t he ori gi nal scale c orres p o n d t o mea n m = 0. 3 0 1 5 a n d S Dl o g = 1. 1 2 o n t he l o g-tra nsf or me d scale.  F urt her 
ass u mi n g e q ual varia nces acr oss ti me p oi nts i n b ot h treat me nt ar ms, a n d wit hi n -s u bject c orrelati o n 0. 5 
bet wee n pre- a n d p ost- treat me nt val ues (as a b o ve), t he sta n dar d de viati o n of c ha n ges will als o be S DD,l o g  
= 1. 1 2.  T he e q ui vale nce mar gi n o n t he l o g- scale will t he n be δ = 3/ 4 * S D D ,l o g = 0. 8 4 2 3.  
 
Base d o n t he T O S T pr oce d ure, e q ui vale nce will be esta blis he d at α = 0. 0 5 si g nifica nce le vel if t he ( 1 -
2 α) × 1 0 0 % CI f or t he differe nce is c o ntai ne d wit hi n t he i nter val ( -δ, δ). T he o verall p -val ue f or t he 
e q ui vale nce test will be t he lar ger of t he p - val ues of t he t w o o ne-si de d tests.  
 
 
1 3. 5 
Sec o n d ar y a n d E x pl or at or y O bjecti v es, E n d p oi nts, A n al ysis Pl a ns  
 
T he sec o n dar y o bjecti ves are t o e val uate t he effects of as piri n treat me nts o n :   
1) t he rati o of cell pr oliferati o n ( Ki-6 7)/a p o pt osis ( T U N E L) i n rectal bi o psies 
2) t he rati o of cell pr oliferati o n ( Ki-6 7)/ necr o pt osis ( p M L K L) i n rectal bi o psies  
3 ) fecal occ ult bl o o d test ( meas ures of a d verse e ve nts) as meas ure d b y st o ol sa m ples  
 
T he e x pl orat or y o bjecti ves are t o e val uate t he effects of as piri n treat me nts o n : 
 
1) C O X -2 i n rectal bi o psies  
             2) BA X  i n rectal bi o psies 
  
3) T R P M 7 i n rectal bi os pies 
4 ) j oi nt i n de x of C O X-2 wit h T R P M 7 e x pressi o n i n rectal bi o psies;  
  
5) j oi nt i n de x of T R P M 7 wit h B A X i n rectal bi o psies; 
  
6) met h ylati o n assa ys usi n g t he Met h ylati o n E PI C Bea d C hi p t o i de ntif y met h ylati o n bi o mar kers  
  
     i n ge nes (i.e. C D K N 2 A (cell c ycle re g ulati o n), M G M T ( D N A re pair), D A P K 1(a p o pt osis),   
   
                  C D H 1(cell i n vasi o n), W N T 1 6 ( W nt pat h wa y) a n d R A S S F 1 ( R A S si g nali n g)) i n v ol ve d i n   
 
                  c ol orectal carci n o ge nesis, a n d ot her e pi ge n o me- wi de met h ylati o n bi o mar kers as meas ure d i n    
                  rectal bi o psies; 
  
7) meta ge n o mics a nal ysis t o meas ure a b u n da nce of E. c oli a n d F us o bacteri u m a n d ot her     
 
  
     micr o bi ota i n rectal s wa bs 
 
T he maj orit y of sec o n dar y a n d e x pl orat or y e n d p oi nts are c o nti n u o us. Bi o mar ker le vels at baseli ne, 9 a n d 
1 2 wee ks, as well as t he c orres p o n di n g c ha n ges fr o m baseli ne, will  be s u m marize d usi n g descri pti ve 
statistics i ncl u di n g mea ns a n d sta n dar d de viati o ns or me dia ns a n d i nter q uartile ra n ge, as well as gra p hical 
met h o ds s uc h as “s pa g hetti pl ots” t hat de pict c ha n ge patter ns o ver ti me. Distri b uti o ns of eac h mar ker will 
be e xa mi ne d, a n d val ues ma y be tra nsf or me d as nee de d t o sta bilize t he varia nce or satisf y t he n or malit y 
ass u m pti o n. C orrelati o n bet wee n bi o mar kers, a n d bet wee n pre - a n d p ost-treat me nt val ues will be 
e xa mi ne d usi n g scatter pl ots wit h o verla ye d s m o ot her pl ots f or ease of vis ual i nter pretati o n.  
 
If t he n or malit y ass u m pti o ns are satisfie d, paire d t-tests will be use d t o e xa mi ne w het her t he bi o mar kers 
c ha n ge fr o m baseli ne t o 1 2 wee ks p ost -treat me nt i n eac h treat me nt ar m. Si g ne d ra n k test will be use d if 
n o s uita ble tra n sf or mati o n ca n be f o u n d. Beca use we e x pect t hat t he c o nti n u o us a n d i nter mitte nt d osi n g 
re gi me ns will res ult i n si milar bi o mar ker c ha n ges, we will use t he T O S T pr oce d ure, si milar t o t he pri mar y 

 
 
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– 3 5 – 
e n d p oi nt, t o test f or e q ui vale nce. T he e q ui vale nce mar gi n will be set as 3/ 4 of t he o bser ve d sta n dar d 
de viati o n of t he mar ker at baseli ne, si milar t o t he pri mar y e n d p oi nt.   
 
A d diti o nal a nal yses will be c o n d ucte d usi n g li near mi xe d effects m o dels wit h re peate d meas ures t o 
f urt her e x pl ore bi o mar ker c ha n ge patter ns o ver ti me acr oss 3 ti me p oi nts, a n d t o c o m pare t he m bet wee n 
ar ms. T hese m o dels use all a vaila ble o bser vati o ns acc o m m o dati n g data t hat are missi n g at ra n d o m, rat her 
t ha n perf or mi n g a c o m plete case a nal ysis. 
 
A place b o ar m is i ncl u de d i n t he sec o n dar y a nal yses b eca use t he variati o ns o n re peate d meas ure me nt of 
t he ne w bi o mar kers of met h ylati o n a n d micr o bi ota a re n ot k n o w n fr o m t he pre vi o us trials, a n d t heref ore 
c ha n ges i n t he treat me nt ar ms are diffic ult t o i nter pret . T he place b o ar m is use d as a refere nce f or 
bac k gr o u n d, as a c o h ort f or a nal ysis.  
 
Fecal occ ult bl o o d tests will be cate g orize d as bi nar y ( prese nt vs. a bse nt) at eac h ti me visit.  Pr o p orti o n of 
patie nts wit h at least o ne p ositi ve test will be c o m pare d bet wee n ar ms usi n g Fis hers e xact test beca use 
i nci de nce of t his a d verse e ve nt is e x pecte d t o be l o w.  
 
E x pl orat or y e n d p oi nts of j oi nt i n de x of C O X- 2 wit h T R P M 7 a n d j oi nt i n de x of T R P M 7 wit h B A X i n 
rectal bi o psies will be a nal yze d si milarl y. I n dices will be calc ulate d usi n g a sc ori n g a p pr oac h base d o n 
fact or a nal ysis. 
 
1 3. 6 
Re p orti n g  a n d E xclusi o ns  
 
T o i m p ute missi n g data we will use M ulti ple I m p utati o n via a Se mi - Para metric Pr o ba bilit y I nte gral 
Tra nsf or mati o n. T his is a n a p pr oac h f or i m p uti n g c o nti n u o us, bi nar y, a n d mi xe d data b y first ma p pi n g 
t hese data t o n or mall y distri b ute d val ues a n d t he n a p pl yi n g m ulti ple i m p utati o n s o t hat distri b uti o nal 
ass u m pti o ns f or t he ori gi nal data ca n be rela xe d. T his m et h o d was de vel o pe d b y Ire ne B. Hele n o ws ki, of 
N ort h wester n U ni versit y, i n 2 0 1 2. 
 
htt p://i n di g o. uic.e d u/ bitstrea m/ ha n dle/ 1 0 0 2 7/ 8 6 5 2/ Hele n o ws ki _Ire ne. p df?se q ue nce = 1  
 
1 3. 7  
E v al u ati o n of T o xicit y 
 
All partici pa nts will be e val ua ble f or t o xicit y fr o m t he ti me of t heir first d ose of as piri n . 
 
1 3. 8  
E v al u ati o n of Res p o nse 
 
All partici pa nts i ncl u de d i n t he st u d y will be  assesse d f or res p o nse t o i nter ve nti o n, e ve n if t here are maj or 
pr ot oc ol de viati o ns.  
 
All of t he partici pa nts w h o met t he eli gi bilit y criteria, recei ve t he st u d y a ge nt will be i ncl u de d i n t he 
i nte nti o n-t o-treat a nal ysis. Si nce we will c ollect rectal bi o psies at baseli ne, wee k 9 a n d 1 2, we will 
i ncl u de t he partici pa nts i n t he a nal ysis if he/s he pr o vi des bi o psies at wee k 0 a n d wee k 9, b ut n ot wee k 1 2.  
Partici pa nts will be e xcl u de d if he/s he o nl y pr o vi des o ne bi o ps y.  All c o ncl usi o ns re gar di n g efficac y will 
be base d o n t hese partici pa nts.  
 
S u ba nal yses ma y be perf or me d o n t he s u bsets of partici pa nts, e xcl u di n g t h ose f or w h o m maj or pr ot oc ol 
de viati o ns ha ve bee n i de ntifie d (e. g., earl y deat h d ue t o ot her reas o ns, earl y disc o nti n uati o n of 
i nter ve nti o n, maj or pr ot oc ol vi olati o ns, etc.). H o we ver, s u ba nal yses ma y n ot ser ve as t he basis f or 
dra wi n g c o ncl usi o ns c o ncer ni n g efficac y, a n d t he reas o ns f or e xcl u di n g partici pa nts fr o m t he a nal ysis 

 
 
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– 3 6 – 
s h o ul d be clearl y re p orte d. F or all meas ure me nts of res p o nse, t he 9 5 % c o nfi de nce i nter vals s h o ul d als o be 
pr o vi de d. 
 
We will c o n d uct a nal ysis b y t he gra de of a de n o mas.  
 
Bi o mar kers fr o m Wee k -9 bi o psies will als o be use d i n t he s u ba nal ysis i n t he i nter mitte nt ar m.  
   
1 3. 9 
I nteri m A n al ysis 
 
T here will be n o i nteri m a nal ysis.  
 
1 3. 1 0 A ncill ar y St u dies  
 
N A  
 
1 4. 
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
 
1 4. 1  
F or m F D A 1 5 7 2 
 
Pri or t o i nitiati n g t his st u d y, t he Pr ot oc ol Lea d I n vesti gat or at t he Lea d or Partici pati n g Or ga nizati o n(s)  
will pr o vi de a si g ne d F or m F D A 1 5 7 2 stati n g t hat t he st u d y will be c o n d ucte d i n c o m plia nce wit h 
re g ulati o ns f or cli nical i n vesti gati o ns a n d listi n g t he i n vesti gat ors, at eac h site t hat will partici pate i n t he 
pr ot oc ol. All pers o n nel directl y i n v ol ve d i n t he perf or ma nce of pr oce d ures re q uire d b y t he pr ot oc ol a n d 
t he c ollecti o n of data s h o ul d be liste d o n F or m F D A 1 5 7 2. 
 
1 4. 2 
Ot her Re q uire d D oc u m e nts  
 
1 4. 2. 1  C urre nt ( wit hi n t w o years) C V or bi os ketc h f or all st u d y pers o n nel liste d o n t he F or m F D A 1 5 7 2 
a n d Dele gati o n of Tas ks f or m f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns. C Vs or 
bi os ketc hes d o n ot nee d t o be u p date d f or partici pati n g st u d y staff after dr u g s hi p me nt a ut h orizati o n 
( D S A).  
   
1 4. 2. 2  C urre nt me dical lice nses ( w here a p plica ble) f or all st u d y pers o n nel liste d o n F or m F D A 1 5 7 2 a n d 
Dele gati o n of Tas ks f or m f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns. 
 
1 4. 2. 3  La b certificati o n ( e. g., C LI A, C A P) a n d la b n or mal ra n ges f or all la bs liste d o n F or m F D A 1 5 7 2 
f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns. 
 
1 4. 2. 4  D oc u me ntati o n of G o o d Cli nical Practice trai ni n g f or all st u d y pers o n nel liste d o n t he F D A F or m 
1 5 7 2 a n d Dele gati o n of Tas ks f or m f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns. 
 
1 4. 2. 5  D oc u me ntati o n of Fe deral wi de Ass ura nce ( F W A) n u m ber f or t he Lea d Or ga nizati o n a n d all 
Partici pati n g Or ga nizati o ns. 
 
1 4. 2. 6  Si g ne d I n vesti gat or’s Br oc h ure/ Pac ka ge I nsert ac k n o wle d ge me nt f or m 
 
1 4. 2. 7  Dele gati o n of Tas ks f or m f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns si g ne d b y 
t he Pri nci pal I n vesti gat or f or eac h site a n d i nitiale d b y all st u d y pers o n nel liste d o n t he f or m 
 

 
 
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– 3 7 – 
1 4. 2. 8  Si g ne d a n d date d N CI, D C P Fi na ncial Discl os ure F or m f or all st u d y pers o n nel liste d o n F or m 
F D A 1 5 7 2 f or t he Lea d Or ga nizati o n a n d all Partici pati n g Or ga nizati o ns 
 
1 4. 3  I nstit uti o n al Re vie w B o ar d A p pr o v al 
 
Pri or t o i nitiati n g t he st u d y a n d recei vi n g a ge nt, t he I n vesti gat ors at t he Lea d Or ga nizati o n a n d t he 
Partici pati n g Or ga nizati o n(s) m ust o btai n writte n a p pr o val t o c o n d uct t he st u d y fr o m t he a p pr o priate I R B. 
S h o ul d c ha n ges t o t he st u d y bec o me necessar y, pr ot oc ol a me n d me nts will be s u b mitte d t o t he D C P PI O 
acc or di n g t o D C P A me n d me nt G ui deli nes. T he D C P -a p pr o ve d a me n de d pr ot oc ol m ust be a p pr o ve d b y 
t he I R B pri or t o i m ple me ntati o n 
 
1 4. 4 
I nf or m e d C o nse nt  
 
All p ote ntial st u d y partici pa nts will be gi ve n a c o p y of t he I R B -a p pr o ve d I nf or me d C o nse nt t o re vie w. 
T he i n vesti gat or will e x plai n all as pects of t he st u d y i n la y la n g ua ge a n d a ns wer all q uesti o ns re gar di n g 
t he st u d y. If t he partici pa nt deci des t o partici pate i n t he st u d y, he/s he will be as ke d t o si g n a n d date t he 
I nf or me d C o nse nt d oc u me nt. T he st u d y a ge nt(s) will n ot be release d t o a partici pa nt w h o has n ot si g ne d 
t he I nf or me d C o nse nt d oc u me nt. S u bjects w h o ref use t o partici pate or w h o wit h dra w fr o m t he st u d y will 
be treate d wit h o ut prej u dice.  
 
Partici pa nts m ust be pr o vi de d t he o pti o n t o all o w t he use of bl o o d sa m ples, ot her b o d y fl ui ds, a n d tiss ues 
o btai ne d d uri n g testi n g, o perati ve pr oce d ures, or ot her sta n dar d me dical practices f or f urt her rese arc h 
p ur p oses. If a p plica ble, state me nt of t his o pti o n ma y be i ncl u de d wit hi n t he i nf or me d c o nse nt d oc u me nt 
or ma y be pr o vi de d as a n a d de n d u m t o t he c o nse nt. A M o del C o nse nt F or m f or Use of Tiss ue f or 
Researc h is a vaila ble t hr o u g h a li n k i n t he D C P we bsite. 
 
Pri or t o st u d y i nitiati o n, t he i nf or me d c o nse nt d oc u me nt m ust be re vie we d a n d a p pr o ve d b y N CI, D C P, 
t he C o ns orti u m Lea d Or ga nizati o n, a n d t he I R B at eac h Or ga nizati o n at w hic h t he pr ot oc ol will be 
i m ple me nte d. A n y s u bse q ue nt c ha n ges t o t he i nf or me d c o nse nt m ust be a p pr o ve d b y N CI, D C P, t he 
C o ns orti u m Lea d Or ga nizati o n’s I R B, a n d t he n s u b mitte d t o eac h or ga nizati o n’s I R B f or a p pr o val pri or 
t o i nitiati o n. 
 
1 4. 5  
S u b missi o n of Re g ul at or y D oc u me nts 
 
All re g ulat or y d oc u me nts are c ollecte d b y t he C o ns ortia Lea d Or ga nizati o n a n d re vie we d f or 
c o m plete ness a n d acc urac y. O nce t he C o ns ortia Lea d Or ga nizati o n has recei ve d c o m plete a n d acc urate 
d oc u me nts fr o m a partici pati n g or ga nizati o n, t he C o ns orti u m Lea d Or ga nizati o n will f or war d t he 
re g ulat or y d oc u ments t o D C P ’s Re g ulat or y C o ntract or: 
 
 
Pa per D oc u me nt/ C D - RO M S u b missi o ns: 
 
Re g ulat or y Affairs De part me nt  
 
C C S Ass ociates , I nc. 
  
2 0 0 1 Gate wa y Place S uite 3 5 0 W  
  
Sa n J ose, C A 9 5 1 1 0 
 
P h o ne: 6 5 0 - 6 9 1- 4 4 0 0 
  
Fa x: 6 5 0- 6 9 1- 4 4 1 0 
 
  
E-mail S u b missi o ns : 
 
re g ulat or y @ccsai nc.c o m 
 

 
 
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Re g ulat or y d oc u me nts t hat d o n ot re q uire a n ori gi nal si g nat ure ma y be se nt electr o nicall y t o t he 
C o ns orti u m Lea d Or ga nizati o n f or re vie w, w hic h will t he n be electr o nicall y f or war de d t o D C P ’s 
Re g ulat or y C o ntract or. 
 
1 4. 6 
Ot her  
 
T his trial will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, G o o d Cli nical Practice ( G C P), a n d t he 
a p plica ble re g ulat or y re q uire me nts.  
 
1 5. 
FI N A N CI N G, E X P E N S E S, A N D/ O R I N S U R A N C E  
 
Partici pa nts will be c o m pe nsate d $ 6 0 0 f or partici pati o n (i.e. C li nic V isit 1 $ 1 0 0, C li nic V isit 2 $ 1 0 0, 
C li nic V isit 3 $ 1 0 0, C li nic V isit 4 $ 3 0 0 ) if all t he pr oce d ures are c o m plete d. T his is pr o vi de d f or t he 
i nc o n ve nie nce of t he bi o ps y pr ot oc ol, a n d t o c o m pe nsate f or a n y fi na ncial c osts d ue t o tra vel.   T he 
partici pa nt c o m pe nsati o n pla n will be pr o-rate d base d o n t he n u m ber of st u d y visits c o m plete d.   
Partici pa nt w h o c o m pletes t he e ntire st u d y will recei ve a t otal of $6 0 0.  
 

 
 
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R E F E R E N C E S  
 
 
( 1)   Je mal A, T h o mas , M urra y T, T h u n M. Ca ncer statistics, 2 0 0 2. C A C a ncer J Cli n  2 0 0 2; 5 2: 2 3- 4 7. 
 
( 2)  Har d y R G, Meltzer SJ, Ja n k o ws ki J A. A B C of c ol orectal ca ncer. M olec ular basis f or ris k fact ors. 
B MJ  2 0 0 0; 3 2 1: 8 8 6- 8 8 9. 
 
( 3)   Nis hi hara R, W u K, L oc h hea d P et al. L o n g-ter m c ol orectal-ca ncer i nci de nce a n d m ortalit y after 
l o wer e n d osc o p y. N E n gl J Me d  2 0 1 3; 3 6 9: 1 0 9 5- 1 1 0 5. 
 
( 4)   Ba xter N N, G ol d wasser M A, Paszat L F, Sas ki n R, Ur bac h D R, Ra be nec k L. Ass ociati o n of 
c ol o n osc o p y a n d deat h fr o m c ol orectal ca ncer. A n n I nt er n Me d 2 0 0 9; 1 5 0: 1- 8. 
 
( 5)   H urlst o ne D P. T he detecti o n of flat a n d de presse d c ol orectal lesi o ns: w hic h e n d osc o pic i ma gi n g 
a p pr oac h? G astr oe nter ol o gy  2 0 0 8; 1 3 5: 3 3 8- 3 4 3. 
 
( 6)  Ya maji Y, Mits us hi ma T, I k u ma H et al. I nci de nce a n d rec urre nce rates of c ol orectal a de n o mas 
esti mate d b y a n n uall y re peate d c ol o n osc o pies o n as y m pt o matic Ja pa nese. G ut  2 0 0 4; 5 3: 5 6 8- 5 7 2. 
 
( 7)   Ri m S H, Seeff L, A h me d F, Ki n g J B, C o u g hli n S S. C ol orectal ca ncer i nci de nce i n t he U nite d 
States, 1 9 9 9- 2 0 0 4 : a n u p date d a nal ysis of data fr o m t he Nati o nal Pr o gra m of Ca ncer Re gistries 
a n d t he S ur veilla nce, E pi de mi ol o g y, a n d E n d Res ults Pr o gra m. C a ncer  2 0 0 9; 1 1 5: 1 9 6 7- 1 9 7 6. 
 
( 8)  Ries L A G, Eis ner M P, K osar y C L et al. S E E R Ca ncer Statistics Re vie w, 1 9 7 5 - 2 0 0 4. N atl C a ncer 
I nst M o n o gr [serial o nli ne] 2 0 0 4. 
 
( 9)   Gi o va n n ucci E. Diet, b o d y wei g ht, a n d c ol orectal ca ncer: a s u m mar y of t he e pi de mi ol o gic 
e vi de nce. J W o me ns He alt h ( L arc h mt )  2 0 0 3; 1 2: 1 7 3- 1 8 2. 
  ( 1 0)   Gazia n o J M, Gl y n n RJ, C hriste n W G et al. Vita mi ns E a n d C i n t he pre ve nti o n of pr ostate a n d 
t otal ca ncer i n me n: t he P h ysicia ns' Healt h St u d y II ra n d o mize d c o ntr olle d trial. J A M A 
2 0 0 9; 3 0 1: 5 2- 6 2. 
  ( 1 1)   C ole B F, Bar o n J A, Sa n dler R S et al. F olic aci d f or t he pre ve nti o n of c ol orectal a de n o mas: a 
ra n d o mize d cli nical trial. J A M A 2 0 0 7; 2 9 7: 2 3 5 1- 2 3 5 9. 
  ( 1 2)   Ulric h C M, P otter J D. F olate a n d ca ncer--ti mi n g is e ver yt hi n g. J A M A 2 0 0 7; 2 9 7: 2 4 0 8- 2 4 0 9. 
  ( 1 3)   V ollset S E, Clar ke R, Le wi n gt o n S et al. Effects of f olic aci d s u p ple me ntati o n o n o verall a n d site-
s pecific ca ncer i nci de nce d uri n g t he ra n d o mise d trials: meta-a nal yses of data o n 5 0 0 0 0 
i n di vi d uals. L a ncet  2 0 1 3. 
  ( 1 4)  Wacta ws ki - We n de J, K otc he n J M, A n ders o n G L et al. Calci u m pl us vita mi n D s u p ple me ntati o n 
a n d t he ris k of c ol orectal ca ncer. N E n gl J Me d  2 0 0 6; 3 5 4: 6 8 4- 6 9 6. 
  ( 1 5)   Bar o n J A, Barr y E L, A h ne n D.J. et al. A cli nical trial of s u p ple me ntati o n wit h vita mi n D a n d/ or 
calci u m f or t he pre ve nti o n of c ol orectal a de n o mas [a bstract] Bar o n J A, Barr y E L, A h ne n D.J. et 
al. 2 0 1 4 A A C R A n n u al Meeti n g  2 0 1 4; 
  ( 1 6)   T h u n MJ, He nle y SJ, Patr o n o C. N o nster oi dal a nti-i nfla m mat ory dr u gs as a ntica ncer a ge nts: 
mec ha nistic, p har mac ol o gic, a n d cli nical iss ues. J N atl C a ncer I nst  2 0 0 2; 9 4: 2 5 2- 2 6 6. 

 
 
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– 4 0 – 
  ( 1 7)   C ha n T A. N o nster oi dal a nti-i nfla m mat or y dr u gs, a p o pt osis, a n d c ol o n-ca ncer c he m o pre ve nti o n. 
L a ncet O nc ol  2 0 0 2; 3: 1 6 6- 1 7 4. 
  ( 1 8)   Bar o n J A. E pi de mi ol o g y of n o n-ster oi dal a nti-i nfla m mat or y dr u gs a n d ca ncer. Pr o g Ex p T u m or 
Res  2 0 0 3; 3 7: 1- 2 4. 
  ( 1 9)   Bar o n J A, C ole B F, Sa n dler R S et al. A ra n d o mize d trial of as piri n t o pre ve nt c ol orectal 
a de n o mas. N E n gl J Me d  2 0 0 3; 3 4 8: 8 9 1- 8 9 9. 
  ( 2 0)  Gia r diell o F M, Ha milt o n S R, Kr us h AJ et al. Treat me nt of c ol o nic a n d rectal a de n o mas wit h 
s uli n dac i n fa milial a de n o mat o us p ol y p osis. N E n gl J Me d  1 9 9 3; 3 2 8: 1 3 1 3- 1 3 1 6. 
  ( 2 1)   Stei n bac h G, L y nc h P M, P hilli ps R K et al. T he effect of celec o xi b, a c ycl o o x y ge nase- 2 i n hi bit or, 
i n fa milial a de n o mat o us p ol y p osis. N E n gl J Me d  2 0 0 0; 3 4 2: 1 9 4 6- 1 9 5 2. 
  ( 2 2)   C o uzi n J. Cli nical trials. Halt of Cele bre x st u d y t hreate ns dr u g's f ut ure, ot her trials. Scie nce  
2 0 0 4; 3 0 6: 2 1 7 0. 
  ( 2 3)   C ha n A T, Ar ber N, B ur n J et al. As piri n i n t he c hem o pre ve nti o n of c ol orectal ne o plasia: a n 
o ver vie w. C a ncer Prev Res ( P hil a)  2 0 1 2; 5: 1 6 4- 1 7 8. 
  ( 2 4)   K u ne G A, K u ne S, Wats o n L F. C ol orectal ca ncer ris k, c hr o nic ill nesses, o perati o ns, a n d 
me dicati o ns: case c o ntr ol res ults fr o m t he Mel b o ur ne C ol orectal Ca ncer St u d y. C a ncer Res  
1 9 8 8; 4 8: 4 3 9 9- 4 4 0 4. 
  ( 2 5)   D u be C, R ost o m A, Le wi n G et al. T he use of as piri n f or pri mar y pre ve nti o n of c ol orectal ca ncer: 
a s yste matic re vie w pre pare d f or t he U. S. Pre ve nti ve Ser vices Tas k F orce. A n n I nter n Me d  
2 0 0 7; 1 4 6: 3 6 5- 3 7 5. 
  ( 2 6)   Se h de v A, O' Neil B H. T he R ole of As piri n, Vita mi n D, E xercise, Diet, Stati ns, a n d Metf or mi n i n 
t he Pre ve nti o n a n d Treat me nt of C ol orectal Ca ncer. C urr Tre at O pti o ns O nc ol  2 0 1 5; 1 6: 3 5 9. 
  ( 2 7)   R ot h well P M, Wils o n M, El wi n C E et al. L o n g-ter m effect of as piri n o n c ol orectal ca ncer 
i nci de nce a n d m ortalit y: 2 0- year f oll o w-u p of fi ve ra n d o mise d trials. L a ncet  2 0 1 0; 3 7 6: 1 7 4 1-
1 7 5 0. 
  ( 2 8)   C ole B F, L o ga n R F, Hala bi S et al. As piri n f or t he c he m o pre ve nti o n of c ol orectal a de n o mas: 
meta -a nal ysis of t he ra n d o mize d trials. J N atl C a ncer I nst 2 0 0 9; 1 0 1: 2 5 6- 2 6 6. 
  ( 2 9)   Is hi ka wa H, M ut o h M, S uz u ki S et al. T he pre ve nti ve effects of l o w-d ose e nteric -c oate d as piri n 
ta blets o n t he de vel o p me nt of c ol orectal t u m o urs i n Asia n patie nts: a ra n d o mise d trial. G ut  
2 0 1 4; 6 3: 1 7 5 5- 1 7 5 9. 
  ( 3 0)  Fi nal re p ort o n t he as piri n c o m p o ne nt of t he o n g oi n g P h ysicia ns' Healt h St u d y. Steeri n g 
C o m mittee of t he P h ysicia ns' Healt h St u d y Researc h Gr o u p. N E n gl J Me d  1 9 8 9; 3 2 1: 1 2 9- 1 3 5. 
  ( 3 1)   C o o k N R, Lee I M, Gazia n o J M et al. L o w- d ose as piri n i n t he pri mar y pre ve nti o n of ca ncer: t he 
W o me n's Healt h St u d y: a ra n d o mize d c o ntr olle d trial. J A M A 2 0 0 5; 2 9 4: 4 7- 5 5. 
  ( 3 2)   C o o k N R, Lee I M, Z ha n g S M, M o ort h y M V, B uri n g J E. Alter nate-da y, l o w -d ose as piri n a n d 
ca ncer ris k: l o n g -ter m o bser vati o nal f oll o w- u p of a ra n d o mize d trial. A n n I nter n Me d  

 
 
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2 0 1 3; 1 5 9: 7 7- 8 5. 
  ( 3 3)  S u n g JJ. Is as piri n f or c ol orectal ca ncer pre ve nti o n o n t he pri me ti me yet? G ut  2 0 1 4; 6 3: 1 6 9 1-
1 6 9 2. 
  ( 3 4)  S ostres C, La nas A. Gastr oi ntesti nal effects of as piri n. N at Rev G astr oe nter ol He p at ol  
2 0 1 1; 8: 3 8 5- 3 9 4. 
  ( 3 5)   R o uti ne as piri n or n o nster oi dal a nti-i nflam mat or y dr u gs f or t he pri mar y pre ve nti o n of c ol orectal 
ca ncer: U. S. Pre ve nti ve Ser vices Tas k F orce rec o m me n dati o n state me nt. A n n I nter n Me d  
2 0 0 7; 1 4 6: 3 6 1- 3 6 4. 
  ( 3 6)  Mc Q uai d K R, Lai ne L. S yste matic re vie w a n d meta -a nal ysis of a d verse e ve nts of l o w - d ose 
as piri n a n d cl o pi d o grel i n ra n d o mize d c o ntr olle d trials. A m J Me d  2 0 0 6; 1 1 9: 6 2 4- 6 3 8. 
  ( 3 7)  Ses hasai S R, Wijes uri ya S, Si va k u mara n R et al. Effect of As piri n o n Vasc ular a n d N o n vasc ular 
O utc o mes: Meta -a nal ysis of Ra n d o mize d C o ntr olle d Trials. Arc h I nter n Me d  2 01 2.  
  ( 3 8)   M ora S. As piri n T hera p y i n Pri mar y Pre ve nti o n: T o Use or N ot t o Use?: C o m me nt o n " Effect of 
As piri n o n Vasc ular a n d N o n vasc ular O utc o mes". Arc h I nter n Me d  2 0 1 2. 
  ( 3 9)   R ot h well P M, Wils o n M, Price J F, Belc h J F, Mea de T W, Me hta Z. Effect of dail y as piri n o n ris k 
of ca ncer metastasis: a st u d y of i nci de nt ca ncers d uri n g ra n d o mise d c o ntr olle d trials. L a ncet  
2 0 1 2; 3 7 9: 1 5 9 1- 1 6 0 1. 
  ( 4 0)   L u bet R A, Sza b o E, C hrist o v K et al. Effects of gefiti ni b (Iressa) o n ma m mar y ca ncers: 
pre ve nti ve st u dies wit h varie d d osa ges, c o m bi nati o ns wit h v or oz ole or tar greti n, a n d bi o mar ker 
c ha n ges. M ol C a ncer T her  2 0 0 8; 7: 9 7 2- 9 7 9. 
  ( 4 1)  Ha na ha n D, Wei n ber g R A. T h e hall mar ks of ca ncer. Cell  2 0 0 0; 1 0 0: 5 7- 7 0. 
  ( 4 2)  Ya n g S Y, Sales K M, F uller B, Seifalia n A M, Wi nslet M C. A p o pt osis a n d c ol orectal ca ncer: 
i m plicati o ns f or t hera p y. Tre n ds M ol Me d  2 0 0 9; 1 5: 2 2 5- 2 3 3. 
  ( 4 3)   Be di A, Pasric ha PJ, A k htar AJ et al. I n hi biti o n of a p o pt osis d uri n g de vel o p me nt of c ol orectal 
ca ncer. C a ncer Res  1 9 9 5; 5 5: 1 8 1 1- 1 8 1 6. 
  ( 4 4)   Ke k u T O, A mi n A, Gala n k o J, Marti n C, Sc hlie be B, Sa n dler R S. A p o pt osis i n n or mal rectal 
m uc osa, baseli ne a de n o ma c haracteristics, a n d ris k of f ut ure a de n o mas. C a ncer E pi de mi ol 
Bi o m arkers Prev  2 0 0 8; 1 7: 3 0 6- 3 1 0. 
  ( 4 5)   Fe dir k o V, B ostic k R M, Fla n ders W D et al. Effects of vita mi n D a n d calci u m s u p ple me ntati o n o n 
mar kers of a p o pt osis i n n or mal c ol o n m uc osa: a ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d 
cli nical trial. C a nce r Prev Res ( P hil a P a) 2 0 0 9; 2: 2 1 3- 2 2 3. 
  ( 4 6)   Bar o n J A, War g o vic h MJ, T ostes o n T D et al. E pi de mi ol o gical use of rectal pr oliferati o n 
meas ures. C a ncer E pi de mi ol Bi o m arkers Prev  1 9 9 5; 4: 5 7- 6 1. 
  ( 4 7)  Bar o n J A. I nter me diate effect mar kers f or c ol orectal ca ncer.  I A R C Sci P u bl 2 0 0 1; 1 5 4: 1 1 3- 1 2 9. 
  ( 4 8)   B ur n J, Bis h o p D T, C ha p ma n P D et al. A ra n d o mize d place b o-c o ntr olle d pre ve nti o n trial of 
as piri n a n d/ or resista nt starc h i n y o u n g pe o ple wit h fa milial a de n o mat o us p ol y p osis. C a ncer Prev 

 
 
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Res ( P hil a)  2 0 1 1; 4: 6 5 5- 6 6 5. 
 
  ( 4 9)    Pas para kis M, Va n de na beele P. Necr o pt osis a n d its r ole i n i nfla m mati o n. N at ure  2 0 1 5; 5 1 7: 3 1 1-
2 0 
 
  ( 5 0)    Wallac h D, Ka n g T B, K o vale n k o A. C o nce pts of tiss ue i nj ur y a n d cell deat h i n i nfla m mati o n: a 
hist orical pers pecti ve. N at Rev I m m u n ol  2 0 1 4; 1 4: 5 1-9.  
 
( 5 1)    Par ker D, Pri nce A. I m m u n ore g ulat or y effects of necr o pt osis i n bacterial i nfecti o ns. Cyt oki ne     
           2 0 1 6; 8 8: 2 7 4- 5. 
 
( 5 2)    Or ozc o S, O berst A. RI P K 3 i n cell deat h a n d i nfla m mati o n: t he g o o d, t he ba d, a n d t he u gl y.  
           I m m u n ol Rev 2 0 1 7; 2 7 7: 1 0 2- 1 2. 
 

 
 
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C O N S E N T F O R M  
 
N CI Pr ot o c ol #: N W U 2 0 1 5 - 0 6- 0 1 
L oc al Pr ot oc ol #: N CI 2 0 1 5- 0 6- 0 1  
Pr ot oc ol V ersi o n D ate:  v 2. 1 9 0 8/ 1 1/ 2 0 2 2 
I nf or m e d C o nse nt Versi o n D ate: 0 8/ 1 1/ 2 0 2 2  
 
 
St u d y Title f or St u d y Partici pa nts: Testi n g as piri n t o pre ve nt c ol orectal ca ncer after 
a de n o ma dia g n osis  
Pr ot oc ol Title: E val uati n g I nter mitte nt D osi n g of As piri n f or C ol orectal Ca ncer 
C he m o pre ve nti o n  
 
I ntr o d ucti o n 
T his is a cli nical trial, a t y pe of researc h st u d y. Y o ur st u d y d oct or will e x plai n t he cli nical trial t o y o u. 
Cli nical trials i ncl u de o nl y pe o ple w h o c h o ose t o ta ke part i n t he researc h. Please ta ke y o ur ti me t o ma ke 
y o ur decisi o n a b o ut v ol u nteeri n g. Y o u ma y disc uss y o ur decisi o n wit h y o ur frie n ds a n d fa mil y. Y o u ca n 
als o disc uss t his st u d y wit h y o ur healt h care tea m. If y o u ha ve a n y q uesti o ns, y o u ca n as k y o ur st u d y 
d oct or f or m ore of a n e x pla nati o n. Y o u s h o ul d o nl y a gree t o partici pate i n t his st u d y w he n y o u are 
c o mf orta ble e n o u g h wit h t he i nf or mati o n s o t hat y o u ca n ma ke a n i nf or me d decisi o n a b o ut j oi ni n g. 
 
W h at is t he us u al a p pr o ac h t o m y p ol y ps ? 
Y o u are bei n g as ke d t o be a part of t his researc h st u d y beca use y o u ha ve ha d o ne or m ore of a certai n t y pe 
of p ol y p (a n a de n o ma) re m o ve d fr o m y o ur c ol o n. Pe o ple w h o are dia g n ose d wit h a de n o mas ha ve a hi g her 
ris k of gr o wi n g m ore of t hese p ol y ps t hat ma y bec o me c ol o n or rectal ca ncer. T he us ual a p pr oac h is t o be 
c hec ke d e ver y 3 t o 5 years b y c ol o n osc o p y wit h re m o val of a n y ne w p ol y ps. 
 
W h at are m y ot her c h oices if I d o n ot t a ke p art i n t his st u d y ?  
If y o u deci de n ot t o ta ke part i n t his st u d y, y o u ha ve ot her c h oices. F or e xa m ple: 
•  
y o u ma y c h o ose t o ha ve t he us ual a p pr oac h descri be d a b o ve 
•  
y o u ma y c h o ose t o ta ke part i n a differe nt st u d y, if o ne is a vaila ble  
•  
or y o u c o ul d deci de n ot t o be treate d f or p ol y p f or mati o n 
 
W h y is t his st u d y bei n g d o ne ?  
Pre vi o us st u dies ha ve s h o w n t hat as piri n use ma y pre ve nt pe o ple w h o ha ve ha d a de n o mas fr o m 
de vel o pi n g c ol o n a n d rectal ca ncer. T he p ur p ose of t his st u d y is t o c o m pare t he safet y a n d effects of t w o 
differe nt d ose sc he d ules of as piri n o n pe o ple a n d t heir ris k of c ol o n a n d rectal ca ncer. I n t his st u d y y o u 
w o ul d get eit her as piri n pills t o ta ke dail y, or as piri n pills t o ta ke dail y o n a n i nter mitte nt sc he d ule ( 3 
wee ks of dail y as piri n f oll o we d b y 3 wee ks of place b o pills ), or place b o pills t o ta ke dail y. T he place b o 
pills l o o k li ke t he st u d y dr u g b ut c o ntai n n o me dicati o n.  Res ults fr o m t his st u d y will la y a f o u n dati o n f or 
f ut ure st u dies tr yi n g t o pre ve nt c ol orectal ca ncer. We w o ul d li ke t o e nr oll a b o ut 9 0 partici pa nts i n t his 
st u d y at Va n der bilt U ni versit y. 
 

 
 
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W h a t are t he st u d y gr o u ps ? 
T his st u d y has t hree st u d y gr o u ps.  
•  
Gr o u p 1 will recei ve t he st u d y dr u g, a dail y pill t hat c o ntai ns 3 2 5 m g as piri n, f or 1 2 wee ks.  
•  
Gr o u p 2 will recei ve t he st u d y dr u g, a dail y pill t hat c o ntai ns 3 2 5 m g as piri n f or 3 wee ks, a n d 
t he n a place b o f or 3 wee ks; t hese 3 wee k o n/ 3-wee k off c ycles will be re peate d f or a t otal of 
1 2 wee ks.   T he place b o pill will l o o k li ke t he st u d y dr u g s o t hat it will n ot be p ossi ble t o 
k n o w w hic h gr o u p y o u are i n. 
•  
Gr o u p 3 will recei ve a place b o, a pill t hat l o o ks li ke t he st u d y dr u g b ut c o ntai ns n o 
me dicati o n, f or 1 2 wee ks. 
 
A c o m p uter will ra n d o ml y p ut y o u i n a st u d y gr o u p — li ke a c oi n t oss—t o deci de w hat gr o u p y o u get 
place d i nt o. T his is d o ne beca use n o o ne k n o ws if o ne st u d y gr o u p is better, t he sa me, or w orse t ha n t he 
ot her gr o u p. O nce y o u are p ut i n a gr o u p, y o u ca n n ot s witc h t o t he ot her gr o u p. Neit her y o u n or y o ur 
d oct or will k n o w if y o u are recei vi n g t he st u d y dr u g or place b o. Y o ur d oct or ca n n ot c h o ose w hic h gr o u p 
y o u will be i n.  
 
 
 
 
 
 
 
 
 
 
 
 
H o w l o n g will I be i n t his st u d y ? 
Y o u will recei ve t he st u d y dr u g f or 3 m o nt hs ( 1 2 wee ks). After y o u fi nis h i nter ve nti o n, t he researc h staff 
or n urse will tele p h o ne or e mail y o u 1 m o nt h after y o ur last visit t o as k y o u a b o ut a n y effects or 
c o n diti o ns.  T he T O T A L d urati o n of t he  st u d y partici pati o n is 4 m o nt hs. 
 
W h at e xtr a tests a n d pr oce d ures will I h a ve if I t a ke p art i n t his st u d y ?  
T he w h ole st u d y will ta ke a b o ut 4 m o nt h s fr o m t he ti me t hat we first call y o u u ntil t he ti me t hat y o u are 
fi nis he d wit h t he st u d y.  M ost of t he tes ts a n d pr oce d ures y o u will nee d f or t his st u d y are si milar t o t h ose 
y o u ha ve ha d bef ore as part of t he us ual a p pr oac h f or y o ur c o n diti o n. H o we ver, m ost of t he tests a n d 
pr oce d ures t hat y o u ha ve f or t he st u d y will be i n a d diti o n t o or m ore ofte n t ha n y o ur u s ual care. 
 
Bef ore y o u be gi n t he st u d y ( Clin ic Visit 1):  
•  Bef ore y o u partici pate i n a n y pr oce d ures t hat are s pecificall y f or t his researc h, y o u will nee d t o 
c o me t o t he Va n der bilt U ni versit y Me dical Ce nter t o rea d a n d disc uss a n y q uesti o ns y o u ma y 
ha ve a n d t o si g n t his c o nse nt f or m. 
•  T o see if y o u ca n be i n t he st u d y, y o u will ha ve t he f oll o wi n g e xtra tests: 
•  
P h ysical a n d vital si g ns  (i ncl u des p ulse, res pirat or y rate, te m perat ure, bl o o d press ure, 
E C O G perf or ma nce stat us ) a n d b o d y meas ure me nts (i ncl u des hei g ht , wei g ht, hi p a n d 
waist circ u mfere nces ) 
•  
Bl o o d test – a b o ut 1 ⅓ ta bles p o o ns of bl o o d ta ke n wit h a nee dle fr o m a vei n i n y o ur 
ar m 
Gr o u p 1  ( 4 0 peo ple)  
As piri n dail y  
Ra n d o mize  
( T he c o m p uter will 
ra n d o ml y p ut y o u i n a 
st u d y gr o u p) 
Y o u a gree t o 
t a ke p art i n t he 
st u dy 
Gr o u p 2  ( 4 0 pe o ple) 
3 wee ks As piri n  
/ 3 wee ks place b o 
 
 
 
Gr o u p 3 ( 1 0 pe o ple)  
Place b o  

 
 
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– 4 5 – 
•  
O pti o nal u ri ne test - y o u will be i nstr ucte d o n h o w t o c ollect a uri ne sa m ple 
•  
St o ol test - y o u will be i nstr ucte d o n h o w t o collect a st o ol sa m ple  
•  
Q uesti o n naires t o c o m plete at h o me  t hat s h o ul d ta ke 3 0 mi n utes. T he q uesti o ns as k 
a b o ut y o ur past me dical hist or y, dr u g aller gies, c urre nt me dicati o ns, c urre nt 
s y m pt o ms or ill nesses, fa mil y hist or y a n d dietar y i nf or mati o n a n d ot her areas i n y o ur 
life t hat ma y be relate d t o c ol orectal ca ncer ris k 
•  
If y o u are w o ma n a ble t o bec o me pre g na nt, y o u will ha ve a uri ne pre g na nc y test. 
Pre g na nt w o me n, w o me n w h o are c urre ntl y breast fee di n g, a n d w o me n c o nsi deri n g a 
pre g na nc y will n ot be all o we d t o partici pate i n t his st u d y.  
 
D uri n g t he st u d y  
D uri n g t he st u d y, y o u will be as ke d t o ma ke f o ur cli nic visits:  
•  
Cli nic Visit 2 ( wit hi n 6 wee ks of Cli nic Visit 1)  
•  
Cli nic Visit 3 ( 9 wee ks after starti n g st u d y a ge nt) 
•  
Cli nic Visit 4 ( 1 2 wee ks after starti n g st u d y a ge nt) a n d  
* St u d y a ge nts are dis pe nse d at Cli nic Visits 2 a n d 3. 
 
D uri n g t hese visits:  
•  Y o u will be as ke d t o c o me t o t he Va n der bilt U ni versit y Me dical Ce nter. At eac h visit, y o u will 
bri n g a st o ol sa m ple wit h y o u.  At t he cli nic, st u d y staff will ta ke a bl o o d sa m ple (a b o ut 1 a n d 
2/ 3 ta bles p o o ns) a n d a n o pti o nal uri ne sa m ple ( 2 ta bles p o o ns). 
•  At visits 2, 3, a n d 4 t he researc h staff or n urse will ta ke y o ur vital si g ns (i ncl u des p ulse, 
res pirat or y rate, te m perat ure, bl o o d press ure) a n d b o d y meas ure me nts (i ncl u des hei g ht, 
wei g ht, hi p a n d waist circ u mfere nces) a n d will as k y o u a b o ut a n y c ha n ges i n y o ur me dicati o ns 
or h o w y o u are feeli n g. If t here are a n y maj or c ha n ges or if y o u are feeli n g u n well y o u ma y 
als o ha ve a p h ysical e xa m b y t he d oct or.  
•  At visits 2, 3, a n d 4, t he d oct or will i nsert a s wa b ge ntl y i nt o y o ur rect u m t o c ollect fecal 
material.  
•  At visits 2, 3, a n d 4, t he d oct or will l o o k at y o ur rect u m usi n g a plastic t u be wit h a li g ht a n d 
will ta ke ar o u n d ei g ht  s mall pieces (a b o ut o ne-fift h of a n i nc h eac h) of t he n or mal tiss ue fr o m 
y o ur rect u m , ri g ht after c ollecti n g t he fecal material a n d t he cells.   
•  At y o ur 2 n d visit, y o u will be gi ve n t he pills t hat ha ve bee n assi g ne d t o y o u – e n o u g h f or ni ne 
wee ks. Y o u will start ta ki n g t he pills o n t hat da y a n d will c o nti n ue ta ki n g t he m f or 9 wee ks. At 
Visit 3, y o u will be gi ve n m ore pills f or t he st u d y a n d will c o nti n ue ta ki n g t he m f or 3 wee ks. 
Y o u will als o be gi ve n a diar y a n d as ke d t o kee p trac k of t he ti me of da y t hat y o u ta ke y o ur 
pills a n d a n y misse d d oses.  
•  At visits 3 a n d 4 y o u will bri n g bac k y o ur pill b ottles a n d a n y u n use d pills. T he researc h staff 
or n urse will c o u nt y o u pills a n d re vie w y o ur st u d y diar y. 
•  Y o u will be calle d or e maile d (t o see h o w y o u are feeli n g) a t otal of 7 ti mes: After y o ur bi o ps y 
visits ( Cli nic Visits 2, 3, a n d 4), i n Wee ks 1, 3, a n d 6 w hile y o u are ta ki n g t he pills , a n d 1 
m o nt h after y o ur last visit ( 1 m o nt h after Cli nic Visit 4). Y o u will als o be gi ve n se veral wa ys 
t o c o ntact us i n case t here is a n y i nf or mati o n y o u nee d us t o k n o w. 
 
Y o ur rectal bi o psies a n d s wa bs will be s hi p pe d t o la bs i n N ort h wester n U ni versit y i n C hica g o a n d 
U ni versit y of N ort h Car oli na at C ha pel Hill f or la b a nal yses. Ot her sa m ples w ill be teste d at t he 
Va n der bilt la b.  
 
All of t he i nf or mati o n t hat y o u pr o vi de will be ke pt strictl y c o nfi de ntial. Y o u will be assi g ne d a n 
i de ntificati o n n u m ber t hat will be use d i n t he st u d y t o st ore y o ur i nf or mati o n. O nl y t he st u d y staff will 
ha ve access t o t he l oc ke d ke y t hat li n ks y o ur i de ntif yi n g i nf or mati o n (f or e xa m ple, na me) wit h y o ur 

 
 
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i de ntificati o n n u m ber.  
 
W h at p ossi ble ris ks c a n I e x pect fr o m t a ki n g p art i n t his st u d y ?  
If y o u c h o ose t o ta ke part i n t his st u d y, t here is a ris k t hat y o u ma y: 
 
L ose ti me at w or k or h o me a n d s pe n d m ore ti me i n t he h os pital or d oct or’s office t ha n us ual. 
 
Be as ke d se nsiti ve or pri vate q uesti o ns w hic h y o u n or mall y d o n ot disc uss. T here is a ris k s o me o ne c o ul d 
get access t o t he pers o nal i nf or mati o n i n y o ur me dical rec or ds or ot her i nf or mati o n researc hers ha ve ke pt 
a b o ut y o u. S o me o ne mi g ht be a ble t o trace t his i nf or mati o n bac k t o y o u. T he researc hers belie ve t he 
c ha nce t hat s o me o ne will i de ntif y y o u is ver y s mall, b ut t he ris k ma y c ha n ge i n t he f ut ure as pe o ple c o me 
u p wit h ne w wa ys of traci n g i nf or mati o n. I n s o me cases, t his i nf or mati o n c o ul d be use d t o ma ke it har der 
f or y o u t o get or kee p a j o b. T here are la ws a gai nst mis use of ge netic i nf or mati o n, b ut t he y ma y n ot gi ve 
f ull pr otecti o n. T he researc hers belie ve t he c ha nce t hese t hi n gs will ha p pe n is ver y s mall, b ut ca n n ot 
pr o mise t hat t he y will n ot occ ur.  
 
T here ca n als o be a ris k i n fi n di n g o ut ne w ge netic i nf or mati o n a b o ut y o u. Ne w healt h i nf or mati o n a b o ut 
i n herite d traits t hat mi g ht affect y o u or y o ur bl o o d relati ves c o ul d be f o u n d d uri n g a st u d y.  
 
Y o u s h o ul d n ot ta ke certai n pai n killers w hile ta ki n g t he st u d y dr u g. T hese i ncl u de M otri n, A d vil, 
Cele bre x, Na pr o xe n a n d ot hers. Y o u s h o ul d tal k t o y o ur d oct or bef ore ta ki n g a n y ne w pai n me dici ne.  
Y o u s h o ul d als o n ot ta ke c ortic oster oi ds, warfari n ( C o u ma di n), he pari n or ot her bl o o d t hi n ners. T hese 
dr u gs i nc rease t he li keli h o o d of de vel o pi n g seri o us ris ks (e. g. blee di n g a n d g astr oi ntesti n al distress ) 
relate d t o as piri n. 
 
T he a spiri n use d i n t his st u d y ma y affect h o w differe nt parts of y o ur b o d y w or k, s uc h as y o ur li ver, 
ki d ne ys, heart, a n d bl o o d. T he st u d y d oct or will be testi n g y o ur bl o o d a n d will let y o u k n o w if c ha n ges 
occ ur t hat ma y affect y o ur healt h.  
 
T here is als o a ris k t hat y o u c o ul d ha ve si de effects. Here are i m p orta nt p oi nts a b o ut si de effects:  
•  
T he st u d y d oct ors d o n ot k n o w w h o will or will n ot h a ve si de effects. 
•  
S o me si de effects ma y g o a wa y s o o n, s o me ma y last a l o n g ti me, or s o me ma y ne ver g o a wa y. 
•  
S o me si de effects ma y i nterfere wit h y o ur a bilit y t o ha ve c hil dre n.  
•  
S o me si de effects ma y be seri o us a n d ma y e ve n res ult i n deat h.  
 
Here are i m p orta nt p oi nts a b o ut h o w y o u a n d t he st u d y d oct or ca n ma ke si de effects less of a pr o ble m: 
•  
Tell t he st u d y d oct or if y o u n otice or feel a n yt hi n g differe nt s o t he y ca n see if y o u are ha vi n g a si de 
effect. 
•  
T he st u d y d oct or ma y be a ble t o treat s o me si de effects. 
 
T he ta bles bel o w s h o w t he m ost c o m m o n si de effects t hat we k n o w a b o ut As piri n , s o me of w hic h ma y be 
seri o us. T here mi g ht be ot her si de effects t hat we d o n ot yet k n o w a b o ut. If i m p orta nt ne w si de effects are 
f o u n d, t he st u d y d oct or will disc uss these wit h y o u. 
 
P ossi ble Si de Effects of As piri n:  
 
C O M M O N, S O M E M A Y B E S E RI O U S  
Ma n y si de effects of as piri n de pe n d o n t he d ose/ n u m ber of ca ps ule s ta ke n.  
T he fre q ue nc y of s o me si de effects is n ot k n o w n.  
•  
Heart b ur n  

 
 
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C O M M O N, S O M E M A Y B E S E RI O U S  
Ma n y si de effects of as piri n de pe n d o n t he d ose/ n u m ber of ca ps ule s ta ke n.  
T he fre q ue nc y of s o me si de effects is n ot k n o w n.  
•  
St o m a c h Cr a m ps   
•  
F e el Li k e T hr o wi n g U p   
•  
Na usea/ v o miti n g, d ys pe psia (i n di gesti o n) 
•  
Dr o wsi ness  
 
R A R E, S O M E M A Y B E S E RI O U S  
Ma n y si de effects of as piri n de pe n d o n t he d ose/ n u m ber of ca ps ules ta ke n.  
T he fre q ue nc y of s o me si de effects is n ot k n o w n.  
•  
Bl e e di n g of t h e St o m a c h or I nt esti n es ( c o u g hi n g u p bl o o d or v o mit t h at l o o ks li k e c off e e gr o u n ds, bl a c k, 
bl o o d y, or t arr y st o ols ) 
•  
St o m a c h or I nt esti n al Ul c er  
•  
D e cr e as e d Bl o o d Pl at el ets    
•  
D e cr e as e d W hit e Bl o o d C ells   
•  
A n e mi a  
•  
Ri n gi n g i n t h e E ars   
•  
H e p atitis c a us e d b y Dr u gs   
•  
Lif e T hr e at e ni n g All er gi c R e a cti o n  
 
 
Ris ks rel ate d t o rect al bi o ps y  
C O M M O N, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple recei vi n g rectal bi o ps y, m ore t ha n 2 0 ma y ha ve: 
•  
O bser ve s o me bl o o d o n t he tiss ue o n t he da y of t he bi o ps y.  
•  
Pai n a n d/ or disc o mf ort fr o m t he rectal bi o ps y.  
 
R A R E, S O M E M A Y B E S E RI O U S  
I n 1 0 0 pe o ple recei vi n g rectal bi o ps y, 3 or fe wer ma y ha ve: 
•  
Blee di n g fr o m t he rect u m . Blee di n g hea vier or m ore persiste nt t ha n t his s h o ul d be re p orte d.  
•  
T he bi o ps y ma y ca use a h ole i n t he rect u m w hic h ma y lea d t o i nfecti o n  
 
Re pr o d ucti ve ris ks:  
Y o u s h o ul d n ot get pre g na nt, breastfee d, or fat her a ba b y w hile i n t his st u d y. T he as piri n use d i n t his 
st u d y c o ul d be ver y da ma gi n g t o a n u n b or n ba b y. If a fe male bec o me pre g na nt i n t he st u d y, s he s h o ul d 
i nf or m t he st u d y d oct or i m me diatel y. 
 
B ot h fe males a n d males m ust use c o ntrace pti o n pri or t o st u d y e ntr y u ntil t he d urati o n of t heir st u d y 
partici pati o n.  C hec k wit h t he st u d y d oct or a b o ut w hat t y pes of birt h c o ntr ol, or pre g na nc y pre ve nti o n t o 
use.  
 
Ris ks relate d t o bl o o d tests: Br uisi n g, s ore ness, or rar el y, i nfecti o n ma y occ ur, or y o u mi g ht feel fai nt as a 
res ult of t he nee dle stic ks t o o btai n bl o o d fr o m y o ur vei n. 
 
Ta ki n g part i n t his st u d y ma y be a n i nc o n ve nie nce t o y o ur ti me wit h t he tele p h o ne or e mail c o ntacts,  t he 
c ollecti o n of all t he sa m ples at t h e cli nic, a n d t he c ollecti o n of t he st o ol sa m ples at h o me.   
 
W h at p ossi ble be nefits c a n I e x pect fr o m t a ki n g p art i n t his st u d y ?  
a) T he be nefits t o scie nce a n d h u ma n ki n d t hat mi g ht  res ult fr o m t his st u d y are: Y o ur ta ki n g part ma y 
pr o vi de i nf or mati o n t hat lea ds t o a safer wa y of pre ve nti n g c ol orectal ca ncer. S ociet y ma y be nefit fr o m a 

 
 
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– 4 8 – 
l o w-c ost, well -t olerate d strate g y t o re d uce deat h fr o m c ol orectal ca ncer. 
 
b) T here will be n o direct be nefits t o y o u f or ta ki n g part i n t his st ud y. Y o u will be i nf or me d of y o ur re nal 
f u ncti o n d uri n g t he st u d y. If it is i ns ufficie nt, y o u ca n c o ns ult wit h y o ur healt hcare pr o vi der. 
 
C a n I st o p t a ki n g p art i n t his st u d y ?  
Yes. Y o u ca n deci de t o st o p at a n y ti me. If y o u deci de t o st o p f or a n y reas o n, it is i m p orta nt t o let t he 
st u d y d oct or k n o w as s o o n as p ossi ble s o y o u ca n st o p safel y. If y o u st o p, y o u ca n deci de w het her or 
n ot t o let t he st u d y d oct or c o nti n ue t o pr o vi de y o ur me dical i nf or mati o n t o t he or ga nizati o n r u n ni n g 
t he st u d y. 
 
T he st u d y d oct or will tell y o u a b o ut ne w i nf or mati o n or c ha n ges i n t he st u d y t hat ma y affect y o ur 
healt h or y o ur willi n g ness t o c o nti n ue i n t he st u d y. 
 
T he st u d y d oct or ma y ta ke y o u o ut of t he st u d y:  
•  
If y o ur healt h c ha n ges a n d t he st u d y is n o l o n ger i n y o ur best i nterest 
•  
If ne w i nf or mati o n bec o mes a vaila ble 
•  
If y o u d o n ot f oll o w t he st u d y r ules 
•  
If t he st u d y is st o p pe d b y t he s p o ns or, I R B or F D A. 
•  
If y o u are n ot a ble t o pr o vi de t he bl o o d, uri ne, or rectal sa m ples. 
 
W h at are m y ri g hts i n t his st u d y ?  
Ta ki n g part i n t his st u d y is y o ur c h oice. N o matter w hat decisi o n y o u ma ke, a n d e ve n if y o ur decisi o n 
c ha n ges, t here will be n o pe nalt y t o y o u. Y o u will n ot l ose me dical care or a n y le gal ri g hts. 
 
F or q uesti o ns a b o ut y o ur ri g hts w hile i n t his st u d y, call t he Va n der bilt U ni ver sit y Me dical Ce nter 
I nstit uti o nal Re vie w B oar d at ( 6 1 5) 3 2 2- 2 9 1 8.  
 
W h at are t he c osts of t a ki n g p art i n t his st u d y ?  
T he as piri n will be s u p plie d at n o c har ge w hile y o u ta ke part i n t his st u d y.  
T he c ost of st u d y- s pecific e xa ms (e. g. p ulse , res pirat or y rate, te m perat ure, bl o o d press ure, hei g ht, a n d 
wei g ht) , tests (e. g. bl o o d, uri ne, st o ol test), rectal s wa b, bi o psies a n d a n y ot her pr oce d ures will be pai d f or 
b y t he st u d y. S o me c osts ass ociate d wit h y o ur care ma y be c o nsi dere d sta n dar d of care, a n d will be bille d 
t o y o u or y o ur i ns ura nce c o m pa n y. Y o u will ha ve t o pa y f or a n y c osts (i ncl u di n g de d ucti bles a n d c o-
pa y me nts) n ot c o vere d b y y o ur healt h i ns urer. Bef ore y o u deci de t o be i n t he st u d y, y o u s h o ul d c hec k 
wit h y o ur healt h pla n or i ns ura nce c o m pa n y t o fi n d o ut e xactl y w hat t he y will pa y f or. 
 
Y o u will be c o m pe nsate d f or partici pati o n :  Cli nic V isit 1 ( $ 1 0 0), C li nic V isit 2 ( $ 1 0 0), C li nic V isit 3 
( $ 1 0 0), Cli nic V isit 4 ( $ 3 0 0) f or u n der g oi n g bi o ps y pr oce d ures, bl o o d dra w, st o ol a n d uri ne c ollec ti o ns 
d uri n g t he st u d y. T his is pr o vi de d f or t he i nc o n ve nie nce of t he bi o ps y pr ot oc ol, a n d t o c o m pe nsate f or a n y 
fi na ncial c osts d ue t o tra vel.  Pa y me nt will  be pr o vi de d a fter eac h visit.   
 
W h at h a p pe ns if I a m i nj ure d or h urt bec a use I t o o k p art i n t his st u d y ? 
If y o u feel y o u ha ve bee n i nj ure d or h urt as a res ult of ta ki n g part i n t he st u d y, it is i m p orta nt t hat y o u tell 
t he st u d y d oct or i m me diatel y. Y o u will get me dical treat me nt if y o u are i nj ure d or h urt as a res ult of 
ta ki n g part i n t his st u d y. 
 

 
 
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T he st u d y s p o ns ors will n ot pa y f or me dical treat me nt f or i nj ur y. Y o ur i ns ura nce c o m pa n y ma y n ot be 
willi n g t o pa y f or st u d y-relate d i nj ur y. If y o u ha ve n o i ns ura nce c o vera ge, y o u w o ul d be res p o nsi ble f or 
a n y c osts. E ve n t h o u g h y o u are i n a st u d y, y o u kee p all of y o ur le gal ri g hts t o recei ve pa y me nt f or i nj ur y 
ca use d b y me dical err ors. 
 
W h o will see m y me dic al i nf or m ati o n ?  
Y o ur pri vac y is ver y i m p orta nt t o us a n d t he researc hers will ma ke e ver y eff ort t o pr otect it.  T he st u d y 
d oct ors ha ve a pri vac y per mit t o hel p pr otect y o ur rec or ds if t here is a c o urt case.  Y o ur i nf or mati o n ma y 
be gi ve n o ut if re q uire d b y la w. F or e xa m ple, certai n states re q uire d oct ors t o re p ort t o healt h b oar ds if 
t he y fi n d a disease li ke t u berc ul osis. H o we ver, t he researc hers will d o their best t o ma ke s ure t hat a n y 
i nf or mati o n t hat is release d will n ot i de ntif y y o u. S o me of y o ur healt h i nf or mati o n, a n d/ or i nf or mati o n 
a b o ut y o ur s peci me n, fr o m t his st u d y will be ke pt i n a ce ntral data base f or researc h. Y o ur na me or c o ntact 
i nf or mati o n will n ot be p ut i n t he data base. 
 
T his st u d y is s p o ns ore d b y Nati o nal Ca ncer I nstit ute, Di visi o n of Ca ncer Pre ve nti o n. T he Nati o nal Ca ncer 
I nstit ute will o btai n i nf or mati o n f or t his cli nical trial u n der data c ollecti o n a ut h orit y Title 4 2 U. S. C. 2 8 5. 
 
T here are or ga nizati o ns t hat ma y i ns pect y o ur rec or ds. T hese or ga nizati o ns are re q uire d t o ma ke s ure y o ur 
i nf or mati o n is ke pt pri vate, u nless re q uire d b y la w t o pr o vi de i nf or mati o n. S o me of t hese or ga nizati o ns 
are: 
•  
T he st u d y s p o ns or s u p p orti n g t he st u d y . 
•  
T he I nstit uti o nal Re vie w B oar d, I R B, is a gr o u p of pe o ple w h o re vie w t he researc h wit h t he g oal 
of pr otecti n g t he pe o ple w h o ta ke part i n t he st u d y. 
•  
T he F o o d a n d Dr u g A d mi nistrati o n a n d t he Nati o nal Ca ncer I nstit ute i n t he U. S. 
 
W here c a n I get m ore i nf or m ati o n ? 
Y o u ma y visit t he N CI We b site at htt p://ca ncer. g o v/ f or m ore i nf or mati o n a b o ut st u dies or ge neral 
i nf or mati o n a b o ut ca ncer. Y o u ma y als o call t he N CI Ca ncer I nf or mati o n Ser vice t o get t he sa me 
i nf or mati o n at: 1- 8 0 0- 4-C A N C E R ( 1 - 8 0 0- 4 2 2- 6 2 3 7). 
 
A descri pti o n of t his cli nical trial will be a vaila ble o n htt p:// w w w. Cli nical Trials. g o v, as re q uire d b y U. S. 
La w. T his We b site will n ot i ncl u de i nf or mati o n t hat ca n i de ntif y y o u. At m ost, t he We b site will i ncl u de 
a s u m mar y of t he res ults. Y o u ca n searc h  t his We b site at a n y ti me. 
 
W h o c a n a ns wer m y q uesti o ns a b o ut t his st u d y ?  
Y o u ca n tal k t o t he st u d y d oct or a b o ut a n y q uesti o ns or c o ncer ns y o u ha ve a b o ut t his st u d y or t o re p ort 
si de effects or i nj uries. Co ntact t he st u d y d oct or Dr. Rei d Ness  at ( 6 1 5) 3 2 2 - 0 1 2 8, Dr. Ris hi Nai k  at ( 6 1 5) 
3 4 3- 0 1 0 9.  
 
S a m ple C ollecti o ns f or L a b or at or y St u dies a n d/ or Bi o b a n ki n g f or P ossi ble 
F ut ure St u dies  
T his secti o n is a b o ut o pti o n al st u dies y o u c a n c h o ose t o t a ke p art i n. 
 
T his part of t he c o nse nt f or m is a b o ut o pti o nal st u dies t hat y o u ca n c h o ose t o ta ke part i n. Y o u will n ot 
get healt h be nefits fr o m a n y of t hese st u dies. T he researc hers lea di n g t his o pti o nal st u d y h o pe t he res ults 
will hel p ot her pe o ple wit h ca ncer i n t he f ut ure. 
 

 
 
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T he res ults will n ot be a d de d t o y o ur me dical rec or ds, a n d y o u or y o ur st u d y d oct or ma y n ot k n o w t he 
res ults. Y o u will n ot be bille d f or t hese o pti o nal st u dies. 
 
Y o u ca n still ta ke part i n t he mai n st u d y e ve n if y o u sa y ‘ n o’ t o a n y or all of t hese st u dies. If y o u si g n u p 
f or b ut ca n n ot c o m plete a n y of t hese st u dies f or a n y reas o n, y o u ca n still ta ke part i n t he mai n st u d y. 
 
If y o u c h o ose t o ta ke part, t he rectal bi o psies, rectal s wa bs, uri ne, st o ol a n d bl o o d sa m ples c ollecte d i n t he 
mai n st u d y t hat are left o ver after t he mai n st u dy will be st ore d f or f ut ure st u dies. St ori n g sa m ples f or 
f ut ure st u dies is calle d “bi o ba n ki n g ” w hic h is bei n g r u n b y t he Nati o nal Ca ncer I nstit ute.    
 
W H A T I S I N V O L V E D ?  
If y o u a gree t o ta ke part, here is w hat will ha p pe n ne xt: 
1)  Y o ur sa m ple a n d s o me relate d healt h i nf or mati o n ma y be st ore d i n t he Bi o ba n k, al o n g wit h 
sa m ples a n d i nf or mati o n fr o m ot her pe o ple w h o ta ke part. T he sa m ples will be st ore d at 
Va n der bilt E pi de mi ol o g y Bi os peci me n C ore d uri n g st u d y u ntil t he e n d of t he st u d y, w he n 
t he y ma y be tra nsferre d t o t he Nati o nal I nstit utes of Healt h.  
2)  Q ualifie d researc hers ca n s u b mit a re q uest t o use t he materials st ore d i n t he Bi o ba n ks. A 
scie nce c o m mittee at t he cli nical trials or ga nizati o n, a n d/ or t he Nati o nal Ca ncer I nstit ute, will 
re vie w eac h re q uest. T here will als o be a n et hics re vie w t o e ns ure t hat t he re q uest is 
necessar y a n d pr o per. Researc hers will n ot be gi ve n y o ur na me or a n y ot her i nf or mati o n t hat 
c o ul d directl y i de ntif y y o u.   
3)  Neit her y o u n or y o ur st u d y d oct or will be n otifie d w he n researc h will be c o n d ucte d or gi ve n 
re p orts or ot her i nf or mati o n a b o ut a n y researc h t hat is d o ne usi n g y o ur sa m ples.  
4)  S o me of y o ur ge netic a n d healt h i nf or mati o n ma y be place d i n ce ntral data bases t hat ma y be 
p u blic, al o n g wit h i nf or mati o n fr o m ma n y ot her pe o ple. I nf or mati o n t hat c o ul d directl y 
i de ntif y y o u will n ot be i ncl u de d. 
 
W H A T A R E T H E P O S SI B L E RI S K S ?  
1)  T he m ost c o m m o n ris ks relate d t o dra wi n g bl o o d fr o m y o ur ar m are brief pai n a n d p ossi bl y a 
br uise.   
2)  T here is a ris k t hat s o me o ne c o ul d get access t o t he p ers o nal i nf or mati o n i n y o ur me dical 
rec or ds or ot her i nf or mati o n researc hers ha ve st ore d a b o ut y o u. 
3)  T here is a ris k t hat s o me o ne c o ul d trace t he i nf or mati o n i n a ce ntral data base bac k t o y o u. 
E ve n wit h o ut y o ur na me or ot her i de ntifiers, y o ur ge netic i nf or mati o n is u ni q ue t o y o u. T he 
researc hers belie ve t he c ha nce t hat s o me o ne will i de ntif y y o u is ver y s mall, b ut t he ris k ma y 
c ha n ge i n t he f ut ure as pe o ple c o me u p wit h ne w wa ys of traci n g i nf or mati o n. 
4)  T here are la ws a gai nst t he mis use of ge netic i nf or mati o n,  b ut t he y ma y n ot gi ve f ull 
pr otecti o n. Ne w healt h i nf or mati o n a b o ut i n herite d traits t hat mi g ht affect y o u or y o ur bl o o d 
relati ves c o ul d be f o u n d d uri n g a st u d y. T he researc hers belie ve t he c ha nce t hese t hi n gs will 
ha p pe n is ver y s mall, b ut ca n n ot pr o mise t hat t he y will n ot occ ur. 
 
A ne w Fe deral la w, calle d t he Ge netic I nf or mati o n N o n discri mi nati o n Act ( GI N A), ge nerall y 
ma kes it ille gal f or healt h i ns ura nce c o m pa nies, gr o u p healt h pla ns, a n d m ost e m pl o yers t o 
discri mi nate a gai nst y o u base d o n y o ur ge netic i nf or mati o n. T his la w ge nerall y will pr otect 
y o u i n t he f oll o wi n g wa ys:  
•  
Healt h i ns ura nce c o m pa nies a n d gr o u p healt h pla ns ma y n ot re q uest y o ur ge netic 
i nf or mati o n t hat we get fr o m t his researc h. 
•  
Healt h i ns ura nce c o m pa nies a n d gr o u p healt h pla ns ma y n ot use y o ur ge netic 
i nf or mati o n w he n ma ki n g decisi o ns re gar di n g y o ur eli gi bilit y or pre mi u ms. 

 
 
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– 5 1 – 
 
E m pl o yers wit h 1 5 or m ore e m pl o yees ma y n ot use y o ur ge netic i nf or mati o n t hat we get fr o m 
t his researc h w he n ma ki n g a decisi o n t o hire, pr o m ote, or fire y o u or w he n setti n g t he ter ms 
of y o ur e m pl o y me nt. All healt h i ns ura nce c o m pa nies a n d gr o u p healt h pla ns m ust f oll o w t his 
la w b y Ma y 2 1,  2 0 1 0. All e m pl o yers wit h 1 5 or m ore e m pl o yees m ust f oll o w t his la w as of 
N o ve m ber 2 1,  2 0 0 9. 
 
Be a ware t hat t his ne w Fe deral la w d oes n ot pr otect y o u a gai nst ge netic discri mi nati o n b y 
c o m pa nies t hat sell life i ns ura nce, disa bilit y i ns ura nce, or l o n g -ter m care i ns ura nce. 
 
H O W WI L L I N F O R M A TI O N A B O U T M E B E K E P T P RI V A T E ?  
Y o ur pri vac y is ver y i m p orta nt t o t he researc hers a n d t he y will ma ke e ver y eff ort t o pr otect it. Here are 
j ust a fe w of t he ste ps t he y will ta ke: 
1)  W he n y o ur sa m ple(s) is se nt t o t he researc hers, n o i nf or mati o n i de ntif yi n g y o u (s uc h as y o ur 
na me) will be se nt. Sa m ples will be i de ntifie d b y a u ni q ue c o de o nl y.  
2)  T he list t hat li n ks t he u ni q ue c o de t o y o ur na me will be ke pt se parate fr o m y o ur sa m ple a n d 
healt h i nf or mati o n. A n y Bi o ba n k a n d Va n der bilt U ni versit y Me dical Ce nter staff wit h access 
t o t he list m ust si g n a n a gree me nt t o kee p y o ur i de ntit y c o nfi de ntial. 
3)  Researc hers t o w h o m Va n der bilt U ni versit y Me dical Ce nter se n ds y o ur sa m ple a n d 
i nf or mati o n will n ot k n o w w h o y o u are. T he y m ust als o si g n a n a gree me nt t hat t he y will n ot 
tr y t o fi n d o ut w h o y o u are. 
4)  I nf or mati o n t hat i de ntifies y o u will n ot be gi ve n t o a n y o ne, u nless re q uire d b y la w. 
5)  If researc h res ults are p u blis he d, y o ur na me a n d ot her pers o nal i nf or mati o n will n ot be use d. 
 
W H A T A R E T H E P O S SI B L E B E N E FI T S ?  
Y o u will n ot be nefit fr o m ta ki n g part. T he researc hers, usi n g t he sa m ples fr o m y o u a n d ot hers, mi g ht 
ma ke disc o veries t hat c o ul d hel p pe o ple i n t he f ut ure.  
 
A R E T H E R E A N Y C O S T S O R P A Y M E N T S ?  
T here are n o c osts t o y o u or y o ur i ns ura nce. Y o u will n ot be pai d f or ta ki n g part. If a n y of t he researc h 
lea ds t o ne w tests, dr u gs, or ot her c o m mercial pr o d ucts, y o u will n ot s hare i n a n y pr ofits. 
 
W H A T I F I C H A N G E M Y MI N D ?  
If y o u deci de y o u n o l o n ger wa nt y o ur sa m ples t o be use d, y o u ca n call t he St u d y C o or di nat or 
( _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _) at ( _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _) w h o will let t he researc hers k n o w. T he n, a n y sa m ple 
t hat re mai ns i n t he ba n k will n o l o n ger be use d a n d relate d healt h i nf or mati o n will n o l o n ger be c ollecte d. 
Sa m ples or relate d i nf or mati o n t hat ha ve alrea d y bee n gi ve n t o or use d b y researc hers will n ot be 
ret ur ne d. 
 
W H A T I F I H A V E M O R E Q U E S TI O N S ?  
If y o u ha ve q uesti o ns a b o ut t he use of y o ur sa m ples f or researc h, c o ntact t he St u d y C o or di nat or 
( _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _) at ( _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _). 
 
Please circle y o ur a ns wer t o s h o w w het her or n ot y o u w o ul d li ke t o ta ke part i n eac h o pti o n  
 
S A M P L E S F O R T H E L A B O R A T O R Y S T U DI E S:  

 
 
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I a gree t o ha ve m y s peci me n c ollecte d a n d I a gree t hat m y s peci me n sa m ple(s) (rectal 
bi o p s y/s wa b, uri ne, st o ol a n d bl o o d) a n d relate d i nf or mati o n ma y be use d  f or t he la b orat or y 
st u d y(ies) descri be d a b o ve. 
 
 
Y E S   
 
N O  
 
I a gree t hat m y st u d y d oct or, or t heir re prese ntati ve, ma y c o ntact me or m y p h ysicia n t o see if I 
wis h t o lear n a b o ut res ults fr o m t his(ese) st u d y(ies).  
 
 
Y E S   
 
N O  
 
S A M P L E S F O R F U T U R E R E S E A R C H S T U DI E S:  
 
M y sa m ples a n d relate d i nf or mati o n ma y be ke pt i n a Bi o ba n k f or use i n f ut ure healt h re searc h. 
 
 
Y E S   
 
N O  
 
I a gree t hat m y st u d y d oct or, or t heir re prese ntati ve, ma y c o ntact me or m y p h ysicia n t o see if I 
wis h t o partici pate i n ot her researc h i n t he f ut ure. 
 
 
Y E S   
 
N O  
 
T his is t he e n d of t he secti o n a b o ut o pti o nal st u dies. 
 
If y o u de vel o p a me dical pr o ble m w hile o n st u d y, ma y we i nf or m y o ur p h ysicia n?  
 
 
Y E S   
 
N O  
 
If yes, w h o m w o ul d y o u li ke us t o i nf or m? 
 
Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ P h o ne N u m ber: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
M y Si g n at ure A greei n g t o T a ke P art i n t he M ai n St u d y  
I ha ve rea d t his c o nse nt f or m or ha d it rea d t o me. I ha ve disc usse d it wit h t he st u d y d oct or a n d m y 
q uesti o ns ha ve bee n a ns were d. I will be gi ve n a si g ne d c o p y of t his f or m. I a gree t o ta ke part i n t he mai n 
st u d y a n d a n y a d diti o nal st u dies w here I circle d ‘ yes’. 
 
Partici pa nt’s si g nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Date of si g nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
Si g nat ure of pers o n(s) c o n d ucti n g t he i nf or me d c o nse nt disc ussi o n _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Date of si g nat ure _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
 

 
 
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A p pe n di x A – Cli nic Visit I nstr ucti o ns  
 
E v al u ati n g I nt er mitt e nt D o si n g of A s piri n f or C ol or e ct al C a n c er C h e m o pr e v e nti o n 
St u d y  
 
C LI NI C A P P OI N T M E N T I N S T R U C TI O N S  
 
 
1.  Y o u ar e s c h e d ul e d f or y o ur cli ni c a p p oi nt m e nt o n  
 
 _ _ _ _ _ _ _ _ _ _ _ _ _ _ at _ _ _ _ _ _ _ _ _ _ _ A M/ P M.  
 
 
2.  I n str u cti o n s f or p ar ki n g a n d h o w t o g et t o t h e cli ni c ar e i n cl u d e d i n t hi s p a c k et. 
 
 
3.  If y o u n e e d t o c h a n g e y o ur a p p oi nt m e nt, pl e a s e c all X X X X X X X X at X X X X X X X X  
t o r e s c h e d ul e. 
 
 
4.  Pl e a s e r e a d t h e d et ail “ St o ol S a m pl e I n str u cti o n s” a n d c oll e ct y o ur st o ol s a m pl e 
b ef or e y o ur cli ni c vi sit. W e pr ef er t h at y o u c oll e ct t h e s a m pl e u p t o 3 d a y s b ef or e 
th e vi sit.   
 
 
5.  R e m e m b er t o pl a c e y o ur fr e e z er i c e p a c k i nt o y o ur fr e e z er at l e a st t w o d a y s 
b ef or e  y o ur cli ni c a p p oi nt m e nt.  
 
 
6.  Pl e a s e r e m e m b er t o bri n g t o y o ur vi sit y o ur st o ol s a m pl e  al o n g wit h t h e i c e p a c k  
i n t h e f o a m c o ol er. 
 
 
7.  If y o u h a v e a n y q u e sti o n s, ple a s e c o nt a ct u s at X X X X X X X X X X.  
 
T h a n k y o u f or y o ur p arti ci p ati o n!  
 
 

 
 
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– 5 4 – 
A p pe n di x B – At -H o me St o ol C ollecti o n I nstr ucti o ns  
 
 
B ef or e y o u c oll e ct y o ur st o ol s a m pl e:  
1.  W e w o ul d li k e y o u t o c oll e ct a st o ol s a m pl e u p  to 3 d a y s b ef or e y o ur cli ni c a p p oi nt m e nt . 
2.  Y o u m a y r e q u e st h el p r e a di n g t h e s e i n str u cti o n s fr o m a m e m b er of y o ur h o u s e h ol d, b ut pl e a s e 
d o n ot l et a n y o n e h a n dl e  t h e c o nt ai n er s, s cr e w t o p s, or pl a sti c b a g s.  
3.  At l e a st 2 d a y s b ef or e y o ur cli ni c a p p oi nt m e nt, pl a c e t h e fr e e z er p a c k i nt o y o ur  fre e z er.  
 
W h e n y o u ar e r e a d y t o c oll e ct y o ur st o ol s a m pl e:  
1.  W a s h y o ur h a n d s wit h s o a p a n d w ar m w at er.  
2.  Uri n at e i nt o t h e t oil et a n d fl u s h.  
3.  Lift t h e t oil et s e at.  
4.  Pl a c e t h e s u p p ort fr a m e o n t h e t oil et b o wl ri m. Pl a c e t h e w hit e pl a sti c b o wl i nt o t h e cir cl e-s h a p e d 
s e cti o n of t h e fr a m e.  
5.  L o w er t h e t oil et s e at a n d p a s s t h e st o ol dir e ctl y i nt o t h e w hit e pl a sti c b o wl. D o n ot mi x t h e st o ol 
s a m pl e wit h a n y uri n e or w at er fr o m t h e t oil et.  
6.  P ut o n t h e gl o v e s a n d o p e n o n e of t h e st o ol c oll e cti o n c o nt ai n er s  ( br o w n c a p) wit h t h e s p o o n 
att a c h e d t o t h e br o w n i n n er li d.  
7.  U si n g t h e s p o o n att a c h e d t o t h e s cr e w t o p, tr a n sf er pi e c e s of st o ol i nt o t h e c o nt ai n er u ntil t h e 
c o nt ai n er i s fill e d h alf w a y. If t h e st o ol i s li q ui d – p o ur . If t h e st o ol i s l o o s e – g e ntl y p o ur.  
8.  S cr e w t h e li d o n t h e c o nt ai n er ti g htl y a n d wi p e off a n y s pill s  fr o m t h e o ut si d e of t h e c o nt ai n er  
wit h a cl e a n p a p er t o w el.  Di s c ar d t h e p a p er t o w el.  
9.  R e p e at st e p s 6, 7, a n d 8 f or t h e ot h er  br o w n c a p  st o ol c oll e cti o n c o nt ai n er s.  
1 0.  O p e n t h e t hi n c oll e cti o n c o nt ai n er wit h t h e li g ht gr e e n li d.  
1 1.  Di p t h e s a m pl e w a n d att a c h e d t o t h e li d i nt o t h e st o ol s a m pl e w hi c h w a s c oll e ct e d i n t h e w hit e 
b o wl. C o v er t h e gr o o v e d p orti o n of t h e s a m pl e w a n d c o m pl et el y wit h st o ol s a m pl e.  
1 2.  R e -i n s ert t h e s a m pl e w a n d i nt o t h e c o nt ai n er a n d p u s h t h e c a p d o w n u ntil a s n a p  i s h e ar d. 
1 3.  Pl a c e all 3 s a m pl e s c oll e cti o n t u b e s ( 2 br o w n c a p s, 1 li g ht gr e e n c a p) i nt o t h e pl a sti c s p e ci m e n  
b a g a n d s e al t h e b a g i n zi p -l o c k f a s hi o n.  
1 4.  Writ e t h e d at e a n d  ti m e of c oll e cti o n  o n t h e b a g wit h a p e n  or m ar k er . 
1 5.  Pl a c e  t h e  s e al e d  b a g  ( c o nt ai ni n g  t h e  c oll e cti o n  c o nt ai n er s)  i nt o  t h e  s e c o n d  pl a sti c  b a g.  
R e m o v e a n y e x c e s s air fr o m t h e b a g a n d s e al t h e s e c o n d b a g.  
1 6.  W a s h y o ur h a n d s wit h s o a p a n d w ar m w at er. Y o u m a y di s c ar d t h e gl o v e s a n d t h e w hit e st o ol 
c oll e cti o n b o wl. T h e fr a m e m a y b e r e u s e d if f ut ur e c oll e cti o n s ar e e x p e c t e d. 
1 7.  Pl a c e t h e s e al e d b a g i n t h e R E F RI G E R A T O R u ntil y o u bri n g it t o y o ur cli ni c a p p oi nt m e nt  
 
T h e d a y of y o ur cli ni c a p p oi nt m e nt:  
1.  P ut t h e s e al e d b a g wit h t h e st o ol s a m pl e s i nt o t h e i n s ul at e d tr a n s p ort b a g  al o n g wit h t h e 
fr e e z er g el  p a c k. 
2.  Bri n g t h e p a c k a g e wit h y o u t o y o ur cli ni c a p p oi nt m e nt.  
 
 
 

 
 
N W U 2 0 1 5 -0 6 -0 1  
Pr ot oc ol Versi o n 2. 1 9 , A u g ust 1 1 , 2 0 2 2 
 
– 6 4 – 
A p pe n di x  D – P artici p a nt Di ar y  
Pr ot oc ol N W U 2 0 1 5- 0 6- 0 1 
Partici pa nt I D: _ _ _ _ _ _ _ _ _ _ _ _ _ 
I nstr ucti o ns: Ta ke o nce per da y wit h f o o d.   
S witc h t o B ottle 2 ( la bele d “Wee ks 4 - 6”) starti n g o n Da y 2 2.   
S witc h t o B ottle 3 ( la bele d “Wee ks 7 - 9”) starti n g o n Da y 4 3.   
S witc h t o B ottle 4 (la bele d “ Wee ks 1 0 -1 2”) after Cli nic Visit 3 .   
 
D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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D A Y: _ _ _  
B OTT L E: _ _ _ _ _ _ _ _ _ _ _ _  
D AT E: _ _ _/ _ _ _ _/ _ _ _ _  
TI M E: _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pl e as e list n e w 
s y m pt o ms, n e w 
m e di c ati o ns, or 
r e as o ns f or miss e d 
d os es: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
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F or use b y st u d y staff 
C o or di nat or’s Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

 
 
– 6 5 –  
A p pe n di x E – S u g geste d St a te me nts f or P artici p a nt C o m m u nic ati o ns 
 
Please use t he f oll o wi n g s u g geste d state me nts f or tele p h o ne or e mail c o ntacts wit h partici pa nts.  
 
Hell o ( p artici p a nt n a me),  
 
T h a nk y o u f or p artici p ati n g i n t he Ev al u ati n g I nter mitte nt D osi n g of As piri n f or C ol orect al C a ncer 
C he m o preve nti o n Tri al.    
 
If y o u will, ple ase re ply  at y o ur e arliest c o nve nie nce  a n d let me k n o w h o w y o ur ex perie nce h as bee n i n 
si nce we l ast s p oke. A ny a n d all eve nts are i m p ort a nt t o rec or d. 
 
1.  H ave y o u ex perie nce d a ny sy m pt o ms or p ossi ble si de effects ?  
2.  H ave y o u t ake n y o ur st u dy me dic ati o n d aily a n d m ar ke d e ac h d ose i n yo ur di ary ? H ave y o u 
misse d a ny d oses ?  
Kee p i n mi n d t o o nly t ake y o ur st u dy me dic ati o n f or 2 1 c o nsec utive d ays a n d t he n t o s witc h t o 
y o ur next b ottle f or 2 1 c o nsec utive d ays.  
3.  H ave t here bee n a ny c h a n ges i n y o ur ot her me di c ati o ns/s u p ple me nts si nce we l ast s p oke ? 
 
As a re mi n der, y o ur ex pecte d b ottle s witc h d ate are : 
St o p b ottle 1/ st art b ottle 2:  (i nsert d ate) 
St o p b ottle 2/ st art b ottle 3:   (i nsert d ate) 
 
O ur next pl a n ne d cli nic a p p oi nt me nt is liste d bel o w. Ple ase pl a n y o ur h o me s peci me n c ollecti o n a n d 
bri n g all st u dy me dic ati o n b ottles wit h y o u t o t his visit.  
 
Cli nic visit 3: (i nsert d ate)  
 
Ple ase c all or e m ail me wit h a ny q uesti o ns.  
 
T h a nk y o u, 
(i nsert c o or di n at or n a me a n d c o nt act i nf or m ati o n)