Clinical trial NCT04033419
Conditions: Cognitive Decline Chemo-brain
Sponsor: UNC Lineberger Comprehensive Cancer Center
Start date: 2019-09-25; Completion date: 2022-04-04
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Purpose: To conduct a one-arm phase II trial to: (1) compare changes in pre- to post-chemotherapy cognitive function in a cohort of patients with breast cancer receiving memantine to historical controls; (2) examine how depression, anxiety, fatigue, baseline Intelligence Quotient (IQ), and cognitive effort relate to objective and self-reported cognitive function; and (3) estimate the feasibility of conducting a clinical trial of memantine for attenuating cognitive decline in patients with breast cancer during chemotherapy.

Participants: Adult patients with stage I-III breast cancer scheduled for adjuvant or neoadjuvant chemotherapy.

Procedures (methods): Cognitive assessments will be performed within one week of initiating and four weeks after completion of chemotherapy. Patients will receive memantine 10 mg twice daily between the pre- and post-chemotherapy study assessments. Cognitive function will be assessed objectively using a computerized cognitive test (Delayed Matching to Sample (DMS) test) and a standard neuropsychological battery. To assess subjective cognitive function, the Patient Reported Outcome Measurement Information System (PROMIS) Cognitive Function measure will be used. Depression, anxiety, fatigue, menopausal status, and sleep will be assessed as covariates.

Detailed description:
This is a one-arm phase II interventional study in patients with breast cancer to investigate whether memantine can prevent cognitive decline during chemotherapy. The investigators will recruit 56 participants referred to the University of North Carolina (UNC) Breast Center and affiliated outpatient clinics for initiation of adjuvant or neoadjuvant chemotherapy, perform a cognitive assessment within one week of initiating and four weeks after completion of chemotherapy, and treat with memantine 10 mg twice daily between the pre- and post-chemotherapy study assessments (estimated duration: 12-26 weeks, depending on the chemotherapy regimen). Cognitive function will be assessed objectively using a computerized cognitive assessment (Delayed Matching to Sample (DMS) test) and a standard neuropsychological battery. To assess subjective cognitive function, the Patient Reported Outcome Measurement Information System (PROMIS) Cognitive Function measure will be used. Depression, anxiety, fatigue, menopausal status, and sleep are comorbidities known to affect cognitive function, and therefore will be assessed as covariates pre- and post-chemotherapy. Depression, anxiety, health-related quality of life (HRQOL) and functional status will be evaluated as secondary outcomes. The feasibility of the investigator's study by monitoring recruitment, retention, and adherence to memantine will be assessed.

Arms: arm 1: Subjects receive memantin
Interventions: intervention 1: Memantine
Intervention descriptions: intervention 1: memantine dose

* Week 1: 5 mg dose once daily
* Week 2: 5 mg dose twice daily
* Week 3: 5 mg each morning/10 mg each evening
* Week 4 through the end of Chemotherapy: 10 mg dose twice daily
* Total duration: 12 - 26 weeks (depending on chemotherapy regimen)

Protocol documents:
Prot_SAP_000.pdf: 
LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
P R O T O C O L A M E N D M E N T # _ _ 1 0 _ _  
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.
( 2) We ha v e m o difie d  Secti o n 5. 3 t o i ncl u de m ore s pecific d ose re d ucti o n a n d
st o p pi n g r ules base d o n t o xicit y gra de, attri b uti o n, a n d effect o n c he m ot hera p y
treat me nt. We h a ve als o clarifie d t hat partici pa nts will be assesse d f or
t o xicities o n a wee kl y basis d uri n g t he titrati o n peri o d.
( 3) We ha v e u p date d Se cti o n 8. 1. 2 t o clarif y t hat t he w orse ni n g of se v erit y a n d
fre q ue n c y of a d v erse e ve nts will be e val uate d w he n assessi n g ca usalit y.
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C 
revie w. 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 4/ 2 3/ 2 1 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 9 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ge s (I R B a p pr o val) 
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 4) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 5) We ha v e a d de d Yara A b d o u, M D as a c o -i n vesti gat or t o t he st u d y. 
 
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C 
revie w. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1 2/ 1 4/ 2 0 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # _ _ 8 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) We ha v e a d de d l a n g ua ge i n Secti o n s 1. 1 , 7. 1, 7. 2 , 7. 4, 7. 5, a n d 9. 1  t o i n dicate 
t hat we ha ve e x pa n d e d st u d y recr uit me nt t o i ncl u d e U N C R E X O nc ol o g y 
cli nics. 
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m 
P R C revie w . 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1 0 /7 / 2 0_ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 7 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 3) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 4) We ha v e a d de d d etails t o Secti o n 1. 1 , Secti o n 5. 6 , Secti o n 7. 1, Secti o n 7. 5, 
Secti o n 9. 1, a n d Secti o n 9. 3  t o clarif y pla ns f or  e xte n de d  l o n git u di nal f oll o w-
u p pr oce d ures f or a s u bset of partici pa nts w h o v ol u ntaril y o pt -i n (i.e. 
c o g niti ve a n d ot her sec o n dar y o utc o me meas ures will be re peat e d  at 6 m o nt hs 
p ost -c he m ot hera p y ). T h e pla n t o offer l o n git u di nal f oll o w -u p fo r a s u bset of 
i ntereste d partici p a nts was i n dicate d a n d a p pr o ve d i n pre vi o us s u b missi o ns, 
b ut t hese c ha n ges pr o vi de t he details of t his pla n.  
( 5) We ha v e a d de d e x pl orat or y o bjecti ves i n Secti o n 2. 3  a n d e x pl orat or y 
e n d p oi nts i n Secti o n 3. 3 t o c oi nci de wit h t he a d diti o n of t he l o n git u di nal 
f oll o w-u p pr oce d ures at 6 m o nt hs p ost -c he m ot hera p y f or a s u bs et of 
partici pa nts.   
( 6) We ha v e u p date d s ur v e y la n g ua ge i n A p pe n di x F t o i ncl u de all ge n der 
i de ntities. 
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m 
P R C revie w . 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 9 /4 / 2 0_ _  I N C O R P O R A T E S T H E A B O V E R E VI SI O N S 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # _ _ 6 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) We ma de a mi n or c ha n g e t o  Secti o n 5. 2 t o re mai n c o nsiste nt wit h a pre vi o us 
a me n d me nt t hat  wi de n e d  t he p ost -c he m ot hera p y assess me nt wi n d o w .  
( 3) We ma de a mi n or c ha n g e t o Secti o n 1. 1 t o re mai n c o nsiste nt a b o ut t he ti mi n g 
of t he baseli ne c o g niti ve assess me nt  t hr o u g h o ut t he pr ot oc ol. 
( 4) We ha v e c ha n g e d  Se cti o ns 5. 8. 1 8, 7. 1, a n d 7. 4 t o s pecif y t hat all partici p a nts 
will be as ke d t o c o m plete t he H or m o nal Stat us Q uesti o n naire at t he p ost -
c he m ot hera p y assess me nt.  
( 5) We ha v e c ha n g e d Secti o n 7. 2 t o i n dicate t hat we ha ve e x p a n de d st u d y 
recr uit me nt t o i ncl u de U N C Hil ls b or o u g h O nc ol o g y Cli nic. 
( 6) We m o difie d  Secti o n 7. 4  t o re mai n c o nsiste nt wit h a pre vi o us a me n d m e nt t hat 
s pecifie d t hat w e will utilize a wider ra n g e of o pti o ns f or disse mi nati o n of 
st u d y assess me nts a n d s ur ve ys (i.e. e m ail, p h o ne, mail, o nli ne, a n d vi de o 
c onfere nci n g met h o ds ).  
( 7) We ha v e ma de c ha n ges t hr o u g h o ut t he pr ot oc ol t o reflect t he a d diti o n of t w o 
ne w sec o n d ar y o utc o me meas ures  ( R V P a n d O T S) t hat ca n be c o m plete d 
virt uall y t o re place o n e meas ure  ( T M T) t hat m ust be c o m plete d i n-pers o n.  
T his c ha n ge will n ot affect o ur statistical pla n a n d is bei n g i m ple me nte d s o 
t hat e ver y as p ect of o ur st u d y ca n be c o m plet e d re m otel y. 
( 8) I n Secti o n 5. 3 a n d 7. 3, we ha ve s pecifie d t hat t o xi cit y assess me nts will occ ur 
at a n i nter val n o gr eater t ha n e ver y t hree wee ks , i nstea d of e v er y 2 t o 3 wee ks 
de pe n di n g o n t he ti mi n g of t he c he m ot hera p y re gi me n . 
( 9) I n Secti o n 5. 3, we ha v e state d t hat partici pa nts ma y  decrease or dis c o nti n ue 
me ma nti ne at a n y ti me, e ve n i n t he a bse nce of a me ma nti ne-ass oci ate d 
t o xicit y.  


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m 
P R C revie w . 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 5/ 2 1 / 2 0_ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 5 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) We ha v e ma de c ha n ges t o Secti o ns 1. 1, 7. 1, a n d 7. 4 t o wi de n t he p ost -
c he m ot hera p y assess me nt wi n d o w . W hile we will ma ke e ver y atte m pt t o 
sc he d ule assess m e nts o n t heir i deal dates, t his will all o w us m ore fle xi bilit y i n 
sc he d uli n g i n li g ht of C O VI D-1 9 p olic y.  
( 3) We ha v e ma de c ha n ges t o Secti o ns 1. 1, 5. 2, a n d 7. 3  t o reflect t he p ot e ntial 
e x pa nsi o n of st u d y d urati o n as a res ult of wi d e ni n g t he p ost -c he m ot hera p y 
f oll o w-u p wi n d o w.   
( 4) We ha v e ma de c ha n ges t o wi de n t he st u d y dr u g start wi n d o w i n Secti o ns 5. 2, 
5. 5, a n d 7. 3 . We will ma ke e ver y atte m pt t o start partici pa nts o n o ur dr u g 
d uri n g t he ori gi nal sc he d ule o utli ne d i n o ur P R C pr ot oc ol, b ut t his will all o w 
f or m ore fl e xi bilit y i n e ns uri n g t hat partici pa nts h a ve recei ve d o ur st u d y dr u g 
pri or t o starti n g c he m ot h era p y.  
( 5) We ha v e ma de m o dificati o ns Secti o n 7. 2 t o utilize a wi der ra n ge of  o pti o ns 
f or disse mi nati o n of st u d y assess me nts a n d s ur ve ys. We pla n t o i m ple me nt 
e mail, p h o ne, mail, o nli ne, a n d vi de o c o nfere nci n g met h o ds of c o m pleti n g 
st u d y assess me nts a n d q uesti o n naires w he n e ver p ossi ble i n cases t hat i n -
pers o n c o m m u nicati o n is restr icte d or pr o hi bite d.  
 
Per  c orres p o n de n ce  wit h t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m 
P R C revie w . 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 3 / 1 3/ 2 0_ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
P R O T O C O L A M E N D M E N T # _ _ 4 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) We ha v e a d de d Ti m ot h y Br ot hert o n, M D as a c o -i n vesti gat or t o t he st u d y. 
( 3) We ha v e a d de d Secti o n 5. 8. 1 8  a n d A p pe n di x O  a n d m o difie d Secti o ns 5. 1, 
5. 7, 7. 1, a n d 7. 4 t o reflect t he a d diti o n of t he M o difie d Brief Me dicati o n 
Q uesti o n naire ( B M Q) -S pecific q uesti o n nair e . T he M o difie d B M Q -S pecific 
will be use d t o assess partici pa nts’ beliefs a b o ut t h e necessit y  a n d c o ncer ns  of 
ta ki n g me ma nti ne. T he s ur ve y will be a d mi nistere d t o partici pa nts at t he p ost-
c he m ot hera p y assess me nt a n d offere d u p o n st u d y wit h dra wal, if a p plica ble.  
 
Per t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C revie w.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1/ 1 3 / 2 0_ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 3 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y  c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 6) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 7) We ha v e a d de d Kirste n N yr o p, P h D as a c o -i n vesti gat or t o t he st u d y. 
 
Per t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C revie w.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1 1 /2 1/ 1 9 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
P R O T O C O L A M E N D M E N T # _ _ 2 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ X _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol.  
( 2) I n Secti o n 7. 2 we ha v e br oa de ne d t he l a n g ua ge re gar di n g t he l ocati o n of st u d y 
assess me nts t o i ncl u de partici pa nts’ h o mes, w hic h will all o w f or m ore 
fle xi bilit y i n c o n d ucti n g c o g niti ve assess me nts pri or t o t he start a n d at t he e n d 
of c he m ot hera p y.  
Eli gi bilit y c ha n ges  
( 1) I n Secti o n 4. 2 we ha v e u p date d o ur eli gi bilit y criteria t o n o l o n ger s pecif y 
se vere re nal i m pair me nt, defi ne d as Cr > 3 m g/ d L or Cr Cl < 3 0 m L/ mi n, or 
t otal bilir u bi n > 2. 5 m g/ d L as e xcl usi o n criteria. T hese la b-b ase d criteria ha ve 
bee n re m o v e d beca use ( 1) neit her are c o ntrai n dicati o ns t o recei vi n g 
me ma nti ne ( n ot liste d o n t he pac ka g e i nsert) a n d are ( 2) n ot a vaila ble i n m ost 
patie nts u ntil t he start c he m ot hera p y (after o ur recr uit me nt wi n d o w).  
 
Per t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C revie w.  
 
 
 
 
 
 
 
 
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 1 0/ 1/ 1 9 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 
P R O T O C O L A M E N D M E N T # _ _ 1 _ _  
 
 
L C C C 1 9 2 1: Me m a nti ne f or P re ve nti o n of C o g niti ve Decli ne d uri n g A dj u v a nt or 
Ne o a dj u v a nt C he m ot her a p y i n P atie nts wit h Bre ast C a ncer  
 
A M E N D M E N T I N C O R P O R A T E S  (c hec k all t h at a p pl y): 
_ X _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ _ Scie ntific c ha n ges (I R B a p pr o val)  
_ _ _ T hera p y c ha n ges (I R B a p pr o val)  
_ _ _ Eli gi bilit y C ha n ges (I R B a p pr o val)  
 
A M E N D M E N T R A TI O N A L E A N D S U M M A R Y:  
 
E dit orial, a d mi nistrati ve c ha n ges  
( 1) T he versi o n date was u p d ate d t hr o u g h o ut t he pr ot o c ol . 
( 2) I n Secti o n 1. 1 we ha v e c ha n ge d t he la n g u a ge ar o u n d t he ti mi n g of c o g niti ve 
assess me nts t o  all o w f or m ore fle xi bilit y i n sc he d uli n g wit h partici pa nts.  
( 3) I n Secti o n 7. 2  we ha v e br oa de ne d  t he all o wa ble m et h o ds of  c o ntact f or  st u d y 
assess me nt s t o i ncl u de o ver t he p h o ne. 
 
Per t he P R C C o or di n at or, t his a me n d me nt is exe m pt fr o m P R C revie w.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
T H E A T T A C H E D V E R SI O N D A T E D _ _ 8/ 2 6/ 1 9 _ _  I N C O R P O R A T E S T H E A B O V E 
R E VI SI O N S  
A T T A C H T O T H E F R O N T O F E V E R Y C O P Y O F P R O T O C O L  
 
 
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
L C C C 1 9 2 1 : 
Me ma nti ne f or Pre v e nti o n of C o g niti ve Decli ne d uri n g  A dj u va nt or  Ne o a dj u va nt 
C he m ot hera p y i n  Patie nts wit h Breast Ca ncer  
 
S h ort Title : Me ma nti ne f or Pre ve nti o n of C o g niti ve Decli ne i n Patie nts wit h Breast Ca ncer  
 
Pri nci p al I n vesti g at or  
Ze v N a k a m ur a, M D  
 
 
 
 
 
E mail: ze v _ na ka m ur a @ m e d. u nc.e d u  
 
Me dic al M o nit or  
Ze v Na ka m ura, M D  
 
 
E mail: ze v _ na ka m ur a @ me d. u nc.e d u  
 
C o -I n vesti g at or(s) 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LI N E B E R G E R C O M P R E H E N SI V E C A N C E R C E N T E R  
 
C LI NI C A L O N C O L O G Y R E S E A R C H P R O G R A M  
 
A pril 2 0 1 7  
U NI V E R SI T Y O F N O R T H C A R O LI N A A T C H A P E L HI L L  
 
 
Bi ost atistici a n  
 
 
 
 
 
  
 
 
 
 
S p o ns or :  Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter  
 
F u n di n g S o urce : N ort h Car oli na Cli nical a n d Tra nslati o nal Scie nces I nstit ute ( N C Tra C S 
I nstit ute), Gra nt #5 K 1 2 H D 0 0 1 4 4 1 -1 9  
 
 
Versi o n 1 D ate : 6/ 2 2 / 2 0 1 9 
Versi o n 2 D ate:  8/ 2 6/ 2 0 1 9  
Versi o n 3 D ate:  1 0/ 1/ 2 0 1 9  
Versi o n 4 D ate:  1 1/ 2 1/ 2 0 1 9  
Versi o n 5 D ate: 1/ 1 3 / 2 0 2 0 
Versi o n 6 D ate: 5 /2 1 / 2 0 2 0 
Versi o n 7 D ate:  9/ 4/ 2 0 2 0  
Versi o n 8 D ate:  1 0/ 7/ 2 0 2 0  
Versi o n 9 D ate:  1 2/ 1 4/ 2 0 2 0  
Versi o n 1 0 D ate:  4/ 2 3/ 2 0 2 1  
 




L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
i 
T A B L E O F C O N T E N T S  
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  .................................................................4  
1. 1  
St u d y S y n o psis  .....................................................................................................4  
1. 2  
Disease Bac k gr o u n d .............................................................................................4  
1. 3  
C urre nt Sta n dar d of Care  .....................................................................................6  
1. 4  
Me ma nti ne  ...........................................................................................................6  
1. 5  
Rati o nale f or Cli nical St u d y .................................................................................7  
2. 0  
S T U D Y O B J E C TI V E S  ..........................................................................................8  
2. 1  
Pri mar y O bjecti ves ...............................................................................................8  
2. 2  
Sec o n dar y O bj ecti ves ...........................................................................................8  
2. 3  
E x pl orat or y  O bjecti ves  ........................................................................................8  
3. 0  
Criteri a f or E v al u ati o n / St u d y E n d p oi nts  ..........................................................8  
3. 1  
Pri mar y E n d p oi nt  .................................................................................................8  
3. 2  
Sec o n dar y E n d p oi nts  ...........................................................................................9  
3. 3  
E x pl orat or y E n d p oi nts  .........................................................................................9  
4. 0  
P A TI E N T E LI GI BI LI T Y  .....................................................................................9  
4. 1  
I n cl usi o n Criteria .................................................................................................9  
4. 2  
E xcl usi o n Criteria  ..............................................................................................1 0  
5. 0  
T R E A T M E N T P L A N  ..........................................................................................1 0  
5. 1  
Sc he ma  ...............................................................................................................1 0  
5. 2  
Treat me nt D osa g e a n d A d mi nistrati o n  ..............................................................1 0  
5. 3  
T o xicities a n d D osi n g Dela ys  ............................................................................1 1  
5. 4  
Pr o hi bite d Me dicati o ns/ Treat me nts  ...................................................................1 2  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
ii 
5. 5  
D urati o n of T hera p y  ...........................................................................................1 3  
5. 6  
D urati o n of F oll o w U p  .......................................................................................1 3  
5. 7  
St u d y Wit h dra wal  ..............................................................................................1 3  
5. 8  
St u d y Meas ures  ..................................................................................................1 4  
6. 0  
D R U G I N F O R M A TI O N  .....................................................................................1 8  
6. 1  
Me ma nti ne Descri pti o n a n d Ma na ge me nt  .........................................................1 8  
7. 0  
E V A L U A TI O N S A N D A S S E S S M E N T S  ...........................................................1 9  
7. 1  
Ti me a n d E ve nts Ta ble  ......................................................................................1 9  
7. 3  
Treat me nt  ...........................................................................................................2 1  
7. 4  
P ost -C he m ot hera p y Assess me nt  ........................................................................2 1  
7. 5  
6 -M o nt h P ost -C he m ot hera p y Assess me nt (s u bset o nl y)  ...................................2 1  
7. 6  
C o nc urre nt C N S Acti ve Me dicati o ns  ................................................................2 2  
7. 7  
De m o gra p hics  ....................................................................................................2 2  
7. 8  
Me dical Hist or y  .................................................................................................2 2  
7. 9  
Ha n dli n g of Bi os peci me ns C ollecte d f or C orrel ati ve Researc h  ........................2 2  
7. 1 0  
Assess me nt of Safet y  .........................................................................................2 3  
7. 1 1  
Assess me nt of Efficac y  ......................................................................................2 3  
8. 0  
A D V E R S E E V E N T S  ...........................................................................................2 3  
8. 1  
Defi niti o ns ..........................................................................................................2 3  
8. 2  
D oc u me ntati o n of n o n -seri o us A Es or S A Rs ....................................................2 6  
8. 3  
S A Es or Seri o us S A Rs  .......................................................................................2 6  
8. 4  
A d verse E v e nt Re p orti n g  ...................................................................................2 7  
8. 5  
Data a n d Safet y M o nit ori n g Pla n  .......................................................................2 7  
9. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  ...............................................................2 8  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
iii 
9. 1  
St u d y Desi g n/ St u d y E n d p oi nts  ..........................................................................2 8  
9. 2  
Sa m ple Size, Accr ual a n d D urati o n of Accr ual  .................................................2 8  
9. 3  
Data A nal ysis Pla ns  ...........................................................................................2 9  
1 0. 0  
S T U D Y M A N A G E M E N T  ...................................................................................3 0  
1 0. 1  
I nstit uti o nal Re vie w B oar d (I R B) A p pr o val a n d C o nse nt .................................3 0  
1 0. 2  
Re q uire d D oc u me nt ati o n  ...................................................................................3 0  
1 0. 3  
Re gistrati o n Pr oce d ures  .....................................................................................3 0  
1 0. 4  
A d here n ce t o t he Pr ot oc ol  ..................................................................................3 1  
1 0. 5  
A me n d me nts t o t he Pr ot oc ol  ..............................................................................3 2  
1 0. 6  
Rec or d Rete nti o n  ...............................................................................................3 2  
1 0. 7  
O bli gati o ns of I n v esti gat ors  ...............................................................................3 2  
1 1. 0  
R E F E R E N C E S  .....................................................................................................3 4  
1 2. 0  
A P P E N DI C E S  ......................................................................................................4 1  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4  
1. 0  
B A C K G R O U N D A N D R A TI O N A L E  
1. 1  
St u d y S y n o psis  
T his is a o ne -ar m p has e II i nter ve nti o nal st u d y  i n patie nts wit h breast ca n cer t o 
i n vesti gate w het her m e ma nti ne ca n  pre ve nt  c o g niti ve decli ne d uri n g  
c he m ot hera p y.  We will recr uit 5 6 partici pa nts  wit h breast c a ncer referre d t o t he 
U N C Breast Ce nter , Hills b or o u g h O nc ol o g y, or  U N C R E X O nc ol o g y cli nics  f or 
i nitiati o n of a dj u va nt or ne oa dj u va nt c h e m ot hera p y, perf or m a c o g niti ve 
assess me nt  at i nitiati o n (ra n ge:  a n y ti me after esta blis hi n g care t o o ne wee k after 
first d ose ) a n d f o ur wee ks after c o m pleti o n of c he m ot hera p y (ra n ge: t w o t o t wel ve 
wee ks after last d ose), a n d treat wit h me ma nti ne 1 0 m g t wice dail y bet wee n t he 
pre - a n d p ost -c he m ot hera p y st u d y assess me nts (esti mate d d urati o n: 1 2 -3 0  wee ks) . 
We will assess c o g niti ve f u ncti o n o bjecti vel y  usi n g a c o m p uterize d c o g niti ve 
assess me nt a n d a sta n d ar d ne ur o ps yc h ol o g ical b atter y. T o assess s u bjecti ve 
c o g niti ve f u ncti o n, we will use t he Patie nt Re p orte d O utc o me Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) C o g niti ve F u n cti o n meas ure . D e pressi o n, a n xiet y,  
fati g ue, me n o pa us al stat us, a n d slee p are c o m or bi dities k n o w n t o affect c o g niti ve 
f u ncti o n, a n d t heref ore will be assesse d  as c o v ariat es  t hr o u g h self-re p ort meas ures 
a n d, i n t he case of me n o p a usal stat us, la b orat or y v al ues. De pressi o n, an xiet y, 
healt h -rel ate d q ualit y of life (H R Q O L ) a n d f u n cti o nal stat us will be e val uat e d as 
sec o n dar y o ut c o mes. C o g niti ve a n d ot her sec o n d ar y o utc o me meas ures will be 
re peat e d i n a s u bset of p artici pa nts w h o o pt-i n f or l o n git u di nal f oll o w-u p at 6 
m o nt hs (ra nge: 4 t o 8 m o nt hs) p ost -c he m ot hera p y. We will als o assess t he 
feasi bilit y of o ur st u d y b y m o nit ori n g recr uit me nt, rete nti o n, a n d a d h ere n ce  t o 
me ma nti ne.   
1. 2  
Dise ase B ac k gr o u n d   
Ca ncer -relat e d c o g niti ve i m pair me nt ( C R CI) refers t o a c o nstellati o n of pr o ble ms 
wit h me m or y, atte nti o n, a n d e xec uti ve f u ncti o n t h at is ass ociate d wit h ca n cer a n d 
its treat me nts. T here are o ver 1 6  milli o n ca ncer s ur vi v ors i n t he U nite d States 1 
an d a n esti mate d 5 . 5 milli o n s uffer fr o m C R CI.2 S pecificall y, u p t o 7 5 % of 
patie nts wit h ca ncer re p ort c o g niti ve deficits d uri n g acti ve treat me nt a n d u p t o 
3 5 % of s ur vi v ors will de m o nstrate c o g niti ve i m pair me nt o n ne ur o ps yc h ol o gical 
assess me nt ( N P A) t hat ca n last years after treat m e nt. 2 C R CI ca n ha v e pr of o u n d 
c o nse q ue nces, i ncl u di n g i na bilit y t o ret ur n t o  w or k ,3, 4 re d uce d q ualit y of life,5 – 7 
a n d d o u b le d ris k of de me ntia8. Gi ve n t he s u bsta ntial pers o nal a n d s o cietal b ur de n 
of C R CI, a n d t he a bse nce of wa ys t o pre ve nt it , a p pr oac hes t h at scree n f or C R CI 
a n d deli ver effecti ve i nter ve nti o ns as s o o n after ca ncer dia g n osis as p ossi bl e are 
nee de d.  
 
M ost i nter ve nti o ns f or C R CI, i ncl u di n g c o g niti ve trai ni n g a n d re h a bilitati o n,9 – 1 1 
p h ysical acti vit y, 1 2, 1 3 a n d me ditati o n 1 4 – 1 6, h o we ver, are a d mi nistere d years after 
ca ncer treat me nt a n d ha v e yi el de d i nc o nsiste nt res ults. Per ha ps t he m ost esse ntial 
st u d y desi g n iss ue im pacti n g t h e efficac y of i nter v e nti o ns is t he ti mi n g of t heir 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5  
deli ver y rel ati ve t o w he n c o g niti ve iss ues are first a p preci ate d .  S pecificall y, 
beca use s y m pt o ms ca n p ersist f or se veral years after ca n cer treat me nt  a n d 
c o g niti ve deficits are ass ociate d wit h u n derl yi n g f u ncti o nal a n d str uct ural brai n 
c ha n ges, t he e xte nt t o w hic h C R CI is re versi ble is n ot clear. 1 7 – 2 2 A n ot her critical 
varia ble  i m pacti n g relia ble i nter pretati o n of i nter ve nti o n efficac y is lac k of 
a gree m e nt a b o ut h o w t o meas ure C R CI. Self -re p ort i nstr u me nts are criticize d as 
p ote ntiall y reflecti n g ot h er c o m or bi dities (e. g. d e pressi o n, a n xiet y, fati g ue) ,2 3 – 2 7 
w hile ot her i n vesti gat ors raise c o n cer ns a b o ut t he se nsiti vit y 2 5 a n d ec ol o gical 
vali dit y 2 8, 2 9 of N P A. F urt her, des pite I nter nati o nal C o g niti o n a n d Ca ncer Tas k 
F orce (I C C T F) g ui deli nes, 3 0 ne ur o ps yc h ol o gical batteries use d i n r esearc h re mai n 
hi g hl y heter o ge ne o us.  
 
E vi de nce  f or p har m ac ot h era pies f or eit her pre v e nti o n  or treat me nt  of C R CI is 
e ve n m ore li mite d t ha n wit h ot her C R CI i nter ve nti o ns . T o date, t he o nl y 
p har mac ol o gic a ge nts st u die d f or C R CI i ncl u d e ps yc h osti m ula nts, s u p ple me nts, 
e p o-sti m ulati n g a ge nts, d o ne pezil (a n acet ylc h oli nesterase i n hi bit or), a n d 
me ma nti ne. Cli nical trials wit h ps yc h osti m ula nts ha ve de m o nstrat e d p o or 
recr uit me nt a n d rete nti o n rates;3 1 – 3 6 s u p ple me nts, i ncl u di n g vita mi n E a n d gi n k g o 
bil o ba , ha ve n ot bee n effi caci o us ;3 7, 3 8 e p o-sti m ulati n g a ge nts ha ve s h o w n  mi xe d 
efficac y,3 9 – 4 3 b ut are n o l o n ger a p pr o priate f or use i n C R CI f oll o wi n g a 2 0 1 1 F o o d 
a n d Dr u g A d mi nistrati o n ( F D A) blac k b o x war ni n g re gar di n g i ncreas e d seri o us 
car di o vas c ular a n d t hr o m b otic e ve nts t hat ma y s h orte n o verall s ur vi val i n patie nts 
wit h ca ncer; 4 4 an d w hile d o ne pezil ma y be a n e n c o ura gi n g o pti o n, 4 5, 4 6 it has n ot 
bee n st u die d f or C R CI pr o p h yla xis.  
 
C o m pare d t o ot her p har mac ot hera pi es, me ma nti ne is partic ularl y pr o misi n g f or 
atte n uati o n of c he m ot hera p y -rel ate d c o g niti ve decli ne i n breast ca n cer f or s e veral 
c o m pelli n g reas o ns. First, its mec ha nis m of acti o n tar gets c yt o ki ne -me di ate d 
da ma ge s us pe cte d t o ca use C R CI. T N F -α, a n i nfla m mat or y c yt o ki ne t hat is 
ele vate d i n ca ncer, has b ee n s h o w n t o c o ntri b ute t o gl uta mate e xcit ot o xicit y 
i m plicate d i n ma n y ne ur o de ge nerati ve dis or ders.4 7 Of i nterest, i n a m uri ne m o del, 
s y ner gistic c o-acti vati o n of T N F -α a n d N -met h yl -D -as partate (N M D A ) rece pt ors 
res ulte d i n ne ur o nal cell deat h, w hic h was pre v e nte d b y me ma nti ne t hr o u g h 
a nta g o nis m of t he N M D A rece pt or. 4 8 Sec o n d, me ma nti ne is well -t olerate d a n d 
d oes n ot i nteract wit h c h e m ot hera pies or ot h er me dicati o ns r o uti nel y use d i n 
breast c a ncer treat me nt. T hir d, me ma nti ne has bee n st u die d f or C R CI pr o p h yla xis 
i n ot her as pects of ca n cer care. 4 9 Br o w n et al. i n vesti gate d me ma nti ne f or 
pre ve nti o n of c o g niti ve i m pair me nt i n patie nts recei vi n g w h ole brai n 
ra di ot hera p y.4 9 C o m pare d t o place b o, me ma nti ne dela ye d ti me t o o verall 
c o g niti ve decli ne a n d re d uce d t he ma g nit u de of decli ne i n me m or y, e xec uti ve 
f u ncti o n, a n d pr ocessi n g s pee d. T here are se v eral cli nical trials u n der wa y b uil di n g 
o n t his pr o misi n g e vi de nce f or c o g niti ve i m pair me nt d ue t o cra ni al ra diati o n, b ut 
me ma nti ne has n ot yet be e n teste d t o miti gate c he m ot hera p y -relate d c o g niti ve 
decli ne.  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6  
1. 3  
C urre nt St a n d ar d of C are  
C urre ntl y, t here is n o sta n dar d of care t o pre ve nt or treat  C R CI . T h e m ost wi del y 
st u die d be ha vi oral i nter v e nti o ns, s uc h as c o g niti ve re ha bilitati o n a n d c o g niti ve 
trai ni n g, re q uire e x pertis e t o a d mi nister a n d are n ot rea dil y a vaila ble t o all 
patie nts. Relati vel y fe w m e dicati o ns  ha ve bee n i n vesti gate d , a n d e v e n i n s mall 
p atie nt sa m ples , res ults ha ve n ot bee n e nc o ura gi n g. Cli nical trials i n 
ps yc h osti m ula nts , w hic h d o see m t o  i m pr o ve f u ncti o n i n certai n c o g niti ve 
d o mai ns , ha ve re v eale d p artic ularl y p o or recr uit me nt a n d rete nti o n r ates .3 1 – 3 6 F or 
e xa m ple, met h yl p he ni dat e, w hic h t o o ur k n o wle d g e is t he o nl y  oral me dicati o n 
e ver st u die d t o pre v e nt c he m ot hera p y -relate d c o g niti ve decli ne , faile d t o 
de m o nstrate a d e q uate a ccr ual .3 4 I n vesti gat ors h y p ot hesize d  t hat t his was relate d t o 
sti g ma a gai nst t he me dicati o n’s esta blis he d i n dicati o n f or c hil d h o o d Atte nti o n-
Deficit/ H y peracti vit y Dis or der.  T he m e dicati o ns ori gi nall y de vel o pe d a n d 
c urrentl y wit h F D A a p pr o val f or Alz h ei mer’s disease, i ncl u di n g d o ne pezil a n d 
me ma nti ne, ma y ha ve t h e m ost pr o mise. T he y are safe, well -t olerate d, wit h 
e nc o ura gi n g, b ut n ot c o n cl usi ve, data i n m ulti -ce nter ra n d o mize d c o ntr olle d 
trials.4 5, 4 6, 4 9. 
1. 4  
Me m a nti ne  
F or t his trial we ha v e c h ose n t o st u d y t he effe cts of me ma nti ne, a n N M D A 
rece pt or a nta g o nist. Me ma nti ne has bee n well st u die d i n lar ge p o p ulati o n 
sa m ples, i ncl u di n g o nc ol o g y p o p ulati o ns, a n d s h o w n t o be safe. 4 9 – 5 1 It has n o 
k n o w n dr u g -dr u g i nteracti o ns wit h c he m ot hera pies use d f or t he treat me nt of 
breast c a ncer or me dicati o ns  c o m m o nl y gi ve n i n ass ociati o n wit h c he m ot hera p y 
(e. g. o n da nsetr o n, fa m oti di ne, me peri di ne, e pi n e p hri ne, s ol u me dr ol, 
de xa met has o ne, aceta mi n o p he n, ne ulasta, f osa pre pita nt).  Me ma nti ne is partiall y 
meta b olize d b y t he li ver (i n de pe n de nt of t h e c yt oc hr o me p 4 5 0  s yste m) a n d 
e xcret e d b y t he ki d ne ys.  
 
Me ma nti ne is c urre ntl y o nl y F D A a p pr o ve d f or m o derate t o se v ere Alz hei mer’s 
disease. Gl uta mate, t h e pri mar y e xcitat or y n e ur otra ns mitter i n t he ce ntral n er v o us 
s yste m, is t h o u g ht t o c o ntri b ute t o t he pat h o ge nesis of Alz hei mer’s disease b y 
o versti m ulati o n of gl ut a mate rece pt ors. 4 7 Gl u ta mate e xcess pre v e nts ma g n esi u m 
i o ns ( M g2 +), w hic h bl oc k t he N M D A rece pt or u n d er p h ysi ol o gic c o n diti o ns, fr o m 
re-e nt eri n g t he c h a n nel p ore , res ulti n g i n a c hr o nicall y o pe n state. T his i n t ur n 
lea ds t o e xcessi ve calci u m ( Ca2 +) i nfl u x a n d s u bse q ue nt ne ur o n al cell deat h 
o bser ve d i n ma n y ne ur o de ge nerati ve dis or der s.4 7 Me ma n ti ne bi n ds t o t he i ntra-
p ore M g
2 + site u n der c o n diti o ns of e xcessi ve sti m ulati o n t o bl oc k t he N M D A 
rece pt or a n d pre ve nt c ell deat h.5 2   C he m ot hera p y -relate d c o g niti ve decli ne is 
p ost ulate d t o be a c o nse q ue nce of gl uta m ate e x cit ot o xicit y as well, me diate d b y 
i m m u ne d ysre g ulati o n. S pecificall y, peri p heral le vels of T N F -α  are ele vat e d i n 
ca ncer, i ncrease d uri n g c he m ot hera p y, a n d are c orrelate d wit h c o g niti ve 
deficits. 2 2, 5 3 – 5 6 T hr o u g h  acti o n o n ne ur o nal T N F rece pt ors , T N F -α  i n creases 
N M D A rece pt or p er mea bilit y t o Ca 2 + a n d ge nerat es e xcessi ve reacti ve o x y ge n 
s pecies, res ulti n g i n ne ur o nal deat h. 5 7  F or t hese reas o ns , N M D A rece pt or 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
7  
a nta g o nis m b y me ma nti ne ma y be  a pr o misi n g a p pr oac h t o miti gat e c o g niti ve 
decli ne  ass oci ate d wit h c he m ot hera p y .  
 
T h o u g h me ma nti ne has n ot yet bee n st u die d f or c h e m ot hera p y -relate d c o g niti ve 
decli ne, t here has bee n o ne cli nical trial  of me ma nti ne f or  C R CI b y Br o w n et al. 
i n patie nts recei vi n g w h ole brai n ra di ot hera p y.4 9 Partici pa nts were ra n d o mize d t o 
me ma nti ne or place b o, w hic h was a d mi nistere d at t he start of ra di ati o n a n d 
c o nti n ue d f or 2 4 w ee ks. At baseli ne, 8, 1 6, a n d 2 4 wee ks, partici pa nts u n der we n t 
a ne ur o ps yc h ol o gical batter y ( H o p ki ns Ver bal Lear ni n g Test -Re vise d, H V L T -R ; 
Trails Ma ki n g Tests A a n d B, T M T -A, T M T -B ; C o ntr olle d Oral W or d 
Ass ociati o n test, C O W A ; a n d t he Mi ni Me ntal Stat us E xa m, M M S E) , p h ysical 
e xa m, brai n i ma gi n g, la b tests, a n d e v al uati o n of p erf or ma n ce stat us.  T h o u g h t heir 
pri mar y o utc o me, c h a n ge i n H V L T -R Dela ye d Recall sc ore at 2 4 wee ks, di d n ot 
reac h st atistical si g nifica nce ( p = 0. 0 5 9), c o m pare d t o p lace b o me ma nti ne d ela ye d 
ti me t o o verall c o g niti ve decli ne a n d re d uce d t he ma g nit u de of decli ne i n t he 
d o mai ns of me m or y ( H V L T -R), e xec uti ve f u ncti o n ( T M T -B), a n d pr o cessi n g 
s pee d ( T M T-A) at se v eral f oll o w -u p ti me p oi nts. 4 9 T here are s e veral cli nical trials 
of me ma nti ne as a n e ur o pr otecti ve a g e nt i n t he setti n g of cra nial ra di ati o n i n a 
variet y of patie nt p o p ulati o ns (a d ult a n d pe diatric; pri mar y brai n t u m or, brai n 
metastases, a n d hea d a n d nec k ca ncers).  
1. 5  
R ati o n ale  f or Cli nic al St u d y 
A n esti mate d  5 . 5 milli o n ca ncer s ur vi v ors i n t he U nite d States  s uffer fr o m 
C R CI ,1, 2 a n d u p t o 7 5 % of patie nts wit h ca ncer re p ort c o g niti ve deficits d uri n g 
acti ve treat me nt .2 O n ne ur o ps yc h ol o gical assess m e nt,  a p pr o xi matel y  3 5 % of 
s ur vi v ors will de m o nstrate c o g niti ve i m pair me nt t hat ca n last years after 
treat me nt.2 C R CI ca n h a ve pr of o u n d c o ns e q ue n ces, i ncl u di n g a d verse me nt al 
healt h o utc o mes, 3, 5 8 – 6 0 i na bilit y t o ret ur n t o w or k,3, 4 re d uce d q ualit y of life,5 – 7 
d o u ble d  ris k of de me ntia,8 a n d i ncrease d m ort alit y .6 1  
 
Gi ve n t hat t here is  c urre ntl y n o esta blis he d wa y t o treat or pre ve nt c he m ot h era p y-
relate d c o g niti ve d ecli ne, a p pr oac h es t h at scree n f or C R CI a n d d eli ver 
i nter ve nti o ns t hat are c ost-effecti ve, a v aila ble i n all ca ncer ce nt ers, a n d ca n be 
easil y i nc or p orat e d i nt o patie nt care are nee d e d.  T he c o urse of  c o g niti ve 
i m pair me nt res ulti n g fr o m ca ncer a n d its treat me nt s are vari a bl e. H owe ver, 
se veral st u dies ha v e de m o nstrate d c o g niti ve iss ues persisti n g years after 
c he m ot hera p y t h at are ass ociate d wit h decreas e d gra y matter v ol u me a n d w hite 
matter c o n necti vit y ,2 1, 6 2, 6 3 hi g hli g hti n g t he i m p orta nce of i n v esti gati n g 
pre ve ntati ve a p pr oac hes. Dr u g t hera pi es ha v e t he p ote ntial t o a d dress t he 
li mitati o ns of access t o care  see n wit h ot her C R CI i nter ve nti o ns. T here h as o nl y 
bee n o ne st u d y e v al uati n g t he use of a dr u g  t o pre ve nt C R CI, a n d it cl ose d 
pre mat urel y d u e t o c halle n ges wit h recr uit me nt .3 4     
 
I n t his o ne-ar m p has e II i nter ve nti o nal st u d y, we e xa mi ne t he use of me m a nti ne 
f or C R CI pre ve nti o n. I n a d diti o n, t he st u d y will ge nerat e val ua ble i nf or mati o n 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
8  
re gar di n g v aria bles, i ncl u di n g de pressi o n, a n xiet y, fati g ue, me n o pa us al stat us, 
slee p, esti mate d pre-ca ncer c o g niti ve f u n cti o n, a n d self -percei ve d c o g niti ve eff ort, 
t hat ma y clarif y t he relati o ns hi p bet wee n self-re p orte d a n d o bjecti vel y meas ure d 
c o g niti ve f u ncti o n. As t his is t he first st u d y i n vesti gati n g t he use of me ma nti ne f or 
atte n uati o n of c o g niti ve decli ne d uri n g c h e m ot hera p y, we will assess feasi bilit y of 
o ur i nter ve nti o n, as meas ure d b y recr uit me nt, ret e nti o n, a n d a d here n ce.  
 
2. 0  
S T U D Y O B J E C TI V E S  
2. 1  
P ri m ar y O bjecti ve s 
2. 1. 1  T o c o m pare c ha n g es i n pre- t o p ost-c h e m ot hera p y c o g niti ve f u ncti o n , as 
meas ure d b y D M S sc ore,  i n o ur c o h ort of patie nts wit h breast ca n cer recei vi n g 
me ma nti ne t o hist orical c o ntr ols.  
2. 2  
Sec o n d ar y O bjecti ves   
2. 2. 1   T o c o m pare pre- t o p ost -c he m ot hera p y c ha n g es i n all ot her o bjecti ve a n d 
self-re p orte d c o g niti ve f u ncti o n meas ures. 
 
2. 2. 2   T o e xa mi ne ass oci ati o ns bet wee n o bjecti ve a n d self -re p ort e d c o g niti ve 
f u ncti o n wit h de pressi o n, a n xiet y, fati g ue, me n o pa usal stat us, base li ne I Q, a n d 
pe rcei v e d c o g niti ve eff ort, cr oss-secti o nall y pre- a n d p ost -c he m ot hera p y . 
 
2. 2. 3   T o e x pl ore t he i m pact of c o g niti ve decli ne o n healt h -relate d q u alit y of life 
( H R Q O L), f u ncti o nal stat us, de pressi o n, a n d a n xi et y.  
 
2. 2. 4   T o e sti mate t he feasi bilit y of c o n d uct i n g a cli nical trial of me ma nti ne f or 
atte n uati n g c o g niti ve decli ne i n patie nts wit h breast ca ncer d uri n g c he m ot h era p y.  
 
2. 2. 5    T o descri be t he s afet y of a d mi nisteri n g me ma nti ne t o patie nts wit h breast 
ca ncer d uri n g c h e m ot hera p y . 
 
2. 3  
E x pl or at or y O bjecti ves  
 2. 3. 1  T o c o m pare pre - t o 6  m o nt h s p ost -c he m ot hera p y c ha n ges i n o bjecti ve a n d 
self-re p orte d c o g niti ve f u ncti o n meas ures. 
 
 2. 3. 2  
T o descri be  c ha n ges i n d e pressi o n, a n xiet y, fati g ue, H R Q O L, a n d 
f u ncti o nal stat us fr o m pr e- t o 6 m o nt hs p ost -c he m ot hera p y . 
3. 0  
Criteri a f or E v al u ati o n / St u d y E n d p oi nts  
3. 1  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt  is c ha n ge i n t he pre - t o p ost-c he m ot hera p y D M S sc ore .  
T he D M S will be q ua ntifie d as perce nt c orrect at 1 2 -sec o n d del a y.  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
9  
3. 2  
Sec o n d ar y E n d p oi nts  
3 . 2. 1 C ha n ges i n ot her o bjecti ve ( H V L T -R , R V P, O T S,  Di git S pa n, C O W A, 
A ni mal Na mi n g Test ) a n d self-re p orte d ( P R O MI S C o g niti ve F u ncti o n) c o g niti ve 
meas ures  will be me as ur e d  fr o m pre- t o p ost-c he m ot hera p y . 
 
 
3. 2. 2   De pressi o n  ( P R O MI S-De pressi o n) , A n xiet y ( P R O MI S -A n xiet y) , fati g ue 
( F u ncti o nal Ass ess me nt of C hr o nic Ill ness T hera p y –  Fati g ue, F A CI T -F), 
me n o pa usal stat us ( H or m o nal Stat us Q uesti o n naire  a n d f ollicle sti m ulati n g 
h or m o ne le vel, F S H ), a n d percei v e d c o g niti ve eff ort ( N A S A-Tas k L o a d I n de x, 
N A S A -T L X)  w ill be meas ure d pre- a n d p ost -c he m ot hera p y.   Baseli ne I Q 
( Wec hsl er A d ult Test of Rea di n g, W T A R) will be meas ure d pre-c he m ot hera p y 
o nl y.  
 
 
3. 2. 3    Healt h -relate d q ualit y of life ( F u ncti o nal Assess me nt of Ca ncer T hera p y –  
Ge neral, F A C T -G) a n d f u ncti o nal stat us (Patie nt -re p orte d Kar n ofs k y Perf or ma nce 
Stat us, Patie nt -K P S) will be meas ure d pre - a n d p ost -c he m ot hera p y . 
 
3. 2. 4    Recr uit me nt will be meas ure d as pr o p orti o n of a p pr oac he d p artici pa nts 
w h o a gree t o e nr oll a n d n u m ber of partici p a nts e nr olle d per m o nt h. Rete nti o n will 
be meas ur e d as pr o p orti o n of e nr olle d partici pa nts w h o c o m plete t he pri mar y 
o utc o me meas ur e pre - a n d p ost -c he m ot hera p y. A d here nce will be meas ure d as 
patie nt -re p ort e d pr o p orti o n of prescri be d d oses of me ma nti ne act uall y ta ke n.  
 
3. 2. 5    Safet y will be meas ure d as t he fre q u e nc y of re p orte d a d verse e ve nts ( A Es). 
3. 3  
E x pl or at or y E n d p oi nts  
3. 3. 1  C ha n ges i n t he D M S, H V L T -R, R V P, O T S, Di git S pa n, C O W A, A ni mal 
Na mi n g Test, a n d P R O MI S C o g niti ve f u ncti o n will be meas ure d fr o m pre - t o 6 
m o nt hs p ost -c he m ot hera p y i n a s u bset of partici p a nts w h o v ol u nteer f or e xte n de d 
l o n git u di nal o bser vati o n. 
 
3. 3. 2  C ha n g es i n P R O MI S -De pressi o n, P R O MI S -A n xi et y, F A CI T -F, F A C T -G, 
a n d Patie nt -K P S will be meas ure d fr o m pre - t o 6 m o nt hs p ost -c he m ot hera p y i n a 
s u bset of partici pa nts w h o v ol u nteer f or e xte n de d l o n git u di nal o bser vati o n.  
 
4. 0  
P A TI E N T E LI GI BI LI T Y  
I n or der t o partici pate i n t his st u d y a partici pa nt  m ust meet A L L  of t he eli gi bilit y 
criteria o utli ne d bel o w.   
4. 1  
I ncl usi o n Criteri a 
Eli gi ble partici pa nts  m ust meet all of t he f oll o wi n g criteria t o be e nr olle d i n t he 
st u d y: 
4. 1. 1  A ble t o pr o vi de i nf or me d c o nse nt  
4. 1. 2  At least 1 8 years of a ge  


L C C C 1 9 2 1  
 
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U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 0  
4. 1. 3  A ble t o s pea k E n glis h  
4. 1. 4   Dia g n ose d wit h breast ca ncer, Sta ges I –  III 
4. 1. 5   Sc he d ule d f or a dj u va nt or ne o a dj u va nt c h e m ot hera p y  
4. 2  
E xcl usi o n Criteri a  
Eli gi ble partici pa nts m ust n ot ha ve a n y of t he f oll o wi n g t o be e nr olle d i n t he 
st u d y: 
4. 2. 1  A hist or y of a d vers e reacti o n t o me ma nti ne  
4. 2. 2  A n ot her ca n cer dia g n osis  wit h a n esti mate d s ur vi val of less t ha n fi ve y ear s 
4. 2. 3  Pre vi o us c he m ot hera p y e x p os ure  
4. 2. 4  Se vere c o g niti ve i m pair me nt, defi ne d as Blesse d Orie ntati o n Me m or y 
C o nce ntrati o n Te st ( B O M C) ≥ 1 1. 
4. 2. 5  Pre g na nc y , c o nfir me d b y a ne gati ve pre g na n c y test wit hi n 3 0 da ys of 
st u d y e nr oll me nt, or breastfee di n g 
4. 2. 6  C urre nt alc o h ol or dr u g a b use  
5. 0  
T R E A T M E N T P L A N  
5. 1  
Sc he m a  
 
5. 2  
Tre at me nt D os a ge a n d A d mi nistr ati o n  
Partici pa nt s will recei ve me ma nti ne be gi n ni n g wit hi n f o ur wee k s pri or t o a n d o ne 
wee k after  c he m ot hera p y i nitiati o n. All patie nts will be gra d uall y titrate d t o 1 0 
m g t wice dail y as f oll o ws: 5 m g dail y i n wee k 1, 5 m g t wice dail y i n wee k 2, 5 
m g eac h m or ni n g a n d 1 0 m g eac h e v e ni n g i n wee k 3,  t he n 1 0 m g t wice dail y i n 
wee k  4 . Participa nts will c o nti n ue 1 0 m g t wice dail y u ntil 4 wee ks (ra n ge: 2 t o  1 2  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 1  
wee ks) after t h e last d ose of c he m ot hera p y . De p e n di n g o n t he c he m ot hera p y 
re gi me n, t otal d urati o n wil l ra n ge fr o m a p pr o xi matel y 1 2-3 0  wee ks.  
 
R E GI M E N D E S C RI P TI O N  
 
A ge nt  
 
R o ute  
 
D ose  
 
Sc he d ule  
Me ma nti ne H Cl  
Oral  
5 m g  dail y  
Wee k 1  
5 m g  t wice dail y 
Wee k 2  
5 m g  eac h m or ni n g, 1 0 m g eac h e ve ni n g  
Wee k 3  
1 0 m g  t wice dail y 
Wee k 4 t o 4 wee ks 
p ost -c he m ot hera p y  
 
 
Prescri bi n g I nf or m ati o n  
F ull prescri bi n g i nf or mati o n f or me ma nti ne ca n be f o u n d at t he f oll o wi n g w e b 
a d dress:   
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da d o cs/la bel/ 2 0 1 3/ 0 2 1 4 8 7s 0 1 0s 0 1 2s 0 1 4
, 0 2 1 6 2 7s 0 0 8l bl. p df 
5. 3  
T o xicities a n d D osi n g Del a ys  
A n y patie nt w h o recei ves treat me nt o n t his pr ot oc ol will be e val ua te d b y t h e 
C R A, PI, or C o -Is f or t o xicit y.  P atie nts will be assesse d  at least w ee kl y d uri n g 
t he titrati o n of me ma nti ne a n d n o less fre q ue nt  t ha n e ver y t hree wee ks  d uri n g 
s yste mic c he m ot hera p y. F or patie nts r ecei vi n g a nti-H E R 2 directe d t hera p y i n 
a d diti o n t o c he m ot hera p y, t o xicit y will o nl y be assesse d d uri n g t he c h e m ot hera p y 
se g me nt of t he re gi me n. 
 
T o xicit y will be assesse d acc or di n g t o t he N CI C o m m o n T o xicit y Criteria f or 
A d verse E v e nts ( C T C A E), versi o n 5 . 0.  
 
I n assessi n g a d verse e v e nts ( A Es) a n d attri b uti o n d uri n g t he c o urse of t his  st u d y, 
we will c o nsi der t h ose A Es  c o m m o nl y ass ociate d wit h me ma nti ne, t he s pecific 
c he m ot hera p y a d mi nistere d, a n d  c h e m ot hera p y -ass ociate d me dicati o ns recei ve d.  
 
T h o u g h all patie nt -re p orte d s y m pt o ms will be rec or de d a n d e x a mi ne d f or t heir 
ass ociati o n wit h me ma nti ne, t he f oll o wi n g m ost c o m m o n si de effects of 
me ma nti ne will be e x plicitl y s olicite d fr o m partici pa nts b y t he st u d y tea m: 
hea dac he, diz zi ness, c o nf usi o n, c o nsti pati o n, diarr hea, a n d fati g ue. 6 4 See secti o n 
6. 1. 7 f or a d diti o nal i nf or mati o n o n me ma nti ne war ni n gs a n d preca uti o ns.  
Differe ntiati o n bet wee n  me ma nti ne -ass ociat e d t o xi cities a n d t o xicities attri b uta ble 
t o alter nati ve a g e nts will be g ui de d b y Assessi n g of Ca usalit y of A d verse E ve nts 
o utli ne d i n 8. 1. 2 . T he treati n g pr o vi der will be n otifie d of a n y p ossi ble, pr o ba ble, 
or defi nite A Es a n d i n v ol ve d i n decisi o ns t o c o nti n ue, d ose re d u ce, or st o p 
me ma nti ne . At a n y ti me, t he partici pa nt ma y deci d e t o d ose re d u ce or disc o nti n ue 
me ma nti ne.  
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 2  
If a partici pa nt e x perie nces a gra d e 1 t o xicit y wit h a pr o ba ble or defi nite 
attri b uti o n t o me ma nti ne, t he partici pa nt will re mai n o n t he sa me  d ose a n d 
s y m pt o ms will be m o nit ore d dail y u ntil t he si de effect is res ol ve d. 
 
If a partici pa nt e x perie nces a gra d e 2 t o xicit y wit h a pr o ba ble or defi nite 
attri b uti o n t o me ma nti ne, t he d ose will be re d u ce d t o 5 m g P O BI D ( or t he l ast 
t olerate d d ose if less) a n d s y m pt o ms will be m o nit ore d dail y u ntil t he si de effect 
is res ol ve d. If n o i m pr o v e me nt, me ma nti ne will be disc o nti n ue d. 
 
If a partici pa nt e x perie nces a gra d e 3 t o xicit y wit h a pr o ba ble or defi nite 
attri b uti o n t o me ma nti ne, t he partici pa nt will disc o nti n ue me ma nti ne.  
 
If a partici pa nt e x perie nces t o xicit y wit h a p ossi ble attri b uti o n t o me ma nti ne, t he 
partici pa nt will re mai n o n t he sa me d ose of me m a nti ne a n d s y m pt o ms will be 
m o nit ore d wee kl y u ntil t he si de effect is res ol v e d.  
 
If a partici pa nt e x perie nces t o xicit y wit h a n u nli kel y or u nrelate d attri b uti o n t o 
me ma nti ne, t he partici pa nt will re mai n o n t he sa me d ose a n d si de effects will be 
m o nit ore d acc or di n g t o t he sc he d ule d o utli ne d i n t he pr ot oc ol (i.e., wee kl y d uri n g 
titrati o n or n o less t ha n e ver y 3 wee ks d uri n g mai nte na nce).  
 
Re gar dless of gra de or relati o ns hi p wit h me ma nti ne, if o ne of t he m e ma nti ne si de 
effects liste d bel o w is t he reas o n f or d ose re d ucti o n of c he m ot hera p y , t he 
partici pa nt will re d uce me ma nti ne t o 5 m g P O BI D ( or t he last t olerate d d ose if 
less) a n d s y m pt o ms will be m o nit ore d dail y u ntil t he si de effect is res ol v e d. If n o 
i m pr o ve me nt, me ma nti ne will be disc o nti n ue d. 
•  Hea dac he  
•  Dizzi ness  
•  C o nf usi o n  
•  C o nsti pati o n  
•  Diarr hea  
•  Fati g ue  
 
Re gar dless of w h et her t h e partici pa nt e x p erie n ces a n y A Es , if creati ni ne cl eara nce 
falls bel o w 3 0 m L/ mi n, t he d ose will als o be decrease d t o 5 m g P O BI D .  If 
creati ni ne cleara nce falls bel o w 5 m L/ mi n, t he st u d y me dicati o n will be st o p pe d.   
5. 4  
Pr o hi bite d Me dic ati o ns/ Tre at me nts  
T here are n o me di cati o ns/treat me nts t hat w o ul d pr o hi bit partici pa nt s fr o m 
i ncl usi o n a n d c o nti n ue d assess me nt i n t his st u d y. 
 
Patie nts o n t he f oll o wi n g me dicati o ns will be c o u nsele d o n p ossi ble i nteracti o ns 
wit h me ma nti ne a n d partic ular ca uti o n will be ta ke n wit h d ose escalati o n a n d si de 
effect m o nit ori n g: dr u gs t hat ma y i ncreas e t he ser u m c o nce ntrati o n of m e ma nti ne 
(al kali nizi n g a ge nts, b u pr o pi o n, car b o nic a n h y dras e i n hi bit ors) a n d dr u gs t hat 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 3  
ma y e n ha nce t he a d v erse/t o xic effects of me ma nti ne (tri met h o pri m a n d ot h er 
N M D A rece pt or a nta g o nists). S u p p orti ve me dicati o ns t y picall y use d d uri n g 
c he m ot hera p y f or breast ca ncer d o n ot ha ve dr u g -dr u g i nteracti o ns wit h 
me ma nti ne.  
5. 5  
D ur ati o n of T her a p y  
Treat me nt will  c o nti n ue u ntil 4 wee ks (ra n g e 2 -1 2  wee ks) after t h e last d ose of 
syste mic c he m ot hera p y or u ntil:  
•  U nacce pta ble a d verse e v e nt(s)  
•  I nter-c urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt , O R  
•  Partici pa nt  deci des t o wit h dra w fr o m t he st u d y  
 
Decisi o ns t o re m o ve a p artici pa nt  fr o m t he trial or disc o nti n uati o n of treat me nt 
bef ore pl a n ne d st u d y c o m pleti o n will be u n derta ke n i n c o nj u ncti o n wit h 
c o ns ultati o n fr o m t he st u d y PI.  
5. 6  
D ur ati o n of F oll o w U p  
F or deter mi nati o n of st u d y e n d p oi nts,  partici pa nts  will be f oll o we d u ntil 
c o m pleti o n of t he pri mar y e n d p oi nt ( a p pr o xi matel y 4 wee ks after  c h e m ot hera p y 
c o m pleti o n ). A s u bset of partici pa nts w h o v ol u nteer f or e xte n de d l o n git u di nal 
f oll o w-u p will be reass ess e d f or e x pl or at or y e n d p oi nts at 6-m o nt hs p ost -
c he m ot hera p y. All p artici pa nts  (i ncl u di n g t hose wit h dra w n f r o m pr ot oc ol t hera p y 
for A Es) will be f oll o w e d after re m o val fr o m st u d y treat me nt as sti p ulate d i n t he 
pr ot oc ol, u nless t he parti ci pa nt deci des t o wit h dra w fr o m t he st u d y.   
5. 7  
St u d y Wit h dr a w al  
Pa rtici pa nts will be re m o ve d fr o m pr ot oc ol t hera p y  a n d t he PI n otifie d w he n a n y 
of t he criteri a liste d i n secti o n 5. 5  a p pl y.  T he reas o n f or disc o nti n uati o n of t he 
pr ot oc ol t hera p y will be d oc u me nte d o n t he e C R F.    
 
If a partici pa nt deci d es t o wit h dra w  fr o m t he st u d y (a n d n ot j ust fr o m pr ot oc ol 
t hera p y) an  eff ort  will be ma de t o c o m plete a n d re p ort st u d y  assess me nts as 
t h or o u g hl y as p ossi ble. At t he ti me of wit h dra wal, t he PI will  atte m pt t o esta blis h 
as c o m pletel y as  p ossi ble t he reas o n f or t he st u d y w it h dra wal.  
•  
T he patie nt will  be as ke d if t he y are willi n g t o all o w f or t he a bstr acti o n of 
rele va nt i nf or m ati o n fr o m t heir me dical rec or d i n or der t o meet sec o n dar y 
o bjecti ves o utli ne d i n t he pr ot oc ol.   
•  
T he patie nt will be as ke d if t he y are willi n g t o c o m p lete t he M o difie d 
Brief Me dicati o n Q uesti o n naire -S pecific at t he ti m e of st u d y wit h dra wal.  
•  
If t he reas o n f or re m o val of a partici p a n t fr o m t he st u d y is a n a d verse 
e ve nt, t he pri nci pal s p ecific e ve nt will be rec or de d o n t he e C R F.   


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 4  
5. 8  
St u d y Me as ures  
Pre - a n d p ost -c h e m ot hera p y assess me nts will eac h ta ke a p pr o xi matel y 7 0 mi n utes 
t o c o m plete. A n o pti o nal 1 0-mi n ute brea k will be offere d d uri n g t he ass ess me nt  t o 
mi ni mize fati g ue . 
 
O B J E C TI V E C O G NI TI V E F U N C TI O N M E A S U R E S  
5. 8 . 1 Del a ye d M atc h i n g t o S a m ple Test ( D MS)  
T he Dela y e d Matc h i n g t o Sa m ple Test ( D M S) is a c o m p uterize d c o g niti ve 
assess me nt of  vis ual w or ki n g me m or y. 6 5, 6 6 T he D M S will be a d mi nistere d usi n g 
C A N T A B ec li pse s oft ware ( Ca m bri d ge C o g niti o n, Ca m bri d ge, U K). T h e 
partici pa nt is s h o w n a n i ma ge wit h f o ur patter ns a n d as ke d t o matc h  patter ns 
si m ulta ne o usl y or after dela y. We will use t he perce nt c orrect at t he 1 2 -sec o n d 
dela y o n t he D M S test f or t he pri mar y a n al ysis. T he D M S will ta ke 7 mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d 
p ost -c he m ot hera p y.  
 
5. 8 . 2 H o p ki ns Ver b al Le ar ni n g Test -Re vise d ( H V L T -R)  
T he H V L T -R is a n o bjecti ve meas ure of ver bal lear ni n g a n d me m or y. 6 7 T he 
e xa mi ner rea ds a list of 1 2 n o u ns t o t h e partici pa nt, w h o re peats as ma n y w or ds as 
re me m bere d. A p pr o xi matel y 2 0 -2 5 mi n utes later , partici pa nts are as ke d t o recall 
as ma n y w or ds as p ossi bl e. T he n, t he e x a mi ner rea ds a list of 2 4 w or ds, i ncl u di n g 
t he 1 2 w or ds fr o m t he ori gi nal list, a n d t he partici pa nt is as ke d t o deter mi ne 
w hic h w or ds were a n d w ere n ot o n t he ori gi nal list. T hese tas ks res ult i n t hree 
s u bscales: t otal recall, dela ye d recall, a n d del a ye d rec o g niti o n. T he H V L T -R will 
ta ke 5 mi n utes t o c o m plete. All partici pa nts w h o are e nr olle d i n t he tri al will be 
e val uate d pre - a n d p ost -c he m ot hera p y.  
 
5. 8. 3  R a pi d Vis u al I nf or m ati o n Pr ocessi n g ( R V P)  
T he Ra pi d Vis ual I nf or m ati o n Pr ocessi n g  Test ( R V P)  is a c o m p uterize d 
assess me nt of pr ocessi n g s pee d .6 8 T he R V P  will be a d mi nistere d usi n g C A N T A B 
ecli pse s oft ware ( Ca m bri d g e C o g niti o n, Ca m bri d ge, U K).  T h e partici pa nt is 
s h o w n a series of  pse u d o -ra n d o m di gits fr o m 2 t o 9 a n d as ke d t o r ec o g nize tar get 
di git se q ue nces b y pressi n g a b utt o n o n t he scree n as q uic kl y as p ossi ble. T he 
R V P will ta ke 7 mi n utes t o c o m plete. All partici pa nts w h o are e nr olle d i n t he trial 
will be e val uate d pre - a n d p ost -c he m ot hera p y.  
 
5. 8. 4  O ne T o uc h St oc ki n gs  of C a m bri d ge  ( O T S) 
T he O ne T o u c h St oc ki n gs of Ca m bri d ge Test ( O T S) is a c o m p uterize d 
assess me nt of e x ec uti ve f u ncti o n .6 8 T he O T S will be a d mi nistere d usi n g 
C A N T A B ecli pse s oft ware ( Ca m bri d ge C o g niti o n, Ca m bri d ge, U K). T h e 
partici pa nt is s h o w n t w o dis pla ys wit h t hree c ol or e d balls prese nte d as stac ks 
s us pe n de d fr o m a b ea m a n d a r o w of n u m bere d b o xes al o n g t he b ott o m of t he 
scree n. I n t he first set of pr o ble ms, t he partici pa nt is as ke d t o m o ve t he balls i n t he 
l o wer dis pla y t o matc h t h at of t he u p per dis pla y. I n t he ne xt set, t he partici pant is 
as ke d t o w or k o ut i n t heir hea d h o w m a n y m o ves are re q uire d t o r eac h t he 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 5  
s ol uti o n t o eac h pr o ble m. T he O T S will ta ke 1 0 mi n utes t o c o m plete. All 
partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d p ost -
c he m ot hera p y.  
 
 
5. 8 .5  D i git S p a n  
T he Di git S pa n is a n o bjecti ve meas ure of atte nti o n a n d w or ki n g me m or y. 6 9  T he 
p artici pa nt is as ke d t o r ecite se q ue nces of n u m bers i n f or war d , b ac k war ds , a n d 
se q ue ntial or der . T he Di git S pa n will ta ke 4 t o 7  mi n utes t o c o m plete . All 
partici pa nts w h o are e nr olle d i n t he trial will be e v al uate d pre - a n d p ost -
c he m ot hera p y . 
 
5. 8 .6  C o ntr olle d Or al W or d Ass oci ati o n Test ( C O W A)  
T he C O W A is a n o bje cti ve meas ure of ver bal fl ue nc y .7 0 T he p artici pa nt is as ke d 
t o na me as ma n y w or ds as s he ca n, e x cl u di n g pr o p er n o u ns, i n o ne mi n ute. T his is 
re peat e d f or a t otal f or t hree differe nt letters. T he C O W A will ta ke 4  mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d 
p ost -c he m ot hera p y.  
 
5. 8 .7  A ni m al N a mi n g Test ( A N T)  
T he A N T is a n o bjecti ve meas ure of se ma ntic fl ue nc y. 7 1 T he partici pa nt is as ke d 
t o na me as ma n y a ni mals as s he ca n i n o n e mi n ute. All partici pa nts will be 
e val uate d pre - a n d p ost -c he m ot hera p y.  
 
5. 8. 8  Wec hsler A d ult Test of Re a di n g ( W T A R)  
T he Wec hsler A d ult Test of Rea di n g ( W T A R) is a n o bjecti ve meas ure of 
i ntelli ge nce q u otie nt.7 2 T he p artici pa nt rea ds 5 0 irre g ularl y s pelle d w or ds t o 
pr o vi de esti mate d pre m or bi d i ntelli ge nce . T he W T A R will ta ke 3 mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre -
c he mot hera p y o nl y.  
 
5. 8. 9  Blesse d Orie nt ati o n Me m or y C o nce ntr ati o n Test ( B O M C)  
T he B O M C is si x -ite m scree ni n g meas ure of c o g niti ve f u ncti o n t hat assesses 
orie ntati o n, la n g ua ge, atte nti o n, c o nce ntr ati o n, a n d me m or y. 7 3 It has g o o d 
relia bilit y a n d vali dit y7 3, 7 4 a n d has bee n i nc or p orat e d i nt o ca ncer -s pecific g eriatric 
assess me nts. A sc ore ≥ 1 1 has bee n use d t o s u g g est se vere c o g niti ve i m pair me nt. 
T he B O M C will ta ke less t ha n 5 mi n utes t o c o m plete. All  partici pa nts w h o are 
e nr olle d i n t he trial will be e val uat e d pre -c he m ot h era p y .       
 
S E L F -R E P O R T C O G NI TI V E F U N C TI O N M E A S U R E  
5. 8 .1 0  M o difie d P atie nt Re p orte d O utc o mes Me as ure me nt I nf or m ati o n 
S yste m –  C o g niti ve F u ncti o n  ( P R O MI S-C o g niti ve F u ncti o n)  
T he Nati o nal I nstit ute of Healt h’s Patie nt -Re p orte d O utc o mes Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) c o ntai ns a c o g niti ve f u ncti o n ba n k.7 5  We will use 
t he P R O MI S C o g niti ve F u ncti o n 8a s h ort f or m. Sc ores f or all P R O MIS meas ures 
are re p orte d o n t he T -sc ore metric i n w hic h t h e mea n = 5 0 a n d sta n dar d de viati o n 
( S D) = 1 0 are ce ntere d o n t he ge neral p o p ulati o n mea ns. Hi g her sc ores re prese nt 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 6  
greater de grees of c o g niti ve c o m plai nts. We will a d d t hree ite ms t o assess s elf-
percei v e d pre -ca n cer c o g niti ve a bilit y  a n d o ne ite m t o e x plicitl y assess me m or y . 
T he P R O MI S C o g niti ve F u ncti o n will ta ke less t h a n 5 mi n utes t o c o m plete. All 
partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d p ost -
c he m ot hera p y.       
 
C O V A RI A T E S A N D S E C O N D A R Y O U T C O M E M E A S U R E S  
5. 8 . 11  M o difie d N A S A T as k L o a d I n de x ( N A S A -T L X)  
T he N A S A Tas k L o a d I n de x ( N A S A -T L X) is a series of si n gle-ite m vis ual a nal o g 
scales t hat as k partici pa nts t o e val uate t heir perf or ma nce acr oss si x d o mai ns. 7 6 
Res p o nses i n eac h d o mai n tra nslate t o a p oi nt sc ore of 1 (l o west) t o 2 1 ( hi g he st). 
F or t he p ur p os es of o ur st u d y, we will as k  partici p a nts  t o self-e val u ate t heir 
perf or ma n ce acr oss f o ur d o mai ns: me ntal de ma n d, perf or ma n ce, eff ort, a n d 
fr ustrati o n. It will be a d mi nistere d f oll o wi n g eac h c o g niti ve tas k  ( D M S, H V L T-R, 
R V P, O T S , Di git S pa n, C O W A, A N T) . T h e N A S A -T L X will ta ke n o greater t ha n  
7 mi n utes t o c o m plete . All partici pa nts w h o are e nr olle d i n t he trial will be 
e val uate d pre - a n d p ost -c he m ot hera p y.       
 
5. 8 . 12  P atie nt Re p orte d O utc o mes Me as ure me nt I nf or m ati o n S yste m –  
De pressi o n ( P R O MI S -D)  
T he Nati o nal I nstit ute of Healt h’s Patie nt -Re p orte d O utc o mes Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) c o ntai ns a de pressi o n ba n k.7 5, 7 7  We will use t he 
P R O MI S De pressi o n 8a s h ort f or m. Hi g her sc ores re pres e nt greater de grees of 
de pressi o n. T he P R O MI S -D will ta ke less t ha n 2 mi n utes t o c o m plete.  All 
partici pa nts w h o are e nr olle d i n t he t rial will be e val uate d pre- a n d p ost -
c he m ot hera p y.  
 
5. 8 . 13  P atie nt Re p orte d O utc o mes Me as ure me nt I nf or m ati o n S yste m –  
A n xiet y  ( P R O MI S-A)  
T he Nati o nal I nstit ute of Healt h’s Patie nt -Re p orte d O utc o mes Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) c o ntai ns a n a n xi ety ba n k. 7 5, 7 7 We will use  t he 
P R O MI S E m oti o nal Dis tress-A n xiet y –  S h ort F or m 6a . Hi g her sc ores re prese nt 
greater de grees of a n xiet y.  T he P R O MI S A n xiet y will ta ke less t ha n 2 mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d 
p ost -c he m ot h era p y.  
 
5. 8 . 14  P atie nt Re p orte d O utc o mes Me as ure me nt I nf or m ati o n S yste m –  
Slee p Dist ur b a nce  
T he Nati o nal I nstit ute of Healt h’s Patie nt -Re p orte d O utc o mes Meas ure me nt 
I nf or mati o n S yste m ( P R O MI S) c o ntai ns slee p b a n k . W e will use t he P R O MI S 
Slee p Dist ur ba nce S h ort F or m. 7 5, 7 8  Hi g her sc ores re pres e nt greater sle e p 
diffic u lties. T he P R O MI S Slee p Dist ur ba nce S h ort F or m will ta ke le ss t ha n 2 
mi n utes t o c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be 
e val uate d pre - a n d p ost -c he m ot hera p y.  
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 7  
5. 8 . 15  F u ncti o n al Assess me nt of C hr o nic Ill ness T her a p y -F ati g ue ( F A CI T -F)  
T he F A CI T -F scale is a 1 3 -ite m scale t hat uses a 5-p oi nt Li kert -t y pe scale ( 0 = n ot 
at all, 1 =a little bit, 2 =s o me w hat, 3 = q uite a bit, 4 = ver y m uc h). 7 9 T he s u g geste d 
F A CI T -F c ut -p oi nt f or si g nifica nt fati g ue is 3 6 o n a 0 t o 5 2 scale (l o wer sc ores 
i n dicati n g greater fati g u e). T he F A CI T-F scal e is writte n at t he 4 t h gra de le vel 
( Le xile fra me w or k) a n d ta kes 2 -3 mi n utes f or a n a vera ge p ers o n t o c o m plete. 
F A CI T -F will be meas ure d pre - a n d p ost -c h e m ot hera p y.  
 
5. 8 . 16  P atie nt -Re p orte d K ar n ofs k y Perf or m a nce St at us ( P atie nt -K P S)  
T he Patie nt -re p orte d K P S pr o vi des a self-c haract erizati o n of f u ncti o nal stat us, 
ra n gi n g fr o m se v erel y/re q uire c o nti n u o us n ursi n g care t o n or mal/ n o 
c o m plai nts/ n o s y m pt o ms of disease. 8 0 Sc ores ra n g e fr o m 3 0  t o 1 0 0 . Hi g her sc ores 
in dicate better f u n cti o n. T he Patie nt -K P S will ta ke less t ha n 2  mi n utes t o 
c o m plete. All partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d 
p ost -c he m ot hera p y.       
 
5. 8 . 17  F u ncti o n al Assess me nt of C a ncer T her a p y -G e ner al ( F A C T -G)  
T he F A C T -G is a 2 7 -ite m patie nt-a d mi nistere d assess me nt of ge neral q ualit y -of -
life meas ures i n ca ncer patie nts. It h as bee n v ali date d i n t he literat ure a n d p er mits 
t he meas ure m e nt of a n u m ber of s y m pt o ms i ncl u di n g na usea, pai n, a n d 
i ns o m nia.8 1 T he F A C T -G will ta ke n o great er t ha n 5 mi n utes t o c o m plete. All 
partici pa nts w h o are e nr olle d i n t he trial will be e val uate d pre - a n d p ost -
c he m ot hera p y.      
 
5. 8. 1 8  H or m o n al  St at us  
We ha v e de vel o p e d a bri ef meas ure t o assess  m ulti ple di me nsi o ns of  h or m o nal 
stat us. F o ur  ite ms i n q uire a b o ut partici pa nts’ me nstr ual c ycles t o as certai n pre-, 
peri -, or p ost-me n o p a usal stat us per t he Sta ges of Re pr o d ucti ve A gi n g W or ks h o p 
+ 1 0 ( S T R A W + 1 0) criteria. 8 2 T hese ite ms will be use d i n c o nj u ncti o n wit h F S H 
le vels t o clarif y partici pa nts’ me n o pa usal stat us. Fi ve ite ms assess h or m o ne 
se nsiti vit y b y i n q uiri n g a b o ut e x perie nces wit h h or m o ne re place me nt t hera p y, oral 
c o ntrace pti ves, a n d m o o d c ha n ges relate d t o me nstr ual c ycle, pre g na n c y, or 
p ost part u m  peri o d . T he H or m o nal Stat us Q uesti o n naire will ta ke fe wer t ha n 5 
mi n utes t o c o m plete. All partici pa nts  will c o m plete t he h or m o nal stat us 
assess me nt  pre - an d p ost -c he m ot hera p y . 
 
5. 8. 1 9  M o difie d Brief Me dic ati o n Q uesti o n n aire  ( B M Q)-S pecifi c  
T he B M Q -S pecific c o ntai ns t w o fi ve -ite m scales assessi n g patie nts’ pers o nal 
beliefs a b o ut t he necessit y a n d c o ncer ns of ta ki n g prescri be d m e dicati o n f or t heir 
ill ness.8 3 , 8 4 We will use a m o difie d versi o n of t his i nstr u me nt c o nsisti n g of 
state me nts s pecific t o me ma nti ne a n d c o g niti o n. T he M o difie d B M Q -S pecific 
uses a 5 -p oi nt Li kert -t y p e scale ( 1 =str o n gl y disa gree t o 5 =str o n gl y a gree) t o 
i n dicate partici pa nts’ a gree me nt wit h eac h state m e nt. T otal sc ores f or t he 
necessit y a n d c o n cer ns s cales ra n ge  fr o m 5 t o 2 5 a n d are calc ul ate d b y s u m mi n g 
t he i n di vi d ual ite m sc ores wit hi n eac h scal e. Hi g h er sc ores re prese nt gr eater belief 
i n efficac y a n d greater c o ncer ns, res pecti vel y. T h e M o difie d B M Q -S pecific will 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 8  
ta ke fe w er t ha n 5 mi n utes t o c o m plete. All parti ci pa nts w h o are e nr olle d i n t he 
trial will be e val uate d p ost-c he m ot hera p y a n d t h ose w h o wit h dra w will be offere d 
t o c o m plete t he assess me nt at t he ti me of st u d y wit h dra wal. 
 
6. 0  
D R U G I N F O R M A TI O N  
6. 1  
Me m a nti ne Descri pti o n a n d M a n a ge me nt  
6. 1 . 1 Mec h a nis m of Acti o n  
Me ma nti ne H Cl is a  l o w t o m o derate affi nit y u nc o m petiti ve ( o pe n-c h a n nel) 
N M D A rece pt or a nta g o nist. It bi n ds prefere ntiall y t o ce ntral ner v o us s yste m 
N M D A rece pt or -o p erate d cati o n c ha n n els. A d diti o nall y, me ma nti ne has 
a nta g o nistic effects at t he 5 H T 3 rece pt or a n d bl oc ks nic oti nic acet ylc h oli ne 
rece pt ors at 1 0-1 6 % p ote nc y relati ve t o its acti o n o n N M D A a n d 5 H T 3 
rece pt ors.6 4  
 
6. 1 . 2 I n dic ati o ns 
Me ma nti ne H Cl is i n dicate d f or t he treat me nt of m o derate t o se v ere d e me ntia of 
t he Alz hei mer t y pe. 
 
6. 1 . 3 H o w S u p plie d  
T he dr u g will be o btai ne d fr o m c o m merci al s u p pl y t hr o u g h U N C P har mac y a n d 
U N C I n v es ti gati o nal Dr u g Ser vice (I D S).  
 
F ull prescri bi n g i nf or mati o n f or (Me ma nti n e H Cl ) is a vaila ble at:  
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da d o cs/la bel/ 2 0 1 3/ 0 2 1 4 8 7s 0 1 0s 0 1 2s 0 1 4
, 0 2 1 6 2 7s 0 0 8l bl. p df 
 
6. 1 . 4  D os a ge a n d A d mi nistr ati o n : 
Partici pa nts  will recei ve a gra d ual d os e titrati o n of me ma nti ne at 5 m g i ncre me nts 
per wee k t o a g oal d ose of 1 0 m g P O b i d. Titrati o n  sc he d ule is as f oll o ws:  
•  Wee k 1: 5 m g d ose o nce dail y  
•  Wee k 2: 5 m g d ose t wice dail y  
•  Wee k 3: 5 m g  eac h m or ni n g /1 0 m g eac h e ve ni n g  
•  Wee k 4 t hr o u g h en d of C he m ot hera p y: 1 0 m g d os e t wice dail y  
 
6. 1 . 5 St or a ge a n d St a bilit y : 
Me ma nti ne H Cl  s h o ul d be st ore d at r o o m te m perat ure ( bet w ee n 5 9 ° t o 7 7° F). 
 
6. 1 . 6  H a n dli n g a n d Dis p os al :  
L ocal re q uir e me nts f or dis p osal of hazar d o us dr u gs will be f oll o we d . 
 
Please see U N C p olic y o n hazar d o us dr u gs:  
htt p://i ntra net. u nc healt hcare . or g/i ntra n et/ h os pital de part me nts/safet y net/ p olicies/ ha
zar d o us dr u gs. p df  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
1 9  
6. 1. 7  A d verse E ve nts Ass oci ate d wit h C o m merci al Dr u g  
I n a meta-a nal ysis of  si x p hase III place b o-c o ntr olle d trials of 9 5 9  patie nts 
recei vi n g me ma nti ne H Cl  f or m o derate t o s e ve re Alz hei mer’s disease, t he m ost 
fre q ue ntl y i de ntifie d si de effects were dizzi n ess ( 6. 3 %), hea d ac h e ( 5. 2 %), 
c o nsti pati o n ( 4. 6 %), a n d s o m n ole nce ( 3. 4 %). 8 5 T he f oll o wi n g ha ve als o b ee n 
re p orte d wit h t he f oll o wi n g fre q ue n cies: c o nf usi o n ( 6 %), h y perte nsi o n  ( 4 %), 
c o u g hi n g  ( 4 %), p ai n ( 3 %), hall uci nati o n ( 3 %), v o miti n g ( 3 %), d ys p nea ( 2 %), a n d 
fati g ue ( 2 %).6 4 A c o m pre he nsi ve list of a d verse effects c a n be f o u n d at t he 
f oll o wi n g we b a d dress: 
htt ps:// w w w.access data.f da. g o v/ dr u gsatf da _ d o cs/la bel/ 2 0 1 3/ 0 2 1 4 8 7s 0 1 0s 0 1 2s 0 1 4
, 0 2 1 6 2 7s 0 0 8l bl. p df 
 
7. 0  
E V A L U A TI O N S A N D A S S E S S M E N T S  
7. 1  
Ti m e a n d E ve nts T a ble  
 
 
Baseli ne ( Pre -
C he m ot hera p y) a 
D uri n g 
C he m ot hera p y  
P ost -C he m ot hera p y b  
6  M o nt hs P ost -
C he m ot hera p y d  
I nf or me d C o nse nt 
•  
 
 
 
De m o gra p hic Data 
F or m  
•  
 
 
 
Ca n cer Hist or y F or m  
•  
 
 
 
B O M C  
•  
 
 
 
D M S  
•  
 
•  
•  
H V L T -R  
•  
 
•  
•  
R V P  
•  
 
•  
•  
O T S  
•  
 
•  
•  
Di git S pa n  
•  
 
•  
•  
C O W A  
•  
 
•  
•  
A N T  
•  
 
•  
•  
W T A R  
•  
 
 
 
M o difie d P R O MI S - 
C o g niti ve F u ncti o n  
•  
 
•  
•  
M o difie d N A S A -T L X  
•  
 
•  
•  
P R O MI S -De pressi o n  
•  
 
•  
•  
P R O MI S -A n xiet y  
•  
 
•  
•  
P R O MI S -Slee p 
Dist ur ba n ce  
•  
 
•  
•  
H or m o nal Stat us  
•  
 
•  
•  
F A CI T -F  
•  
 
•  
•  
Patie nt -K P S  
•  
 
•  
•  
F A C T -G  
•  
 
•  
•  
F ollicle Sti m ulati n g 
H or m o ne Le vel  
•  
 
• c 
 
C N S -Acti ve 
Me dicati o ns  
•  
•  
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 0  
A d verse E ve nts F or m  
 
•  
 
 
A d here n ce  
 
•  
 
 
Alter nati ve C R CI 
treat me nts 
 
 
•  
 
M o difie d Brief 
Me dicati o n 
Q uesti o n naire ( B M Q) -
S pecific  
 
 
•  
 
 
a. Pr e -c h e m ot h er a p y a s s e s s m e nt s will o c c ur a n y ti m e b et w e e n e st a bli s hi n g c ar e i n t h e U N C 
Br e a st , Hill s b or o u g h O n c ol o g y, or U N C R E X C a n c er C e nt er cli ni c s  a n d o n e w e e k aft er t h e st art of 
c h e m ot h er a p y  
b. P o st -c h e m ot h er a p y a s s e s s m e nt s will o c c ur 4 w e e k s aft er (r a n g e: 2 -1 2  w e e k s aft er ) l a st d o s e of 
c h e m ot h er a p y  
c. F S H l e v el will b e o bt ai n e d p o st -c h e m ot h er a p y o nl y i n p arti ci p a nt s w h o r e p ort e d still h a vi n g 
m e n str u al c y cl e s at t h e pr e -c h e m ot h er a p y a s s e s s m e nt  
d. 6 -m o nt h p o st -c h e m ot h er a p y a s s e s s m e nt s  will o c c ur  o nl y i n a s u b s et of p arti ci p a nt s w h o 
v ol u nt e er f or e xt e n d e d l o n git u di n al f oll o w -u p   
 
7. 2   
Pre -St u d y ( B aseli ne) Assess m e nts  
Patie nts referre d t o t he U NC  Breast Ce nter , Hills b or o u g h O nc ol o g y , a n d U N C 
R E X O nc ol o g y  cli nics will be c o nsi dere d f or e nr oll me nt i n t his trial.  Pri or t o 
c he m ot hera p y i nitiati o n , t he C R A  or PI  will re v ie w t he trial wit h t he partici pa nt , 
c o nfir m eli gi bilit y , a n d o btai n i nf or me d c o nse nt . T he partici pa nt  will c o m plete  a 
c o g niti ve assess me nt batt er y, e val u ati n g vis ual w or ki n g me m or y ( D M S), ver bal 
lear ni n g a n d me m or y ( H V L T-R), pr ocessi n g s pee d ( R V P), e xec uti ve f u ncti o n 
(O T S ), atte nti o n a n d w or ki n g me m or y ( Di git S pa n), ver bal fl u e nc y ( C O W A), 
se ma ntic fl ue nc y ( A N T), a n d i ntelli ge nce q u otie nt ( W T A R). Self -re p ort e d 
c og niti ve eff ort ass ociate d wit h eac h tas k will be e val uate d usi n g t he N A S A -T L X.  
T he  partici pa nt  will als o c o m plete  self-re p ort ass ess me nts of c o g niti ve f u ncti o n 
( P R O MI S-M o difie d C o g niti ve F u ncti o n), de pressi o n ( P R O MI S -D ), a n xiet y 
( P R O MI S-A ), h or m o nal stat u s, slee p ( P R O MI S-Slee p Dist ur ba nce), fati g ue 
( F A CI T-F), f u ncti o nal st at us ( Patie nt -K P S),  a n d H R Q O L ( F A C T -G). See 
A p pe n dices A  –  P . F ollicle sti m ulati n g h or m o ne ( F S H) le vels will be dra w n t o ai d 
i n deter mi nati o n of h or m o n al stat us. F oll o wi n g c o m pleti o n of a ll pre-st u d y 
( baseli ne) assess me nts, p artici pa nts will be c o m pe nsate d f or t heir ti me wit h a gift 
car d. Partici p a nts m ust c o m plete all as pects of t he st u d y visit i n or der t o recei ve 
t he c o m pe nsati o n. T he C R A or i n vesti gat ors will als o c o n d uct a re vie w of 
electr o nic me di cal rec or ds t o o btai n baseli ne i nf or mati o n re gar di n g 
me dical/s ur gical hist or y,  t he partici pa nt’ s ca ncer a n d ca ncer treat me nt, a n d 
de m o gra p hic i nf or m ati o n.  All st u d y -relate d i nteracti o ns will be c o n d ucte d i n 
pri vate r o o ms at U N C Breast, Hills b or o u g h O nc ol o g y, a n d U N C R E X Ca n cer 
Ce nter cli nics;  i n pri vate r o o ms at partici pa nts’ h o mes; o ver t he p h o ne ; a n d b y 
vi de o c o nfere nci n g after c o nfir mi n g t hat s u bjects are  i n a pri vate l ocati o n. St u d y 
assess me nts a n d q uesti o n naires will be offere d b y e mail a n d mail as is necessar y 
a n d feasi ble.  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 1  
7. 3  
Tre at me nt  
If t he partici p a nt  meets all i ncl usi o n/e xcl usi o n criteria  a n d pr o vi des i nf or m e d 
c o nse nt, s he will recei ve me ma nti ne be gi nni n g wit hi n f o ur wee ks b ef ore a n d o ne 
wee k after  c he m ot hera p y i nitiati o n  u ntil t he p ost -c he m ot hera p y ass ess me nt, 
a p pr o xi matel y f o ur wee ks after t he last d ose of c h e m ot hera p y  (esti mate d t otal 
d urati o n of me ma nti ne:  1 2 -3 0  wee ks) . T olera bilit y of  me ma nti ne a nd me dicati o n 
a d here n ce will be s eriall y assesse d f or t h e d urati o n of treat me nt. Patie nts will be 
assesse d at a n i nter val n o greater t ha n e v er y t hree wee ks . F or patie nts r ecei vi n g 
a nit-H E R 2 directe d t h era p y i n a d diti o n t o c he m ot hera p y, t o xicit y will o nl y be  
assesse d d uri n g t he c he m ot hera p y se g me nt of t h e re gi me n. T olera bilit y will be 
assesse d as d escri be d i n s ecti o n 5. 3. Me dicati o n a d here nce will be trac ke d usi n g 
n u m ber of patie nt -esti mate d misse d d oses si nce last assess me nt.  
7. 4  
P ost -C he m ot her a p y Assess m e nt  
T h e partici pa nt  will c o m plete a p ost -c h e m ot hera p y assess me nt a p pr o xi mat el y 4 
wee ks after t he e n d of c h e m ot hera p y (ra n ge: 2 t o 1 2  wee ks p ost -c h e m ot hera p y). 
T he C R A will meet wit h t he partici pa nt  t o c o m plete a c o g niti ve assess me nt f or 
vis ual w or ki n g me m or y ( D M S), ver bal lear ni n g a n d me m or y ( H V L T -R), 
pr ocessi n g s pee d ( R V P), e xec uti ve f u ncti o n ( O T S ), atte nti o n a n d w or ki n g 
me m or y ( Di git S pa n), ver bal fl ue nc y ( C O W A), a n d se ma nt ic fl ue nc y ( A N T). T he 
pa rtici pa nt will als o c o m plete self -re p ort assess m e nts f or c o g niti ve f u n cti o n 
( P R O MI S-M o difie d C o g niti ve F u ncti o n), c o g niti ve eff ort ( N A S A -T L X), 
de pressi o n ( P R O MI S -D), a n xiet y ( P R O MI S -A n xiet y), slee p dist ur ba n ce 
( P R O MI S-Slee p Dist ur ba nce), fati g ue ( F A CI T -F),  f u ncti o nal stat us ( K P S), 
h or m o nal stat us,  H R Q O L ( F A C T -G) , a n d b eliefs a b o ut t he necessit y a n d 
c o ncer ns of ta ki n g me ma nti ne ( M o difie d B M Q -S pecific) . See A p pe n di ces A –  Q . 
I n p artici pa nts w h o were n ot classifie d as p ost-me n o pa usal at st u d y e ntr y, F S H 
le vels will be dra w n. T h e partici pa nts will als o be as ke d if t he y e n g a ge d i n a n y 
ot her acti vities or recei ve d me dicati o ns d uri n g t he st u d y peri o d t hat t he y belie ve  
preser ve d  t heir c o g niti ve f u ncti o n. W he n ass ess me nts ca n n ot be c o m plete d, t his 
will be n ote d i n t h e e C R F.  F oll o wi n g c o m pleti o n of all p ost -c he m ot hera p y 
assess me nts, partici pa nts will be c o m pe nsate d  f or t heir ti me wit h a gift car d. 
Partici pa nts m ust c o m plete all as pects of t he st u d y visit i n or der t o recei v e t he 
c o m pe nsati o n.  As wit h t he pre -c he m ot hera p y assess me nt, t he p ost -c he m ot hera p y 
assess me nt will be c o n d u cte d i n pri vate r o o ms at U N C Breast, Hills b or o u g h 
O nc ol o g y, a n d U N C R E X Ca ncer Ce nt er cli nics;  i n pri vate r o o ms at partici pa nts’ 
h o mes ; o ver t he p h o ne ; a n d b y vi de o c o nfere nci n g after c o nfir mi n g t hat s u bjects 
are i n a pri vate l ocati o n. T he p ost -c he m ot hera p y assess me nt  a n d q uesti o n naires 
will be offere d b y e mail a n d mail as is necess ar y a n d feasi ble.  
7. 5  
6 -M o nt h P ost -C he m ot her a p y Assess m e nt ( s u bset o nl y) 
Partici pa nts w h o at t he ti me of i nitial c o nse nt in dicate i nterest i n bei n g o bser ve d 
o ver e xte n d e d l o n git u di nal f oll o w -u p will c o m plete a n a d diti o nal assess me nt 6 
m o nt hs after c o m pleti n g c he m ot hera p y (ra n g e: 4 t o 8 m o nt hs p ost -c he m ot hera p y) . 
T he C R A will meet wit h t he partici pa nt t o c o m plete a c o g niti ve a ssess me nt f or 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 2  
vis ual w or ki n g me m or y ( D M S), ver bal lear ni n g a n d me m or y ( H V L T -R), 
pr ocessi n g s pee d ( R V P), e xec uti ve f u ncti o n ( O T S), atte nti o n a n d w or ki n g 
me m or y ( Di git S pa n), ver bal fl ue nc y ( C O W A), a n d se ma ntic fl ue nc y ( A N T). T he 
partici pa nt will als o c o m ple te self-re p ort assess m e nts f or c o g niti ve f u n cti o n 
( P R O MI S-M o difie d C o g niti ve F u ncti o n), c o g niti ve eff ort ( N A S A -T L X), 
de pressi o n ( P R O MI S -D), a n xiet y ( P R O MI S -A n xiet y), slee p dist ur ba n ce 
( P R O MI S-Slee p Dist ur ba nce), fati g ue ( F A CI T -F), f u ncti o nal stat us ( K P S), 
h or m o nal stat us,  a n d H R Q O L ( F A C T -G). See A p pe n dices A –  P . F oll o wi n g 
c o m pleti o n of all p ost -c h e m ot hera p y ass ess me nts, partici pa nts will be 
c o m pe nsate d f or t heir ti me wit h a gift car d. Partici pa nts m ust c o m plete all as pects 
of t h is st u d y visit i n or der t o recei ve t he c o m pe nsati o n. As wit h t he pre -a n d p ost -
c he m ot hera p y assess me nt s, t his will be c o n d ucte d i n pri vate r o o ms at U N C 
Breast, Hills b or o u g h O n c ol o g y, a n d U N C R E X Ca ncer C e nter cli nics;  i n pri vate 
r o o ms at partici pa nts’ h o mes; o ver t he p h o ne ; a n d b y vi de o c o nfere nci n g after 
c o nfir mi n g t hat s u bjects are i n a pri vate l ocati o n. T he p ost -c he m ot hera p y 
assess me nt a n d q uesti o n naires will be offere d b y e mail a n d mail as is necessar y 
a n d feasi ble.  
 
7. 6  
C o n c urre nt C N S A cti ve  Me dic ati o ns  
All c o ncurre n t C N S acti ve me dicati o n s, i ncl u di n g ps yc h osti m ula nts, 
acet ylc h oli nesterase i n hi bit ors, ot her N M D A rece pt or a nta g o nists, 
a nti de pressa nts, a n xi ol yti cs, a nti ps yc h otics, a ntie pile ptics,  a n d a nti hista mi nes  will 
b e d oc u me nte d at Baseli ne/ Scree ni n g  a n d thr o u g h o ut t he st u d y as s u m marize d i n 
t he Ti me a n d E ve nts Ta ble i n Secti o n 7. 1 .  
7. 7  
De m o gr a p hics  
De m o gra p hic i nf or mati o n ( date of birt h, ge n d er, race , e d ucati o nal le v el) will be 
rec or de d b y t he C R A fr o m re vie w of me di cal rec or ds at baseli ne. 
7. 8  
Me dic al Hist or y  
Rele va nt me dical hist or y, i ncl u di n g hist or y of c urre nt disease , a n d i nf or mati o n 
re gar di n g u n d erl yi n g diseases will be a bstr acte d fr o m me dical rec or ds at b aseli ne . 
7. 9  
H a n dli n g of Bi os peci me ns C ollecte d f or C orrel ati ve Rese a rc h  
Bi o s peci me ns f or t his st u d y will be  c ollecte d b y a certifie d p hle b ot o mist a n d 
st ore d i n t he Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter ( L C C C) ass ociate d 
la b orat or y.  Eac h sa m ple will be assi g ne d a u ni q ue c o de n u m ber a n d n o 
i de ntifia ble pers o nal h ealt h i nf or mati o n ( P HI) will be o n t he s peci me n la bel.  
Researc h ers  wit h I R B -a p pr oval f or access t o P HI f or eac h partici p a n t i n t his st u d y 
will be a ble t o li n k s peci me ns t o rel e va nt me dical i nf or mati o n.   
 
St or a ge Ti m e:  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 3  
•  
T he bi os peci me n will be use d first a n d f ore m ost f or researc h p ur p oses 
o utli ne d wit hi n t he c o nfi nes of t his pr ot oc ol. Sa m ples will be 
discar de d/ destr o y e d aft er rele va nt dat a are c ollect e d f or t his st u d y, u nless 
c o nse nt was o btai ne d fr o m t he patie nt t o use h er bl o o d  f or ot her researc h 
p ur p oses (e. g., c o nse nt f or m was si g ne d b y t he patie nt).  I n t his circ u msta nce, 
bi os peci me ns ma y be st ore d  f or n o l o n g er t ha n 1 5 years. 
 
C o m pli a nce St ate me nt  
Bi os peci me n c ollecti o n f or t his st u d y will be c o n d ucte d i n f ull acc or d a nce wit h all 
a p plica ble U ni versit y of N ort h Car oli na ( U N C) R esearc h P olicies a n d Pr oce d ures 
a n d all a p plica ble Fe d eral a n d state la ws a n d re g ul ati o ns i ncl u di n g 4 5 C F R 4 6, 
a n d t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) Pri vac y 
R ule. A n y e pis o de of n o nc o m plia nce will be d oc u me nte d.  
 
T he i n vesti gat ors will perf or m t he st u d y i n acc or da nce wit h t his pr ot oc ol, will 
o btai n c o nse nt a n d asse nt ( u nless a wai v er is gra nt e d), a n d will re p ort u ne x pecte d 
pr o ble ms i n acc or da nce wit h T he U N C I R B P olic ies a n d Pr oce d ures a n d all 
fe deral re q uir e me nts. C ollecti o n, rec or di n g, a n d re p orti n g of data will be acc urate 
a n d will e ns ure t he pri v ac y, healt h, a n d welfare of researc h partici pa nts  d uri n g 
a n d after t he st u d y.  
7. 1 0  
Assess m e nt of S afet y  
A n y patie nt w h o rece i ves at least o ne d ose of st u d y t hera p y o n t his pr ot oc ol will 
be e val ua bl e f or t o xicit y. Eac h patie nt will be ass esse d at least wee kl y d uri n g t he 
titrati o n of me ma nti ne a n d n o less fre q ue nt t ha n e ver y t hree wee ks d uri n g 
s yste mic c he m ot hera p y f or t he de vel op me nt of a n y t o xicit y acc or di n g t o t he Ti me 
a n d E ve nts ta ble.  T o xicit y will be assesse d acc or di n g t o t he N CI C T C A E versi o n 
5 . 
7. 1 1  
Assess m e nt of Effic ac y  
All partici pa nts  w h o e nr oll , recei ve at least o ne d ose of st u d y me dicati o n, a n d 
c o m plete t he pri mar y o ut c o me meas ure will be a n al yze d.    
  
8. 0  
A D V E R S E E V E N T S  
8. 1  
Defi niti o n s  
8. 1. 1  A d verse E ve nt ( A E)  
A n a d vers e e ve nt ( A E) is a n y u nt o war d me dical o cc urre nce (e. g., a n a b n or mal 
la b orat or y fi n di n g, s ym pt o m, or disease te m p orall y ass ociate d wit h t he use of a 
dr u g) i n a patie nt or cli nical i n vesti gati o n partici p a nt a d mi nistere d a 
p har mace utical pr o d uct a n d w hic h d oes n ot necess aril y ha ve a ca us al rel ati o ns hi p 
wit h t his treat me nt. A n A E ca n t heref ore be a n y u nfa v ora bl e a n d u ni nte n de d si g n 
(i ncl u di n g a n a b n or mal l a b orat or y fi n di n g), s y m pt o m, or disease te m p orall y 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 4  
ass ociate d wit h t he use of a me dici nal pr o d u ct, w het her or n ot r elate d t o t h e 
me dici nal pr o d uct.   
 
H os pitalizati o n f or ele cti ve s ur ger y or r o uti ne cli nical pr oce d ures t hat are n ot t he 
res ult of a n A E (e. g., s ur gical i nserti o n of ce ntral li ne) nee d n ot be c o nsi dere d 
A Es a n d s h o ul d n ot be rec or de d as a n A E.  
8. 1. 2  S us pecte d A d verse Re a cti o n  ( S A R) 
A s us pecte d a d v erse reacti o n ( S A R) is a n y A E f or w hic h t here is a r e as o n a ble 
p ossi bility  t hat t he dr u g is t he ca use.  R e as o n a ble p ossi bility  mea ns t hat t here is 
e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E. A 
s us pecte d a d v erse reacti o n i m plies a lesser de gree of cert ai nt y a b o ut ca usali t y 
t ha n a d vers e reacti o n, w hic h mea ns a n y a d v erse e v e nt ca use d b y a dr u g.   
 
Ca usalit y assess me nt t o a st u d y dr u g is a me dical j u d g me nt ma de i n c o nsi derati o n 
of t he f oll o wi n g fact ors: te m p oral rel ati o ns hi p of t he A E t o st u d y dr u g e x p os ure, 
k n o w n mec ha nis m of acti o n or si de effect pr ofile of st u d y treat me nt, ot her rece nt 
or c o nc o mita nt dr u g e x p os ures, n or mal cli nical c o urse of t he dise ase u n der 
i n vesti gati o n, a n d a n y ot her u n derl yi n g or c o nc urre nt me dical c o n diti o ns. Ot her 
fact ors t o c o nsi der i n c o nsi deri n g dr u g as t he ca us e of t he A E:  
•  Si n gle occ urre n ce of a n u nc o m m o n e ve nt k n o w n t o be str o n gl y ass ociate d 
wit h dr u g e x p os ure (e. g., a n gi oe de ma, he patic i nj ur y, Ste ve ns -J o h ns o n 
S y n dr o me)  
•  O ne or m ore o cc urre n ces of a n e ve nt n ot c o m m o nl y ass ociate d wit h dr u g 
e x p os u re, b ut ot her wise u nc o m m o n i n t he p o p ulati o n (e. g., te n d o n 
r u pt ure); ofte n m or e t ha n o nce occ urre nce fr o m o n e or m ulti ple st u dies 
w o ul d be nee d e d bef ore t he s p o ns or c o ul d deter mi ne t hat t here is 
re as o n a ble p ossi bility t hat t he dr u g ca us e d t he e v e nt.   
•  A n a g gre g ate a n al ysis of s pecific e v e nts o bser ve d i n a cli nical trial t hat 
i n dicates t he e ve nts o cc ur m ore fre q ue ntl y i n t he dr u g treat me nt gr o u p 
t ha n i n a c o nc urre nt or hist orical c o ntr ol gr o u p 
 
 
 
Assessi n g C a us alit y of A d verse E ve nts  
T he li keli h o o d of ca usalit y of all A E’s will be gra de d as descri be d bel o w.  
Gi ve n t hat p ote ntial si de effects of me ma nti ne o v erla p wit h t h ose d ue t o 
c he m ot hera p y (a n d ma n y ot her me dicati o ns), we will c o nsi der n ot o nl y 
t he prese n ce/a bse n ce of t he A E, b ut als o w orse ni n g i n t he se verit y or 
fre q ue n c y of t he A E i n assessi n g ca usalit y. 
 
U nrelate d:   A d v erse e ve nt a n d/ or its se verit y or fre q ue nc y  are clearl y d ue 
t o e xtra ne o us ca uses (e. g., u n derl yi n g disease, e n vir o n me nt) 
 
U nli kel y ( m ust ha ve 2):   A d verse e ve nt  a n d/ or its se verit y or fre q ue n c y:   
1. d oes n ot ha ve te m p oral relati o ns hi p t o i nter ve nti o n  
2. c o ul d n ot rea dil y ha ve bee n pr o d uce d b y t he partici pa n t’s cli nical state 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 5  
3. c o ul d ha ve bee n d ue t o e n vir o n me ntal or ot her i nter ve nti o ns  
4. d oes n ot f oll o w a k n o w n patter n  of res p o nse t o i nter ve nti o n  
5. d oes n ot rea p p ear or w orse n wit h rei ntr o d ucti o n of i nter ve nti o n  
 
P ossi ble ( m ust ha ve 2):  A d verse e ve nt  a n d/ or its se verit y or fre q ue n c y : 
1. has a reas o na ble te m p oral relati o ns hi p t o i nter ve nti o n  
2. c o ul d n ot rea dil y ha ve bee n pr o d uce d b y t he partici pa n t’s cli nical state  
3. c o ul d n ot ha ve bee n d ue t o e n vir o n me ntal or ot her i nter ve nti o ns  
4. f oll o ws a k n o w n patter n of res p o nse t o i nter ve nti o n  
 
Pr o ba ble ( m ust ha ve 3):  A d verse E v e nt  a n d/ or its se verit y  or fre q ue n c y : 
1. has a reas o na ble te m p oral relati o ns hi p t o i nter ve nti o n  
2. c o ul d n ot rea dil y ha ve bee n pr o d uce d b y t he partici pa n t’s cli nical state 
or ha ve bee n d ue t o e n vir o n me ntal or ot her i nter ve nti o ns  
3. f oll o ws a k n o w n patter n of res p o nse t o i nter ve n ti o n 
4. disa p pears or d ecreas es wit h re d ucti o n i n d ose or cessati o n of 
i nter ve nti o n 
 
Defi nite ( m ust ha ve all 4):  A d verse E v e nt  a n d/ or its se verit y or fre q ue nc y : 
1. has a reas o na ble te m p oral relati o ns hi p t o i nter ve nti o n  
2. c o ul d n ot rea dil y ha ve bee n pr o d uc e d b y t he partici pa n t’s cli nical state 
or ha ve bee n d ue t o e n vir o n me ntal or ot her i nter ve nti o ns  
3. f oll o ws a k n o w n patter n of res p o nse t o i nter ve nti o n  
4. disa p pears or d ecreas es wit h re d ucti o n i n d ose or cessati o n of 
i nter ve nti o n 
 
8. 1. 3  U ne x pecte d A E  or S A R  
A n A E or S A R is c o nsi dere d u ne x p ecte d if  t he s p ecificit y or se v erit y of it is n ot 
c o nsiste nt wit h t he a p plica ble pr o d uct i nf or m ati o n (e. g., pac k a ge i nsert/s u m mar y 
of pr o d uct c h aracteristics f or a n a p pr o ve d pr o d u ct).  U ne x pect e d als o refers t o A Es 
or S A Rs t hat a re me nti o n e d i n t he I B as occ urri n g wit h a class of dr u gs or as 
a ntici pate d fr o m t he p h ar mac ol o gical pr o perties of t he dr u g, b ut are n ot 
s pecificall y me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n.   
8. 1. 4  Seri o us A E  or S A R  
A n A E or S A R is c o nsi dere d seri o us if, i n t he vie w of eit her t he i n v esti gat or or 
s p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h;  
•  Is life-t hreate ni n g ( places t he partici pa nt  at i m me diate ris k of deat h 
fr o m t he e ve nt as it occ urre d); 
•  Re q uires i n patie nt h os pitalizati o n ( > 2 4 h o urs) or pr ol o n gati o n of 
e xisti n g h os pitalizati o n; *  
•  Res ults i n  c o n ge nital a n o mal y/ birt h defect;  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 6  
•  Res ults i n a persiste nt or si g nifica nt i nca pacit y or s u bsta ntial 
disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u ncti o ns;  
•  I m p ort a nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-
t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d a s eri o us 
a d verse dr u g e x perie nce 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 or partici pa nt  a n d ma y 
re q uire me di cal or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes 
liste d i n t he defi niti o n.  F or re p orti n g p ur p os es, als o c onsi der t he 
occ urre nces of pre g n a nc y as a n e ve nt w hic h m ust be re p ort e d as a n 
i m p orta nt me dical e ve nt. 
 
* H os pitalizati o n f or a ntici pate d or pr ot oc ol s pe cifi e d pr oce d ures s uc h as 
a d mi nistrati o n of c he m ot hera p y, ce ntral li ne i nserti o n, metastasis i nter ve nti o n al 
t hera p y, resecti o n of pri mar y t u m or, or electi ve s ur ger y, will n ot be c o nsi dere d 
seri o us a d vers e e v e nts. 
 
Pre g na nc y t hat occ urs d uri n g t he st u d y m ust als o be re p ort e d as a n S A E.  
8. 2  
D oc u me nt ati o n of n o n -seri o us A Es or S A Rs  
F or n o n -s eri o us AE s or S A Rs, d oc u me ntati o n m ust be gi n fr o m da y 1 of st u d y 
treat me nt a n d c o nti n ue t hr o u g h t he 3 0 da y f oll o w-u p peri o d after treat me nt is 
disc o nti n ue d.   
 
C ollecte d i nf or mati o n s h o ul d be rec or de d i n t he C ase Re p ort F or ms ( C R F) f or 
t hat patie nt.  Please i ncl u de a descri pti o n of t he e v e nt, its se verit y or t o xicit y 
gra de, o nset a n d res ol ve d dates (if a p plica ble), a n d t he relati o ns hi p t o t he st u d y 
dr u g.  D oc u me ntati o n s h o ul d occ ur at least m o nt hl y .  
8. 3  
S A E s or Seri o us S A R s  
8. 3. 1  Ti mi n g  
After i nf or m e d c o nse nt b ut pri or t o i nitiati o n of st u d y me dicati o ns, o nl y S A Es 
ca use d b y a pr ot oc ol -ma n date d i nter ve nti o n will be c ollecte d (e. g. S A Es relate d t o 
i n vasi ve pr oce d ures s uc h as bi o psies, me dicati o n was h o ut ).  
 
F or a n y ot h er e x p erie nce or c o n diti o n t hat meets t he defi niti o n of a n S A E or a  
seri o us S A R, rec or di n g of t he e ve nt m ust be gi n fr o m da y 1 of st u d y treat m e nt a n d 
c o nti n ue t hr o u g h t he 3 0 da y f oll o w -u p peri o d after treat me nt is disc o nti n ue d.  
8. 3. 2  D oc u me nt ati o n  a n d N otific ati o n  
S A Es or Seri o us S A Rs m ust be rec or de d i n t he S A E c o ns ole wit hi n O nc ore ™ f or 
t hat patie nt wit hi n 2 4 h o urs of lear ni n g of its occ urre nce.  A d diti o nall y, t he 
N C C N Pr oject Ma na ger  m ust als o be n otifie d via e mail of all S A Es wit hi n 2 4 
h o urs of lear ni n g of its occ urre nce .  


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 7  
8. 4  
A d verse E ve nt R e p orti n g  
8. 4. 1  I R B Re p orti n g Re q uire me nts: 
U N C : 
•  T he U N C -I R B will be n otifie d of all S A Es t hat q ualif y as a n 
U na ntici pate d Pr o ble m as per t he U N C I R B P olicies usi n g t he I R B’s we b -
base d re p orti n g s yste m (see secti o n 1 0 . 4. 3) wit hi n 7 da ys of t he 
I n v esti gat or bec o mi n g a ware of t he pr o ble m.   
8. 4. 2  F u n di n g S o urce (e. g. M a n uf act urer) Re p orti n g Re q uire me nts:  
N/ A  
8. 5  
D at a a n d S afet y M o nit o ri n g  Pl a n  
T his is a P hase II, si n gle site st u d y of 5 6  i n di vi d uals t o gat her preli mi nar y data o n t he 
effic ac y  a n d feasi bilit y  of me ma nti ne  i n patie nts wit h breast ca n cer recei vi n g 
c he m ot hera p y . We will f oll o w o ur sta n dar d pr ot o c ol f or m o nit ori n g of cli nical trials.  
Partici pa nts  are s cree ne d t o e ns ure t hat t here are n o c o ntrai n dicati o ns t o t heir 
partici pati o n.  
 
T he st u d y PI, Dr. Na k a m ura , will be res p o nsi ble f or c o nti n u o us m o nit ori n g of patie nt 
safet y d uri n g t he trial.  F or n o n-seri o us A d verse E ve nts ( A Es), d oc um e ntati o n will be gi n 
fr o m t he first da y of st u d y treat me nt a n d c o nti n ue t hr o u g h t he 3 0 -da y f oll o w -u p peri o d 
after treat me nt is disc o nti n ue d. C ollecte d i nf or mati o n will be rec or de d i n Case Re p ort 
F or ms ( C R F) f or t hat patie nt. A descri pti o n of t he e ve nt, its se verit y or t o xi cit y gra de, 
o nset a n d res ol ve d d ates (if a p plica ble), a n d t he relati o ns hi p t o t he st u d y dr u g will be 
i ncl u de d.  F or a n y e x peri e nce or c o n diti o n t hat meets t he defi niti o n of a seri o us a d verse 
e ve nt ( S A E), rec or di n g of t he e ve nt wi ll be gi n after si g ni n g of t he i nf or me d c o nse nt a n d 
c o nti n ue t hr o u g h t he 3 0 -da y f oll o w -u p peri o d af ter treat me nt is disc o nti n ue d. T hese 
e ve nts will be rec or de d i n t he C R F f or t hat patie nt wit hi n 2 4 h o urs  of lear ni n g of its 
occ urre nce.  If t he e ve nt is b ot h seri o us A N D u ne x pecte d, it will als o be rec or de d o n t he 
Me d Watc h F or m 3 5 0 0 A, as per 2 1 C F R 3 1 2. 3 2, a n d f or war de d t o t he F D A i n acc or da nce 
wit h 2 1 C F R 3 1 4. 8 0 (f or mar kete d dr u gs) . T he  U N C I R B will be n otifie d of all S A Es t hat 
q ualif y as a n U n a ntici pat e d Pr o b le m (seri o us, u ne x pecte d, a n d relate d) as p er t he U N C 
I R B p olicies. I n acc or da n ce wit h t hese p olicies, a n a g gre gat e d list of all S A Es will be 
s u b mitte d t o t he U N C I R B a n n uall y at t he ti me of st u d y re ne wal. 
 
Peri o dic re vie w, at a n i nt er val of e ver y si x m o nt hs t o a n n uall y, b y t he Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter Data Safet y C o m mittee ( L C C C D S M C), Pr ot oc ol Re vie w 
C o m mittee ( P R C), a n d Office of H u ma n Researc h Et hics ( O H R E) Bi o me dical I R B will 
pr o vi de o versi g ht of t he PI ’s c o nti n u o us m o nit ori n g.  F or eac h D S M C re vi e w, s u m mar y 
i nf or mati o n re gar di n g t o xicit y a n d accr ual patter ns will be pre pare d a n d s u b mitte d b y t he 
PI.  S pecifi c i nf or mati o n s u b mitte d f or re vie w i ncl u des: ( 1) T he n u m ber of patie nts 
e nr olle d, c o nse nt e d, c o ns e nte d b ut n ot treate d, c urre ntl y bei n g treate d, c o m plete d 
treat me nt, t he n u m ber of patie nts w h o di d n ot c o m plete treat me nt a n d t h e reas o ns f or 
c o mi n g off st u d y; ( 2) Gra de 3 or greater re p orte d A d verse E v e nts t o date; ( 3) Seri o us 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 8  
A d verse E v e nts a n d U na ntici pate d Pr o ble ms si nce last re p ort, wi t h ass ura nce of re p orti n g 
t o i nter nal a n d e xter nal r e g ulati n g b o dies; ( 4) E xce pti o ns i n eli gi bilit y or treat me nt a n d 
si g nifica nt pr ot oc ol de viati o ns/ vi olati o ns; ( 5) Si g nifica nt literat ur e re p orti n g 
de vel o p me nts t hat ma y affect t he s afet y of p artici pa nts or  t he et hics of t he st u d y; ( 6) 
S u m maries of tea m meeti n gs t hat ha ve occ urre d si nce t he last r e p ort; ( 7) Res ults of 
i nteri m a nal yses re q uir e d b y t he pr ot oc ol.  We will als o be s u b mitti n g a preli mi nar y 
re p ort of res p o nse a n d ot her e n d p oi nts liste d i n t he pri mar y a n d s ec o n dar y o bjecti ves of 
t he pr ot oc ol f or D S M C re vie w. 
 
T h o u g h n o f or mal a pri ori  st o p pi n g r ules are pr o p ose d f or t he st u d y, i n t he e ve nt of a 
seri o us or u ne x pecte d a d verse e v e nt or fre q ue nt o cc urre nce of less seri o us u ne x pecte d or 
e x pecte d a d vers e e v e nts we will c o ns ult wit h t he O H R E a n d D S M C as t o w het her t he 
trial s h o ul d c o nti n ue. 
 
9. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
9. 1  
St u d y Desi g n/ St u d y E n d p oi nts  
T his is a o ne -ar m i nter ve nti o nal pil ot st u d y i n partici pa nts recei vi n g 
c he m ot hera p y f or breast ca ncer t o e val u at e if me ma nti ne ca n pre ve nt c o g niti ve 
decli ne. We will recr uit 5 6  patie nts fr o m t he U N C Breast , Hills b or o u g h 
O nc ol o g y, a n d U N C R E X Ca ncer Ce nt er cli nics, treat wit h me ma nti ne 1 0 m g 
t wice dail y, a n d s yste maticall y e val uate c o g niti ve f u ncti o n, me ntal healt h, 
H R Q O L, a n d f u n cti o nal stat us at baseli ne a n d at t he e n d of c h e m ot hera p y  (a n d 
a gai n at 6 m o nt hs p ost -c he m ot hera p y i n a s u bset of partici pa nts) . We will als o 
seriall y assess t olera bilit y of  a n d a d here n ce wit h me ma nti ne.   
 
T he pri mar y effic ac y e n d p oi nt is c o g niti ve decli ne meas ure d as a c h a n ge i n D M S 
sc ore. Sc ores ra n g e fr o m 0 -1 0 0 %, defi n e d b y t he perce nt of c orrect a ns wers o n 
t he me m or y test. Sec o n d ar y e n d p oi nts i ncl u de ot h er meas ures of c o g niti ve 
f u ncti o n ( H V L T-R , R V P, O T S , Di git S pa n, C O W A, A N T, a n d P R O MI S 
C o g niti ve F u ncti o n), de pressi o n, a n xiet y,  H R Q O L, a n d f u ncti o nal stat us.  T he 
T M T -A a n d -B will als o be e val uat e d as sec o n dar y e n d p oi nts i n  t he s u bset of 
partici pa nts w h o c o m plet e d t he st u d y pri or t o t he re m o val of t hese m eas ures.  
9. 2  
S a m ple Size, Accr u al  a n d D ur ati o n of Accr u al  
T h o u g h c he m ot hera p y is k n o w n t o res ult i n c o g niti ve decli ne, t he st u d y b y 
Ja nelsi ns re p orts a 5 % i ncreas e i n sc ores o n t he D M S ( 8 3 % t o 8 8 %) i n patie nts 
wit h breast ca n cer fr o m pre -t o p ost-c h e m ot hera p y. 6 8 A n  increase i n sc ore  i n s pite 
of c o g niti ve decli ne  is c o nsiste nt wit h t he well -descri be d p he n o me na  of practice 
effect s i n b ot h healt h y a n d ca ncer p o p ulati o ns wit h re peat n e ur o ps yc h ol o gi cal 
testi n g.8 6 I n o ur sa m ple e x p ose d t o me ma nti ne, we h y p ot hesize t hat o ur sa m ple 
will ha ve a n 8 % i ncreas e i n t he D M S sc ore as c o m pare d t o t he 5 % i ncreas e i n 
breast c a ncer c o ntr ols  descri be d i n Ja nelsi ns st u d y . 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
2 9  
F or t he pri mar y o bjecti ve of c o g niti ve c ha n g e, a p aire d t -test wit h a 0. 0 5 o n e -
si de d si g nifica nce le v el will ha ve 8 0 % p o wer t o detect a n effect size of 0. 3 7 6  wit h 
a sa m ple size of 4 5. S pecificall y, p atie nts wit h breast ca ncer de m o nstr ate a 
5 %  i ncrease i n t he D M S pre- t o p ost- c h e m ot hera p y; 6 8 t h us, 5 %  is t he n ull 
h y p ot hesize d c ha n g e. T h e alter nati ve h y p ot h esis  is t hat patie nts recei vi n g 
me ma nti ne will e x perie n ce less c h e m ot hera p y -rel ate d c o g niti ve decli ne, a n d will 
ha ve a n 8 % i n crease . Usi n g t hese h y p ot hesiz e d v al ues, i n c o m bi nati o n wit h 
sa m ple size b u d getar y c o nstrai nts, we c h ose t he fi nal sa m ple size of 4 5. Wit h 4 5 
patie nts, we will ha ve 8 0 % p o wer t o test if t he c ha n ge sc ores i n o ur st u d y 
p o p ulati o n are si g nifica ntl y differe nt  t ha n t he hist orical c o ntr ol da ta re p ort e d b y 
Ja nelsi ns (ass u mi n g a 3 % mea n i ncrease, a n d sta n dar d de viati o n of t he i n creas e of 
7. 9 7 %) . T his st u d y will pr o vi de preli mi nar y dat a a n d effect sizes t o p o wer a 
f ut ure, lar g er place b o-c o ntr olle d st u d y.  
 
T o acc o u nt f or dr o p o ut of u p t o 2 0 %, we will e nr oll 5 6 partici pa nts. T he U N C 
Ca ncer Re gistr y rec or ds de m o nstrate t hat 5 3 7 sta ge I -III breast ca n cer pati e nts 
were referre d t o t he N C Ca ncer H os pital f or c he m ot hera p y bet wee n 2 0 1 6 a n d 
2 0 1 7. We esti mate t hat w e will e nr oll at least 3 3 % of eli gi ble  partici pa nts, b ase d 
o n o ur e x peri e nce wit h pre vi o us i nter ve nti o n st u dies, all o wi n g us t o recr uit o ur 
tar get wit hi n o ne year. 
9. 3  
D at a A n al ysi s Pl a ns 
T he pri mar y o utc o me is c ha n ge i n t he D M S sc ore. A paire d t -test will test if t he 
c ha n ge i n D M S sc ore fr o m pre - t o p ost-c he m ot hera p y is statisticall y differe nt 
fr o m hist orical  c o ntr ols . Pre- t o p ost-c he m ot hera p y , as well as pre- t o 6 m o nt hs 
p ost -c he m ot hera p y,  c ha n ges  i n all ot her c o g niti ve meas ures will als o be e val uate d 
usi n g paire d t -tests.  
 
Li near re gressi o n m o dels will be use d t o cr oss -secti o nall y e val uate ass ociati o ns 
bet wee n d e pressi o n ( P R O MI S -D ), a n xiet y ( P R O MI S-A ), slee p ( P R O MI S-Slee p 
Dist ur ba nce ), m e n o pa usal stat us, fati g ue ( F A CI T-F), esti mate d pre -ca ncer I Q 
( W T A R), a n d c o g niti ve eff ort ( N A S A-T L X) wit h b ot h o bjecti ve ( D M S , H V L T-
R, C O W A, A N T, Di git S pa n ) a n d self-re p orte d ( P R O MI S) meas ures of c o g niti ve 
f u ncti o n at baseli ne a n d p ost-c he m ot hera p y. Li ne ar mi xe d effects m o dels will 
e val uate ass ociati o ns acr oss pre - a n d p ost - ti me p oi nts. 
 
Li near re gressi o n m o deli n g will descri be t he ass o ciati o ns bet wee n pre - t o p ost-
c he m ot hera p y c o g niti ve c ha n ges ( D M S, H V L T -R, C O W A, A N T, Di git S pa n, 
P R O MI S) wit h p ost -c he m ot hera p y de pressi o n a n d a n xiet y ( P R O MI S), H R Q O L 
( F A C T-G) , a n d p erf or m a nce stat us ( K P S) . 
 
Descri pti ve statistics will be use d t o esti mate feasi bilit y: 1.)  recr uit me nt rat e ( % of 
i n vite d partici pa nts  w h o e nr oll), 2.) attriti o n ( % of e nr olle d partici pa nts w h o  are 
n ot eli gi ble f or a nal ysis of t he pri mar y o utc o me), a n d 3.) a d here nce t o treat me nt 
( % self-re p orte d d oses of me ma nti ne ta ke n).   
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 0  
W e will ta b ulate all A Es, t he d ose at w hic h t he y o cc urre d, a n d if t he y l e d t o 
d osi n g dela ys or re m o val fr o m t he st u d y. 
1 0. 0  S T U D Y M A N A G E M E N T  
1 0. 1  
I nstit uti o n al Re vie w B o ar d (I R B) A p pr o v al a n d C o nse nt 
It is e x p ecte d t hat t he I R B will ha ve t he pr o per re prese ntati o n a n d f u n cti o n i n 
acc or da nce wit h fe d erall y ma n date d re g ul ati o ns. T he I R B s h o ul d a p pr o ve t he 
c o nse nt f or m a n d pr ot oc ol.  
 
I n o btai ni n g a n d d o c u me nti n g i nf or me d c o nse nt, t he i n vesti gat or s h o ul d c o m pl y 
wit h t he a p plica ble re g ulat or y re q uir e me nt(s), a n d s h o ul d a d here t o G o o d Cli nical 
Practice ( G C P) a n d t o et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n 
of Helsi n ki.  
 
 
 
Bef ore recr uit me nt a n d e nr oll me nt o nt o t his st u d y, t he patie nt will be gi ve n a f ull 
e x pla nati o n of t he st u d y a n d will be gi ve n t he o p p ort u nit y t o re vie w t he c o nse nt 
f or m. Eac h c o nse nt f or m m ust i ncl u de all t he rele va nt ele me nts c urre ntl y re q uire d 
b y t he F D A Re g ul ati o ns a n d l ocal or state re g ulati o ns. O nce t his esse ntial 
i nf or mati o n has bee n pr o vi de d t o t he patie nt a n d t he i n vesti gat or is ass ure d t hat 
t he patie nt u n dersta n ds t he i m plicati o ns of partici pati n g i n t he st u d y, t he patie nt 
will be as ke d t o  gi ve c o nse nt t o partici pate i n t he st u d y b y si g ni n g a n 
I R B-a p pr o ve d c o nse nt f or m.  
 
Pri or t o a patie nt’s partici pati o n i n t he trial, t he writte n i nf or me d c o nse nt f or m 
s h o ul d be si g ne d a n d pers o nall y date d b y t he patie nt a n d b y t he pers o n w h o 
c o n d ucte d t he i nf or me d c o nse nt disc ussi o n. 
1 0. 2  
Re q uire d D oc u me nt ati o n  
Bef ore t he st u d y ca n be i nitiate d at a n y site, t he f oll o wi n g d oc u me ntati o n m ust be 
pr o vi de d t o t he Cli nical Pr ot oc ol Office ( C P O) at t he U ni versit y of N ort h Car oli na.  
•  A c o p y of t he official I R B a p pr o val letter f or t he pr ot oc ol a n d i nf or me d 
c o nse nt  
•  C Vs a n d me dical lice ns ure f or t he pri nci pal i n vesti gat or a n d a n y 
ass ociate i n vesti gat ors w h o will be i n v ol ve d i n t he st u d y  
•  A c o p y of t he I R B -a p pr o ve d c o nse nt f or m  
1 0. 3  
Re gistr ati o n Pr o ce d ures  
Patie nt e nr oll m e nt i n t he st u d y will be trac ke d i n O n Core ® . T his will all o w t he 
U N C Li ne ber ger C o m pre he nsi ve Ca ncer Ce nter t o trac k accr ual i nt o t he st u d y. F or 
all p ote ntiall y eli gi ble a n d i ntereste d patie nts, eli gi bilit y criteria m ust be c o nfir me d  
pri or t o re gistrati o n b y t he PI. 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 1  
1 0. 4  
A d here nce t o t he Pr ot oc ol  
E xce pt f or a n e mer ge nc y sit uati o n i n w hic h pr o per care f or t h e pr otecti o n, safet y, 
a n d well -bei n g of t h e st u d y patie nt re q uires alter nati ve treat me nt, t he st u d y s hall 
be c o n d ucte d e xactl y as descri be d i n t he a p pr o ve d pr ot oc ol.   
1 0. 4. 1  E mer ge nc y M o dific ati o ns  
U N C i n vesti gat ors ma y i m ple me nt a de viati o n fr o m, or a c ha n g e of, t he pr ot oc ol 
t o eli mi nate a n i m me diate hazar d(s) t o trial p artici pa nts  wit h o ut pri or U N C I R B 
ap pr o val.   
 
F or a n y s u c h e mer ge nc y m o dificati o n i m ple me nte d, a  U N C I R B m o dificati o n 
f or m m ust be c o m plete d b y U N C Researc h Pers o n nel  wit hi n fi ve ( 5) b usi n ess 
da ys of ma ki n g t he c h a n ge.   
1 0. 4. 2  Si n gle P atie nt/ P artici p a nt  E xce pti o ns  
A n y re q uest t o e nr oll a si n gle partici pa nt  w h o d oes n ot meet all t he eli gi bilit y 
criteria of t his st u d y re q uires t he a p pr o val of t he U N C Pri nci pal I n v esti gat or a n d 
t he U N C I R B.  
1 0. 4. 3  Ot her Pr ot oc ol De vi ati o ns/ Vi ol ati o ns  
Acc or di n g t o U N C’s I R B, a pr ot oc ol de viati o n  is a n y u n pla n ne d varia nce fr o m a n 
I R B a p pr o ve d pr ot oc ol t hat:  
•  Is g e nerall y n ote d or rec o g nize d after it occ urs 
•  Has n o s u bsta nti ve effect o n t he ris ks t o researc h p artici pa nts  
•  Has n o s u bsta nti ve effect o n t he scie ntific i nte grit y of t he researc h pla n 
or t he val ue of t h e data c ollecte d  
•  Di d n ot res ult fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
i n vesti gat or(s).  
 
A n u n pla n ne d pr ot oc ol v aria nce is c o nsi dere d a vi olati o n  if t he varia nce meets 
a n y of t he f oll o wi n g criteria :  
•  Has har me d or i ncrease d t he ris k of har m t o o ne or m ore researc h 
partici pa nts.  
•  Has da ma ge d t h e scie ntific i nte grit y of t he data c ollecte d f or t he st u d y. 
•  Res ults fr o m willf ul or k n o wi n g misc o n d uct o n t he part of t he 
i n vesti gat or(s). 
•  De m o nstrates seri o us or c o nti n ui n g n o nc o m plia nce wit h fe deral 
re g ulati o ns, State la ws, or U ni versit y p olicies. 
 
If a de vi ati o n or vi olati o n occ urs please f oll o w t he g ui deli nes bel o w: 
 
Pr ot oc ol D e vi ati o ns: U N C or Affiliate pers o n nel will rec or d t he de vi ati o n i n 
O n C ore ® , a n d re p ort t o a n y s p o ns or or data a n d s afet y m o nit ori n g c o m mittee i n 
acc or da nce wit h t heir p olicies.  De viati o ns s h o ul d be s u m marize d a n d re p orte d t o 
t he I R B at t he ti me of c o nti n ui n g re vie w. 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
3 2  
 
Pr ot oc ol Vi ol ati o ns: Vi olati o ns s h o ul d be re p ort e d b y U N C pers o n nel wit hin o ne 
( 1) wee k of t he i n vesti gat or bec o mi n g a ware of t he e ve nt usi n g t he sa me I R B 
o nli ne mec ha nis m use d t o re p ort U na ntici p ate d Pr o ble ms.   
 
U n a ntici p ate d Pr o ble ms :  A n y e ve nts t hat meet t he criteri a f or “ U na ntici p ate d 
Pr o ble ms” as defi ne d b y U N C ’s I R B m ust be re p orte d b y t he s t u d y pers o n nel 
usi n g t he I R B’s we b -bas e d re p orti n g s yste m.   
 
1 0. 5  
A me n d me nts t o t he Pr ot oc ol  
S h o ul d a me n d me nts t o t he pr ot oc ol be re q uire d, t h e a me n d me nts will be 
ori gi nate d a n d d oc u me nt e d b y t he Pri nci pal I n vesti gat or at U N C.  It s h o ul d als o 
be n ote d t hat w he n a n a me n d me nt t o t he pr ot oc ol s u bsta ntiall y alters t he st u d y 
desi g n or t he p ote ntial ris k t o t he patie nt, a re vise d c o nse nt f or m mi g ht be 
re q uire d.   
 
T he writte n a me n d m e nt, a n d if re q uir e d t he a me n de d c o nse nt f or m, m ust be se nt 
t o U N C’s I R B f or a p pr o val pri or t o i m ple me ntati o n.   
1 0. 6  
Rec or d R ete nti o n  
St u d y d oc u me ntati o n i ncl u des all e C R Fs , data c orrecti o n f or ms or q u eries, s o urce 
d oc u me nts, S p o ns or c orres p o n de nce t o I n vesti gat ors , m o nit ori n g l o gs/letters, a n d 
re g ulat or y d oc u m e nts (e. g., pr ot oc ol a n d a me n d m e nts, I R B c orres p o n d e nce a n d 
a p pr o val, si g ne d patie nt c o nse nt f or ms).  
 
S o urce d oc u me nts i ncl u d e all rec or di n gs of o bser vati o ns or n otati o ns of cli nical 
acti vities a n d all re p orts a n d rec or ds necessar y f or t he e val uati o n a n d 
rec o nstr ucti o n of t h e cli nical researc h st u d y. 
 
G o ver n me nt a g e nc y re g ulati o ns a n d directi ves re q uire t hat all st u d y 
d oc u me nt ati o n pertai ni n g t o t he c o n d uct of a cli nical trial m ust be retai n e d b y t he 
st u d y i n vesti gat or.  I n t he case of a st u d y wit h a dr u g see ki n g re g ulat or y a p pr o val 
a n d mar keti n g, t hese d o c u me nts s hall be retai ne d f or at least t w o years after t he 
last a p pr o val of mar keti n g a p plicati o n i n a n I nter n ati o nal C o nfere n ce o n 
Har m o nizati o n (I C H) re gi o n.  I n all ot her cas es, st u d y d oc u me nts s h o ul d be ke pt 
o n file u ntil t hree years after t he c o m pleti o n a n d fi nal st u d y re p ort of t his 
i n vesti gati o nal st u d y. 
1 0. 7  
O bli g ati o ns of I n vesti g at ors  
T he Pri nci pal I n vesti gat or is res p o nsi ble f or t he c o n d uct of t he cli nical trial at t he 
site i n acc or da nce wit h Title 2 1 of t he C o de of Fe deral Re g ulati o ns a n d/ or t he 
Declarati o n of Helsi n ki.  T he Pri nci pal I n vesti gat or is res p o nsi ble f or pers o nall y 
o verseei n g t he tr eat me nt of all st u d y patie nts.  T he Pri nci pal I n v esti gat or m ust 
ass ure t hat all st u d y site pers o n nel, i ncl u di n g s u b -i n vesti gat ors a n d ot her st u d y 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
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staff me m bers, a d here t o t he st u d y pr ot oc ol a n d all F D A/ G C P/ N CI re g ulati o ns 
a n d g ui deli nes re g ar di n g cli nical trials b ot h d uri n g a n d after st u d y c o m pleti o n.  
 
T he Pri nci pal I n vesti gat or will be res p o nsi ble f or ass uri n g t hat all t he re q uire d 
data will be c ollecte d a n d e ntere d i nt o t he e C R Fs . Peri o dicall y, m o nit ori n g visits 
will be c o n d ucte d a n d t h e Pri nci pal I n vesti gat or will pr o vi de access t o his/ her 
ori gi nal rec or ds t o p er mit verificati o n of pr o per e ntr y of data. At t he c o m pleti o n 
of t he st u d y, all e C R Fs  will be re vie we d b y t he Pri nci pal I n vesti gat or a n d will 
re q uire his/ her fi nal si g nat ure to verif y t h e acc urac y of t he data.  
 
 


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1 1. 0  R E F E R E N C E S  
1.  
Bl uet h ma n n S M, Mari ott o A B, R o wla n d J H. A ntici pati n g t he “sil ver ts u na mi”: 
Pre vale nce traje ct ories a n d c o m or bi dit y b ur de n a m o n g ol der ca ncer s ur vi v ors i n 
t he Unite d States. Ca ncer E pi de mi ol Bi o mar kers Pre v. 2 0 1 6;  
2.  
Ja nelsi ns M C, Kesler S R, A hles T A, M orr o w G R. Pre vale nce, mec h a nis ms, a n d 
ma na ge me nt of ca ncer -relate d c o g niti ve i m pair me nt. I nt Re v Ps yc hiatr y. 
2 0 1 4; 2 6( 1): 1 0 2 – 1 3.  
3.  
Wefel J S, Le n zi R, T heri a ult  R, B uz dar A U, Cr uic ks ha n k S, Me yers C A. 
“ C he m o brai n” i n breast c arci n o ma?: a pr ol o g ue. C a ncer. 2 0 0 4 A u g; 1 0 1( 3): 4 6 6 –
7 5.  
4.  
Bra dle y CJ, Ne u mar k D, L u o Z, Be d nare k H, Sc he n k M. E m pl o y me nt o utc o mes 
of me n treat e d f or pr ost ate ca n cer. J Natl Ca ncer I nst. 2 0 0 5 J ul; 9 7( 1 3): 9 5 8 – 6 5.  
5.  
Me h nert A, Sc her wat h A, Sc hir mer L, Sc hlei mer B, Peterse n C, Sc h ulz -
Ki n der ma n n F, et al. T he ass ociati o n bet wee n ne ur o ps yc h ol o gical i m pair m e nt, 
self-percei ve d c o g niti ve deficits, fati g ue a n d h ealt h relate d q ualit y of life i n breas t 
ca ncer s ur vi v ors f oll o wi n g sta n dar d a dj u va nt v ers us hi g h -d ose c he m ot hera p y. 
Patie nt E d uc C o u ns. 2 0 0 7 A pr; 6 6( 1): 1 0 8 – 1 8.  
6.  
M yers S B, Ma n ne S L, Kissa ne D W, Oz ga M, K as h y D A, R u bi n S, et al. S ocial -
c o g niti ve pr ocesses ass ociate d wit h fear of rec urre nce a m o n g w o me n n e wl y 
dia g n ose d wit h g y nec ol o gical ca n cers. G y n ec ol O nc ol. 2 0 1 3 Ja n; 1 2 8( 1): 1 2 0 – 7.  
7.  
V o n A h D, R ussell K M, St or ni ol o A M, Car pe nter J S. C o g niti ve D ysf u ncti o n a n d 
Its Relati o ns hi p t o Q ualit y of Life i n Breast Ca n cer S ur vi v ors. O nc ol N urs F or u m. 
2 0 0 9 Ma y; 3 6( 3): 3 2 6 – 3 6.  
8.  
Hefli n L H, Me y er o witz B E, Hall P, Lic hte nstei n P, J o ha nss o n B, Pe derse n N L, et 
al. Ca ncer as a ris k fact or f or l o n g -ter m c o g niti ve deficits a n d de me ntia. J Natl 
Ca ncer I nst. 2 0 0 5; 9 7( 1 1): 8 5 4 – 6.  
9.  
C herrier M M, A n d ers o n K, Da vi d D, Hi ga n o C S, Gra y H, C h urc h A, et al. A 
ra n d o mize d trial of c o g niti ve re ha bilitati o n i n ca ncer s ur vi v ors. Life Sci. 2 0 1 3 
Oct; 9 3( 1 7): 6 1 7 – 2 2.  
1 0.  
Erc oli L M, Castell o n S A, H u nter A M, K wa n L, Ka h n -Mills B A, Cer ni n P A, et al. 
Assess me nt of t he feasi bilit y of a re ha bilitati o n i nter ve nt i o n pr o gra m f or breast 
ca ncer s ur vi v ors wit h c o g niti ve c o m plai nts. Brai n I ma gi n g Be h a v. 2 0 1 3 
Dec; 7( 4): 5 4 3 – 5 3.  
1 1.  
Sc h u urs A, Gree n HJ. A feasi bilit y st u d y of gr o u p c o g niti ve re ha bilitati o n f or 
ca ncer s ur vi v ors: e n h a nci n g c o g niti ve f u ncti o n a n d q ualit y of  life. 
Ps yc h o o nc ol o g y. 2 0 1 3 Ma y; 2 2( 5): 1 0 4 3 – 9.  
1 2.  
Zi m mer P, Ba u ma n n F T, O berste M, Wri g ht P, Gart he A, Sc he n k A, et al. Effects 
of e xercise i nter ve nti o ns a n d p h ysical acti vit y be h a vi or o n ca n cer relate d c o g niti ve 
i m pair me nts: A s yste matic re vie w. V ol. 2 01 6, Bi o Me d Researc h I nter nati o nal. 
2 0 1 6.  
1 3.  
E hlers D K, A g ui ña g a S, C os ma n J, Se vers o n J, Kra mer A F, Mc A ule y E. T he 
effects of p h ysical a cti vit y a n d fati g ue o n c o g niti v e perf or ma nce i n breast c a ncer 
s ur vi v ors. Breast Ca ncer Res Treat. 2 0 1 7; 1 6 5( 3): 6 9 9– 7 0 7 .  
1 4.  
H off ma n CJ, Ersser SJ, H o p ki ns o n J B, Nic h olls P G, Harri n gt o n J E, T h o mas P W. 
Effecti ve n ess of mi n df ul ness -base d stress re d u cti o n i n m o o d, breast - a n d 


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e n d ocri ne -relat e d q ualit y of life, a n d well-bei n g i n sta ge 0 t o III breast c a ncer: A 
ra n d o mize d, c ontr olle d trial. J Cli n O nc ol. 2 0 1 2; 3 0( 1 2): 1 3 3 5 – 4 2.  
1 5.  
Mil b ur y K, C ha o ul A, Bie gler K, Wa n g yal T, S pel ma n A, Me yers C A, et al. 
Ti beta n s o u n d me ditati o n f or c o g niti ve d ysf u ncti o n: Res ults of a ra n d o mize d 
c o ntr olle d pil ot trial. Ps yc h o o nc ol o g y. 2 0 1 3; 2 2( 1 0) : 2 3 5 4– 6 3.  
1 6.  
J o h ns S A, Br o w n L F, Bec k-C o o n K, Tali b T L, M o na ha n P O, Giesler R B, et al. 
Ra n d o mize d c o ntr olle d pil ot trial of mi n df ul ness -base d stress r e d ucti o n c o m pare d 
t o ps yc h oe d ucati o nal s u p p ort f or persiste ntl y fati g ue d breast a n d c ol orectal ca ncer 
sur vi v ors. S u p p ort Care Ca ncer. 2 0 1 6; 2 4( 1 0): 4 0 8 5 – 9 6.  
1 7.  
A bra ha m J, H a ut M W, M ora n M T, Fil b ur n S, Le mi ue x S, K u wa bara H. A dj u va nt 
c he m ot hera p y f or breast ca ncer: effects o n cere bral w hite matter see n i n diff usi o n 
te ns or i ma gi n g. Cli n Breast Ca ncer. 2 0 0 8 Fe b; 8( 1): 8 8 – 9 1.  
1 8.  
de R uiter M B, Re ne ma n L, B o o ger d W, Velt ma n DJ, Caa n M, D o ua u d G, et al. 
Late effects of hi g h -d ose a dj u va nt c he m ot hera p y o n w hite a n d gra y matter i n 
breast c a ncer s ur vi v ors: c o n ver gi n g res ults fr o m m ulti m o dal ma g netic res o na nce 
i ma gi n g. H u m Brai n Ma p p. 2 0 1 2 Dec; 3 3( 1 2): 2 9 7 1– 8 3.  
1 9.  
J u n g M S, Z ha n g M, As kre n M K, Ber ma n M G, Peltier S, Ha yes D F, et al. 
C o g niti ve d ysf u ncti o n a n d s y m pt o m b ur de n i n w o me n treate d f or breast ca ncer: a 
pr os pecti ve be h a vi oral a n d f M RI a nal ysis. Brai n I ma gi n g Be h a v. 2 0 1 7; 1 1( 1): 8 6 –
9 7.  
2 0.  
C o nr o y S K, Mc D o nal d B C , S mit h DJ, M oser L R, West J D, Ka me n d ulis L M, et al. 
Alterati o ns i n brai n str uct ure a n d f u n cti o n i n breast ca ncer s ur vi v ors: effect of 
p ost -c he m ot hera p y i nter val a n d relati o n t o o xi dati ve D N A da ma ge. Breast Ca ncer 
Res Treat. 2 0 1 3 Ja n; 1 3 7( 2): 4 9 3 – 5 0 2.  
2 1.  
I n a ga ki M, Y os hi ka w a E, Mats u o ka Y, S u ga wara Y, Na ka n o T, A kec hi T, et al. 
S maller re gi o nal v ol u mes of brai n gra y a n d w hite matter de m o nstrate d i n breast 
ca ncer s ur vi v ors e x p ose d t o a dj u va nt c he m ot hera p y. Ca ncer. 2 0 0 7 
Ja n; 1 0 9( 1): 1 4 6– 5 6.  
2 2.  
Kesler S, Ja n elsi ns M, K o o va k katt u D, Pales h O, M ustia n K, M orr o w G, et al. 
Re d uce d hi p p oca m p al v ol u me a n d ver bal me m or y perf or ma n ce ass ociate d wit h 
i nterle u ki n-6 a n d t u m or necr osis fact or -al p ha le v els i n c he m ot hera p y -treate d breast 
ca ncer s ur vi v ors. Brai n Be ha v I m m u n.  2 0 1 3 Mar; 3 0 S u p pl: S 1 0 9 -1 6.  
2 3.  
Je n ki ns V, S hilli n g V, De utsc h G, Bl o o mfiel d D, M orris R, Alla n S, et al. A 3-year 
pr os pecti ve st u d y of t he effects of a dj u va nt tr eat me nts o n c o g niti o n i n w o me n wit h 
earl y sta ge breast ca ncer. Br J Ca ncer. 2 0 0 6; 9 4( 6): 8 2 8 – 3 4.  
2 4.  
Castell o n S A, Ga nz P A, B o wer J E, Peterse n L, A bra ha m L, Gree n d ale G A. 
Ne ur oc o g niti ve perf or m a nce i n breast ca n cer s ur vi v ors e x p ose d t o a dj u va nt 
c he m ot hera p y a n d ta m o xife n. J Cli n E x p Ne ur o ps yc h ol. 2 0 0 4; 2 6( 7): 9 5 5 – 6 9.  
2 5.  
S hilli n g V, Je n ki ns V. Se lf-re p ort e d c o g niti ve pr o ble ms i n w o me n recei vi n g 
a dj u va nt t hera p y f or breast ca ncer. E ur J O n c ol N urs. 2 0 0 7; 1 1( 1): 6 – 1 5.  
2 6.  
S hilli n g V, Je n ki ns V, M orris R, De utsc h G, Bl o o mfiel d D. T he effects of a dj u va nt 
c he m ot hera p y o n c o g niti o n i n w o me n wit h breast ca ncer - Preli mi nar y res ults of 
a n o bser vati o nal l o n git u di nal st u d y. Breast. 2 0 0 5;  
2 7.  
Va n Da m F S A M, Sc ha ge n S B, M uller MJ, B o o ger d W, V. D. Wall E, Dr o o glee ver 
F ort u y n M E, et al. I m p air me nt of c o g niti ve f u ncti o n i n w o me n recei vi n g a dj u va nt 
treat me nt f or hi g h -ris k breast ca n cer: Hi g h-d os e v ers us sta n dar d -d ose 


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c he m ot hera p y. J Natl Ca ncer I nst. 1 9 9 8;  
2 8.  
Be n der C M, Pacella M L, Serei ka S M, Br ufs k y A M, V o gel V G, Rast o gi P, et al. 
W hat d o percei ve d c o g niti ve pr o ble ms reflect? J S u p p ort O nc ol. 2 0 0 8; 6( 5): 2 3 8 –
4 2 .  
2 9.  
D o w nie F P, Mar Fa n H G, H o ué dé -T c he n N, Yi Q, Ta n n oc k I F. C o g niti ve 
f u ncti o n, fati q ue, a n d m e n o pa usal s y m pt o ms i n breast ca n cer patie nts recei vi n g 
a dj u va nt c he m ot hera p y: E val uati o n wit h patie nt i nter vie w after f or mal ass ess me nt. 
Ps yc h o o nc ol o g y. 2 0 0 6 ; 1 5( 1 0): 9 2 1– 3 0.  
3 0.  
Wefel J S, Var d y J, A hles T, Sc ha ge n S B. I nter nati o nal C o g niti o n a n d Ca ncer Tas k 
F orce rec o m me n dati o ns t o har m o nise st u dies of c o g niti ve f u ncti o n i n patie nts wit h 
ca ncer. La n cet O n c ol. 2 0 1 1 J ul; 1 2( 7): 7 0 3 – 8.  
3 1.  
Ge hri n g K, Pat war d ha n S Y, C olli ns R, Gr o ves M D, Etzel CJ, Me yers C A, et al. A 
ra n d o mize d trial o n t he efficac y of met h yl p he ni date a n d m o dafi nil f or i m pr o vi n g 
c o g niti ve f u ncti o ni n g a n d s y m pt o ms i n patie nts wit h a pri mar y brai n t u m or. J 
Ne ur o o nc ol. 2 0 1 2; 1 0 7( 1): 1 6 5 – 7 4.  
3 2.  
B oele  F W, D o u w L, De Gr o ot M, Va n T h uijl H F, Cleij ne W, Hei ma ns JJ, et al. 
T he effect of m o d afi nil o n fati g ue, c o g niti ve f u n cti o ni n g, a n d m o o d i n pri mar y 
brai n t u m or patie nts: A m ultice nter ra n d o mize d c o ntr olle d trial. Ne ur o O n c ol. 
2 0 1 3; 1 5( 1 0): 1 4 2 0 – 8.  
3 3.  
Me y ers C A, Weitz ner M A, Vale nti ne A D, Le vi n V A. Met h yl p he ni date t hera p y 
i m pr o ves c o g niti o n, m o o d, a n d f u ncti o n of brai n t u m or patie nts. J Cli n O nc ol 
[I nter net]. 1 9 9 8; 1 6( 7): 2 5 2 2– 7. A vaila ble fr o m: 
htt p:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 9 6 6 7 2 7 3  
3 4.  
Mar Fa n H G, Cle m o ns M, X u W, C he mer y ns k y I, Bre u nis H, Bra ga n za S, et al. A 
ra n d o mise d, place b o-c o ntr olle d, d o u ble -bli n d trial of t he effects of d -
met h yl p he ni date o n fati g ue a n d c o g niti ve d ysf u n cti o n i n w o me n u n der g oi n g 
a dj u va nt c he m ot hera p y f or breast c a ncer. S u p p ort Ca re Ca ncer [I nter net]. 
2 0 0 8; 1 6( 6): 5 7 7 – 8 3. A vaila ble fr o m: 
htt p:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 7 9 7 2 1 1 0  
3 5.  
K o hli S, Fis her S G, Tra Y, Jac o b A da ms M, Ma pst o ne M E, Wes nes K A, et al. T he 
effect of m o dafi nil o n c o g niti ve f u ncti o n i n breast ca ncer s ur vi v ors. Ca n cer. 
2 0 0 9; 1 1 5( 1 2): 2 6 0 5 – 1 6.  
3 6.  
L u n d orff L E, J ø nss o n B H, Sj ø gre n P. M o dafi nil f or atte nti o nal a n d ps yc h o m ot or 
d ysf u ncti o n i n a d va nce d ca ncer: A d o u ble -bli n d, ra n d o mise d, cr oss -o v er tri al. 
Palliat Me d. 2 0 0 9; 2 3( 8): 7 3 1 – 8.  
3 7.  
Bart o n D L, B ur ger K, N o v ot n y PJ, Fitc h T R, K o hli S, S o ori G, et al. T he use of 
Gi n k g o bil o ba f or t he pre ve nti o n of c he m ot hera p y -relate d c o g niti ve d ysf u n cti o n i n 
w o me n recei vi n g a dj u va nt treat me nt f or breast c a ncer, N 0 0 C 9. S u p p ort Care 
Ca ncer. 2 0 1 3; 2 1( 4): 1 1 8 5 – 9 2.  
3 8.  
C ha n A S, C he u n g M C, La w S C, C ha n J H. P hase II St u d y of Al p ha -T oc o p h er ol i n 
I m pr o vi n g t he C o g niti ve F u ncti o n of Patie nts with Te m p oral L o be Ra di o n ecr osis. 
Ca ncer. 2 0 0 4;  
3 9.  
C ha n g J, C o ut ure F A, Y o u n g S D, La u C Y, Lee M c Watters K. Wee kl y 
A d mi nistrati o n of E p oeti n Alfa I m pr o v es C o g niti o n a n d Q ualit y of Life i n Patie nts 
wit h Breast Ca ncer R ecei vi n g C he m ot hera p y. S u p p ort Ca ncer T h er [I nter net]. 
2 0 0 4; 2( 1): 5 2 – 8. A vaila bl e fr o m: 


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htt p://li n ki n g h u b.else vier.c o m/retrie ve/ pii/ S 1 5 4 3 2 9 1 2 1 3 6 0 1 0 8 3  
4 0.  
O’ S ha u g h ness y J A, V u k elja SJ, H ol mes F A, Sa vi n M, J o nes M, R o yall D, et al. 
Feasi bilit y of q ua ntif yi n g t he effects of e p o eti n alf a t hera p y o n c o g niti ve f u ncti o n 
i n w o me n wit h breast c a ncer u n der g oi n g a dj u va nt or ne oa dj u va nt c h e m ot hera p y. 
Cli n Breast Ca ncer. 2 0 0 5; 5( 6): 4 3 9 – 4 6.  
4 1.  
O’ S ha u g h ness y J a. Effects of e p oeti n alf a o n c o g niti ve f u ncti o n, m o o d, ast he nia, 
a n d q ualit y of life i n w o me n wit h breast c a ncer u n der g oi n g a dj u va nt 
c he m ot hera p y. Cli n Breast Ca ncer [I nt er net]. 2 0 0 2; 3 S u p pl 3( Dece m ber): S 1 1 6 – 2 0. 
A vaila ble fr o m: htt p:// d x. d oi. or g/ 1 0. 3 8 1 6/ C B C. 2 0 0 2.s. 0 2 2  
4 2.  
Ic o n o m o u G, K o utras  a, Karai vaz o gl o u K, Kalli olias G D, Assi ma k o p o ul os K, 
Ar g yri o u  a a, et al. Effect of e p oeti n al p ha t hera p y o n c o g niti ve f u ncti o n i n 
a nae mic p atie nts wit h s oli d t u m o urs u n der g oi n g c he m ot hera p y. E ur J Ca n cer Care 
( E n gl) [I nter net]. 2 0 0 8; 1 7( 6): 5 3 5– 4 1. A vaila ble fr o m: 
htt p:// w w w. nc bi. nl m. ni h. g o v/ p u b me d/ 1 8 7 0 7 6 2 1  
4 3.  
Ma ssa E, Ma de d d u C, L uss o M R, Gra mi g na n o G, Ma nt o va ni G. E val uati o n of t he 
effecti ve ness of tr eat me nt wit h er yt hr o p oieti n o n a ne mia, c o g niti ve f u ncti o ni n g 
a n d f u ncti o ns st u die d b y c o m pre he nsi ve g eriatri c assess me nt i n el derl y ca n cer 
patie nts wit h a ne mia rela te d t o ca ncer c h e m ot hera p y. Crit Re v O nc ol He mat ol. 
2 0 0 6 Fe b; 5 7( 2): 1 7 5 – 8 2.  
4 4.  
A d mi nistrati o n U S F a n d D. F D A dr u g safet y c o m m u nicati o n: Er yt hr o p oiesis -
sti m ulati n g a ge nts ( E S As): Pr ocrit, E p o ge n a n d Ara nes p. [I nter net]. 2 0 1 1. 
A vaila ble fr o m: 
htt p:// w w w.f d a. g o v/ Dr u gs/ Dr u g Safet y/ P ost mar ket Dr u g Safet yI nf or mati o nf or Patie n
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4 5.  
La wre n ce J A, Griffi n L, Balc ue va E P, Gr otel us c h e n D L, Sa m uel T A, Less er GJ, et 
al. A st u d y of d o ne pezil i n fe male breast c a ncer s ur vi v ors wit h self -re p orte d 
c og niti ve d ysf u ncti o n 1 t o 5 years f oll o wi n g a dj u v a nt c he m ot hera p y. J Ca n cer 
S ur vi v. 2 0 1 5;  
4 6.  
Ra p p S R, Case L D, Peiffer A, Na u g ht o n M M, C ha n M D, Stie ber V W, et al. 
D o ne pezil f or irra di ate d brai n t u m or s ur vi v ors: A p hase III ra n d o mize d place b o -
c o ntr olle d cli nical trial. J Cli n O nc ol. 2 0 1 5; 3 3( 1 5): 1 6 5 3– 9.  
4 7.  
Z o u J Y, Cre ws F T. T N F α p ote ntiates gl uta mate ne ur ot o xicit y b y i n hi biti n g 
gl uta mate u pta ke i n or ga n ot y pic brai n slice c ult ures: Ne ur o pr ot ecti o n b y N F κ B 
i n hi biti o n. Brai n Res. 2 0 0 5; 1 0 3 4( 1– 2): 1 1 – 2 4.  
4 8.  
Fl o de n A M, Li S, C o m bs C K. Beta -a m yl oi d -sti m ulate d micr o glia i n d uce n e ur o n 
deat h via s y ner gistic sti m ulati o n of t u m or necr osis fact or al p ha a n d N M D A 
rece pt ors. J Ne ur os ci [I nt er net]. 2 0 0 5; 2 5( 1 0): 2 5 6 6– 7 5. A vaila ble fr o m: 
htt p:// w w w. nc bi. nl m. ni h. g o v/e ntrez/ q uer y.fc gi?c m d = Retrie ve & d b = P u b M e d & d o pt
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6 6  
4 9.  
Br o w n P D, P u g h S, Laac k N N, Wefel J S, K h u ntia D, Me yers C, et al. M e ma nti ne 
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PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
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3 8  
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3 9  
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L o n git u di nal Traject or y a n d C haracterizati o n of Ca ncer -R elate d C o g niti ve 
I m pair me nt i n a Nati o n wi de C o h ort St u d y. J Cli n O nc ol. 2 0 1 8 
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7 2.  
Wec hsler D. Wec hsler T est of A d ult Rea di n g: W T A R. Ps yc h ol o gical C or p orati o n; 
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As sess me nt. 2 0 1 1 Se p; 1 8( 3): 2 6 3– 8 3.  
7 8.  
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Assess me nt. 2 0 1 1 Se p; 1 8( 3): 2 6 3 – 8 3.  
7 9.  
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8 0.  
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Pr os pecti ve e val u ati o n of pr o g n ostic varia bles fr o m patie nt -c o m plete d 


L C C C 1 9 2 1  
 
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4 0  
q uesti o n naires. N ort h Ce ntral Ca ncer Treat me nt Gr o u p. J Cli n O nc ol [I nt er net]. 
1 9 9 4; 1 2( 3): 6 0 1 – 7. A vaila ble fr o m: htt p:// w w w. nc bi. nl m. ni h. g o v/ p u b me d / 8 1 2 0 5 6 0 
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8 4.  
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8 5.  
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8 6.  
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c o g niti ve w or ks h o p. A n n als of O nc ol o g y. 2 0 0 8.  
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 1  
1 2. 0  A P P E N DI C E S  
 
 
A p pe n di x A: Del a ye d M atc h i n g t o S a m ple Test ( D M S) 
 
 
 
T he partici pa nt is s h o w n a c o m ple x vis ual i ma ge. 
 
 
 
 
T he i ma ge is hi d de n fr o m t he partici pa nt, a n d t he partici pa nt is s h o w n f o ur si milar
 
i ma ges si m ulta ne o usl y or after a 4 - or  1 2 -s ec o n d d ela y.  
 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 2  
T he partici pa nt m ust sele ct t he i ma ge t hat e xactl y matc hes t he sa m ple.  
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 3  
A p pe n di x B : R a pi d Vis u al I nf or m ati o n Pr ocessi n g ( R V P) 
 
 
T he partici pa nt is  as k e d t o rec o g nize a tar get di git se q ue nce o ut of a series of 
pse u d o -ra n d o m di gits fr o m 2 t o 9. 
 
 
 
T he partici pa nt presses a b utt o n o n t he  b ott o m of t he  scree n as q uic kl y as p ossi ble 
after t he y  rec o g ni ze t he t ar get di git se q ue nce.  
 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 4  
 
 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 5  
A p pe n di x C : O ne T o uc h  St oc ki n gs of C a m bri d ge  (O T S ) 
 
 
T he partici pa nt is s h o w n t w o dis pla ys wit h t hree c ol ore d balls prese nt e d as stac ks 
s us pe n de d fr o m a b ea m a n d a r o w of n u m bere d b o xes al o n g t he b ott o m of t he 
scree n. 
 
 
 
I n t he first set of pr o ble ms , t he partici pa nt is as ke d t o m o ve t he balls i n t he l o wer 
dis pla y t o matc h t hat of t he u p per dis pla y.  
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 6  
 
 
T he n, t he partici p a nt is s h o w n a d diti o nal pr o ble ms a n d as ke d t o w or k o ut i n her 
hea d h o w ma n y m o ves are re q uir e d t o reac h t he s ol uti o n.  
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 7  
A p pe n di x D : H o p ki ns Ver b al Le ar ni n g Test -Re vise d ( H V L T -R)  
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 8  
A p pe n di x E : Tr ail M a ki n g Test ( T M T)  
 
Test P art A:  
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
4 9  
Test P art B:  
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 0  
A p pe n di x F : P atie nt Re p orte d O utc o mes Me as ure me nt 
I nf or m ati o n S yste m –  M o difie d C o g niti ve F u ncti o n  
 
Ple ase res p o n d t o e ac h q uesti o n or st ate m e nt b y m ar ki n g o ne b o x per r o w.  
 
I n t he p ast 7 d a ys... 
 
 
 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 1  
 
Bef ore m y c a ncer di a g n osis …  
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 2  
A p pe n di x G : M o difie d N A S A T as k L o a d I n de x ( N A S A -T L X)  
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 3  
A p pe n di x H : Wec hsler A d ult Test of Re a di n g ( W T A R)  
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 4  
A p pe n di x I: P R O MI S-De pressi o n  
 
Ple ase res p o n d t o e ac h q uesti o n or st ate m e nt b y m ar ki n g o ne b o x per r o w.  
 
I n t he p ast 7 d a ys...  
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 5  
A p pe n di x J : P R O MI S-A n xiet y  
 
Ple ase res p o n d t o e ac h q uesti o n or st ate m e nt b y m ar ki n g o ne b o x per r o w.  
 
I n t he p ast 7 d a ys... 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 6  
A p pe n di x K : P R O MI S-Slee p Dist ur b a nce  
 
Ple ase res p o n d t o e ac h q uesti o n or st ate m e nt b y m ar ki n g o ne b o x per r o w.  
 
I n t he p ast 7 d a ys... 
 
 
I n t he p ast 7 d a ys... 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 7  
A p pe n di x L : Fu ncti o n al Assess me nt of C hr o nic Ill ness T her a p y -
F ati g ue ( F A CI T -F)  
 
Bel o w is a list of state me nts t hat ot her pe o ple wit h y o ur ill ness ha ve sai d are 
i m p orta nt. Ple ase ci rcl e or m ar k o ne n u m be r per li ne t o i n dic ate y o ur 
res p o nse as it a p plies t o t he p ast 7 d a ys . 
 
 
 
 
 
 




L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
5 9  
A p pe n di x N : F u ncti o n al Assess me nt of C a ncer T her a p y -Ge ner al 
( F A C T-G)  
 
Bel o w is a list of state me nts t hat ot her pe o ple wit h y o ur ill ness ha ve sai d are 
i m p orta nt. Ple ase ci rcl e or m ar k o ne n u m be r per li ne t o i n dic ate y o ur 
res p o nse as it a p plies t o t he p ast 7 d a ys . 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6 0  
 
 
 
 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6 1  
A p pe n di x O : Blesse d Orie nt ati o n Me m or y C o nce ntr ati o n 
( B O M C) 
 
 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6 2  
A p pe n di x P : H or m o n al St at us F or m 
 
 
 
 
 


L C C C 1 9 2 1  
 
C O N FI D E N TI A L  
PI:  Ze v N a k a m ur a  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
 
 
 
A pril 2 0 1 7  
 
6 3  
A p pe n di x Q : M o difie d Brief Me dic ati o n Q uesti o n n aire ( B M Q)-
S pecific  
 
•  We w o ul d li ke t o as k y o u a b o ut y o ur pers o nal vie ws a b o ut me ma nti ne (t he 
me dicati o n y o u t o o k f or t his st u d y).  
 
•  I n t he ite ms bel o w, “c o g niti o n” refers t o y o ur me m or y, c o nce ntrati o n, a n d 
o verall t hi n ki n g a bilit y.  
 
•  Please i n dic ate t he e xte nt t o w hic h y o u a gree or disa gree wit h t he m b y circli n g 
t he a p pr o pri ate n u m ber. 
 
•  T here are n o  ri g ht or wr o n g a ns wers. We ar e i ntereste d i n y o ur pers o nal vie ws.