Pre-operative Window Study of Interval Exercise Training as a Therapy for Endometrial Cancer
Phase: NA
Conditions: Endometrial Cancer
Sponsor: UNC Lineberger Comprehensive Cancer Center

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   
 
 
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 8 3 9: Pre - o perati ve Wi n d o w St u d y of I nter val E xercise Trai ni n g as a T hera p y f or 
E n d o metrial Ca 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):    
     E dit orial, a d mi nistrati ve c ha n ges  
     Scie ntific c ha n ges  
     St u d y Desi g n c ha n ges  
X  Eli gi bilit y C ha n ges  
 
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:  
T his a me n d me nt will c ha n ge t he B MI i ncl usi o n criteria t o hel p wit h accr ual. We are decreasi n g 
t he l o wer B MI li mit of 3 0 t o 2 5k g/ m 2, t o i ncl u de b ot h o bese a n d o ver wei g ht w o me n as all w o ul d 
p ote ntiall y be nefit fr o m HII T . T he u p per li mit will re mai n 5 5 k g/ m 2. 
 
List of U p d ates t o Pr ot oc ol:  
1.  U p date d Secti o ns 1. 1, 1. 2, a n d 1. 3 t o reflect i ncl usi o n of o bese/ o ver wei g ht w o me n  
2.  U p date d Secti o n 2. 2. 2. 2 i n E x pl orat or y O bjecti ves t o i ncl u de o bese/ o ver wei g ht a nal ysis  
3.  U p date d Secti o ns 4. 1 a n d 5. 3 t o reflect ne w B MI ra n ge of 2 5 -5 5 k g/ m 2  
4.  U p date d Secti o ns 5. 1, 5. 3, a n d 5. 3. 6 t o reflect i ncl usi o n of o bese/ o ver wei g ht w o me n.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D  Se pte m ber 1 0, 2 0 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   
 
 
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 8 3 9: Pre - o perati ve Wi n d o w St u d y of I nter val E xercise Trai ni n g as a T hera p y f or 
E n d o metrial Ca 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):  
_ _ E dit orial, a d mi nistrati ve c ha n ges 
_ _ Scie ntific c ha n ges  
_ X _ St u d y Desi g n c ha n ges  
_ _ Eli gi bilit y C ha n ges  
 
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:  
T his a me n d me nt c ha n ge d t he st u d y desi g n fr o m a t w o -ar m ra n d o mize d st u d y t o a si n gle -ar m 
( HII T ar m o nl y) st u d y. T his c ha n ge is a res ult of a sl o wer t ha n e x pecte d accr ual d ue t o t he 
C O VI D -1 9 pa n de mic. T he pa n de mic halte d all recr uit me nt f or 6 m o nt hs; u p o n re o pe ni n g ne w 
patie nt a p p oi nt me nts f or earl y sta ge ca n cers are d o w n a p pr o xi matel y 3 0 %.  O ur tea m has alrea d y 
gai n e d a n i ncre di ble a m o u nt of i nsi g ht a n d s o me g o o d data  t hat ca n be use d t o i nf or m f ut ure 
st u dies t o s u p p ort e n d o metrial ca ncer. P er t he rec o m me n dati o n of o ur rec e nt L C C C P R C re vie w, 
we met wit h o ur pr o gra m officer a b o ut t he sl o wer t ha n e x pecte d accr ual, a n d o ur pr o gra m officer 
a gree d wit h c ha n gi n g t his st u d y t o a si n gle ar m i nter ve nti o n st u d y. All ne w accr uals will  be 
assi g ne d t o t he HII T ar m. We pla n t o ha ve a t otal of 2 0 e val ua ble patie nts i n t he HII T ar m at t he 
e n d of t his st u d y. Here, ‘e val ua ble’ mea ns t o ha ve c o m plete pre- HII T a n d p ost -HII T data.  
 
List of U p d ates t o Pr ot oc ol:  
1.  U p date d Secti o n s 1. 1  a n d 1. 3 t o s h o w t hat t his is n o l o n ger a ra n d o mize d trial.  
2.  Re m o ve d st u d y o bjecti ves i n Secti o n 2. 1. 2  
3.  Re m o ve d sec o n d pri mar y e n d p oi nt i n Secti o n 3. 1. 2  
4.  U p date d sc he ma i n Secti o n 5. 1 a n d re m o ve d me nti o n of c o ntr ol ar m  
5.  Re m o ve d all c o m paris o ns a n d e x pla nati o ns re gar di n g t he c o ntr ol ar m i n Secti o n 5. 2  
6.  A d de d me nti o n of C o m ple x At y pical H y per plasia patie nts a n d re m o ve d c o ntr ol gr o u p 
c o m paris o ns i n Secti o n 5. 3  
7.  Re m o ve d c o ntr ol gr o u p c o m paris o ns i n Secti o ns 5. 3. 5, 5. 3. 6 a n d 5. 3. 7  
8.  Ti me a n d E ve nts Ta ble i n Secti o n 6. 1 u p date d t o s h o w t hat V O 2 is o pti o nal d uri n g p ost-
o p  
9.  St u d y Desi g n i n Secti o n 8. 1 u p date d t o s h o w t hat t his is n o w a o ne ar m trial wit h o nl y 
HII T partici pa nts  
1 0.  Sa m ple Size Descri pti o n a n d Data A nal ysis were u p date d i n Secti o ns 8. 2  
 
 
 
 
 
   
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D  M arc h 2 3, 2 0 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   
 
 
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 # 3 
 
 
L C C C 1 8 3 9: Pre - o perati ve Wi n d o w St u d y of I nter val E xercise Trai ni n g as a T hera p y f or 
E n d o metrial Ca 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): 
_ _ E dit orial, a d mi nistrati ve c ha n ges  
_ _ Scie ntific c ha n ges  
_ _ St u d y Desi g n c ha n ges  
_ X _ Eli gi bilit y C ha n ges  
 
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:  
T his a me n d me nt e x pa n ds eli gi bilit y criteria t o reflect t he patie nts see n i n o ur cli nic. Eli gi bilit y 
n o w i ncl u des t h ose wit h a dia g n osis of c o m ple x e n d o metrial h y per plasia, w hic h has si milar 
bi ol o g y as it is  a prec urs or t o  e n d o metrial ca ncer . T he B MI a n d a ge re q uire me nts were als o 
u p date d t o reflect t he patie nt p o p ulati o n see n i n cli nic a n d b o ost accr ual.  
 
List of U p d ates t o Pr ot oc ol:  
1.  Eli g i bilit y criteria 4. 1. 1 u p date d t o i ncl u de c o m ple x e n d o metrial h y per plasia  
2.  Eli gi bilit y criteria 4. 1. 4 was delete d d ue t o re d u n da nc y  
3.  A ge ra n ge e x pa n de d i n 4. 1. 2 t o i ncl u de patie nts 3 0 -7 5 years of a ge i nstea d of 4 0 -7 5 
years ol d.  
4.  T he u p per li mit of B MI was c ha n ge d i n 4. 1. 3 t o a ma xi m u m of 5 5.  
5.  Sc he ma 5. 1 u p date d t o i n dicate V O 2 pea k at p ost -s ur gical testi n g is o pti o nal.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D  A u g ust 1 4, 2 0 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   
 
 
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 # 2 
 
L C C C 1 8 3 9: Pre - o perati ve Wi n d o w St u d y of I nter val E xercise Trai ni n g as a T hera p y f or 
E n d o metrial Ca 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  
_ X _ St u d y Desi g n c ha n ges  
_ X _ Eli gi bilit y C ha n ges  
 
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:  
T his a me n d me nt all o ws e nr oll me nt of partici pa nts wit h a sta n dar d of care s ur ger y sc he d ule d less 
t ha n 3 wee ks fr o m c o nse nt date. T his a me n d me nt als o a dj usts t he i nter ve nti o n fr o m HII T sessi o n 
2 x a wee k o ver 3 w ks, t o 4 t o 8 t otal HII T sessi o ns. T his is d o ne t o facilitate e nr oll me nt.  
 
List of U p d ates t o Pr ot oc ol:  
1.  St u d y S y n o psis 1. 1: U p date d t o reflect c ha n ge of HII T i nter ve nti o n fr o m 3 wee ks t o 4 - 8 
sessi o ns 
2.  I ncl usi o n Criteria 4. 1. 8: Ti meli ne of 2 da ys fr o m c o nse nt t o d o baseli ne testi n g re m o ve d 
3.  I ncl usi o n Criteria 4. 1. 9: Ti meli ne f or p ost-s ur ger y testi n g a n d Sta n dar d of Care ( S O C) visit 
c ha n ge d t o 2 -4 wee ks f oll o wi n g s ur ger y  
4.  Sc he ma 5. 1:  U p date d t o reflect c ha n ge of HII T i nter ve nti o n fr o m 3 wee ks t o 4 -8 sessi o ns, 
t he re m o val of 2 da ys fr o m c o nse nt t o perf or m baseli n e testi n g, a n d t he ti meli ne f or p ost-
s ur ger y testi n g a n d S O C visit. T he para gra p hs f oll o wi n g sc he ma were als o u p date d t o 
reflect c ha n g e of HII T i nter ve nti o n fr o m 3 wee ks t o 4- 8 sessi o ns 
5.  D urati o n of st u d y 5. 2: U p date d t o reflect t he var yi n g ti mi n g of st u d y a n d t he c ha n ge fr o m  3 
wee ks t o 4 - 8 sessi o ns. T he ti me o n st u d y is dictate d b y S O C treat me nt.  
6.  St u d y details 5. 3: U p date d t o reflect c ha n ge of HII T i nter ve nti o n fr o m 3 wee ks t o 4 - 8 
sessi o ns 
7.  St u d y details 5. 3. 6: Fasti n g i ns uli n, gl uc ose, a n d li pi d le vels re m o v e d. Clarifie d H g B A 1 C 
will o nl y be c ollecte d pri or t o i nter ve nti o n  
8.  Ti me a n d E ve nts ta ble 6. 1: H g B A 1 C deli neate d i n ta ble. U p date d t o reflect c ha n ge of HII T 
i nter ve nti o n fr o m 3 wee ks t o 4- 8 sessi o ns.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T H E A T T A C H E D V E R SI O N D A T E D  J u ne 7 , 2 0 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   
 
 
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  
 
L C C C 1 8 3 9: Pre - o perati ve Wi n d o w St u d y of I nter val E xercise Trai ni n g as a T hera p y f or 
E n d o metrial Ca 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  
_ _ _ T hera p y c ha n ges  
_ X _ Eli gi bilit y C ha n ges  
 
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:  
T his pr ot oc ol a me n d me nt reflects t he c h a n ge i n ma na ge me nt of t his st u d y t o t he Li ne ber ger 
C o m pre he nsi ve Ca ncer Ce nter Office of Cli nical a n d Tra nslati o nal Researc h ( O C T R). St u d y 
ma na ge me nt secti o ns were u p date d t o reflect c o m m o n practices of O C T R. A d diti o n all y, t he 
i nitial st u d y visit has bee n a dj uste d t o all o w t he patie nt t o c o m plete t he visit at t he ti me of 
e nr oll me nt or ret ur n t o a U N C e xercise a n d s p ort scie nce la b orat or y t o c o m plete t he e nr oll me nt 
visit. Details ha ve als o bee n a d de d t o clearl y i de ntif y  t he pr oce d ures at eac h ti me p oi nt.  
 
List of u p d ates t o pr ot oc ol:  
9.  T he a d diti o n of e n d p oi nts a n d c orrecti o n of f or matti n g c ha n ge d t he secti o n n u m bers 
t hr o u g h o ut t he pr ot oc ol.  
1 0.  F or ease of re p orti n g i n cli nicaltrials. g o v, t he pri mar y o bjecti ves i n secti o n 2. 1 were br o ke n 
a part i nt o t w o se parate o bjecti ves.  
1 1.  Sec o n dar y o bjecti ves were c ha n ge d t o E x pl orat or y d ue t o t he nat ure of t he e n d p oi nts.  
1 2.  Pri mar y e n d p oi nts were a d de d i n secti o n 3. 1  
1 3.  I ncl usi o n criteria 4. 1. 5 was clarifie d f or scree ni n g p ur p oses ( pre vi o usl y  2. 2. 5) 
1 4.  I ncl usi o n criteria 4. 1. 6, 4. 1. 7, 4. 1. 8, a n d 4. 1. 9 were a d de d t o e ns ure s u bject w o ul d be a ble 
t o c o m plete st u d y acti vities 
1 5.  Sc he ma a n d c orres p o n di n g s u perscri pts were c ha n ge d i n secti o n 5. 1 t o clarif y t he e ve nts at 
eac h ti me p oi nt.  ( pre vi o usl y 3. 1)  
1 6.  D urati o n of st u d y a dj uste d i n secti o n 5. 2 t o acc o u nt f or t he o pti o n of baseli ne testi n g at a 
da y ot her t ha n e nr oll me nt ( pre vi o usl y 3. 2)  
1 7.  St u d y details i n secti o n 5. 3 were u p date d t o clarif y tiss ue pr oc ure me nt ti mi n g a n d a m o u nt 
( pre vi o usl y 3. 2). Als o, gift car d a m o u nt was i ncrease d fr o m $ 5 0 t o $ 1 0 0.  
1 8.  Secti o n 5. 3 ( St u d y Details) a n d 6. 1 ( Ti me a n d E ve nts Ta ble) were u p date d t o i ncl u de t he 
use of te xt messa gi n g via t he C H AI -c ore we bsite d uri n g t he HII T i nter ve nti o n.  
1 9.  P ote ntial ris ks of t he st u d y were re m o ve d fr o m pre vi o us secti o n 4. 3. 8 a n d m o ve d t o secti o n 
7. 1 i n c o nc or da nce wit h O C T R pr ot oc ol str uct ure  
2 0.  T he pre vi o us ti me a n d e ve nts ta ble was re place d t o o utli ne all st u d y visits i n Secti o n 6. 1 
( pre vi o usl y 4. 1) 
2 1.  Secti o ns; 7. 0 E X P E C T E D RI S K S A N D U N A N TI C P A T E D P R O B L E M S, 8. 3 Data 
Ma na ge me nt/ A u dit, 9. 2 Re q uire d d oc u me ntati o n, 9. 4 re gistrati o n pr oce d ures, were u p date d 
t o reflect p olicies of O C T R. 
2 2.  St u d y will be usi n g a R E D Ca p data base s o refere nce t o t hat was a d de d t o Secti o n 8 .3.   
 
 
T H E A T T A C H E D V E R SI O N D A T E D M arc h 1 , 2 0 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  

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 
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  
3  
1. 1  St u d y S y n o psis ............................................................................................................ 3  
1. 2  Bac k gr o u n d ................................................................................................................. 4  
1. 3  P ur p ose a n d Rati o nale ................................................................................................. 7  
2. 0  
S T U D Y O BJ E C TI V E S  
7  
2. 1  Pri mar y O bjecti ve  ....................................................................................................... 7  
2. 2  E x pl orat or y O bjecti ves  ............................................................................................... 8  
3. 0  
S T U D Y E N D P OI N T S  
8  
3. 1  Pri mar y E n d p oi nts  ...................................................................................................... 8  
4. 0  
P A TI E N T E LI GI BI LI T Y 
9  
4. 1  I ncl usi o n Criteria ........................................................................................................ 9  
4. 2  E xcl usi o n Criteria  ....................................................................................................... 9  
5. 0  
S T U D Y P L A N  
1 0  
5. 1  Sc he ma  ...................................................................................................................... 1 0  
5. 2  D urati o n of St u d y  ...................................................................................................... 1 1  
5. 3  St u d y Details ............................................................................................................. 1 1  
6. 0  
TI M E A N D E V E N T S T A B L E  
1 6  
6. 1  Ti me a n d E ve nts Ta ble ............................................................................................. 1 6  
7. 0  
E X P E C T E D RI S K S A N D U N A N TI CI P A T E D P R O B L E M S  1 7  
7. 1  E x pecte d Ris ks:  ......................................................................................................... 1 7  
7. 2  Defi niti o n  .................................................................................................................. 1 8  

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 
7. 3  Re p orti n g................................................................................................................... 1 8  
7. 4  Data a n d Safet y M o nit ori n g Pla n  .............................................................................. 1 8  
8. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S 
1 8  
8. 1  St u d y Desi g n ............................................................................................................. 1 8  
8. 2  Sa m ple Size a n d Accr ual  .......................................................................................... 1 9  
8. 3  Data Ma na ge me nt/ A u dit  ........................................................................................... 2 0  
9. 0  
S T U D Y M A N A G E M E N T  
2 0  
9. 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 ........................................ 2 0  
9. 2  Re q uire d D oc u me ntati o n .......................................................................................... 2 1  
9. 3  Re gistrati o n Pr oce d ures  ............................................................................................ 2 1  
9. 4  A d here nce t o t he Pr ot oc ol ......................................................................................... 2 1  
9. 5  A me n d me nts t o t he Pr ot oc ol ..................................................................................... 2 2  
9. 6  Rec or d Rete nti o n ...................................................................................................... 2 3  
9. 7  O bli gati o ns of I n vesti gat ors  ...................................................................................... 2 3  
1 0. 0  
R E F E R E N C E S  
2 3  
 
 
 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
3 
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  
E n d o metrial ca ncer ( E C) is t he f o urt h m ost c o m m o n ca ncer a m o n g w o me n i n t he U S. E C 
is i ncreasi n g i n fre q ue nc y, d ue t o t he risi n g o besit y e pi de mic. O besit y a n d dia betes are 
c o m m o n fact ors ass ociate d wit h i ncrease d ris k of de vel o pi n g E C 1- 3 a n d i ncrease d ris k of 
deat h, 4- 8 wit h a p pr o xi matel y 6 0 % of E C patie nts bei n g o bese. I n a d diti o n, E C p atie nts 
h a ve t he hi g hest c o -m or bi dit y i n de x a m o n g c a ncers a n d are m ost li kel y t o die of 
c ar di o v asc ul ar dise ase. 9 , 1 0 T h us, i m pr o ve me nts i n car di o meta b olic healt h are critical f or 
decreasi n g m ortalit y i n E C.  
 
Gi ve n t he i nter pla y bet wee n o besit y, i ns uli n resista nce, a n d E C, we ha ve e x pl ore d t he a nti -
t u m ori ge nic effects of t he a nti-dia betic dr u g metf or mi n. I n o ur m o use m o del of E C, o besit y 
res ulte d i n a  d o u bli n g of  t u m or  size a n d i ncrease d E C li pi d bi os y nt hesis. Metf or mi n 
s h o we d i ncrease d efficac y a gai nst E Cs i n o bese vs. lea n mice, re versi n g t he detri me ntal 
meta b olic effects of o besit y. I n o ur p hase 0 cli nical trial i n o bese E C patie nts, 1 1 metf or mi n 
decrease d E C pr oliferati o n, s u p p orti n g a li n k bet wee n meta b olis m a n d t u m or bi ol o g y. T his 
w or k le d t o a p hase 2/ 3 E C trial e val uati n g metf or mi n vs. place b o.  
 
Si mil ar  t o  metf or mi n,  a   p ote nti al str ate gy  f or  i m pr ovi n g  t he  met a b olic  milie u  a n d  
decre asi n g t u m or size i n E C p atie nts is t o i ncre ase p hysic al activity . Hi g h -i nte nsit y 
i nter val trai ni n g ( HII T) is a n e xercise strate g y w here s h ort i nte nse e xercise peri o ds are 
i nters perse d wit h rec o ver y peri o ds. HII T re q uires as little as 1 0 mi n of e xercise per sessi o n 
( 2  ti mes/ wee k)  a n d  res ults  i n  ra pi d  i m pr o ve me nt  i n  car di ores pirat or y  fit ness  a n d  
mit oc h o n drial f u ncti o n, ofte n i n as little as 2 wee ks. 1 2 HII T is safe i n a variet y of patie nts, 
i ncl u di n g t h ose wit h heart fail ure,1 3 str o ke,1 4 ca ncer, 1 5 a n d c hr o nic o bstr ucti ve p ul m o nar y 
disease, 1 6 wit h hi g h t olera bilit y a n d fe w a d verse e ve nts. O ur preli mi nar y e vi de nce 1 7 -1 9 
s u g gests t hat HII T is a pr o misi n g a p pr oac h f or ma xi mizi n g car di ores pirat or y a n d meta b olic 
a da ptati o ns, i ncl u di n g i ns uli n se nsiti vit y a n d gl yce mic c o ntr ol, beca use it all o ws f or s h ort 
e xercise b o uts wit h rest peri o ds, yet res ults i n c o m para ble/ greater be nefits t o tra diti o nal 
m o derate i nte nsit y e xercise. 2 0 , 2 1 Rece ntl y, pre -o perati ve car di ores pirat or y fit ness has bee n 
rec o g nize d t o e n ha nce p ost-o perati ve ca ncer rec o ver y o utc o mes. 2 2 , 2 3 We ha ve pre vi o usl y 
de m o nstrate d  t hat  a  h o me -base d  HII T  i nter ve nti o n,  bef ore  b o ne  marr o w  tra ns pla nt,  
i m pr o ve d car di ores pirat or y fit ness a n d tra ns pla nt o utc o mes.2 4 HII T pr o gra ms are hi g hl y 
a da pta ble a n d ca n be s uccessf ull y i m ple me nte d at h o me, wit h n o a d verse e ve nts, a n d yiel d 
i m pactf ul p h ysi ol o gical o utc o mes. T o d ate, t he use of HII T i n E C p atie nts h as n ot bee n 
previ o usly  ev al u ate d,  i ncl u di n g  t he  effects  of  HII T  o n  c ar di o met a b olic  he alt h,  p ost -
o per ative o utc o mes, or as a p ote nti al n ovel tre at me nt str ate gy f or t his o besity -drive n 
dise ase.   
 
T h us, we will ev al u ate t he a nti -c a ncer effects of HII T  i n a pre-o perati ve wi n d o w st u d y i n 
o bese/ o ver wei g ht E C patie nts. F or t his trial, patie nts will c o m plete 4 t o 8  sessi o ns of h o me -
base d HII T, pri or t o h ysterect o m y. We h y p ot hesize t hat HII T will i m pr o ve t he meta b olic 
e n vir o n me nt  a n d  re d uce  t u m or  gr o wt h,  as  reflecte d  i n  b ot h  m olec ular  a n d  meta b olic  
bi o mar kers, s pecificall y o besit y, i ns uli n resista nce, V O 2pea k, u pre g ulati o n of i ns uli n/I G F -

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
5 
w hic h o besit y f uels t u m or gr o wt h. I n s u m m ary, o besity cre ates a u ni q ue t u m or-e n h a nci n g 
e nvir o n me nt t h at s h o ul d be str ate gic ally a n d t her a pe utic ally t ar gete d t o i m pr ove o utc o mes 
f or o bese/ over wei g ht E C p atie nts. P ote nti al i nterve nti o ns i ncl u de metf or mi n as ex pl ore d 
i n o ur previ o us w ork a n d HII T as will be ex pl ore d i n t his pr o p os al.  
 
Metf or mi n h as a nti -E C effects. Gi ve n t he i nter pla y bet wee n o besit y, i ns uli n resista nce, 
a n d E C, we ha ve e x pl ore d t he a nti -t u m ori ge nic effects of t he a nti-dia betic dr u g metf or mi n 
i n  pre-cli nical  E C  m o dels.  Metf or mi n  is  t h o u g ht  t o ha ve a nti -t u m ori ge nic effects vi a 
decreasi n g  circ ulati n g  i ns uli n/ gl uc ose  le vels,  i n hi biti n g  mit oc h o n drial  c o m ple x  I,  
acti vati n g A M P K a n d i n hi biti n g i ns uli n/I G F -1/ m T O R a n d li pi d si g nali n g pat h wa ys.  I n o ur 
L K B 1 fl/flp 5 3 fl/fl m o use m o del of E C, o besit y res ulte d i n a d o u bli n g of t u m or size a n d 
i ncrease d  E C  li pi d  bi os y nt hesis  ( ma n uscri pt  i n  pre p).3 8 Mirr ori n g  o ur  L K B 1
fl/flp 5 3 fl/fl 
meta b ol o mic fi n di n gs i n mice, alterati o ns i n t he e x pressi o n of meta b olicall y rele va nt ge nes 
relate d t o li pi d meta b olis m a n d t o t he i ns uli n/I G F-1 si g nali n g pat h wa y i n e n d o metri oi d 
E Cs were ass ociate d wit h ele vate d B MI i n T he Ca ncer Ge n o me Atlas ( T C G A) data base. 3 9 
Metf or mi n ha d i ncrease d efficac y a gai nst E Cs i n o bese vs. lea n mice, re versi n g t he  
detri me ntal meta b olic effects of o besit y i n t he t u m ors via s h u nti n g fatt y aci ds t o beta -
o xi dati o n as o p p ose d t o li pi d bi os y nt hesis ( Fi g 2 ).3 8 We h y p ot hesize t hat t his meta b olic 
o bese si g nat ure u n derlies metf or mi n’s i m pr o ve d efficac y i n treati n g o besit y-dri ve n t u m ors.  
 
I n o ur p hase 0 cli nical trial i n o bese E C patie nts ,1 1 we  f o u n d a fa v ora ble res p o nse t o s h ort -
ter m metf or mi n treat me nt, i ncl u di n g re d uce d pr oliferati o n a n d decrease d e x pressi o n of t he 
I G F-1 rece pt or a n d tar gets of A M P K/ m T O R pat h wa y. Metf or mi n res p o n ders ha d hi g her 
pre- treat me nt le vels of fatt y aci ds/ gl yc oli pi ds i n t heir ser u m, s u g gesti ve of a m ore i ns uli n 
resista nce p he n ot y pe pre dicti n g i ncrease d be nefit t o t his dr u g. T o get her, t hese fi n di n gs 
s u p p ort a li n k bet wee n meta b olis m a n d t u m or bi ol o g y. T his w or k le d t o a p hase 2/ 3 E C 
trial e val uati n g metf or mi n vs. place b o pl us paclita xel/car b o plati n i n a d va nce d/rec urre nt 
e n d o metri al ca ncer ( G O G 2 8 6 B). I n a si mil ar p h ase 0 cli nic al tri al, we pr o p ose t o assess 
HII T as a met a b olic tre at me nt of E C.   
 
HII T as a t her a pe utic i nter ve nti o n f or E C.  Alt h o u g h metf or mi n s h o ws pr o mise i n t he 
treat me nt of E C, a n ot her i n n o vati ve a p pr oac h w o ul d be a n e xercise i nter ve nti o n t hat ma y 
Fi g ur e 2 . S c h e m ati c of t h e i m p a ct of o b e sit y o n t h e e n d o m etri al t u m or s i n L K B 1 fl/flp 5 3 fl/fl mi c e a n d 
r e s ulti n g  eff e ct  of  m etf or mi n  tr e at m e nt.  M etf or mi n  r e v er s e s  o b e sit y-dri v e n  u pr e g ul ati o n  of  li pi d  
bi o s y nt h e si s vi a  s h u nti n g of fr e e f att y a ci d s t o b et a -o xi d ati o n. R e d =i n cr e a s e d; Gr e e n = d e cr e a s e d  

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
6 
si milarl y i m pact E C gr o wt h t hr o u g h i m pr o ve me nts of t he meta b olic e n vir o n me nt of t he 
patie nts a n d t heir t u m ors. I n parallel, e xercise i nter ve nti o ns ma y als o affect l o n g -ter m 
car di o vasc ular  o utc o mes  i n  E C  patie nts  as  well  as  u ni q uel y  i m pr o ve  p ost -o perati ve 
o utc o mes, as h ysterect o m y is m ost ofte n t he first ste p i n treat me nt. We ha ve pre vi o usl y 
s h o w n t hat 7 0 % of E C s ur vi v ors are m oti vate d t o ma ke be ha vi oral c ha n ge f oll o wi n g t heir 
ca ncer dia g n osis, b ut ha ve a l o w s uccess rate of i ncreasi n g p h ysical acti vit y a n d l osi n g 
wei g ht wit h o ut i nter ve nti o n. 4 0 U nf ort u natel y, e xercise a n d wei g ht ma na ge me nt strate gies 
are rarel y i nte grate d i nt o E C care, m ostl y d ue t o t he lac k of res o urces a n d b ur de ns i n 
deli ver y of t hese i nter ve nti o ns. 
 
HII T has gai ne d atte nti o n as a ti me -efficie nt 
a n d  effecti ve  met h o d  f or  i m pr o vi n g  b o d y  
c o m p ositi o n
 a n d
 a u g me nti n g
 
car di ores pirat or y  healt h  i n  a  variet y  of  
p o p ulati o ns, i ncl u di n g t he o bese / o ver wei g ht 
a n d cli nical p o p ulati o ns. 4 1 , 4 2 HII T has bee n 
s h o w n  t o  sti m ulate  a  n u m ber  of  s keletal  
m uscle  a da ptati o ns  t hat  a u g me nt  fat  
o xi dati o n  a n d  o x y ge n  utilizati o n. 4 1 As  a  
res ult of e n ha nce d mit oc h o n drial bi o ge nesis 
a n d  u pre g ulate d  e nz y mes,  a  n u m ber  of  
meta b olic
 para meters
 are
 i m pr o ve d
 
f oll o wi n g  i nter val  trai ni n g.4 2 Ma n y  rece nt  
st u dies  ha ve  de m o nstrate d  t hat  s h orter  
d urati o n  i nter val  base d  e xercise  ( 3 0  sec  – 4  mi n)  ma y  be  m ore  a d va nta ge o us  t ha n  
tra diti o nal c o nti n u o us e xercise, res ulti n g i n greater i m pr o ve me nts i n car di ores pirat or y 
fit ness, s keletal m uscle o xi dati ve ca pacit y, a n d a c o nc o mita nt i m pr o ve me nt i n i ns uli n 
sensiti vit y. 4 3 -4 6 HII T has pre vi o usl y bee n s h o w n t o i ncrease s keletal m uscle mit oc h o n drial 
bi o ge nesis f oll o wi n g a si n gle sessi o n. 4 7 D ue t o t he u n derl yi n g mit oc h o n drial d ysf u ncti o n 
o bser ve d  i n  E C  t u m or  cells,  HII T  ma y  be  a n  effecti ve  strate g y  t o  ra pi dl y  i m pr o ve  
mit oc h o n drial f u ncti o n pri or t o s ur ger y. I m p orta ntl y, HII T pr o gra ms are hi g hl y a da pta ble, 
a n d ca n be s uccessf ull y i m ple me nte d at h o me wit h n o a d verse e ve nts, a n d still yiel d 
i m pactf ul p h ysi ol o gical o utc o mes. H o me -base d trai ni n g utilizi n g hi g her i nte nsit y i nter vals 
of  e xercise  ma y offer  se veral  a d va nta ges, i ncl u di n g m o dificati o ns t o fit t he nee ds of 
patie nts,  a da pta bilit y  t o  t he  h o me  setti n g,  a n d  re q uire me nt  of  less  o verall  ti me  t ha n  
tra diti o nal a p pr oac hes t o i m pr o ve fit ness. O ur preli mi nar y data ha ve de m o nstrate d t hat i n 
o ver wei g ht  a n d  o bese  a d ults  ( 2 0 -5 0  years  ol d),  3  w ks  of  HII T  res ults  i n  si g nifica nt  
i m pr o ve me nts  i n  mar kers  of  car di o vasc ular  healt h  ( 8. 7 %  i ncrease  i n  V O 2pea k), 
tri gl yceri des ( 6. 9 % decrease), H D L ( 2. 3 % i ncrease), a n d i ns uli n ( 1 5. 5 % decrease) (Fi g 
3 ).1 8 , 1 9 We ha ve als o de m o nstrate d t hat HII T is feasi ble i n pre -b o ne marr o w tra ns pla nt 
patie nts, wit h 7 0 % c o m pleti n g 6 w ks of trai ni n g pri or t o tra ns pla nt. 2 4 C ollecti vel y, t hese 
preli mi nar y data s h o w t he o verall feasi bilit y of HII T, s u p p orti n g t he hi g h a p plica bilit y of 
HII T i n a n o bese/ o ver wei g ht p o p ulati o n wit h E C.  
 
I N N O V A TI O N: ( 1) We will use a pre-o perati ve wi n d o w st u d y desi g n t o assess t he  
efficac y of HII T i n i n hi biti n g E C pr oliferati o n t hat will als o i ncl u de a n assess me nt of 
 
Fi g ure 3.  Meta b olic bl o o d mar kers bef ore ( P R E) 
a n d
 after
 ( P O S T)
 3 -w ks
 of
 HII T
 i n
 
o ver wei g ht/ o bese s u bjects.  

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
7 
p ote ntial m olec ular a n d meta b olic bi o mar kers of res p o nse t o t his t hera p y. T his st u d y is 
i n n o vati ve i n t hat it will deli neate t he effect of HII T o n e n d o metrial t u m or gr o wt h a n d 
i ntra-t u m oral i ns uli n/li pi d si g nali n g pat h wa ys as well as t he car di o meta b olic healt h of E C 
patie nts. T his will be t he first  tri al of HII T i n E C p atie nts.  
 
( 2) HII T is a well-t olerate d, ti me-efficie nt, a n d effecti ve e xercise a p pr oac h t hat ra pi dl y 
i m pr o ves  car di ores pirat or y  fit ness,  h y peri ns uli ne mia,  h y perli pi de mia,  a n d  b o d y  
c o m p ositi o n, w hic h ma y be partic ularl y usef ul i n o besit y- dri ve n E C.  
 
( 3) U ni q ue as pects of HII T i ncl u de t hat it re q uires mi ni mal ti me c o m mit me nt ( 1 0 mi n of 
e xercise 2 ti mes/ w k) a n d is tail ore d t o  i n di vi d uals base d o n baseli ne a bilities (f oll o wi n g a 
well -de vel o pe d pr ot oc ol), ma ki n g it a pr o gra m li kel y t o be s ustai na ble a n d t olera ble f or 
w o me n wit h E C.  
 
( 4) HII T is a maj or de part ure fr o m t he wa y p h ysical acti vit y is rec o m me n de d f or E C 
patie nts. I nitial disc o veries fr o m t his st u d y c o ul d facilitate a c ha n ge i n pre - a n d p ost -
o perati ve a p pr oac hes f or t he ma na ge me nt of E C.  
1. 3  
P ur p ose a n d R ati o n ale 
T o date, t he use of HII T i n E C patie nts has n ot bee n pre vi o usl y e val uate d, i ncl u di n g t he 
effects of HII T o n car di o meta b olic healt h, p ost -o perati ve o utc o mes, or as a p ote ntial n o vel 
treat me nt strate g y f or t his o besit y-dri ve n disease. T h us, we will e val uate t he a nti-ca ncer 
effects of HII T i n a pre -o perati ve wi n d o w st u d y i n o bese E C patie nts. We h y p ot hesize t hat 
HII T  will i m pr o ve t he meta b olic e n vir o n me nt a n d re d uce t u m or gr o wt h, as reflecte d i n 
b ot h  m olec ular  a n d  meta b olic  bi o mar kers,  s pecificall y  o besit y / o ver wei g ht,  i ns uli n  
resista nce,  V O2pea k,  u pre g ulati o n  of  i ns uli n/I G F -1  si g nali n g,  a n d  fatt y  aci d/li pi d  
bi os y nt hesis. 
 
If  t he  HII T  i nter ve nti o n  is  efficaci o us  i n  i n hi biti n g  t u m or  gr o wt h/ pr oliferati o n  a n d  
i m pr o vi n g t he meta b olic e n vir o n me nt of o bese / o ver wei g ht w o me n, f ut ure st u dies w o ul d 
e x pl ore its use as ( 1) a n a dj u nct t o tra diti o nal ra diati o n/c he m ot hera p y treat me nt, ( 2) a n 
o besit y/ o ver wei g ht ma na ge me nt strate g y i n E C s ur vi v ors, a n d ( 3) a pre - o perati ve strate g y 
t o o pti mize s ur gical o utc o mes. T hese eff orts ha ve great p ote ntial t o brea k t he o besit y-E C 
li n k, ulti matel y i m pr o vi n g o utc o mes f or E C patie nts. 
2. 0  
S T U D Y O B J E C TI V E S   
2. 1  
Pri m ar y O bjecti ve  
2. 1. 1  Deter mi ne t he a nti -pr oliferati ve effect of HII T o n t he e n d o metri u m of 
w o me n wit h E C b y c o m pari n g e n d o metrial bi o ps y sa m ples of patie nts 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
9 
4. 0  
P A TI E N T E LI GI BI LI T Y  
4. 1  
I ncl usi o n Criteri a 
4. 1. 1  P atie nts wit h a dia g n osis of e n d o metri oi d hist ol o g y ca ncer  or c o m ple x 
e n d o metrial h y per plasia w h o  are t o u n der g o h ysterect o m y a n d sta gi n g 
4. 1. 2  Bet wee n 3 0- 7 5 years ol d  
4. 1. 3  B o d y mass i n de x of 2 5- 5 5 k g/ m 2  
4. 1. 4  Pres u me d cli nicall y earl y sta ge disease  ( disease c o nfi ne d t o uter us o nl y) 
4. 1. 5  Ha ve access t o a S mart P h o ne  
4. 1. 6  Ha ve access t o e mail  
4. 1. 7  A gree t o visit t he e xercise a n d s p ort scie nce la b orat or y pri or t o s ur ger y  f or 
baseli ne testi n g if e nr oll me nt pr oce d ures ca n n ot be d o ne o n t he sa me da y.  
4. 1. 8  A gree t o visit cli nic 2 t o 4 wee ks after s ur ger y f or S O C f oll o w - u p a n d p ost 
s ur ger y visit, or willi n g t o ret ur n t o e xercise a n d s p ort scie nce la b orat or y 2 
t o 4 wee ks p ost -s ur ger y  
4. 2  
E xcl usi o n Criteri a  
4. 2. 1  M eets A merica n C olle ge of S p orts Me dici ne G ui deli nes f or p h ysical a cti vit y 
( 1 5 0 mi n utes / wee k) 
4. 2. 2  C urre ntl y d oi n g HII T 
4. 2. 3  H os pitalizati o n f or a str o ke, heart attac k, or heart fail ure, or ha d s ur ger y f or 
bl oc ke d arteries i n t he past 3 m o nt hs  
4. 2. 4  Acti ve dia g n osis of ps yc h osis or c urre nt u nc o ntr olle d s u bsta nce a b use 
dis or der 
4. 2. 5  I ns uli n- de pe n de nt dia betes 
4. 2. 6  C urre ntl y i n a n ot her E C i nter ve nti o n 
4. 2. 7  Se vere de me ntia or ot her me m or y l oss c o n diti o n 
4. 2. 8  Se vere me ntal healt h dis or der 
4. 2. 9  Se verel y i m paire d heari n g or s peec h  
4. 2. 1 0  I na bilit y t o s pea k E n glis h 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 0 
4. 2. 1 1  M usc ul os keletal or ne ur o m usc ular c o n diti o n t hat li mits p h ysical acti vit y  
4. 2. 1 2  A n y c o n diti o n, i n t he o pi ni o n of t he i n vesti gat ors, w hic h w o ul d pr o hi bit safe 
partici pati o n.  
 
 
5. 0  
S T U D Y P L A N  
5. 1  
Sc he m a  
 
1After c o nse nt, st u d y c o or di nat or ca n re q uest arc hi val e n d o metrial bi o ps y 
2Details of testi n g meas ure me nts are a vaila ble i n t he Ti me a n d E ve nts Ta ble . T he baseli ne  
testi n g visit ca n occ ur eit her at t he cli nic visit or t he partici pa nt ca n ret ur n t o t he e xercise 
p h ysi ol o g y la b i n Fetzer Hall.  S u bjects will recei ve i nstr ucti o n o n t heir pers o nalize d HII T 
i nter ve nti o n. T he pers o nalize d HII T i nter ve nti o n will be a dj uste d s o t he partici pa nts ca n 
c o m plete 4 - 8 HII T sessi o ns, wit h 2 4 h o urs of rest ti me, pri or t o s ur ger y.   
3S ur ger y will ta ke place per S O C  a n d will n ot be dictate d b y t he st u d y. E n d o metrial bi o ps y 
will ta ke place after se dati o n b y s ur ge o n, h ysterect o m y s peci me n will be re m o ve d as part 
of S O C testi n g  
4P ost -s ur gical testi n g a n d S O C p ost-s ur gical visit will ta ke place 2-4 wee ks after S O C 
s ur ger y. T he V O2 pea k testi n g is o pti o nal at t his visit.  
 
T his pr oject is a p hase 0 cli nical trial i n w hic h all patie nts w h o u n der g o s ur gical sta gi n g 
f or E C will partici pate i n t he HII T i nter ve nti o n gr o u p t hat will c o m plete 4 t o 8 sessi o ns of 
h o me- base d HII T pri or t o h ysterect o m y . T he effect of HII T o n pr oliferati o n a n d a p o pt osis 
will be c o m pare d bet wee n pre -i nter ve nti o n e n d o metrial bi o psies a n d p ost-i nter ve nti o n 
e n d o metrial  tiss ue/ h ysterect o m y  s peci me ns.  E x pressi o n  of  re g ulat ors  of  i ns uli n/I G F -
1/fatt y aci d/li pi d s y nt hesis pat h wa ys will be c o m pare d pre - a n d p ost - HII T i nter ve nti o n i n 
E Cs.  
 
Base d  o n  o ur  preli mi nar y  data,  HII T  s h o ul d  ra pi dl y  lea d  t o  i m pr o ve me nts  i n  
car di o meta b olic healt h i n E C patie nts wit hi n  4 t o 8 sessi o ns (a p pr o xi matel y 2 -3 w ks of 
HII T) . T o assess t he be nefits of HII T i n E C, we pr o p ose a c o m pre he nsi ve assess me nt of 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 1 
car di o vasc ular a n d meta b olic bi o mar kers of HII T res p o nse a m o n g w o me n e nr olle d i n t his 
p hase 0 st u d y t hat i ncl u des tra diti o nal ( V O 2pea k, B MI, H g B A 1 C ) a n d n o vel ( meta b ol o mic 
pr ofili n g)  assess me nts  of  o besit y / o ver wei g ht,  i ns uli n  resista nce,  a n d  car di ores pirat or y  
fit ness.  
 
We pre dict t hat t he HII T i nter ve nti o n will res ult i n decrease d pr oliferati o n a n d i ncrease d 
a p o pt osis w he n c o m pari n g t u m ors pre- a n d p ost -HII T . Base d o n o ur e x perie nce wit h t his 
HII T pr ot oc ol  i n vari o us s pecial p o p ulati o ns, E C patie nts are a ntici pate d t o de m o nstrate 
g o o d c o m plia nce a n d re p ort s ufficie nt t olera bilit y t o t he i nter ve nti o n . I n a d diti o n, we 
a ntici pate  t hat  h y peracti vati o n  of  t he  i ns uli n/I G F -1/ A M P K/ m T O R  pat h wa y  a n d  
sti m ulati o n of fatt y aci d/li pi d bi os y nt hetic pat h wa ys will be f o u n d  i n t he e n d o metrial 
t u m ors pre -HII T, a n d HII T t hera p y will res ult i n i n hi biti o n of d o w nstrea m tar gets of t hese 
meta b olic  pat h wa ys . M ore o ver,  we  e x pect  B MI,  waist -t o-hi p  rati o,   a n d H g B A 1 C t o 
decrease.  Ele vate d pre -treat me nt ser u m le vels of fatt y aci ds a n d gl yc oli pi ds s h o ul d be 
f o u n d i n t h ose o bese/ o ver wei g htw o me n w h o best res p o n d t o HII T, i n dicati ve of a m ore 
i ns uli n-resista nt meta b olic p he n ot y pe i n HII T-res p o n ders. T his i ns uli n resista nt meta b olic 
pr ofile s h o ul d i m pr o ve wit h HII T treat me nt.  
5. 2  
D ur ati o n of St u d y  
T his st u d y will last a p pr o xi matel y 1 0 wee ks t otal. D ur i n g a S O C visit, s u bjects will be 
c o nse nte d pri or t o h ysterect o m y. HII T e xercise will be a h o me -base d pr o gra m i n t he 
i nter ve ni n g  wee ks  bet wee n  S O C  cli nic  visit  a n d  S O C  s ur ger y.  S u bjects  ca n  u n der g o  
baseli ne  testi n g  o n  t he  da y  of  t heir  S O C  a p p oi nt me nt  i n  t he  N ort h  Car oli na  Ca ncer  
H os pital, or ret ur n t o a n e xercise p h ysi ol o g y la b i n Fetzer Hall after t heir c o nse nt visit . All 
s u bjects will be directe d t o c o m plete 4 t o 8 sessi o ns of t he at h o me e xercise pr o g ra m, l o g 
e xercise i n st u d y we bsite, a n d s y nc Fit bit data. At S O C s ur ger y, e n d o metrial bi o ps y a n d 
h ysterect o m y s peci me ns will be c ollecte d. At a S O C p ost -o perati ve a p p oi nt me nt, 2 t o 4 
wee ks p ost -s ur ger y, p ost-testi n g will occ ur f or all s u bjects .  
5. 3  
St u d y Det ails  
O bese  a n d  o ver wei g ht  ( B MI ≥2 5- 5 5  k g/ m 2)  w o me n  wit h  t y pe  I  E C  (e n d o metri oi d  
hist ol o g y) a n d c o m ple x at y pical h y per plasia ( C A H) will be recr uite d fr o m t he G y nec ol o gic 
O nc ol o g y cli nic at U N C -C H. T he Di visi o n of G y nec ol o gic O nc ol o g y at U N C -C H of w hic h 
Dr. Bae -J u m p is a me m ber has 1 0 cli nicall y acti ve g y nec ol o gic o nc ol o gists w h o care f or 
a n d treat a b o ut 2 5 0 w o me n per year wit h ne wl y dia g n ose d E C. O besit y rates a m o n g t he 
E C patie nts treate d at U N C are a p pr o xi matel y 6 2 %, wit h m ost of re mai ni n g w o me n bei n g 
o ver wei g ht. T h us, recr uit me nt t o t his cli nical trial s h o ul d be s uccessf ul i n 1 2 -1 8 m o nt hs. 
O ur pre vi o us re p orte d p hase 0 cli nical trial of metf or mi n easil y recr uite d 2 0 patie nts i n 1 2 
m o nt hs.  
 
W o me n wit h e n d o metrial ca ncer or c o m ple x at y pical h y per plasia are us uall y dia g n ose d b y 
e n d o metrial bi o ps y eit her o btai ne d i n t he office usi n g a pi pelle de vice or i n t he o perati n g 
r o o m b y dilati o n a n d c uretta ge ( D & C). O ur sta n dar d practice f or o utsi de e n d o metrial 
bi o psies is t o o btai n t he bl oc ks a n d ha ve t he bi o psies re vie we d b y t he pat h ol o gists at U N C -
C H  f or  c o nfir mati o n  of  dia g n osis.  T heref ore,  all  pre -o perati ve  e n d o metrial  bi o psies,  

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 2 
w het her o btai ne d at U N C -C H or at a referri n g i nstit uti o n, will be a vaila ble f or a nal ysis i n 
t his st u d y. T he preferre d treat me nt ma na ge me nt f or w o me n wit h E C  a n d C A H is s ur gical 
sta gi n g, w hic h i ncl u des t otal h ysterect o m y, bilateral sal pi n g o- o o p h orect o m y, a n d l y m p h 
n o de assess me nt . O nce e nr olle d o n t his pre-o perati ve wi n d o w st u d y, patie nts will u n der g o 
baseli ne p h ysi ol o gical testi n g t o deter mi ne pea k car di ores pirat or y fit ness ( V O2pea k) a n d 
ma xi m u m heart rate ( H R). T his p h ysi ol o gical testi n g will t he n be use d t o c o nstr uct a n 
i n di vi d ualize d HII T i nter ve nti o n, c o nsisti n g of 4 t o 8  at-h o me trai ni n g  sessi o ns, w hic h will 
be c o m plete d pri or t o s ur gical sta gi n g. T he effect of HII T  will be c o m pare d bet wee n pre -
treat me nt  e n d o metrial  bi o psies  a n d  t heir  c orres p o n di n g  p ost- treat me nt  h ysterect o m y  
s peci me ns, wit h pr oliferati o n (i.e. Ki -6 7 stai ni n g) as t he pri mar y e n d p oi nt of i nterest.  I n 
a d diti o n, e nr olle d patie nts will u n der g o re peat e n d o metrial bi o ps y p ost -HII T i nter ve nti o n 
at t he ti me of t heir s ur gical sta gi n g ; t his is bei n g d o ne t o e ns ure t hat we are acc uratel y 
e val uati n g t he effects of t he HII T i nter ve nti o n o n t he e n d o metrial t u m ors t he msel ves a n d 
n ot differe nces  f o u n d d ue t o t he t y pe of s peci me n e xa mi ne d (i.e. e n d o metrial bi o ps y 
s peci me n o btai ne d i n cli nic vers us h ysterect o m y s peci me n o btai ne d at t he ti me of s ur ger y). 
T h us,  we  pla n  t o  c o m pare  pre -treat me nt  e n d o metrial  bi o psies  t o  b ot h  p ost-treat me nt 
e n d o metrial bi o psies a n d h ysterect o m y s peci me ns. Efficac y, t olera bilit y, a d here nce, a n d 
e xercise  e nj o y me nt  will  be  assesse d  bef ore   an d  after  t he  i nter ve nti o n  as  sec o n dar y  
o utc o mes. All w o me n e nr olle d will recei ve a $ 1 0 0 gift car d f or partici pati n g i n t his st u d y.  
 
P ote ntial pr os pecti ve s u bjects will be i de ntifie d i n t he f oll o wi n g wa ys : st u d y staff ma y 
re vie w t he me dical rec or ds of patie nts liste d o n t he cli nic sc he d ule t o deter mi ne if a patie nt 
meets  eli gi bilit y  criteria  f or  t his  researc h  st u d y  pri or  t o  t he  patie nt  meeti n g  wit h  t he  
p h ysicia n. Alter nati vel y, patie nts ma y be referre d t o t he  researc h tea m b y t heir U N C 
p h ysicia n, o utsi de p h ysicia n, self-refer or ma y be disc usse d at disease s pecific c o nfere nces. 
I n all cases, a me m ber of t he researc h tea m will re vie w t he me dical rec or d t o see if t he 
patie nt meets basic eli gi bilit y criteria. T he patie nt’s p h ysicia n will prese nt o pti o ns t o t he 
patie nt a n d, if t he patie nt is i ntereste d, t he researc h st u d y c o or di nat or will c o nse nt t he 
patie nt a n d HI P A A a ut h orizati o n will be s o u g ht. 
 
P ote ntial pr os pecti ve s u bjects will be see n i n pri vate cli nic r o o ms b y t he p h ysicia n a n d t he 
tea m me m ber t hat will be i nf or mi n g a n d c o nse nti n g t he s u bject. T he p ur p ose of t his st u d y 
a n d t he ris ks a n d si de effects of HII T t hera p y will be a d dresse d i n t he c o nse nt a n d ver ball y 
e x plai ne d t o t he patie nts. T he p ur p ose of ser u m a n d tiss ue c ollecti o n a n d t he ris k t o t hese 
pr oce d ures will be ver ball y e x plai ne d t o t he patie nts. I nf or me d c o nse nt will be o btai ne d 
fr o m t he patie nts b y t he st u d y c o or di nat or.  
 
I n or der t o e ns ure rete nti o n of s u bjects d uri n g t he pr o p ose d HII T i nter ve nti o n, s u bjects will 
be c o ntacte d wee kl y b y st u d y staff. T hese sc he d ule d calls or te xt messa ges  will e ns ure t hat 
t he s u bjects ha ve n o q uesti o ns a b o ut t he i nter ve nti o n, t hat t he y are t olerati n g HII T wit h o ut 
a n y si g nifica nt a d verse effects , t hat t he y are s y nci n g t heir Fit bits, a n d t o ma ke s ure t he y 
are l o g gi n g i n t heir e xercises o n t he we bsite e ver y ti me t he y w or k o ut. F urt her m ore, 
s u bjects will be pr o vi de d m ulti ple c o ntact n u m bers f or st u d y pers o n nel t o c o ntact wit h 
q uesti o ns or c o ncer ns  a b o ut t he HII T i nter ve nti o n ( da y or ni g ht).  
 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 4 
5. 3. 1  Str uct ure d I nter vie w:  
A str uct ure d o ne - o n-o ne i nter vie w will occ ur wit h partici pa nts after c o m pleti o n of 
t he HII T pr o gra m. T he i nter vie w will be use d t o lear n a b o ut barriers a n d c o ncer ns 
t he y e x perie nce d wit h re gar d t o t he c urre nt trai ni n g pr ot oc ol; prefere nce of e xercise 
m o de a n d i nstr ucti o n; a n d o pi ni o ns o n w hat i nf or mati o n partici pa nts w o ul d fi n d 
hel pf ul t o i m pr o ve t he at -h o me trai ni n g e x perie nce. W hile we d o n ot i nte n d t o 
f or mall y a nal yze t he i nter vie w res p o nses, we d o a ntici pate t hat t he y will be usef ul 
f or refi ni n g o ur i nter ve nti o n pr o gra m f or f ut ure trials.   
5. 3. 2  T oler a bilit y,  Fe asi bilit y,  C o m pli a nce,  a n d  A d here nce:  A d here nce a n d 
t olera bilit y
 will
 be 
e val uate d
 base d
 o n
 n u m ber
 of
 sessi o ns
 
atte n de d/c o m plete d,  m o dificati o ns,  s uc h  as  c ha n ge  i n  m o de,  n u m ber  of  
trai ni n g  da ys  per  wee k,  a n d  rec o ver y  da ys  nee de d  bet wee n  sessi o ns  t o  
c o m plete trai ni n g.  T he p h ysical acti vit y e nj o y me nt scale 4 9 will be gi ve n t o 
assess partici pa nt e nj o y me nt of e xercise d uri n g t he baseli ne a n d p ost -s ur gical 
testi n g visit. 
5. 3. 3  T o deter mi ne if HII T decre ases pr olifer ati o n a n d i n d uces a p o pt osis i n 
t he e n d o metri al t u m ors, tiss ue micr oarra ys ( T MAs) will be c o nstr ucte d a n d 
i m m u n o hist oc he mical  (I H C)a nal ysis  perf or me d  t o  assess  Ki -6 7  stai ni n g  
( mar ker of pr oliferati o n) a n d cas pase-3 e x pressi o n ( mar ker of a p o pt osis). T he 
perce nta ge of Ki -6 7 p ositi ve cells, ter me d t he Ki -6 7 i n de x, will be calc ulate d 
pre- a n d p ost -treat me nt. A p o pt osis will be e val uate d b y c ha n ges i n acti vate d 
cas pase-3 e x pressi o n. I n di vi d ual sli des will be di gitize d a n d a nal yz e d usi n g 
t he A peri o Sca n Sc o pe ( A peri o Tec h n ol o gies, Vista, C A). T his w or k will be 
perf or me d wit h t he e x pertise of t he U N C -C H Tra nslati o na l Pat h ol o g y La b 
( T P L). 
5. 3. 4  T o  test  if  HII T  alter ati o ns  i n hi bits  d o w nstre a m  t ar gets  of  t he  
i ns uli n/I G F-1/ A M P K/ m T O R si g n ali n g p at h w a y , I H C a nal yses of t he E Cs 
will be perf or me d t o deter mi ne e x pressi o n of ke y tar gets of t he i ns uli n/I G F -
1/ m T O R pat h wa y pre - a n d p ost -i nter ve nti o n, i ncl u di n g p-I R S-1, p -I G F 1 R, p-
A M P K, p -m T O R, p -A kt, p - S 6, a n d p-4 E B P - 1.  
5. 3. 5  T o  assess  i m pr o ve me nt  i n  c ar di ores pir at or y  fit ness  wit h  t he  HII T  
i nter ve nti o n, pea k o x y ge n c o ns u m pti o n ( V O 2pea k) will be meas ure d pre - 
a n d p ost-HII T . V O 2pea k is t he g ol d sta n dar d f or i de ntif yi n g fit ness le vel a n d 
e val uati n g car di o vasc ular effects. T his test will be use d t o esta blis h i n di vi d ual 
trai ni n g  i nte nsit y.  All  partici pa nts  will  perf or m  a  ra m p  base d  c ycli n g  
er g o meter  test  wit h  res pirat or y  gases  c o nti n u o usl y  m o nit ore d  wit h  o pe n -
circ uit s pir o metr y usi n g a cali brate d meta b olic cart ( Tr ue O ne 2 4 0 0 ®, Par v o -
Me dics, I nc., Pr o v o, U T). Data will be a vera ge d o ver 1 5 -sec o n d i nter vals, 
wit h t he hi g hest 1 5 -sec o x y ge n c o ns u m pti o n, mi n ute ve ntilati o n, a n d heart 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 5 
rate rec or de d as t he pea k o x y ge n c o ns u m pti o n ( V O2pea k), ti me t o e x ha usti o n, 
a n d ma xi m u m heart rate, res pecti vel y .  
5. 3. 6  T o c orrel ate i m pr o ve me nt i n o besit y / o ver wei g ht a n d i ns uli n resist a nce 
wit h  res p o nse  t o  HII T  tre at me nt,  B MI,  waist -t o-hi p  rati o,  b o d y  
c o m p ositi o n, H g B A 1 C, a n d dia betes stat us will be d oc u me nte d pre- a n d p ost -
i nter ve nti o n. H g B A 1 C will be o btai ne d pre -i nter ve nti o n o nl y f or all s u bjects. 
B o d y  c o m p ositi o n  a n d  visceral  fat  will  be  deter mi ne d  usi n g  p orta ble  
ultras o n o gra p h y as pre vi o usl y vali date d b y o ur gr o u p. 4 8 T he H o me ostasis 
M o del Assess me nt Sc ore [fasti n g i ns uli n ( micr o u nits/ ml) X fasti n g gl uc ose 
( m m ol/ 2 2. 5)], a meas ure me nt of i ns uli n resista nce, will be calc ulate d pri or t o 
a n d after t he i nter ve nti o n.  
5. 3. 7  T o test if t he met a b olic pr ofiles of bl o o d a n d t u m or c orres p o n d t o HII T 
res p o nsi ve ness , u ntar gete d  meta b ol o mic/li pi d o mic  a nal ysis  will   be 
perf or me d o n ( 1) bl o o d pre - a n d p ost - HII T a n d ( 2) t u m or pre - a n d p ost -HII T 
i nter ve nti o n.  Meta b olic  pr ofiles  of  bl o o d  a n d  t u m or  will  be  c o m pare d  
bet wee n  pre - a n d  p ost -i nter ve nti o n  a n d  t he  HII T gr o u p.  U ntar gete d  
meta b ol o mic  a n d  li pi d o mic  pr ofili n g  will  be  perf or me d  usi n g  Ultra hi g h  
Perf or ma nce Li q ui d C hr o mat o gra p h y -Ta n de m Mass S pectr osc o p y ( U P L C -
M S -M S) a n d Differe ntial M o bi lit y S pectr osc o p y-M S -M S ( D M S -M S -M S).  
Uri ne is als o bei n g ba n ke d pre - a n d p ost -HII T  i nter ve nti o n f or p ote ntial f ut ure 
meta b ol o mic/li pi d o mic a nal ysis.   
5. 3. 8  Re m o v al of P atie nts fr o m Pr ot oc ol - Patie nts will be re m o ve d fr o m t he 
st u d y if t he y i n dicate t hat t he y n o l o n ger wis h t o partici pate. Patie nts will be 
re m o ve d fr o m st u d y w he n a n y of t he e xcl usi o n criteria liste d i n eli gi bilit y 
criteria a p pl y.  
 
 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 6 
 
6. 0  
TI M E A N D E V E N T S T A B L E  
6. 1  
Ti me a n d E ve nts T a ble   
        
 
  
P r e -o p o r 
N e w vi sit  
B a s eli n e T e sti n g Vi sit 1 
At h o m e 
i nt e r v e nti o n2  
S u r g e r y  
P o st S u r gi c al T e sti n g 
Vi sit  
S O C 
a p p oi nt m e nt  
D uri n g S O C a p p oi nt m e nt 
or at A p pli e d P h ysi ol o g y 
L a b  
4 t o 8 S essi o ns  
As sc h e d ul e d p er 
S O C  
S O C a p p oi nt m e nt                
2 t o 4 w ks p ost-s ur g er y 
C o ns e nt  
X  
  
  
  
  
Eli gi bilit y Ass ess m e nt  
X  
  
  
  
  
Arc hi v al Tiss u e R etri e v al  
X  
  
  
  
  
Uri n e S a m pl e  
X  
  
  
X   
 
Bl o o d S a m pl e  
X  
  
  
X   
 
E nr oll m e nt  
 
X  
 
 
 
W aist a n d Hi p M e as ur e m e nts  
  
X  
  
  
X  
V O 2 p e a k  
  
X  
  
  
X 3  
B o d y M ass ultr as o u n d  
  
X  
  
  
X  
Visc er al f at ultr as o u n d  
  
X  
  
  
X  
Fit bit Fitti n g  
  
X  
  
  
 
I ntr o d ucti o n t o Fit n ess Pl a n 
  
X  
  
  
 
E x ercis e E nj o y m e nt Sc al e  
  
X  
 
  
X  
C o m pl eti o n of Fit n ess pl a n  
  
  
X  
  
  
S y nc Fit bit d at a  
  
  
X  
  
  
P artici p a nt W e bsit e L o gi n  
  
  
X  
  
  
E n d o m etri al bi o ps y  
  
  
  
X  
  
H yst er ect o m y S p eci m e n  
  
  
  
X  
  
Cl osi n g i nt er vi e w  
  
  
  
  
X  

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 7 
1Baseli ne visit ca n occ ur d uri n g S O C visit at ti me of c o nse nt a n d e nr oll me nt, or t he s u bject 
will ha ve t he o pti o n t o ret ur n t o ca m p us a n d perf or m visit at t he e xercise p h ysi ol o g y la b at 
Fetzer Hall. If s u bject c o m mits t o ret ur n f or baseli ne visit, b ut fails  t o ret ur n, t he s u bject 
will n ot be e nr olle d o n t he st u d y, a n d a ne w s u bject ca n be e nr olle d i n t hat s p ot.  
2A t h o me i nter ve nti o n be gi ns wit h first HII T sessi o n . D uri n g t his ti me, s u bject will be 
calle d or te xte d b y t he st u d y tea m t o re mi n d t he s u bject t o l o gi n t o we bsite, s y nc data, a n d 
tr o u bles h o ot tec h nical diffic ulties.  
3T he V O 2 pea k testi n g is o pti o nal at t his visit.  
 
7. 0  
E X P E C T E D RI S K S A N D U N A N TI CI P A T E D P R O B L E M S  
7. 1  
E x pecte d Ris ks:  
7. 1. 1  HII T:  
T he ris ks of s h ort -ter m HII T treat me nt are mi ni mal f or t hese patie nts. Mil d m uscle 
s ore ness ass ociate d wit h be gi n ni n g a n y ne w e xercise pr o gra m is p ossi ble. T he 
e xercise pr o gra m will be i n di vi d ualize d f or eac h patie nt, re d uci n g t he c ha nces of 
s ore ness.  Wit h a n y  e xercise,  t here  is  a  s mall  ris k  f or  s y nc o pe,  as  well  a  
car di o vasc ular e ve nt. Beca use of t he s h ort nat ure of t he hi g h i nte nsit y b o uts, ris k 
of s y nc o pe is re d uce d; rest peri o ds als o all o w f or greater bl o o d fl o w, re d uci n g ris k 
of s y nc o pe. Patie nts at ris k f or a n y s uc h car di o vasc ular e ve nt will be e xcl u de d. 
T hese t y pes of a d verse e ve nts as a res ult of HII T, are e xtre mel y rare.  
7. 1. 2  Bl o o d Dr a w s & Uri ne C ollecti o n:  
Patie nts  will  nee d  t o  u n der g o  bl o o d  dra ws  at  t he  be gi n ni n g  a n d  e n d  of  HII T  
treat me nt. T he sec o n d bl o o d dra w will be d o ne u n der ge neral a nest hesia at t he ti me 
of  s ur gical  sta gi n g.  Ris ks  t o  bl o o d  dra ws  are  mi ni mal  a n d  i ncl u de  pai n  a n d  
disc o mf ort, i nfecti o n a n d he mat o ma. T h us, t hese w o me n ha ve little i ncrease d ris k 
sec o n dar y  t o  bl o o d  dra ws.  Bl o o d  will  be  o btai ne d  b y  p hle b ot o mists or  b y  
a nest hesi ol o gists/ n urse a nest hetists i n t he o perati n g r o o m. Patie nts will nee d t o 
u n der g o uri ne c ollecti o n at t he be gi n ni n g a n d e n d of HII T treat me nt. Ris ks t o uri ne 
c ollecti o n are mi ni mal.  
7. 1. 3  E n d o metri al bi o ps y : 
E n d o metrial  Bi o ps y  is  a  c o m m o n  g y nec ol o gic  pr oce d ure  perf or me d  i n  t he  
o ut patie nt setti n g. T he ris ks of re peat e n d o metrial bi o ps y at t he ti me of s ur ger y are 
mi ni mal f or t hese patie nts, gi ve n t hat t he y will be u n der ge neral a nest hesia a n d are 
t o u n der g o i m mediate h ysterect o m y. E n d o metrial bi o ps y will be perf or me d usi n g 
a sta n dar d pi pelle de vice, r o uti nel y use d i n o ur o ut patie nt cli nic. T he m ost c o m m o n 
ris ks t o t he patie nt f or t his pr oce d ure are cra m pi n g a n d a vas o-va gal res p o nse. Ot her 
m uc h rarer ris ks i ncl u d e uteri ne blee di n g ( us uall y d ue t o pre vi o usl y u n dia g n ose d 
c oa g ul o pat hies), uteri ne perf orati o n ( 0. 1 – 1. 3 %), pel vic i nfecti o n a n d bactere mia 
( < 1 %). T hese patie nts will alrea d y be fa miliar wit h t he pr oce d ure of e n d o metrial 
 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 8 
7. 1. 4  Bre ac h of C o nfi de nti alit y:  
Researc h data will be st ore d i n a sec ure, pass w or d -pr otecte d ser ver accessi ble 
s olel y t o trai ne d st u d y staff. All data a n d s peci me ns st ore d i n t he researc h data base 
will be gi ve n a u ni q ue researc h I D t hat will be bli n de d t o i n vesti gat ors wit h t he 
e xce pti o n of t he St u d y C o or di nat or, w h o will f u ncti o n as a n h o nest br o ker. T he 
St u d y C o or di nat or will be trai ne d a n d certifie d i n researc h et hics a n d HI P A A te nets.   
7. 2  
Defi niti o n  
As defi ne d b y U N C’s I R B, u na ntici pate d pr o ble ms  i n v ol vi n g ris ks t o st u d y s u bjects 
or ot hers ( U PI R S O) refers t o a n y i nci de nt, e x perie nce, or o utc o me t hat: 
•  
Is u ne x pecte d (i n ter ms of nat ure, se verit y, or fre q ue nc y) gi ve n (a) t he 
researc h pr oce d ures t hat are descri be d i n t he pr ot oc ol-relate d d oc u me nts, 
s uc h  as  t he  I R B-a p pr o ve d  researc h  pr ot oc ol  a n d  i nf or me d  c o nse nt  
d oc u me nt;  a n d  ( b)  t he  c haracteristics  of  t he  s u bject  p o p ulati o n  bei n g  
st u die d; 
•  
Is relate d or p ossi bl y relate d t o a s u bject’s partici pati o n i n t he researc h; a n d  
•  
S u g gests t hat t he researc h places s u bjects or ot hers at a greater ris k of har m 
(i ncl u di n g p h ysical, ps yc h ol o gical, ec o n o mic, or s ocial har m) relate d t o t he 
researc h t ha n was pre vi o usl y k n o w n or rec o g nize d. 
7. 3  
Re p orti n g  
A n y U PI R S O  t hat occ urs d uri n g t he c o n d uct of t his st u d y a n d t hat meets all t hree 
criteria liste d i n 9. 4. 3 m ust be re p orte d t o t he U N C I R B usi n g t he I R B’s we b -base d 
re p orti n g s yste m.   
7. 4  
D at a a n d S afet y M o nit ori n g Pl a n 
T he Pri nci pal I n vesti gat or will pr o vi de c o nti n u o us m o nit ori n g of patie nt safet y i n 
t his trial wit h peri o dic re p orti n g t o t he Data a n d Safet y M o nit ori n g C o m mittee 
( D S M C) as re q uire d.  
Meeti n gs/telec o nfere nces will be hel d at a fre q ue nc y de pe n de nt o n st u d y accr ual, 
a n d i n c o ns ultati o n wit h t he st u d y Bi ostatisticia n.  At t hese meeti n gs, t he researc h 
tea m will disc uss all iss ues rele va nt t o st u d y pr o gress, i ncl u di n g e nr oll me nt, safet y, 
re gulat or y, data c ollecti o n, etc. a n d t he tea m will pr o d uce s u m maries or mi n utes of 
t hese meeti n gs. T hese s u m maries will be a vaila ble f or i ns pecti o n w he n re q ueste d 
b y a n y of t he re g ulat or y b o dies c har ge d wit h t he safet y of h u ma n s u bjects a n d t he 
i nte grit y of data  i ncl u di n g, b ut  n ot li mite d t o, t he o versi g ht  Office of H u ma n 
Researc h  Et hics  ( O H R E)  Bi o me dical  I R B,  t he  O nc ol o g y  Pr ot oc ol  Re vie w  
C o m mittee  ( P R C)  or  t he  N ort h  Car oli na  Tra C S  I nstit ute  Data  a n d  Safet y  
M o nit ori n g B oar d ( D S M B).  
8. 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
8. 1  
St u d y Desi g n  
T his pr oject was ori gi nall y desi g ne d as a ra n d o mize d, pr os pecti ve, p hase 0 cli nical 
trial i n w hic h half of t he patie nts w h o u n der g o s ur gical sta gi n g f or E C will be 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
1 9 
ra n d o mize d t o a HII T i nter ve nti o n gr o u p recei vi n g 4 t o 8 sessi o n of h o me-base d 
HII T (a p pr o xi matel y 2 -3 w ks of HII T), a n d t he ot her half recei vi n g sta n dar d of care 
treat me nt (i.e. n o e xercise i nter ve nti o n), pri or t o h ysterect o m y. T he effect of HII T 
o n  pr oliferati o n  a n d  a p o pt osis  will  be  c o m pare d  bet wee n  pre -i nter ve nti o n 
e n d o metrial  bi o psies  a n d  p ost -i nter ve nti o n  h ysterect o m y/e n d o metrial  bi o ps y  
s peci me ns.  E x pressi o n  of  re g ulat ors  of  i ns uli n/I G F-1/fatt y  aci d/li pi d  s y nt hesis  
pat h wa ys will be c o m pare d pre- a n d post- HII T i nter ve nti o n i n E Cs.   
 
Sl o w accr ual d ue t o  C O VI D -1 9 pa n de mic pre ve nt us fr o m c o m pleti n g t he st u d y i n 
ti me. As C O VI D -1 9 pa n de mic is still o n -g oi n g, we deci de d t o c ha n ge t he st u d y 
desi g n t o a pr os pecti ve si n gle ar m st u d y wit h all ne w accr uals assi g ne d t o t he HII T 
ar m, till we ha ve a t otal of 2 0 e val ua ble (i.e., wit h c o m plete pre - a n d p ost -HII T 
data)  patie nts i n t he HII T ar m .   
8. 2  
S a m ple Size a n d Accr u al  
T he ori gi n al s a m ple size descri pti o n:  Base d  o n data fr o m o ur pre vi o us st u dies, 1 1 , 
5 0 we  e x pect  a  differe nce  of  1 3 %  ( S D  =  1 4 %)  f or  pre -p ost  c ha n ge  i n  Ki - 6 7 
pr oliferati o n, a n d a differe nce of 1. 7 ( S D = 1. 8) ml· k g· mi n −1  f or pre-p ost c ha n ge i n 
V O 2pea k, a n d attriti o n n ot greater t ha n 1 0 %. U n der t hese ass u m pti o ns, ha vi n g 2 2 
( 2 0 e val ua ble) s u bjects per ar m w o ul d detect t he e x pecte d differe nces i n b ot h 
pri mar y  e n d p oi nts  wit h  at  least  7 5 %  p o wer  a n d  2 -si de d  α = 0. 0 2 5  ( B o nferr o ni 
a dj ust me nt).  
 
T he u p d ate d s a m ple size descri pti o n:  Base d o n data fr o m o ur pre vi o us st u dies, 1 1 , 
5 0 we e x pect a differe nce of 1 0. 3 % ( S D = 1 4 %) f or pre -p ost c ha n ge i n Ki - 6 7 
pr oliferati o n, a n d a differe nce of 1. 8 ( S D = 2. 5 ) ml· k g· mi n−1  f or pre-p ost c ha n ge i n 
V O 2pea k  i n t he HII T ar m, a n d attriti o n n ot greater t ha n 1 0 %. Hist oricall y , t he pre-
p ost  c ha n ge  i n Ki -6 7  a n d  i n  V O 2pea k  u n der  us ual  care  are  0.  U n der  t hese  
ass u m pti o ns,  ha vi n g  2 0 e val ua ble  s u bjects  i n  t he  HII T  ar m  w o ul d  detect  t he  
e x pecte d differe nces i n b ot h pri mar y e n d p oi nts wit h at least 8 0 % p o wer a n d 2 -si de d 
α = 0. 0 2 5 ( B o nferr o ni a dj ust me nt).  
 
D at a A n al ysis Pl a ns  
T he ori gi n al d at a a n al ysis pl a n:  A p pr o priate descri pti ve statistics f or rele va nt 
varia bles  (e. g.,  Ki -6 7  pr oliferati o n,  V O 2pea k,  p -m T O R  e x pressi o n,  ti me  t o  
e x ha usti o n, etc.) will be calc ulate d b y ar m a n d b y ti me ( baseli ne a n d wee k 3).  F or 
pre- p ost c ha n ges of Ki -6 7 a n d V O 2pea k, t he t w o pri mar y e n d p oi nts (a n d si milarl y 
f or ot her varia bles), differe nces bet wee n gr o u ps ( HII T vs. n o-HII T) i n Ki -6 7 ( or 
V O 2pea k) will be a nal yze d usi n g a nal ysis of c o varia nce ( A N C O V A) wit h baseli ne 
Ki - 6 7 ( or V O2pea k) use d as t he c o v ariate. 
 
O ur pri mar y a nal ysis will f oll o w t he i nte nt -t o-treat (I T T) pri nci ple, li ke f or ma n y 
ra n d o mize d cli nical trials. F or t he pri mar y a nal ysis, we will use a c o nser vati ve ( b ut 
vali d)  a p pr oac h,  a n d  o nl y  i ncl u de  ke y  c o variates  li ke  baseli ne  Ki 6 7  le vel,  
stratificati o n fact ors, i n a d diti o n t o HII T (treat me nt assi g n me nt).  I n t he e x pl orat or y 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 0 
a nal ysis, we will i ncl u de a d here nce a n d ot her c o variates i n t he m o del. Fi n di n gs 
fr o m e x pl orat or y a nal ysis will be use d f or h y p ot hesis ge nerati o n. 
 
T he u p d ate d d at a a n al ysis pl a n:  A p pr o priate descri pti ve statistics f or rele va nt 
varia bles  (e. g.,  Ki -6 7  pr oliferati o n,  V O 2pea k,  p -m T O R  e x pressi o n,  ti me  t o  
e x ha usti o n, etc.) will be calc ulate d b y ar m a n d b y ti me ( baseli ne a n d wee k 3).   
 
O ur pri mar y a nal ysis will be o n pre - p ost c ha n ges i n Ki -6 7 a n d V O 2pea k  f or patie nts 
i n t he HII T ar m a n d t o test w het her t he differe nces were si g nifica ntl y differe nt fr o m  
0 usi n g Wilc o x o n si g ne d ra n k test.       
 
F or n o w, t here are 1 0 patie nts ra n d o mize d t o t he us ual care ar m ha ve c o m plete d t he 
st u d y. T o ma ke g o o d use of t he data, we will c o n d uct a n e x pl orat or y a nal ysis  t o 
c o m pare t he differe nces bet wee n gr o u ps ( HII T vs. n o -HII T) i n Ki -6 7 ( or V O 2pea k), 
w hic h  will be a nal yze d usi n g a nal ysis of c o varia nce ( A N C O V A) wit h baseli ne Ki -
6 7 ( or V O 2pea k) use d as t he c o variate  (we will als o c o n d uct s i milar e x pl orat or y 
a nal yses  f or ot her varia bles). We ma y als o i ncl u de a d here nce a n d ot her c o variates 
i n  t he  m o del.  Fi n di n gs  fr o m  e x pl orat or y  a nal ysis  will  be  use d  f or  h y p ot hesis  
ge nerati o n. 
8. 3  
D at a M a n a ge me nt / A u dit 
T he Office of Cli nical & Tra nslati o nal Researc h ( O C T R)  will ser ve as t he 
c o or di nati n g ce nter f or t his trial. Data will be st ore d i n a sec ure, pass w or d -
pr otecte d, we b- base d platf or m usi n g R E D Ca p mai ntai ne d b y t he N ort h Car oli na 
Tra nslati o nal a n d Cli nical Scie nces I nstit ute ( N C Tra C S) a n d accessi ble s olel y t o 
trai ne d st u d y staff. S y nce d Fit bit data, as well as we bsite data e ntr y b y 
partici pa nts, will als o be sec urel y st ore d a n d pass w or d - pr otecte d b y C H AI C ore, 
a n N HI -f u n de d c ore facilit y t hat pr o vi des ser vices i n be ha vi oral i nter ve nti o n 
researc h. Partici pa nt data files c ollecte d via t he st u d y c o or di nat or will be ke pt i n 
o ne a nal ytic data set t hat will c o m bi ne  all cli nical a n d de m o gra p hic data a n d 
relate d tiss ue data as a de-i de ntifie d dataset f or a nal ysis. T he li n k bet wee n t he 
partici pa nt's i de ntif yi n g a n d researc h i nf or mati o n will be ke pt se parate fr o m data 
files a n d sec ure. T his a nal ytic data set will be place d o n a sec ure ser ver f or 
retrie val b y t he st u d y i n vesti gat or/a nal yst. 
 
As a n i n vesti gat or i nitiate d st u d y, t his trial will als o be a u dite d b y t he Li ne ber ger 
Ca ncer Ce nter a u dit c o m mittee e ver y si x or t wel ve m o nt hs, de pe n di n g o n t he 
partici pati o n of affiliate sites.  
9. 0  
S T U D Y M A N A G E M E N T  
9. 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 pecte 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 ncti o n i n 
acc or da nce wit h fe derall y ma n date d re g ulati 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.  

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 1 
I n o btai ni n g a n d d oc 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 uire 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 int 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 ulati 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.  
9. 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  Office  of  Cli nical  &  Tra nslati o nal  Researc h  ( O C T R)  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 c o p y of t he I R B- a p pr o ve d c o nse nt f or m  
9. 3  
Re gistr ati o n Pr oce d ures  
All s u bjects m ust be re gistere d wit h t he Li ne ber ger C o m pre he nsi ve Ca ncer 
Ce nter, a n d e ntere d i nt o t he we b base d cli nical researc h platf or m, O nc ore ® . 
9. 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 he pr otecti o n, safet y, 
a n d well -bei n g of t he 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.   
9. 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 ge of, t he pr ot oc ol t o 
eli mi nate a n i m me diate hazar d(s) t o trial s u bjects wit h o ut pri or U N C I R B a p pr o val.  
 
F or a n y s uc 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 ness da ys of 
ma ki n g t he c ha n ge.   
9. 4. 2  Si n gle P atie nt/ S u bject E xce pti o ns  
Eli gi bilit y  si n gle  s u bject  e xce pti o ns  are  n ot  per mitte d  f or  Li ne ber ger  
C o m pre he nsi ve  Ca ncer  Ce nter  I n vesti gat or  I nitiate d  Trials  u n der  a n y  

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 2 
circ u msta nces. Ot her t y pes of si n gle s u bject e xce pti o ns ma y be all o we d if pr o per 
re g ulat or y  re vie w  has  bee n  c o m plete d  i n  acc or da nce  wit h  Li ne ber ger  
C o m pre he nsi ve Ca ncer Ce nter’s Si n gle S u bject E xce pti o ns P olic y.  
9. 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 ge 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 partici 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 he 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 varia 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 he 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 viati 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 De vi ati o ns: U N C pers o n nel will rec or d t he de viati o n i n O n C ore ® ( or 
ot her a p pr o priate data base set u p f or t he st u d y), a n d re p ort t o a n y s p o ns or or data 
a n d safet 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. 
 
Pr ot oc ol Vi ol ati o ns: Vi olati o ns s h o ul d be re p orte d b y U N C pers o n nel wit hi n 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 PI R S O .   
 
U n a ntici p ate d Pr o ble ms  I n v ol vi n g Ris ks t o S u bjects or Ot hers ( U PI R S O: 
A n y e ve nts t hat  meet  t he criteria f or “ U na ntici pate d Pr o ble ms” as defi ne d b y 
U N C’s I R B (see secti o n 7. 2 ) m ust be re p orte d b y t he St u d y C o or di nat or usi n g t he 
I R B’s we b- base d re p orti n g s yste m.   
9. 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 he a me n d me nts will be ori gi nate d 
a n d d oc u me nte 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.   

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 3 
T he writte n a me n d me nt, a n d if re q uire 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.   
9. 6  
Rec or d Rete nti o n  
St u d y d oc u me ntati o n i ncl u des all Case Re p ort F or ms, data c orrecti o n f or ms or 
q ueries,  s o urce  d oc u me nts,  S p o ns or -I n vesti gat or  c orres p o n de nce,  m o nit ori n g  
l o gs/letters,  a n d  re g ulat or y  d oc u me nts  (e. g.,  pr ot oc ol  a n d  a me n d me nts,  I R B  
c orres p o n de 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 de 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 he cli nical researc h st u d y.  
 
G o ver n me nt a ge 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 ntati o n 
pertai ni n g  t o  t he  c o n d uct  of  a  cli nical  trial  m ust  be  retai ne 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 oc 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 nati o nal C o nfere nce o n Har m o nizati o n 
(I C H) re gi o n.  I n all ot her cases, 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 pl eti 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. 
9. 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 versee i n g t he treat me nt of all st u d y patie nts.  T he Pri nci pal I n vesti 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 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 gar 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 at eac h i nstit uti o n or site 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 o nt o t he Case Re p ort F or ms. 
Peri o dicall y, m o nit ori n g visits will be c o n d ucte d a n d t he Pri nci pal I n vesti gat or wi ll 
pr o vi de access t o his/ her ori gi nal rec or ds t o per 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 case re p ort f or ms 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 t o verif y t he acc ura c y 
of t he data.  
1 0. 0  R E F E R E N C E S  
1. 
K o E M, et al. T he c o m ple x tria d of o besit y, dia betes a n d race i n T y pe I a n d II 
e n d o metrial  ca ncers:  Pre vale nce  a n d  pr o g n ostic  si g nifica nce.  G y nec ol  O nc ol.  
2 0 1 4; 1 3 3( 1): 2 8- 3 2. E p u b 2 0 1 4/ 0 4/ 0 1. d oi: 1 0. 1 0 1 6/j. y g y n o. 2 0 1 4. 0 1. 0 3 2. P u b Me d P MI D: 
2 4 6 8 0 5 8 8. 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 4 
2. 
Setia wa n V W, et al. T y pe I a n d II e n d o metrial ca ncers: ha ve t he y differe nt ris k 
fact ors?
 J
 Cli n
 O nc ol.
 2 0 1 3; 3 1( 2 0): 2 6 0 7-1 8.
 E p u b
 2 0 1 3/ 0 6/ 0 5.
 d oi:
 
1 0. 1 2 0 0/J C O. 2 0 1 2. 4 8. 2 5 9 6. P u b Me d P MI D: 2 3 7 3 3 7 7 1; P M CI D: 3 6 9 9 7 2 6. 
3. 
Sc h ma n dt  R E,  et  al.  U n dersta n di n g  o besit y  a n d  e n d o metrial  ca ncer  ris k:  
o p p ort u nities  f or  pre ve nti o n.  A m  J  O bstet  G y nec ol.  2 0 1 1; 2 0 5( 6): 5 1 8 -2 5.  E p u b  
2 0 1 1/ 0 8/ 0 2. d oi: 1 0. 1 0 1 6/j.aj o g. 2 0 1 1. 0 5. 0 4 2. P u b Me d P MI D: 2 1 8 0 2 0 6 6. 
4. 
C hia V M, et al. O besit y, dia betes, a n d ot her fact ors i n relati o n t o s ur vi val after 
e n d o metrial ca ncer dia g n osis. I nt J G y nec ol Ca ncer. 2 0 0 7; 1 7( 2): 4 4 1-6. P u b Me d P MI D: 
1 7 3 6 2 3 2 0. 
5. 
Calle E E, et al. O ver wei g ht, o besit y, a n d m ortalit y fr o m ca ncer i n a pr os pecti vel y 
st u die d c o h ort of U. S. a d ults. T he Ne w E n gla n d j o ur nal of me dici ne. 2 0 0 3; 3 4 8( 1 7): 1 6 2 5-
3 8. P u b Me d P MI D: 1 2 7 1 1 7 3 7. 
6. 
Stei ner E, et al. Dia betes mellit us is a m ulti variate i n de pe n de nt pr o g n ostic fact or i n 
e n d o metrial carci n o ma: a cli nic o pat h ol o gic st u d y o n 3 1 3 patie nts. E ur J G y naec ol O nc ol. 
2 0 0 7; 2 8( 2): 9 5- 7. P u b Me d P MI D: 1 7 4 7 9 6 6 8. 
7. 
Are m H, et al. Pre dia g n osis b o d y mass i n de x, p h ysical acti vit y, a n d m ortalit y i n 
e n d o metrial ca ncer patie nts. J o ur nal of t he Nati o nal Ca ncer I nstit ute. 2 0 1 3; 1 0 5( 5): 3 4 2 - 9. 
E p u b 2 0 1 3/ 0 1/ 0 9. d oi: 1 0. 1 0 9 3/j nci/ djs 5 3 0. P u b Me d P MI D: 2 3 2 9 7 0 4 1; P M CI D: 3 5 8 9 2 5 6.  
8. 
Sec or d  A A,  et  al.  B o d y  mass  i n de x  a n d  m ortalit y  i n  e n d o metrial  ca ncer:  A  
s yste matic  re vie w  a n d  meta-a nal ysis.  G y nec ol  O nc ol.  2 0 1 6; 1 4 0( 1): 1 8 4 -9 0.  E p u b  
2 0 1 5/ 1 1/ 0 3. d oi: 1 0. 1 0 1 6/j. y g y n o. 2 0 1 5. 1 0. 0 2 0. P u b Me d P MI D: 2 6 5 2 4 7 2 2. 
9. 
War d  K K,  et  al.  Car di o vasc ular  disease  is  t he  lea di n g  ca use  of  deat h  a m o n g  
e n d o metrial
 ca ncer
 patie nts.
 G y nec ol o gic
 o nc ol o g y.
 2 0 1 2; 1 2 6( 2): 1 7 6 -9.
 d oi:
 
1 0. 1 0 1 6/j. y g y n o. 2 0 1 2. 0 4. 0 1 3. P u b Me d P MI D: 2 2 5 0 7 5 3 2. 
1 0. 
K o ut o u ki dis D A, et al. O besit y, diet, p h ysical acti vit y, a n d healt h -relate d q ualit y of 
life i n e n d o metrial ca ncer s ur vi v ors. N utr Re v. 2 0 1 5; 7 3( 6): 3 9 9-4 0 8. E p u b 2 0 1 5/ 0 5/ 2 7. d oi: 
1 0. 1 0 9 3/ n utrit/ n u u 0 6 3. P u b Me d P MI D: 2 6 0 1 1 9 1 4; P M CI D: P M C 4 4 7 7 7 0 0. 
1 1. 
Sc h uler  K M,  et  al.  A nti pr oliferati ve  a n d  meta b olic  effects  of  metf or mi n  i n  a  
pre o perati ve wi n d o w cli nical trial f or e n d o metrial ca ncer. Ca ncer Me d. 2 0 1 5; 4( 2): 1 6 1 - 7 3. 
E p u b 2 0 1 4/ 1 1/ 2 5. d oi: 1 0. 1 0 0 2/ca m 4. 3 5 3. P u b Me d P MI D: 2 5 4 1 7 6 0 1; P M CI D: 4 3 2 9 0 0 1. 
1 2. 
W h yte LJ, et al. Effect of 2 wee ks of s pri nt i nter val trai ni n g o n healt h -relate d 
o utc o mes i n se de ntar y o ver wei g ht/ o bese me n. Meta b olis m. 2 0 1 0; 5 9( 1 0): 1 4 2 1 -8. P MI D: 
2 0 1 5 3 4 8 7. 
1 3. 
Wisl øff U, et al. S u peri or car di o vasc ular effect of aer o bic i nter val trai ni n g vers us 
m o derate c o nti n u o us trai ni n g i n heart fail ure patie nts: a ra n d o mize d st u d y. Circ ulati o n. 
2 0 0 7; 1 1 5( 2 4): 3 0 8 6- 9 4. P MI D: 1 7 5 4 8 7 2 6. 
1 4. 
As ki m T, et al. Hi g h -i nte nsit y aer o bic i nter val trai ni n g f or patie nts 3-9  m o nt hs after 
str o ke. A feasi bilit y st u d y. P h ysi ot her Res I nt. 2 0 1 4; 1 9( 3): 1 2 9- 3 9. P MI D: 2 4 3 7 5 9 7 8. 
1 5. 
Pers o o n  S,  et  al.  Desi g n  of  t he  E Xercise  I nter ve nti o n  after  Ste m  cell  
Tra ns pla ntati o n ( E XI S T) st u d y: a ra n d o mize d c o ntr olle d trial t o e val uate t he effecti ve ness 
a n d c ost -effecti ve ness of a n i n di vi d ualize d hi g h i nte nsit y p h ysical e xercise pr o gra m o n 
fit ness a n d fati g ue i n patie nts wit h m ulti ple m yel o ma or ( n o n-) H o d g ki n's l y m p h o ma 
treate d  wit h  hi g h  d ose  c he m ot hera p y  a n d  a ut ol o g o us  ste m  cell  tra ns pla ntati o n.  B M C  
Ca ncer. 2 0 1 0; 1 0: 6 7 1. P M CI D: P M C 3 0 1 6 2 9 3. 
1 6. 
Gl oec kl R, et al. I nter val vers us c o nti n u o us trai ni n g i n l u n g tra ns pla nt ca n di dates: 
a ra n d o mize d trial. J Heart L u n g Tra ns pla nt. 2 0 1 2; 3 1( 9): 9 4 3- 4 1. P MI D: 2 2 8 8 4 3 8 1. 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 5 
1 7. 
S mit h -R ya n  A E.  E nj o y me nt  of  hi g h -i nte nsit y  i nter val  trai ni n g  i n  a n  
o ver wei g ht/ o bese  c o h ort:  a  s h ort  re p ort.  Cli nical  p h ysi ol o g y  a n d  f u ncti o nal  i ma gi n g.  
2 0 1 7; 3 7( 1): 8 9- 9 3. d oi: 1 0. 1 1 1 1/c pf. 1 2 2 6 2. P u b Me d P MI D: 2 6 0 9 6 0 2 1; P M CI D: 4 6 8 4 8 1 0.  
1 8. 
S mit h -R ya n  A E,  et  al.  Hi g h -i nte nsit y  i nter val  trai ni n g:  M o d ulati n g  i nter val  
d urati o n i n o ver wei g ht/ o bese me n. T he P h ysicia n a n d s p orts me dici ne. 2 0 1 5; 4 3( 2): 1 0 7 - 1 3. 
d oi: 1 0. 1 0 8 0/ 0 0 9 1 3 8 4 7. 2 0 1 5. 1 0 3 7 2 3 1. P u b Me d P MI D: 2 5 9 1 3 9 3 7; P M CI D: 4 4 2 7 2 4 1. 
1 9. 
S mit h -R ya n A E, et al. Effects of hi g h -i nte nsit y i nter val trai ni n g o n car di o meta b olic 
ris k fact ors i n o ver wei g ht/ o bese w o me n. J o ur nal of s p orts scie nces. 2 0 1 6; 3 4( 2 1): 2 0 3 8- 4 6. 
d oi: 1 0. 1 0 8 0/ 0 2 6 4 0 4 1 4. 2 0 1 6. 1 1 4 9 6 0 9. P u b Me d P MI D: 2 6 9 3 4 6 8 7; P M CI D: 5 0 1 0 5 3 3. 
2 0. 
Hel ger u d J, et al. Aer o bic hi g h -i nte nsit y i nter vals i m pr o ve V O 2 ma x m ore t ha n 
m o derate
 trai ni n g.
 Me d
 Sci
 S p orts
 E xerc.
 2 0 0 7; 3 9( 4): 6 6 5 -7 1.
 d oi:
 
1 0. 1 2 4 9/ mss. 0 b 0 1 3e 3 1 8 0 3 0 4 5 7 0. P u b Me d P MI D: 1 7 4 1 4 8 0 4. 
2 1. 
Mila n o vic Z, et al. Effecti ve ness of Hi g h -I nte nsit y I nter val Trai ni n g ( HI T) a n d 
C o nti n u o us E n d ura nce Trai ni n g f or V O 2 ma x I m pr o ve me nts: A S yste matic Re vie w a n d 
Meta -A nal ysis of C o ntr olle d Trials. S p orts me dici ne ( A uc kla n d, N Z. 2 0 1 5; 4 5( 1 0): 1 4 6 9 -
8 1. d oi: 1 0. 1 0 0 7/s 4 0 2 7 9- 0 1 5- 0 3 6 5- 0. P u b Me d P MI D: 2 6 2 4 3 0 1 4. 
2 2. 
Ba nerjee S, et al. Vi g or o us i nte nsit y aer o bic i nter val e xercise i n bla d der ca ncer 
patie nts pri or t o ra dical c ystect o m y: a feasi bilit y ra n d o mise d c o ntr olle d trial. S u p p orti ve 
care i n ca ncer : official j o ur nal of t he M ulti nati o nal Ass ociati o n of S u p p orti ve Care i n 
Ca ncer. 2 0 1 7. d oi: 1 0. 1 0 0 7/s 0 0 5 2 0- 0 1 7 - 3 9 9 1- 2. P u b Me d P MI D: 2 9 1 8 1 8 0 4. 
2 3. 
Ric har ds o n K, et al. Fit f or s ur ger y? Pers pecti ves o n pre o perati ve e xercise testi n g 
a n d  trai ni n g.  Britis h  j o ur nal  of  a naest hesia.  2 0 1 7; 1 1 9(s u p pl _ 1):i 3 4 -i 4 3.  d oi:  
1 0. 1 0 9 3/ bja/ae x 3 9 3. P u b Me d P MI D: 2 9 1 6 1 4 0 2. 
2 4.  
W o o d W A, et al. Pers o nalize d h o me- base d i nter val e xercise trai ni n g ma y i m pr o ve 
car di ores pirat or y  fit ness  i n  ca ncer  patie nts  pre pari n g  t o  u n der g o  he mat o p oietic  cell  
tra ns pla ntati o n.  B o ne  Marr o w  Tra ns pla nt.  2 0 1 6; 5 1( 7): 9 6 7-7 2.  E p u b  2 0 1 6/ 0 3/ 2 2.  d oi:  
1 0. 1 0 3 8/ b mt. 2 0 1 6. 7 3. P u b Me d P MI D: 2 6 9 9 9 4 6 7; P M CI D: P M C 4 9 3 5 5 9 1. 
2 5.  
Sie gel R L, et al. Ca ncer statistics, 2 0 1 8. C A Ca ncer J Cli n. 2 0 1 8; 6 8( 1): 7- 3 0. E p u b 
2 0 1 8/ 0 1/ 1 0. d oi: 1 0. 3 3 2 2/caac. 2 1 4 4 2. P u b Me d P MI D: 2 9 3 1 3 9 4 9. 
2 6. 
K ha n de kar MJ, et al. M olec ular mec ha nis ms of ca ncer de vel o p me nt i n o besit y. 
Nat ure  re vie ws  Ca ncer.  2 0 1 1; 1 1( 1 2): 8 8 6 -9 5.  E p u b  2 0 1 1/ 1 1/ 2 5.  d oi:  1 0. 1 0 3 8/ nrc 3 1 7 4.  
P u b Me d P MI D: 2 2 1 1 3 1 6 4. 
2 7. 
G u nter MJ, et al. A Pr os pecti ve E val uati o n of I ns uli n a n d I ns uli n -li ke Gr o wt h 
Fact or -I as Ris k Fact ors f or E n d o metrial Ca ncer. Ca ncer E pi de mi ol Bi o mar kers Pre v. 
2 0 0 8; 1 7( 4): 9 2 1- 9. P u b Me d P MI D: 1 8 3 9 8 0 3 2. 
2 8. 
Mc Ca m p bell A S, et al. O vere x pressi o n of t he i ns uli n -li ke gr o wt h fact or I rece pt or 
a n d  acti vati o n  of  t he  A K T  pat h wa y  i n  h y per plastic  e n d o metri u m.  Cli n  Ca ncer  Res.  
2 0 0 6; 1 2( 2 1): 6 3 7 3- 8. P u b Me d P MI D: 1 7 0 8 5 6 4 8. 
2 9. 
Ge hri g P A, et al. Pr o misi n g n o vel t hera pies f or t he treat me nt of e n d o metrial ca ncer. 
G y nec ol
 O nc ol.
 2 0 1 0; 1 1 6( 2): 1 8 7 -9 4.
 E p u b
 2 0 0 9/ 1 1/ 1 2.
 d oi:
 
1 0. 1 0 1 6/j. y g y n o. 2 0 0 9. 1 0. 0 4 1. P u b Me d P MI D: 1 9 9 0 3 5 7 2; P M CI D: 4 1 0 3 6 6 3. 
3 0. 
De des KJ, et al. E mer gi n g t hera pe utic tar gets i n e n d o metrial ca ncer. Nat ure re vie ws 
Cli nical o nc ol o g y. 2 0 1 1; 8( 5): 2 6 1 -7 1. E p u b 2 0 1 1/ 0 1/ 1 2. d oi: 1 0. 1 0 3 8/ nrcli n o nc. 2 0 1 0. 2 1 6. 
P u b Me d P MI D: 2 1 2 2 1 1 3 5. 
3 1. 
C he u n g  L W,  et  al.  Hi g h  fre q ue nc y  of  PI K 3 R 1  a n d  PI K 3 R 2  m utati o ns  i n  
e n d o metrial ca ncer el uci dates a n o vel mec ha nis m f or re g ulati o n of P T E N pr otei n sta bilit y. 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 6 
Ca ncer disc o ver y. 2 0 1 1; 1( 2): 1 7 0 -8 5. E p u b 2 0 1 1/ 1 0/ 1 1. d oi: 1 0. 1 1 5 8/ 2 1 5 9 - 8 2 9 0. C D- 1 1-
0 0 3 9. P u b Me d P MI D: 2 1 9 8 4 9 7 6; P M CI D: 3 1 8 7 5 5 5. 
3 2. 
Ka n d ot h C, et al. I nte grate d ge n o mic c haracterizati o n of e n d o metrial carci n o ma. 
Nat ure.  2 0 1 3; 4 9 7( 7 4 4 7): 6 7 -7 3.  E p u b  2 0 1 3/ 0 5/ 0 3.  d oi:  1 0. 1 0 3 8/ nat ure 1 2 1 1 3.  P u b Me d  
P MI D: 2 3 6 3 6 3 9 8; P M CI D: 3 7 0 4 7 3 0. 
3 3. 
Wallace D C. A mit oc h o n drial para di g m of meta b olic a n d de ge nerati ve diseases, 
a gi n g,  a n d  ca ncer:  a  da w n  f or  e v ol uti o nar y  me dici ne.  A n n ual  re vie w  of  ge netics.  
2 0 0 5; 3 9: 3 5 9- 4 0 7.  E p u b  2 0 0 5/ 1 1/ 1 6.  d oi:  1 0. 1 1 4 6/a n n ure v. ge net. 3 9. 1 1 0 3 0 4. 0 9 5 7 5 1.  
P u b Me d P MI D: 1 6 2 8 5 8 6 5; P M CI D: 2 8 2 1 0 4 1. 
3 4. 
Ki m J A, et al. R ole of mit oc h o n drial d ysf u ncti o n i n i ns uli n resista nce. Circ ulati o n 
researc h.
 2 0 0 8; 1 0 2( 4): 4 0 1-1 4.
 E p u b
 2 0 0 8/ 0 3/ 0 1.
 d oi:
 
1 0. 1 1 6 1/ CI R C R E S A H A. 1 0 7. 1 6 5 4 7 2. P u b Me d P MI D: 1 8 3 0 9 1 0 8; P M CI D: 2 9 6 3 1 5 0. 
3 5. 
B ola n d M L, et al. Mit oc h o n drial d ysf u ncti o n i n ca ncer. Fr o ntiers i n o nc ol o g y. 
2 0 1 3; 3: 2 9 2. E p u b 2 0 1 3/ 1 2/ 1 9. d oi: 1 0. 3 3 8 9/f o nc. 2 0 1 3. 0 0 2 9 2. P u b Me d P MI D: 2 4 3 5 0 0 5 7; 
P M CI D: 3 8 4 4 9 3 0. 
3 6. 
O' Fla na ga n C H, et al. A wei g ht y pr o ble m: meta b olic pert ur bati o ns a n d t he o besit y -
ca ncer  li n k. H or m o ne  m olec ular  bi ol o g y  a n d  cli nical  i n vesti gati o n.  2 0 1 5; 2 3( 2): 4 7 - 5 7. 
E p u b 2 0 1 5/ 0 7/ 1 5. d oi: 1 0. 1 5 1 5/ h m bci - 2 0 1 5-0 0 2 2. P u b Me d P MI D: 2 6 1 6 7 9 8 2; P M CI D: 
4 8 3 9 9 8 2. 
3 7. 
I nter nati o nal A ge nc y f or Researc h o n Ca ncer, Gl o b oca n. Ca ncer E pi de mi ol o g y 
Data base. 2 0 0 2. 
3 8. 
S ulli va n S, Tra n, A Q, Clar k, L H, Ha n, J, Z ha n g, L, G u o, H, Yi n, Y, Bate ma n, N, 
H o o d, B L, C o nra ds, T P, Ha milt o n m, C A, Ma x well, G L, Lee, D, Z h o u, C, Ma k o ws ki, L, 
Bae -J u m p,  V L.  Re versal  of  o besit y-dri ve n  a g gressi ve ness  of  e n d o metrial  ca ncer  b y  
metf or mi n. 4 8t h A n n ual Meeti n g of t he S ociet y of G y nec ol o gic O nc ol o g y, Marc h 2 0 1 7, 
Nati o nal Har b or, M D 2 0 1 7. 
3 9. 
R o q ue D R, et al. Ass ociati o n bet wee n differe ntial ge ne e x pressi o n a n d b o d y mass 
i n de x a m o n g e n d o metrial ca ncers fr o m T he Ca ncer Ge n o me Atlas Pr oject. G y nec ol O nc ol. 
2 0 1 6; 1 4 2( 2): 3 1 7- 2 2.  E p u b  2 0 1 6/ 0 6/ 1 2.  d oi:  1 0. 1 0 1 6/j. y g y n o. 2 0 1 6. 0 6. 0 0 6.  P u b Me d  
P MI D: 2 7 2 8 8 5 4 4; P M CI D: 4 9 6 1 5 5 9. 
4 0. 
Clar k L H, et al. E n d o metrial Ca ncer S ur vi v ors' Perce pti o ns of Pr o vi der O besit y 
C o u nseli n g a n d Atte m pte d Be ha vi or C ha n ge: Are We Seizi n g t he M o me nt? I nt J G y nec ol 
Ca ncer.  2 0 1 6; 2 6( 2): 3 1 8 -2 4.  E p u b  2 0 1 5/ 1 1/ 2 1.  d oi:  1 0. 1 0 9 7/I G C. 0 0 0 0 0 0 0 0 0 0 0 0 0 5 9 6.  
P u b Me d P MI D: 2 6 5 8 8 2 3 4. 
4 1. 
B o utc her  S H.  Hi g h -i nte nsit y  i nter mitte nt  e xercise  a n d  fat  l oss.  J  O bes.  
2 0 1 1; 2 0 1 1: 8 6 8 3 0 5.  E p u b  2 0 1 0/ 1 1/ 3 0.  d oi:  1 0. 1 1 5 5/ 2 0 1 1/ 8 6 8 3 0 5.  P u b Me d  P MI D:  
2 1 1 1 3 3 1 2; P M CI D: 2 9 9 1 6 3 9. 
4 2. 
West o n K S, et al. Hi g h -i nte nsit y i nter val trai ni n g i n patie nts wit h lifest yle-i n d uce d 
car di o meta b olic disease: a s yste matic re vie w a n d meta -a nal ysis. Britis h j o ur nal of s p orts 
me dici ne. 2 0 1 4; 4 8( 1 6): 1 2 2 7- 3 4. E p u b 2 0 1 3/ 1 0/ 2 3. d oi: 1 0. 1 1 3 6/ bjs p orts- 2 0 1 3- 0 9 2 5 7 6 
bjs p orts- 2 0 1 3- 0 9 2 5 7 6 [ pii]. P u b Me d P MI D: 2 4 1 4 4 5 3 1. 
4 3. 
Ba braj  J A,  et  al.  E xtre mel y  s h ort  d urati o n  hi g h  i nte nsit y  i nter val  trai ni n g  
s u bsta ntiall y i m pr o ves i ns uli n acti o n i n y o u n g healt h y males. B mc E n d ocri ne Dis or ders. 
2 0 0 9; 9: 3. E p u b 2 0 0 9/ 0 1/ 3 0. d oi: 1 0. 1 1 8 6/ 1 4 7 2- 6 8 2 3- 9- 3 

L C C C 1 8 3 9  
 
C O N FI D E N TI A L  
PI: Vic kie B ae -J u m p, M D  
 
U NI V E R SI T Y O F N O R T H C A R O LI N A  
Se pte m ber 1 0 , 2 0 2 1 
 
 
 
2 7 
1 4 7 2- 6 8 2 3- 9- 3 [ pii]. P u b Me d P MI D: 1 9 1 7 5 9 0 6; P M CI D: 2 6 4 0 3 9 9. 
4 4. 
C oc ks M, et al. S pri nt i nter val a n d m o derate -i nte nsit y c o nti n u o us trai ni n g ha ve 
e q ual  be nefits  o n  aer o bic  ca pacit y,  i ns uli n  se nsiti vit y,  m uscle  ca pillarisati o n  a n d  
e n d ot helial e N O S/ N A D( P) H o xi dase pr otei n rati o i n o bese me n. J o ur nal of P h ysi ol o g y. 
2 0 1 5. d oi: 1 0. 1 1 1 3/j p h ysi ol. 2 0 1 4. 2 8 5 2 5 4. P u b Me d P MI D: 2 5 6 4 5 9 7 8. 
4 5. 
Gre mea u x V, et al. L o n g -ter m lifest yle i nter ve nti o n wit h o pti mize d hi g h-i nte nsit y 
i nter val  trai ni n g  i m pr o ves  b o d y  c o m p ositi o n,  car di o meta b olic  ris k,  a n d  e xercise  
para meters i n patie nts wit h a b d o mi nal o besit y. A merica n J o ur nal of P h ysical Me dici ne a n d 
Re ha bilitati o n.
 2 0 1 2; 9 1( 1 1): 9 4 1 -5 0.
 E p u b
 2 0 1 2/ 0 8/ 0 3.
 d oi:
 
1 0. 1 0 9 7/ P H M. 0 b 0 1 3e 3 1 8 2 6 4 3ce 0. P u b Me d P MI D: 2 2 8 5 4 9 0 2. 
4 6. 
Kessler  H S,  et  al.  T he  p ote ntial  f or  hi g h -i nte nsit y  i nter val  trai ni n g  t o  re d uce  
car di o meta b olic disease ris k. S p orts Me dici ne. 2 0 1 2; 4 2( 6): 4 8 9 -5 0 9. E p u b 2 0 1 2/ 0 5/ 1 7. d oi: 
1 0. 2 1 6 5/ 1 1 6 3 0 9 1 0- 0 0 0 0 0 0 0 0 0- 0 0 0 0 0 
2 [ pii]. P u b Me d P MI D: 2 2 5 8 7 8 2 1. 
4 7. 
Jac o bs  R A,  et  al.  I m pr o ve me nts  i n  e xercise  perf or ma nce  wit h  hi g h-i nte nsit y 
i nter val trai ni n g c oi nci de wit h a n i ncrease i n s keletal m uscle mit oc h o n drial c o nte nt a n d 
f u ncti o n.
 J o ur nal
 of
 a p plie d
 p h ysi ol o g y.
 2 0 1 3; 1 1 5( 6): 7 8 5-9 3.
 d oi:
 
1 0. 1 1 5 2/ja p pl p h ysi ol. 0 0 4 4 5. 2 0 1 3. P u b Me d P MI D: 2 3 7 8 8 5 7 4. 
4 8. 
S mit h -R ya n A E, et al. Utilit y of ultras o u n d f or b o d y fat assess me nt: vali dit y a n d 
relia bilit y c o m pare d t o a m ultic o m part me nt criteri o n. Cli nical p h ysi ol o g y a n d f u ncti o nal 
i ma gi n g. 2 0 1 6. d oi: 1 0. 1 1 1 1/c pf. 1 2 4 0 2. P u b Me d P MI D: 2 7 9 8 1 8 1 0; P M CI D: 5 4 7 4 2 1 4. 
4 9. 
Ke n dziers ki D, et al. P h ysical acti vit y e nj o y me nt scale: t w o vali dati o n st u dies. J 
S p ort E xerc Ps yc h ol. 1 9 9 1; 1 3: 5 0- 6 4.  
5 0. 
N oet her G. Sa m ple size deter mi nati o n f or s o me c o m m o n n o n para metric tests. 
J A S A. 1 9 8 7; 8 2: 6 4 5- 4 7.