Clinical trial NCT03180294
Conditions: Breast Carcinoma Cervical Carcinoma Ovarian Carcinoma Postmenopausal Uterine Corpus Cancer Vaginal Carcinoma Vulvar Carcinoma
Sponsor: NRG Oncology
Start date: 2017-05-31; Completion date: 2021-02-22
Enrollment: 230 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II randomized trial studies how well bupropion hydrochloride works in improving sexual desire in women with breast or gynecological cancer. Bupropion hydrochloride may work by boosting sexual desire, energy, or motivation without causing intolerable or undesirable side effects.

Detailed description:
PRIMARY OBJECTIVES:

I. Measure the ability of two dose levels of bupropion hydrochloride (bupropion), 150 or 300 mg of extended release, to improve sexual desire more than a placebo at 9 weeks (8 weeks on the target dose) as measured by the desire subscale of the female sexual function index (FSFI).

SECONDARY OBJECTIVES:

I. Evaluate the side effects of 150 and 300 mg bupropion extended release and differentiate these side effects from those observed in the placebo arm.

II. Evaluate the effect of 150 and 300 mg of bupropion extended release on the Patient Reported Outcomes Measurement Information System (PROMIS) fatigue scale, PROMIS sexual desire and satisfaction measure, patient health questionnaire (PHQ)-4, and the FSFI total score, at 5 and 9 weeks, as well as the desire subscale score of the FSFI at 5 weeks.

III. Evaluate the effect of 150 and 300 mg of bupropion extended release on the global impression of change scale and the patient's perception of risk versus (vs.) benefit at 5 weeks (4 weeks at target dose) and 9 weeks (8 weeks at target dose).

Patients are randomized to 1 of 3 arms.

Arms: arm 1: One Bupropion 150 mg XL capsule by mouth (PO) in a.m. daily for one week; one Bupropion 150 mg XL capsule and one placebo capsule daily for 8 weeks; one placebo capsule daily for one 1 week (titration off). arm 2: One Bupropion 150 mg XL capsule PO in a.m. daily for one week; two Bupropion 150 mg XL capsules PO in a.m. daily for 8 weeks (300 mg target dose); one Bupropion 150 mg XL capsule PO in a.m. daily for 1 week (titration off) arm 3: One placebo capsule PO in a.m. daily for 1 week; two placebo capsules PO in a.m. daily for 8 weeks; one placebo capsule PO in a.m. daily for 1 week (titration off)
Interventions: intervention 1: Bupropion 150 mg XL intervention 2: Placebo
Intervention descriptions: intervention 1: By mouth intervention 2: By mouth

Protocol documents:
Prot_SAP_000.pdf: 
NRG ONCOLOGY 
 
NRG-CC004 
 
(ClinicalTrials.gov NCT #: 03180294) 
 
 
PHASE III DOUBLE BLIND DOSE FINDING TRIAL OF BUPROPION VERSUS 
PLACEBO FOR SEXUAL DESIRE IN WOMEN WITH BREAST OR GYNECOLOGIC 
CANCER 
 
 
 
Amendment 3:  June 7, 2019 


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NRG ONCOLOGY 
NRG-CC004 
 (ClinicalTrials.gov NCT #NCT03180294) 
 
PHASE II DOUBLE BLIND DOSE FINDING TRIAL OF BUPROPION VERSUS 
PLACEBO FOR SEXUAL DESIRE IN WOMEN WITH BREAST OR GYNECOLOGIC 
CANCER 
 
This trial is sponsored by the National Cancer Institute (NCI) and will be led by NRG Oncology. 
 
 
Site participation limited to NRG Oncology NCORP sites and sites listed below (07-JUN-2019) 
Duke University Medical Center  
Memorial Sloan Kettering Cancer Center 
University of Michigan Comprehensive Cancer Center 
University of Oklahoma Health Sciences Center 
University of California San Diego Moores Cancer Center 
UCLA / Jonsson Comprehensive Cancer Center 
 
Coordinating Center:  
NRG Oncology 
Four Penn Center; 1600 JFK Blvd; Suite 1020; Philadelphia, PA 19103 
 
Study Team (07-JUN-2019) 
Principal Investigator 
Deb Barton, PhD, RN 
Mary Lou Willard French Endowed Chair, 
Oncology Nursing 
Professor, School of Nursing 
University of Michigan 
400 N. Ingalls, Room 4304 
Ann Arbor, MI 48109 
Phone/Fax: 734-763-3868/734-647-2416 
debbartn@med.umich.edu 
 
Breast Oncology Co-Chair 
Patricia Ganz, MD 
Jonsson Comprehensive Cancer Center, 
UCLA  
650 Charles Young Drive – South 
Room A2-125 CHS Box 956900-6900 
Los Angeles, CA 90095 
Phone/Fax310-206-1404/310-206-3566  
pganz@mednet.ucla.edu 
 
 
Gynecologic Oncology Co-Chair 
Steve Plaxe, MD 
University of California San Diego 
Moores Cancer Center 
3855 Health Sciences Drive 
La Jolla, CA 92093 
Phone/Fax: 858-822-6199/858-822-6319 
splaxe@ucsd.edu 
 
 
 
Quality of Life Co-Chair 
Bridget Koontz, MD 
Duke Cancer University Medical Center 
Radi 
ation Oncology Department 
30 Medicine Circle, Room 05151, Box 3085 
Durham, NC 27710 
Phone/Fax: 919-668-5213/919-668-7345  
bridget.koontz@duke.edu 
 
 


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Quality of Life Co-Chair 
Jeanne Carter, PhD 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
Phone/Fax: 646-888-5077/646-888-4919  
carterj@mskcc.org 
Statistician  
Stephanie Pugh, PhD 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-717-0850/Fax: 215-928-0153 
pughs@nrgoncology.org 
 
 
 
NRG Oncology Contact Information 
Data Management 
For questions concerning eligibility or 
data submission 
Roseann Bonanni, CTR, CCRP 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-3223/Fax: 215-930-8840 
bonannir@nrgoncology.org 
 
Tiffani Simpson-Small, RN, MPH 
NRG Oncology 
1818 Market Street, Suite 1720 
Philadelphia, PA 19103 
215-574-4164/Fax: 215-930-8840 
smallt@nrgoncology.org 
Protocol Development: 
For questions concerning protocol and 
informed consent versions & 
amendments 
Erica Field, MPH, MHA 
NRG Oncology 
1818 Market Street Suite 1720 
Philadelphia, PA 19103 
215-940-8824/Fax: 215-574-0300 
fielde@nrgoncology.org  
Cancer Prevention and Control 
Committee (CPC) Chair 
Lisa Kachnic, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol Agent 
Agent 
Supply 
NSC # 
IND # 
IND Sponsor 
Bupropion 
Provided 
N/A 
Exempt 
N/A 
 
Participating Sites (07-JUN-2019) 
x U.S. (NRG Oncology NCORP and sites listed on the cover page) 
 
 
Document History 
 
Version Date 
Amendment 3 
June 7, 2019 
Amendment 2 
June 8, 2018 
Amendment 1 
September 8, 2017 
Activation 
March 13, 2017 
 
 
 
 
  
 
 
This protocol was designed and developed by NRG Oncology. It is intended 
to be used only in conjunction with institution-specific IRB approval for 
study entry.  No other use or reproduction is authorized by NRG Oncology 
nor does NRG Oncology assume any responsibility for unauthorized use of 
this protocol. 


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NRG ONCOLOGY 
 
NRG-CC004 
 
PHASE II DOUBLE BLIND DOSE FINDING TRIAL OF BUPROPION VERSUS 
PLACEBO FOR SEXUAL DESIRE 
 
CONTACT INFORMATION (07-JUN-2019) 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the  
Regulatory Submission Portal 
(Sign in at www.ctsu.org,         
and select  Regulatory > 
Regulatory Submission.) 
 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-2878 
to receive further instruction 
and support. 
 
Contact  the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient 
enrollment section of the protocol 
for instructions on using the 
Oncology Patient Enrollment 
Network (OPEN) which can be 
accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
at ctsucontact@westat.com. 
 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Refer to the 
data submission section of the 
protocol for further instructions.  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific page of the CTSU member’s website located at (https://www.ctsu.org).  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation Program 
- Identity and Access Management (CTEP-IAM) registration system and requires user log on with 
CTEP-IAM username and password.  
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU website is located at https://www.ctsu.org. 
 
 


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TABLE OF CONTENTS 
SCHEMA  ........................................................................................................................................7 
1. 
OBJECTIVES ......................................................................................................................8 
1.1 
Primary Objective ....................................................................................................8 
1.2 
Secondary Objectives...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Preliminary data supporting dopamine reduction with estrogen 
deprivation. ............................................................................................................10 
2.2 
Preliminary data with dopaminergic agents. ..........................................................11 
3. 
PATIENT SELECTION, ELIGIBILITY AND INELIGIBILITY CRITERIA .................14 
3.1 
Patient Selection Guidelines ..................................................................................14 
3.2 
Eligibility Criteria ..................................................................................................14 
3.3 
Ineligibility Criteria  ..............................................................................................15 
4. 
REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP ..........16 
5. TREATMENT PLAN/Regimen description..............................................................................18 
5.1 
Study agent.............................................................................................................18 
5.2 
General Concomitant Medication and Supportive Care Guidelines  .....................19 
5.3 
Emergency Unblinding Procedure .........................................................................20 
5.4 
Duration of Therapy ...............................................................................................20 
5.5 
Drug Discontinuation .............................................................................................20 
6. TREATMENT MODIFICATIONS/MANAGEMENT  ............................................................21 
7. 
ADVERSE EVENTS REPORTING REQUIREMENTS .................................................21 
7.1   
Protocol Agents ......................................................................................................21 
7.2  
Adverse Events and Serious Adverse Events  .......................................................21 
7.3 
Adverse Events for Commercial Study Agents .....................................................22 
7.4 
Expedited Reporting of Adverse Events  ...............................................................23 
8. 
Investigator REGISTRATION and STUDY ENTRY PROCEDURES  ...........................25 
8.1  
Registration and Study Entry Procedures ..............................................................25 
8.2 
Patient Enrollment  ................................................................................................28 
9.0 
DRUG INFORMATION ...................................................................................................29 
9.1 
Commercial Agent  ................................................................................................30 
10. 
Pathology/BIOSPECIMEN................................................................................................31 
11. 
SPECIAL studies (Non-Tissue) .........................................................................................31 
11.1 Patient Reported Outcomes and Toxicity Measures  .................................................31 


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11.2 
Optional Online Completion of Patient-Reported QOL Assessments  ..................34 
12. 
DATA AND RECORDS ...................................................................................................36 
12.1 
Data Management/Collection  ...............................................................................36 
12.2 
Summary of Data Submission ...............................................................................37 
12.3 
Data Quality Portal  ...............................................................................................37 
12.4 
Global Reporting/Monitoring ................................................................................38 
13. 
STATISTICAL CONSIDERATIONS...............................................................................38 
13.1 
Study Design ..........................................................................................................38 
13.2 
Study Endpoints .....................................................................................................38 
13.3 
Primary Objectives Study Design ..........................................................................38 
13.4 
Study Monitoring of Primary Objectives ...............................................................40 
13.5 
Accrual/Study Duration Considerations ................................................................40 
13.6 
Secondary or Exploratory Endpoints (including correlative science aims) ...........41 
13.7 
Gender/Ethnicity/Race Distribution.......................................................................44 
APPENDIX I  ................................................................................................................................51 
APPENDIX II  ...............................................................................................................................52 
APPENDIX III ...............................................................................................................................53 
APPENDIX IV...............................................................................................................................55 
APPENDIX V ................................................................................................................................56 
 
 
 


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Step 1: REGISTRATION 
Postmenopausal women with a history of breast or gynecologic 
cancer who have completed surgery, chemotherapy, and/or 
radiation at least 6 months previously. Completion of PHQ4 
and FSFI. 
STRATIFICATION  

Current SSRI use (yes vs. no),  

Aromatase inhibitor use (yes vs. no), and  

Prior pelvic treatment (none vs. pelvic surgery and/or pelvic RT) 
Step 2: RANDOMIZATION  
 
Arm C 

Placebo 1 capsule in a.m. 
x 1 week 

Placebo (2 placebo 
capsules) PO in a.m. x 8 
weeks 

Placebo 1 capsule in a.m. 
daily x 1 week (titration 
off) 
Arm A 

Bupropion 150  mg XL  in 
a.m. x 1 week 

Bupropion 150 mg XL 
(one 150 mg XL and one 
placebo capsule) PO in 
a.m. x 8 weeks 

Placebo one capsule in 
a.m. x 1 week (titration 
off) 
Arm B 

Bupropion 150 mg XL 
in a.m. x 1 week 

Bupropion 300 mg XL 
(two 150mg capsules) 
PO in a.m. x 8 weeks 
(target dose) 

Bupropion 150 mg  XL  
in a.m. x 1 week 
(titration off) 
Optional open label bupropion 
at 150 mg XL once per day, 
may increase to 300 mg XL 
(two 150 mg XL at same time) 
if desired week 2 
preference/response 
 Off study 
 
   NRG CC004 
SCHEMA (08-JUN-2018) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
*Pelvic surgery could be any of the following: hysterectomy, oophorectomy, salpingectomy, 
organ prolapse surgery, vaginal mesh implant, laproscopic removal of endometriosis, any 
surgical removal of endometriosis, minor debulking surgery 
 
XL: extended release 


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1. OBJECTIVES 
1.1 
Primary Objective 
Measure the ability of two dose levels of bupropion, 150 or 300 mg of extended release, 
to improve sexual desire more than a placebo at 9 weeks (8 weeks on the target dose) as 
measured by the desire subscale of the FSFI.   
 
1.2 
Secondary Objectives 
1.2.1    Evaluate the side effects of 150 and 300 mg bupropion extended release and differentiate 
these side effects from those observed in the placebo arm. 
1.2.2    Evaluate the effect of 150 and 300 mg of bupropion extended release on the PROMIS 
fatigue scale, PROMIS sexual desire and satisfaction measure, PHQ-4, and the FSFI total 
score, at 5 and 9 weeks, as well as the desire subscale score of the FSFI at 5 weeks. 
1.2.3    Evaluate the effect of 150 and 300 mg of bupropion extended release on the Global 
Impression of Change scale and the patient’s perception of risk vs. benefit at 5 weeks (4 
weeks at target dose) and 9 weeks (8 weeks at target dose). 
 
2. BACKGROUND 
Prevalence and importance of female sexual health as a survivorship issue. 
According to the American Cancer Society, as of January, 2014, there were 14.5 million 
cancer survivors (Cancer Facts & Figures 2015). Of the female survivors (7,607,230), 55% of 
those have been diagnosed with breast or some form of gynecologic cancer (Cancer 
Treatment and Survivorship Facts & Figures 2014-2015). By 2024, the number of survivors 
is expected to grow to 19 million, with over half of those, 9.6 million, being female. 
Therefore, addressing chronic negative sequelae for women in the aftermath of a cancer 
diagnosis and its treatments becomes a health imperative.  
 
One prevalent consequence of treatment in some types of cancer is decreased sexual health, 
particularly for women with estrogen sensitive tumors due to estrogen deprivation. Sexual 
health can be defined as well being in relation to sexuality, which is a core aspect of 
humanity (WHO Reproductive Health Topics: Sexual Health 2015) The prevalence of sexual 
health concerns for female cancer survivors in published data ranges from 30 to 100% (Speer 
et al. 2015, Gilbert et al. 2011, Andersen et al. 2007, Burwell et al. 2006, Krychman and 
Millheiser 2013, Biglia et al. 2010) and the descriptive literature is fairly consistent 
demonstrating specific problems that comprise the concept of sexual health as including 
lubrication, dyspareunia, desire, body image, increased fatigue, and relationship concerns 
(Ganz et al. 1998, Carmack Taylor et al. 2004). Changes in sexual health are common after 
surgery, chemotherapy, radiation therapy, and endocrine therapy (estrogen inhibition), and 
although some studies demonstrate improvement over time, other studies reveal that negative 
sexual health can persist over many years (Burwell et al. 2006). The issues related to sexual 
health and functioning may be slightly different for survivors of breast versus gynecologic 
cancer, but existing literature demonstrates much overlap and almost identical importance 
with sexual changes being one of the most commonly reported after treatment for both 
groups (Burwell et al. 2006, Ganz and Greendale 2007). Perhaps most importantly, sexual 
function is important enough for female cancer survivors that they continue to be sexually 
active despite significant discomfort. A 5-year longitudinal study by Malinovszky showed 
that women with breast cancer note continued decline in pleasure and increase in pain with 


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intercourse over 5 years despite a return to usual sexual activity by 2 years (Malinovszky et 
al. 2006). These data provide support for the idea that sexual behavior is a necessary part of 
life that women may engage in despite pain and reduced pleasure. Efforts to improve this 
scenario are needed. 
 
The Principal Investigator of this concept has a program of research to improve sexual health 
outcomes in female survivors of breast and gynecologic cancer, as sexual related issues are 
similar in these two female cancer groups. Since female sexual health is a multi-component 
concept that is influenced by the various specific symptoms reviewed in the paragraph above 
(self-image, vaginal atrophy, desire, relationships and fatigue), a multi-faceted approach is 
warranted. This is supported by an inspirational early editorial by Dr. Ganz (Ganz and 
Greendale 2007) stating that as sexual desire, responsiveness and satisfaction, in essence 
sexual health, can be affected by numerous things, when attempting to evaluate treatment, 
several issues must be considered. Therefore, the study represented in this proposal is one of 
4 interventions being tested for related components of sexual health that together will 
comprise a multi-component intervention targeted toward 4 known prevalent predictors of 
sexual health in female cancer survivors: vaginal atrophy, self-image, sexual desire and 
partner concerns. Dr. Barton already completed a study addressing vaginal atrophy (Alliance 
N10C1) and is currently recruiting women for a randomized phase II study evaluating 
hypnosis for self-image. The study proposed in this concept addresses the construct of sexual 
desire and if this study is positive, it will be added to other effective treatments for the above 
mentioned predictors to provide a comprehensive approach to sexual health that can be 
individualized to meet a woman’s needs.  
 
What is sexual desire?   
There is a lot of controversy in the literature about what constitutes female sexual desire, 
often called libido (Bancroft 2005, van Anders 2012). It is clear that sexual desire/libido in 
women is multifactorial and more complex than the similar concept in men, where there is 
more of a linear relationship between arousal and desire. In women, the relationship is not 
linear and it is confounded by relationships and self-image (Basson, 2004). It is also likely 
true that sexual desire may be a bit more complex in women with a cancer history compared 
to women without cancer. Specifically, in the cancer literature when exploring female sexual 
health, there is, conceptually, support that energy (perhaps fatigue) plays a role in sexual 
health and declines as a result of a cancer diagnosis and treatment (Wilmoth et al. 2004).  
Data from our recent vaginal Dehydroepiandrosterone (DHEA) study demonstrate that at 
baseline, vitality explained 13% of overall sexual function (unpublished data). In addition, at 
baseline, women in our vaginal DHEA study reported vigor/energy levels right around the 
50% point (53 out of 100 with higher numbers being better) on the vitality subscale of the 
Medical Outcomes Scale Short Form-36. Further, linear regression modeling of overall 
sexual function at baseline found vitality to be a significant predictor (p=.001) in addition to 
the variables of relationship, severity and bother of vaginal symptoms, and chemically 
induced menopause (unpublished data).       
 
Other studies report findings consistent with ours ( WHO Reproductive Health Topics: 
Sexual Health 20015, Ganz 1998, Carmack Taylor 2004, Ganz and Greendale 2007).  In 
another investigation evaluating sexual outcomes in women with a history of gynecologic 


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cancer, fatigue (measured with the Fatigue Symptom Inventory-revised) was significantly 
correlated with both sexual responsiveness and global satisfaction as measured by the Female 
Sexual Function Index and the Global Sexual Satisfaction Scale, respectively, all well 
validated measures (Carpenter et al. 2009). Based on the aforementioned data, we are 
conceptualizing sexual desire as a term that incorporates having the motivation and necessary 
energy to want to engage in sexual intimacy activity, not only intercourse.  
 
There is also controversy about the role of testosterone in female sexual desire. (Bancroft 
2005, van Anders 2012). The most commonly studied intervention that has been found 
effective in women with hypoactive sexual desire disorder (HSDD) without cancer has been 
transdermal testosterone. However, this intervention has not been effective in improving 
sexual desire/libido in women with a history of cancer (Barton et al. 2007). In research 
performed by Dr. Barton, testosterone was not found to be effective in improving libido in 
female cancer survivors (Barton et al. 2007) despite significant increases in testosterone 
concentrations and contrary to evidence of its benefit in women with hypoactive sexual 
desire disorder (HSDD) or women post menopause (Braunstein et al. 2005, Buster et al. 
2005, Chudakov et al. 2007, Davis et al. 2008, Davis et al. 2006, Goldstat et al. 2003, 
Nathorrst-Boos et al. 2006, Shifren et al. 2000, Shifren et al. 2006, Simon et al. 2005). In 
addition, translational data from that clinical trial demonstrated a lack of significant 
association between testosterone and sexual health outcomes (Barton, Loprinzi et al. 2007).  
 
However, the neurotransmitter, dopamine, has been better characterized than testosterone as 
potentially having a role in sexual motivation or desire in women (Bancroft 2005, Frohlich et 
al. 1999, Hull et al. 1999).  Specific areas of the brain have been found to be associated with 
sexual desire, including the medial preoptic nucleus, nucleus accumbens, and the ventral 
tegmental area. This has been substantiated in functional MRI studies evaluating brain 
function in HSDD compared to women with no such history (Bianchi-Demicheli 2011, 
Arnow et al. 2009). The neurotransmitters that are active in these areas and believed to be 
important in reward-motivation and pleasure are dopamine, norepinephrine, oxytocin and 
melanocortin (Versace et al. 2013). In fact, dopamine is thought to be essential in order to 
promote excitatory neural inputs that are needed for behavior involving motivation. 
Therefore, sexual desire is not simply a response to being aroused; it is embedded in a neural 
response that involves memory, pleasure and emotion and is influenced by positive cues as 
well as inhibition of nonsexual cues (Brom et al. 2014).   
 
2.1 
Preliminary data supporting dopamine reduction with estrogen deprivation. 
Animal and human data provide evidence that estrogen deprivation is associated with a loss 
of dopamine. In one study, after 30 days, estrogen deprivation per ovariectomy in primates 
resulted in over a 30% decrease in dopaminergic cells in the substantia nigra (Hull et al. 
1999). In a study comparing ovariectomized rats with and without estrogen replacement, 
estrogen deprivation reduced striatal dopamine release and locomotor activity while estrogen 
replacement improved both locomotor activity and dopamine release (Bianchi-Demicheli 
2011). Finally, a study in postmenopausal women was conducted to evaluate the impact of 
estrogen therapy on dopaminergic activity. Investigators evaluated dopaminergic tone using a 
measured response of growth hormone to apomorphine, which is a validated measure of 
dopamine tone. Women receiving estrogen therapy had a higher dopaminergic response 


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compared to women who were not receiving estrogen (Arnow et al. 2009).  
 
There are further data to support that inflammatory conditions may have overlap with 
neurologic processes that involve dopamine (Dantzer et al. 2014). The relationship is 
complex, but simply put, areas of the brain that are rich with dopaminergic neurons have also 
been found to be impacted by inflammation (Felger and Miller 2012). Hence, dopamine 
function can be impacted by inflammation (Felger and Miller 2012). Interferon alpha therapy 
is used in these studies to simulate inflammatory processes. In a study in rhesus monkeys, 
after 4 weeks of interferon therapy, dopamine release was reduced when measured by both in 
vivo microdialysis and PET neuroimaging (Felger et al. 2013). An investigation performed 
by Capuron and colleagues demonstrated the same results after 6 weeks of interferon alpha 
administration given to medically stable adults with hepatitis C virus (Capuron et al. 2012).  
Hence, investigators successfully linked pro-inflammatory cytokine activity (a biomarker 
profile associated with fatigue which has also been associated with women diagnosed with 
breast cancer who have fatigue) with decreased activation of brain areas associated with 
reward and decreased dopamine.  
 
In summary, these data support the hypothesis that women post cancer treatment who are 
estrogen deficient may have reduced dopaminergic activity that negatively impacts their 
sexual desire. This situation may be compounded by persistent fatigue that is also associated 
with increased inflammation, which may also be impacting dopaminergic areas of the brain. 
Treatment with a dopaminergic agent may improve sexual motivation outcomes and may 
also, secondarily, improve fatigue. Our working hypothesis is that fatigue may mediate 
sexual desire, however, the mechanism of interest is dopamine, not inflammation, and the 
primary outcome of interest is sexual desire, not fatigue. 
        
2.2 
Preliminary data with dopaminergic agents. 
Despite compelling physiologic data linking dopamine to reward stimuli, motivation and 
reward centers that are critical to sexual desire and data associating estrogen depletion with 
reduced dopamine activity, dopaminergic agents have not been rigorously studied for sexual 
desire in female cancer survivors. In fact, one concern is that few dopaminergic agents have a 
side effect profile conducive to use in a supportive care trial.   
 
Bupropion is a dopaminergic agent worth evaluating with promise to improve sexual desire 
in women with a history of cancer. It is an antidepressant that is chemically distinct as an 
inhibitor of dopamine and noradrenaline reuptake (GlaxoSmithKline 2011).  Bupropion is 
approved for seasonal affective disorder, major depressive disorder (Micromedex Healthcare 
Series 2008),  and smoking cessation.(GlaxoSmithKline 2015). It has been available in the 
US since 1989 as an immediate release formulation, with the sustained release formulation 
becoming available 2003 (Fava et al. 2005). Bupropion has been used in sexual medicine 
clinics to reverse the lack of libido instigated with the use of selective serotonin reuptake 
inhibitor (SSRI) antidepressants. There are limited, but promising, data to support rigorous 
phase II trials to evaluate whether a dose of bupropion would be beneficial to women with a 
history of cancer in boosting sexual desire/energy/motivation without causing intolerable or 
undesirable side effects (Clayton et al. 2006, Croft et al. 1999, Gitlin et al. 2002, Safarinejad 
2011, Segraves et al. 2004, Mathias et al. 2004, Moss et al. 2006).  


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There have been several studies of bupropion in women without cancer with decreases in 
sexual desire. At least four of these studies were randomized placebo controlled trials and all 
demonstrated positive effects of bupropion on sexual desire and other domains of sexual 
function (Clayton et al. 2006, Croft et al. 1999, Gitlin et al. 2002, Safarinejad 2011, Segraves 
et al. 2004). One well-designed double blind trial recruited patients with depression and 
randomized them to bupropion plus sertraline placebo, sertraline plus bupropion placebo or 
double placebos (Croft et al. 1999). The bupropion dose used was 150 mg to 400 mg per day 
of the slow release formula. About 40% of the patients in each arm also had sexual desire 
disorder, but normal sexual functioning. By day 42, significantly fewer patients on bupropion 
still had sexual desire disorder compared to both the sertraline and placebo, despite both 
antidepressant groups experiencing significant and clinically meaningful improvements in 
their depression (Croft et al. 1999). Of note, there was also significantly less orgasmic 
dysfunction in the group receiving bupropion, similar to that in the placebo group, and 
significantly less than the sertraline group. In a randomized placebo-controlled trial of 218 
women who were premenopausal and experiencing decreased libido from treatment with 
SSRI’s, bupropion sustained relaease (SR) 150 mg BID versus placebo was evaluated over 12 
weeks, as adjunctive treatment to their current SSRI antidepressant. The Female Sexual 
Function Index (FSFI) questionnaire was used as the primary endpoint. Statistically significant 
improvements in every domain of sexual function were seen in this study compared to placebo, 
with the exception of pain (Safarinejad 2011), with sexual desire improving the most of all 
domains. The sexual desire subscale improved from 2.2 (below the cut off indicating 
dysfunction) to 4.1 (above the cut off indicating normal desire). Significant improvement in 
the FSFI desire subscale began at the 4 week data point, improved further at 8 weeks and 
improved slightly more at 12 weeks.  In this study, depression was already managed with the 
SSRI, so the bupropion/placebo was intended to target the physiological changes caused by 
the SSRI that negatively impacted sexual desire. 
 
Two studies have been completed in a cancer population. In 20 women with breast cancer, an 
open label trial evaluated 150 mg daily of bupropion for 8 weeks for improvement in sexual 
function. By 4 weeks, women had a mean score on the Arizona Sexual Experience Scale that 
was below the cut off for dysfunction, despite baseline values being above the dysfunction 
cutoff. This improvement was maintained at week 8. The overall improvement on the measure 
was 20% (Mathias et al. 2006). The second study in 21 breast cancer survivors evaluated 
bupropion at a dose of 150 to 300 mg per day for fatigue, depression and quality of life (Moss 
et al. 2006). Bupropion significantly improved fatigue and depression after 4 weeks of a stable 
dose of bupropion. The study did divide the sample into depressed versus non-depressed 
participants using a cut-off score of >17 on the Hamilton Depression Rating Scale. When they 
examined fatigue improvement in this non-depressed group (N=12), there were still significant 
improvements on the total Brief Fatigue Inventory (BFI)  and interference subscales (total 
score at baseline 6.5, at 4 weeks 4.5, p=.03). Therefore, the impact of fatigue in this study does 
not appear to be secondary to improvement in depression. 
 
Recently, a new dopamine and norepinephrine reuptake inhibitor, flibanserin, was approved 
by the FDA to improve hypoactive sexual desire disorder in premenopausal women, but has 
not been studied in female cancer survivors (Sprout Pharmaceuticals 2015).  Flibanserin was 


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however studied in preclinical models and several human clinical trials that began to be 
published in 2012. It gained FDA approval in early summer of 2015 based on three phase III 
randomized controlled trials (Katz et al. 2013, Thorp et al. 2012, Derogatis et al. 2012) with 
co-primary endpoints of sexually satisfying events and the desire subscale of the FSFI.  
 
The positive results and subsequent FDA approval of flibanserin supports the proof of 
concept that dopaminergic agents may improve sexual desire. However, flibanserin was only 
studied in premenopausal women with hypoactive sexual desire disorder, which is likely 
physiologically and psychosocially, a very different situation than women with a history of 
cancer who are postmenopausal and severely estrogen deficient. There are a few other 
reasons why flibanserin is not being suggested as the dopaminergic agent to be studied in this 
proposal. 
 
First, the approved dose had a withdrawal rate in all three studies of 25-30%, half due to 
adverse events (Sprout Pharmaceuticals 2015). The most common adverse events were 
dizziness, somnolence, nausea, fatigue and insomnia. This would be a particularly unwanted 
side effect profile in women with a history of cancer who already likely have fatigue that is 
contributing to their lack of sexual desire. To use an agent that can cause somnolence or 
fatigue is in direct contradiction to our hypothesis that fatigue is the mediating factor for 
sexual desire in a population of female cancer survivors. Second, there appears to be 
theoretically, one key difference in the mechanism of flibanserin and bupropion. That 
difference is that flibanserin is believed to increase dopamine and norepinephrine, but also to 
decrease serotonin (Sprout Pharmaceuticals 2015), whereas bupropion is not thought to affect 
serotonin (GlaxoSmithKline 2015, Fava et al. 2005). This difference may contribute to the 
undesirable side effect profile of flibanserin related to fatigue and somnolence (as these are 
symptoms of low serotonin). This may also be important in a population of estrogen deficient 
female cancer survivors as low serotonin may also be the etiology behind hot flashes and 
therefore, this population may already be serotonin deficient. Therefore, evaluating a drug 
with the intended mechanism of action (dopamine and norepinephrine inhibitor) but without 
additional unwanted activity (decreasing serotonin), a drug without sedating properties that is 
FDA approved for other indications, a drug with a long history of use without significant 
problems, and a drug that is available generically and thus more cost effective, would be of 
more interest.  
 
To this end, we plan to evaluate two doses of bupropion versus a placebo in postmenopausal 
women with a history of breast or gynecologic cancer and low desire to see if there are 
positive effects in these populations without unwanted side effects. As demonstrated in the 
trials with flibanserin (listed in the section “sample and power analysis”) and Dr. Barton’s 
earlier trial evaluating transdermal testosterone for sexual desire (Barton et al. 2004) there is 
a placebo effect present in this research.  Therefore, in order to evaluate whether a phase III 
trial is warranted, it is critical that this phase II dose finding study include a placebo arm in 
order to better determine the estimated effect of both doses of bupropion. This study is 
seeking a positive risk/benefit balance for women struggling with decreased sexual desire 
and will evaluate an effect size, dose, and the best primary endpoint to guide a larger 
definitive phase III clinical trial.    
 


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3. PATIENT SELECTION, ELIGIBILITY AND INELIGIBILITY CRITERIA 
 
 
Note: Per NCI guidelines, exceptions to inclusion and exclusion criteria are not 
permitted.  For questions concerning eligibility, please contact the Biostatistical/Data 
Management Center (via the contact list on the NRG web site).  
 
3.1 
Patient Selection Guidelines  
Although the guidelines provided below (in Section 3.1.1) are not inclusion/exclusion 
criteria, investigators should consider these factors when selecting patients for this trial. 
Investigators also should consider all other relevant factors (medical and non-medical), as 
well as the risks and benefits of the study therapy, when deciding if a patient is an 
appropriate candidate for this trial. 
3.1.1 Patients must have the psychological and cognitive ability and general health that permits 
completion of the study requirements and required follow up. 
 
 
3.2 
Eligibility Criteria (08-Jun-2018) 
Prior to Step 1 Registration 
A patient cannot be considered eligible for this study unless ALL of the following 
conditions are met. 
3.2.1 Score of <9 on the PHQ-4. 
3.2.2 Patients must have a FSFI desire subscale baseline score less than 3.3 
 
NOTE-Both the PHQ4 and FSFI must be completed by the patient and data entered 
in OPEN at Step 1  registration to determine eligibility within 10 days prior to 
registration. Both of these scores will be calculated in the OPEN system once 
submitted as part of Step 1 registration.  An error message will appear once you 
begin Step 2 registration if one or both of  the scores make the patient ineligible. In 
this situation, continue  to complete Step 2 with the reason the patient will not 
continue on the study as “Other” and specify ineligible. 
3.2.3 Diagnosis of breast or gynecologic cancer, all types (examples are DCIS, LCIS, invasive 
breast, ovarian, endometrial, vulvar, cervical and vaginal); 
3.2.4 Completed definitive therapy consisting of surgery, chemotherapy or radiation therapy at 
least 180 days ago (may continue on Herceptin or endocrine therapy);  
3.2.5 Post-menopausal as defined by at least ONE of the following:  
 12 months (365 days) without a period,  
 Bilateral oophorectomy;   
 Chemically induced menopause as long as there are no plans to stop during the 
study; 
 For women 57 and under, if at least one ovary and woman has had hysterectomy, 
must have  FSH (>30mIU/mL) and estradiol in menopausal range per institution’s 
laboratory (generally that is <10 for ultra sensitive assay: <25-30 otherwise); 
(Note: women 58 and older do not have to have hormonal tests) 
  At least one ovary intact, with a uterus, and 180 days without a period with FSH 
(>30mIU/mL) and estradiol in menopausal range per institution’s laboratory 
(generally that is <10 for ultra sensitive assay: <25-30 otherwise) (Note: women 58 
and older do not have to have hormonal tests);; 
3.2.6 Age ≥ 18;  


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3.2.7 History, Physical and Performance Status of 2 or less within 180 days prior to registration. 
3.2.8 Adequate renal and hepatic function  
 AST and ALT < 2.5x ULN 
 Total bilirubin <1.5x ULN 
 Glomerular filtration rate >60ml/min. OR ≤ ULN creatinine per institution normals 
3.2.9 For breast cancer patients only, endocrine therapies are allowed (such as aromatase 
inhibitors, but not current tamoxifen. Prior tamoxifen is permitted with a 30 day wash 
out period).    
3.2.10 Vaginal estrogen is allowed, for all protocol disease sites, if dose equal to or less than that 
in estring (<7.5 mcg) and it has been used for at least 30 days with no plans to stop or alter 
use during the course of the study.  
3.2.11 Antidepressants for mood and hot flashes, including SSRI’s (that are not CYP2D6 
substrates) will be allowed if patients have been on for the last 60 days and the dose is not 
expected to change during the course of the study. Only subthreshold or low dose 
antidepressants will be allowed, not antidepressants that have been titrated up to the highest 
doses for depression management (examples but not a comprehensive list are Lexapro 5-
10 mg, Celexa 10 – 20 mg and Effexor –up to 75 mg is allowed).  
3.2.12 The patient must provide study-specific informed consent prior to study entry/screening. 
3.2.13 Women who report that their motivation/desire for sexual intimacy has decreased since her 
cancer diagnosis. 
3.2.14 Able to swallow whole capsules. 
3.2.15 Proficient in English (due to number of questionnaires not validated in other languages). 
3.2.16 Completion of the FSFI and PHQ4.  Both questionnaries will be required and data entered 
at the time of step 1 registration. 
 
Prior to Step 2 Randomization 
3.2.17 Completion of the following baseline quality of life forms: PHQ4, FSFI, PROMIS sexual 
function and satisfaction, PROMIS fatigue short form 8a, Impact of Treatment Scale, 
PRO-CTCAE items, and Revised Dyadic Adjustment Scale. These quality of life forms 
will be required and data must be entered in RAVE at step 2 registration. If available 
at the time of step 1 registration, step 2 registration can take place immediately after step 
1, but cannot occur more than 30 days after step 1.  Women who do not currently have a 
partner do not have to complete the Revised Dyadic Adjustment Scale.  Enter “no 
partner” for this form.  
 
3.3 
Ineligibility Criteria (9/8/17) 
Patients with any of the following conditions are NOT eligible for this study. 
3.3.1 Diagnosis of depression, Major Depressive Disorder (MDD), suicidal ideations or anxiety 
disorders in the past 5 years per the medical chart based on DSM IV diagnoses. 
3.3.2    Seizure disorders 
3.3.3    Current or history of anorexia or bulimia in the past 5 years 
3.3.4    Allergy to bupropion 
3.3.5    Use of drugs primarily metabolized by CYP2D6; these are called CYP2D6 substrates.  
This is because bupropion is a strong CYP2D6 inhibitor so it will decrease the rate of 
metabolism of drugs that are CYP2D6 substrates (see Appendix I for a PARTIAL list of 
drugs and resources to look up drugs) 


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3.3.6    Stage IV cancer  
3.3.7    History of Parkinson’s Disease, multiple sclerosis or fibromyalgia  
3.3.8    Extensive pelvic exenteration surgery, surgeries which include partial or total 
vaginectomy with or without reconstruction; radical vulvectomy with or without remove 
of clitoris     
3.3.9    Women who are currently undergoing or planning to undergo reconstruction surgery 
during the course of the study. Women who have completed reconstruction surgery must 
be 30 days from surgery. 
3.3.10 Oral or transdermal estrogen therapy is not allowed 
3.3.11 Males are not permitted to participate 
3.3.12 Patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbituates, and 
antiepileptic drugs after chronic use 
3.3.13 Patients who discontinue MAO-I’s within 14 days prior to starting the investigational 
drug 
3.3.14 Poorly controlled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg) 
on three or more readings in the past 12 months. 
3.3.15 Patients with active bipolar disorder 
3.3.16 Patients with impaired decision making as determined by the treating physician 
3.3.17 Concurrent use of bupropion 
3.3.18 Concomitant invasive malignancy requiring treatment other than non-melanomatous skin 
cancer. 
3.3.19 Previous or concurrent use of flibanserin. 
 
4. REQUIREMENTS FOR STUDY ENTRY, TREATMENT, AND FOLLOW-UP  
 
PRE-TREATMENT ASSESSMENTS (07-Jun-2019) 
Prior to Step 1 Registration 
Assessments 
Prior to Step 1 Registration 
 (calendar days) 
Diagnosis of breast or gynecologic cancer (DCIS, LCIS, 
invasive breast, ovarian, endometrial, vulvar cervical and 
vaginal) 
X  
Completed definitive therapy consisting of surgery, 
chemotherapy and/OR radiation therapy (patients may continue 
on Herceptin,  endocrine therapy or perjeta) 
X (180 days) 
Post menopausal as defined in Section 3.2.5 
X (365 days) 
History/Physical/Performance Status 
X (180 days) 
Concomitant medication review 
X (14 days) 
Adequate renal and hepatic function (See Section 3.2.8) 
X (180 days) 
PHQ4* and Female Sexual Function Index (FSFI) 
X (10 days) 
 
 
 
 
 
Prior to Step 2 Registration 


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Assessments 
Prior to Step 2 Registration 
Patient Reported Ouctomes**  
 PRO-CTCAE 
 PROMIS sexual function and satisfaction 
 PROMIS fatigue short form 8a 
 Impact of Treatment Scale 
 Revised Dyadic Adjustment Scale 
X  
(Need to be completed and data 
entered at Step 2 Registration) 
*See Appendix III for details on how to report emergent and non-emergent issues related to 
PHQ-4 scoring and reporting.  If participants score 6-8 on the PHQ-4 at any of the time points, 
they should be offered mental health resources (see Appendix III).  If participants score 9 or 
higher, they should receive an immediate referral for an assessment (see Appendix III).   
 
**Patient reported outcomes are recommended to be completed at the time of consenting and at 
step 1 visit.  They can also be completed at the time of step 2 as the PHQ4 and FSFI must be 
uploaded and reviewed in order for the patient to move on to step 2. 
 
ASSESSMENTS DURING TREATMENT 
Assessments 
Week 1  
Week 2 
Week 5  
Week 7 
Week 9  
Female Sexual 
Function index 
 
 
X  
 
X  
PROMIS sexual 
function and 
satisfaction 
 
 
X  
 
X  
PROMIS fatigue 
short form 8a 
 
 
X  
 
X  
PHQ-4 
 
 
X  
 
X  
Global Impression 
of Change and 
satisfaction with 
treatment 
 
 
 
 
X  
PRO-CTCAE* 
X 
X 
X 
X 
X 
Solicited Adverse 
Event Assessment 
(CTCAE)** 
X 
X 
X 
X 
X 
Collection of 
study drug dose   
X 
X 
X 
X 
X 
Adverse Event 
Assessment# 
X 
X 
X 
X 
X 
Concurrent 
Medications 
X 
X 
X 
X 
X 
Risk Benefit Form 
 
 
 
 
X 
*PRO-CTCAE and **CTCAE should be completed at the end of week 1, 2, and 7 in 
addition to weeks 5 and 9 to ensure patient is tolerating the study drug. These 
questionnaires may be completed by telephone, mail or an office visit and documented in 
the patient’s record. Patients who consent to VisionTree will complete the PRO-CTCAE 
form in VisionTree Optimal Care (VTOC). 


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# Adverse Event Assessments (CTCAE) will be collected by telephone or an office visit.  
 
ASSESSMENTS FOR PATIENTS CONTINUING ON BUPROPION (See Appendix II) 
Assessments 
Week 4 and 8 (if patient continues on 
bupropion) 
Female Sexual Function Index 
X 
PHQ-4 
X 
PROMIS fatigue short form 8a 
X 
PROMIS sexual function and satisfaction 
X 
Adverse Event Assessment 
X 
 
Patient-Reported Outcomes 
All patient-reported outcomes completed during and after treatment should be completed within 
the following timeframes: 
 Week 1 (day 7) during treatment: Days 5-11 during treatment 
 Week 2 (day 14) during treatment: Days 12-23 during treatment 
 Week 5 (day 35) during treatment: Days 30-41 during treatment 
 Week 7 (day 49) during treatment: Days 44-55 during treatment 
 Week 9 (day 63) during treatment: +/- 1 week (days 56-70) 
 Week 4 during open label: +/- 1 week 
 Week 8 during open label: +/- 1 week 
 
5. TREATMENT PLAN/REGIMEN DESCRIPTION 
Two doses of bupropion XL, 150 and 300 mg, will be tested over 8 weeks at the target dose 
as a response has been seen within that time frame; however, we will evaluate effects at 5 
weeks (4 weeks at the target dose) as a secondary outcome to evaluate time to benefit for a 
larger, well powered study. 
 
The drug will be titrated and taken as described below. There will be a one week titration, 8 
weeks at the target dose, and one week titration off of the drug.  Patients should be instructed 
that the study drug needs to be increased and decreased slowly, over one week, and therefore 
doses should not be skipped nor should their assigned treatment be stopped abruptly.  Any 
issues with tolerating or staying on the study drug should be discussed with their study 
doctor.   
 
5.1 
Study agent (08-Jun-2018) 
Protocol treatment must begin within 21 days after randomization. 
 
5.1.1 Study drug and placebo will be identical looking capsules.  Patients will be randomized 
to treatment arm, A, B, or C.  Each arm will have a designated study treatment kit that 
will contain 4 bottles labeled 1, 2A and 2B, and 3.  All patients in each arm will follow 
the exact same procedure for taking their assigned treatment.  A patient instruction sheet 
will be included in each kit.  Instruct patients to read and follow the directions carefully. 
Patients should also be instructed to call the research personnel if they have any 
intolerance and wish to stop the study drug. Patients should not stop the medication on 
their own and they should not alter the number of pills taken. 


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The study agent will be taken orally for a total of 10 weeks according to the treatment 
arm assignment below. Do not chew, cut or crush the tablets. 
            Arm A  
 
Days 1-7 (1 week): Bupropion 150mg XL every morning. Patients will take one 
capsulefrom bottle marked 1.  
 
Days 8-63 (8 weeks): Bupropion 150mg XL and one placebo capsule every 
morning.Patients will take one capsule from the bottle marked 2A and one capsule from 
the bottle marked 2B. 
 
 
 
Days 64-70 (1 week): Placebo capsule every morning (tritration off week). Patients will 
take one capsule every morning from the bottle marked 3. 
           
            Arm B 
 
Days 1-7 (1 week): Bupropion 150mg XLevery morning. Patients will take one capsule 
every morning from the bottle marked 1.  
             
 
Days 8-63 (8 weeks): Bupropion 300mg XL every morning. Patients will take one 
capsule form the bottle marked 2A and one capsule from the bottle marked 2B for a daily 
dose of 300mg. 
 
            Days 64-70 (1 week): Bupropion 150 XL every morning (titration off week). Patients will 
take one capsule every morning from the bottle marked 3. 
 
            Arm C 
 
Days 1-7 (1 week): One placebo capsule every  morning. Patients will take one capsule 
from the bottle marked 1. 
             
 
Days 8-63 (8 weeks): Two placebo capsules every morning. Patients will take one 
capsule from the bottle marked 2A and one capsule from the bottle marked 2B.  
 
Days 64-70 (1 week): One placebo capusule every morning (titration off week). Patients 
will take one capsule every morning from the bottle marked 3. 
 
Patients who have been on the placebo arm can be offered the opportunity to receive 
bupropion 150 or 300 mg XL for a total of 8 weeks.  This includes a week to titrate up 
and a week to titrate down if the desired dose is 300 mg XL.  See Appendix II for further 
details. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines (08-Jun-2018) 
5.2.1 Prohibited Therapies 
 Oral or transdermal estrogen. 
 Medications metabolized by CYP 2D6 as in Appendix I, such as tamoxifen, other 
SSRIs. 
 Flibanserin 


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5.2.2 Participation in Other Trials  
Participation in other symptom trials is allowed as long as the trial does not focus on the 
management of sexual health or fatigue in any way. 
 
5.3 
Emergency Unblinding Procedure (08-Jun-2018) 
The decision to break the unblinding code must be based on a serious adverse event 
unexpected for the study drug and related to the study drug or extraordinary clinical 
circumstance for which knowledge of drug assignment will affect clinical judgment. The 
blind ordinarily should be broken for unexpected adverse events related to the study drug 
(e.g., safety reports submitted to the FDA and all participating investigators). All cases 
that are emergently unblinded must be reported to the NCI Central IRB (CIRB). 
 
Sites can call NRG Headquarters during business hours (8:30 AM to 5 PM ET), at 215-
574-3150 and ask to speak to the Supporting Study Statistician. For after hours, weekends, 
and holidays, call 215-940-8902. 
 
Optional Open Label Phase 
Patients who have been on the placebo arm can be offered the opportunity to receive 
bupropion 150 or 300 mg XL for a total of 8 weeks.  This includes a week to titrate up and 
a week to titrate down if the desired dose is 300 mg XL.  NRG Headquarters will unblind 
patients on the placbo arm only once all study data has been submitted. Patients who were 
randomized to the placebo arm will have a new form located in the week 10 folder in Rave 
called “Patient Crossover” once all data has been submitted for all nine weeks.  If the 
patient decides to crossover and has previously consented to participate in VisionTree, the 
RA must go back into the patient’s Vision Tree account and activate the  placebo template  
See Appendix II for further details. 
 
5.4 
Duration of Therapy 
For the double-blind portion of the study in the absence of treatment delays due to 
adverse event(s), treatment may continue as specified, over 10 weeks, or until one of the 
following criteria applies: 
 Intercurrent illness that prevents further administration of treatment, 
 Unacceptable adverse event(s), as described in Section 7 
 Patient decides to withdraw consent for participation in the study, or 
 General or specific changes in the patient's condition render the patient 
unacceptable for further treatment in the judgment of the investigator. 
 
5.5 
Drug Discontinuation (08-Jun-2018) 
Drug must be discontinued for patients who have documented allergic reaction at any 
grade.  Due to the nature of the blinding, drug cannot be dose reduced and due to the 
nature of bupropion and the need to titrate, drug cannot be stopped and restarted.  Hence,  
participants who experience any grade 1, 2 or 3 (expected) event that is not tolerable 
will have study drug discontinued upon discussion between the provider and participant.  
Grade 3 unexpected events attributable to the study drug will result in permanent study 
drug discontinuation.  Any grade 4 event will result in permanent study drug 
discontinuation. 


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Patients who wish to stop therapy due to intolerable side effects or any other desire to 
withdraw early from the study will need to titrate off of the study drug. For instances of 
early treatment discontinuation, NRG will not reveal treatment assignment but will require 
all patients taper off study drug by one capsule from bottle 3 for one week and then can 
stop the study drug.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. TREATMENT MODIFICATIONS/MANAGEMENT (08-JUN-2018) 
Due to the nature of the blinding, patients will not be allowed to modify their dose.  If 
patients are experiencing unwanted side effects, they may discontinue study drug as outlined 
in Section 5.5.   
 
If a patient forgets to take their morning dose, but remembers within 6 hours, they can still 
take their assigned dose.  If it is over 6 hours, they should wait until the next day.  Patients 
should NOT take extra doses. 
 
During the phone contact time points described in section 7.3.1, assess the tolerability of any 
reported adverse events. Discontinue the study drug per section 5.5. 
 
NOTE: PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action  
 
7. ADVERSE EVENTS REPORTING REQUIREMENTS 
7.1   
Protocol Agents 
Commercial Agents 
The commercial agents in NRG-CC004 are bupropion 150mg XL. 
 
 
7.2  
Adverse Events and Serious Adverse Events (08-Jun-2018) 
7.2.1 This study will utilize the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 for CTEP-AERS (CTEP Adverse Event Reporting System) CAERs 
CTCAE 5.0 
Grade 
Action 
Grade 1, 2 or 
3 (expected) 
Discontinue study drug for any adverse events that 
participants find not tolerable after discussion between the 
provider and participant. 
Grade 3 
unexpected 
and 
attributable to 
study drug 
Discontinue study drug permanently 
Grade 4, 1st 
appearance 
Discontinue permanently 


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reporting of adverse events (AEs), located on the CTEP web site, 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.   
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 will be utilized until March 31, 2018, 
for all AE reporting, CTEP-AERS reporting and case report forms. CTCAE version 5.0 
will be utilized for CTEP-AERS reporting beginning April 1, 2018. All study case report 
forms will continue to use CTCAE version 4.0. All appropriate treatment areas should 
have access to a copy of CTCAE versions 4.0 and 5.0, which can be downloaded from 
the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
7.2.2 Definition of an Adverse Event (AE) 
Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  Therefore, an AE can be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not 
considered related to the medicinal (investigational) product (attribution of unrelated, 
unlikely, possible, probable, or definite). (International Conference on Harmonisation 
[ICH], E2A, E6).  
 
7.3 
Adverse Events for Commercial Study Agents (08-Jun-2018) 
Refer to the package insert for detailed pharmacologic and safety information 
Side effects at doses of 300 mg/day (XL or SR formulation) with a prevalence of 5% or 
greater are listed: headache (XL 34%, SR 26%, plac 23%), nausea (XL & SR 13%, plac 
8%), dry mouth (XL 26%, SR 17%, plac 7%), constipation (XL 9%, SR 10%, plac 7%), 
insomnia (SR 11%, plac 6%), infection (plac 6%, SR 8%, XL 9%)  and diarrhea (plac 
6%, SR 5%, XL 7%) and dizziness (XL 6%, SR 7%, plac 5%) (GlaxoSmithKine 2011, 
Micromedex Healthcare Series 2008, GlaxoSmithKline 2015, Fava et al. 2005, 
Dailymed). In addition, bupropion can be associated with anorexia, resulting in 5 pound 
weight loss in studies for about 23% of participants versus 11% on placebo, the XL is 
associated with nasopharyngeal effects (13% versus 12% placebo) and the SR 
formulation is associated with tremors (6% versus 1% in placebo).  
 
Note the black box warning for suicidal thoughts and behaviors in patients being treated 
for depression and neuropsychiatric reactions in patients taking bupropion sustained 
release for smoking cessation. Please see the package insert for a detailed discussion of 
the black box warning.   
 
The following adverse events must be reported expeditiously:  any grade psychiatric 
serious adverse events  
 
7.3.1 Solicited Adverse Events and PRO-CTCAE  
Clinician graded CTCAE is the AE (adverse event) safety standard. PRO-CTCAE items 
are to complement CTCAE reporting. Patients will respond to PRO-CTCAE items but no 
protocol directed action will be taken. The specific PRO-CTCAE items for this protocol 


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can be found on the forms section of the CTSU protocol webpage and is titled “NRG-
CC004 NCI PRO-CTCAE Item Library.” PRO-CTCAE is not intended for expedited 
reporting, real time review or safety reporting. PRO-CTCAE data are exploratory and not 
currently intended for use in data safety monitoring or adverse event stopping rules. 
 
NOTE: PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action 
 
 
 
 
Collect the following solicited adverse events (CTCAE v.4):  tremor, dizziness, 
insomnia, headache, dry mouth, anorexia, nausea, constipation, nasal congestion and 
pharyngolaryngeal pain.  
 
The patient will complete the PRO-CTCAE items dizziness, insomnia, headache, dry 
mouth, decreased appetite, nausea, constipation and the RA will assess for the solicited 
AEs (CTCAE v. 4 items) at phone contact points with the patient. This will include at the 
end of weeks 1, 2, 5, 7 and 9. These phone call points are associated with key events in 
the study. The end of week 1 is to evaluate the ability to titrate to the assigned dose. Even 
though the CRA  will be blinded, it will be important for study personnel to contact 
patients at the end of week 1 to evaluate whether they experienced any unwanted effects 
that would result in their unwillingness to continue with the study. The end of week 2 
coincides with being at the target dose and this contact is again to evaluate whether there 
are tolerance issues. The end of week 5 is a time when some secondary endpoints need to 
be completed so this contact will serve as that reminder as well as AE evaluation. The 
end of week 7 contact will encourage continued engagement in the study and the end of 
week 9 is the end of the study when the measures will also need to be completed. 
 
Solicited Adverse Events CTCAE v. 4 
PRO-CTCAE Iterms with (Attributes) 
Dizziness 
Dizziness (severity, interference) 
Insomnia 
Insomnia (severity, interference) 
Headache 
Headache (frequency, severity, 
interference) 
Dry mouth 
Dry mouth (severity) 
Anorexia 
Decreased appetite (severity, interference) 
Nausea 
Nausea (frequency, severity) 
Constipation 
Constipation (severity) 
Tremor 
 
Nasal congestion 
 
Pharyngolaryngeal pain 
 
 
7.4 
Expedited Reporting of Adverse Events (08-Jun-2018) 
All serious adverse events that meet expedited reporting criteria defined in the reporting 
table below will be reported via the CTEP Adverse Event Reporting System, CTEP-
AERS, accessed via the CTEP web site,  
https://eapps-ctep.nci.nih.gov/ctepaers/pages/task?rand=1390853489613 
 
Submitting a report via CTEP-AERS serves as notification to the NRG 
Biostatistical/Data Management Center and satisfies NRG requirements for expedited 


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adverse event reporting. 
 
In the rare event when Internet connectivity is disrupted, a 24-hour notification must be 
made to the NRG Biostatistical/Data Management Center by phone, (number to be 
provided). An electronic report must be submitted immediately upon re-establishment of 
the Internet connection. 
 
7.4.1 Expedited Reporting Methods 
 CTEP-AERS-24 Hour Notification requires that a CTEP-AERS 24-hour notification 
is electronically submitted within 24 hours of learning of the adverse event. Each 
CTEP-AERS24-hour notification must be followed by a complete report within 5 
days. Supporting source documentation is requested by NRG as needed to complete 
adverse event review. Supporting source documentation should include the protocol 
number, patient ID number, and CTEP-AERS ticket number on each page. For 
instructions to submit supporting documentation to the NRG Oncology at 1-215-574-
3191.  
 A serious adverse event that meets expedited reporting criteria outlined in the AE 
Reporting Tables but is assessed by the CTEP-AERS as “an action not 
recommended” must still be reported to fulfill NRG safety reporting obligations. Sites 
must bypass the “NOT recommended” assessment; the CTEP-AERS allows 
submission of all reports regardless of the results of the assessment.  
 
7.4.2 Expedited Reporting Requirements for Adverse Events  
 
 
Any Phase Study Utilizing a Commercial Agent1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor ANY Serious Adverse Events, whether or not they are considered 
related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered 
serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-AERS within 
the timeframes detailed in the table below. 
Attribution 
 
Grade 3 
Grade 4 
Grade 5 
Unexpected 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
Unlikely 
 
 
10 day 
10 day 


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Possible 
Probable 
Definite 
 
10 day 
24-h/5 day 
 
24-h/5 day 
24-h/5 day 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning of the 
AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and 
have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
 
Unexpected Grade 4 and all Grade 5 AEs 
 
 
Inclusions to expedited reporting:  any grade psychiatric serious adverse events.  
 
7.4.3 Reporting to the Site IRB/REB 
Investigators will report serious adverse events to the local Institutional Review Board 
(IRB) or Research Ethics Board (REB) responsible for oversight of the patient according 
to institutional policy. 
 
8. INVESTIGATOR REGISTRATION AND STUDY ENTRY PROCEDURES (07-JUN-
2019) 
8.1  
Registration and Study Entry Procedures  
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., 
clinical site staff requiring write access to OPEN, Rave, or acting as a primary site 
contact) must complete their annual registration using CTEP’s web-based Registration 
and Credential Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
 IVR — MD, DO, or international equivalent; 
 NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
 AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications (e.g., Roster Update Management System (RUMS), OPEN, Rave,); 
 Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
 Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 


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Documentation Required 
IVR NPIVR AP 
A 
AB 
FDA Form 1572 
✔ 
✔ 
Financial Disclosure Form 
✔ 
✔ 
✔ 
NCI Biosketch (education, training, employment, license, 
and certification) 
✔ 
✔ 
✔ 
GCP training 
✔ 
✔ 
✔ 
Agent Shipment Form (if applicable) 
✔ 
 
 
 
 
CV (optional) 
✔ 
✔ 
✔ 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all 
CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In addition, IVRs and 
NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
 Addition to a site roster; 
 Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
 Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
 
Additional information is located on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR 
Help Desk by email at RCRHelpDesk@nih.gov. 
 
 
8.1.1 Cancer Trials Support Unit Registration Procedures  
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
IRB Approval  
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 


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network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by emailing the email address above or calling 1-888-651-
CTSU (2878). 
Sites using their local IRB or REB, must submit their approval to the CTSU Regulatory 
Office using the Regulatory Submission Portal located in the Regulatory section of the 
CTSU website. Acceptable documentation of local IRB/REB approval includes: 
 Local IRB documentation; 
 IRB-signed CTSU IRB Certification Form; and/or 
 Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form. 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria to complete processing of the 
IRB/REB approval record: 
 Holds an Active CTEP status; 
 Rostered at the site on the IRB/REB approval and on at least one participating 
roster; 
 If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
 Includes the IRB number of the IRB providing approval in the Form FDA 1572 in 
the RCR profile; and 
 Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements for Protocol NRG-CC004 Site Registration 
Additional requirements to obtain an approved site registration status include: 
 An active Federal Wide Assurance (FWA) number; 
 An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); 
 Study Agent Shipment Form (SASF) (see section 8.1.3); and 
 Compliance with all protocol-specific requirements (PSRs) 
 
Upon site registration approval in RSS, the enrolling site may access OPEN to complete 
enrollments. The enrolling site will select their credentialed provider treating the subject 
in the OPEN credentialing screen, and may need to answer additional questions related to 
treatment in the eligibility checklist.   
 
8.1.2 Downloading Site Registration Documents:   
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be associated 
with the LPO or a PO on the protocol.  


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 Log on to the CTSU members’ website (https://www.ctsu.org) using your CTEP-
IAM username and password; 
 Click on Protocols in the upper left of your screen 
o Enter the protocol number in the search field at the top of the protocol tree, 
or 
o Click on the By Lead Organization folder to expand, then select NRG 
Oncology and protocol number NRG-CC004; 
 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB initiative, IRB data will load 
automatically to the CTSU as described above.)  
 
Submitting Regulatory Documents:  
Submit required forms and documents to the CTSU Regulatory Office via the 
Regulatory Submission Portal on the CTSU website.  
To access the Regulatory Submission Portal log on to the CTSU members’ website  
Regulatory  Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in 
order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
You can verify your site’s registration status on the members’ side of the CTSU website.  
 Log on to the CTSU members’ website; 
 Click on Regulatory  at the top of your screen; 
 Click on Site Registration;  
 Enter your 5-character CTEP Institution Code and click on Go. 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol requirements 
for individuals participating on the protocol or the enrolling investigator’s status with the 
NCI or their affiliated networks. 
 
8.1.3 Pre-Registration Requirements for the Initial Shipment of bupropion  
All site pre-registration requirements must be met before registering the first case. 
Institutions must electronically complete (versus hand write) a SASF available on the 
NRG web site. The completed SASF document must be submitted to the CTSU via the 
Regulatory Submission portal (sign in at www.ctsu.org, and select the Regulatory 
Submission sub-tab under the Regulatory tab).  
 
8.2 
Patient Enrollment (08-Jun-2018) 
Patient registration and randomization can occur only after evaluation for eligibility is 
complete, eligibility criteria have been met, and the study site is listed as ‘approved’ in the 


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CTSU RSS.  Patients must have signed and dated all applicable consents and authorization 
forms.   
 
8.2.1 Oncology Patient Enrollment Network (OPEN)  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access:   
 A valid CTEP-IAM account; 
 To perform enrollments or request slot reservations:  Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold 
a minimum of an AP registration type; 
 Have an approved site registration for a protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR.  
Prior to accessing OPEN, site staff should verify the following: 
 Patient has met all eligibility criteria within the protocol stated timeframes; and  
 All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
In the event that the OPEN system is not accessible, participating sites can contact NRG 
web support for assistance with web registration at websupport@acr.org or call the NRG 
Registration Desk at 215-571-3191, Monday through Friday, 8:30 a.m. to 5:00 p.m. ET. 
The registrar will ask the site to fax in the eligibility checklist and will need the registering 
individual’s e-mail address and/or return fax number. This information is required to assure 
that mechanisms usually triggered by the OPEN web registration system (e.g. drug 
shipment and confirmation of registration) will occur.  
 
9.0 DRUG INFORMATION  
 


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9.1 
Commercial Agent (08-Jun-2018)  
 
Sites must refer to the package insert for detailed pharmacologic and safety information.  
 
The use of drug(s) or combination of drugs in this protocol meet the criteria described 
under Title 21 CFR 312.2(b) for IND exemption. 
 
9.1.1 Adverse Events 
 
Please refer to the package insert and Section 7.3. 
 
9.1.2 Availability/Supply (07-JUN-2019) 
Bupropion 150 mg XL and Matching Placebo will be distributed by a vendor Clinical 
Research Services, a division of RxCrossroads by McKesson.. The investigator, or 
responsible party designated by the investigator, must maintain a careful record of the 
receipt, distribution, and return of all drugs received from Clinical Research Services 
according to good clinical practices.  
 
The Study Agent Shipment Form (SASF) must be submitted to the CTSU Regulatory 
Office via the Regulatory Submission Portal as soon as the individual responsible for the 
study agent has been identified. The SASF is available on the NRG website.   
 
The drug supply will not be shipped by Clinical Research Services until the patient has 
been randomized. NRG Oncology will notify Clinical Research Services to initiate each of 
these shipments after randomization of the patient. Clinical Research Services will ship 
drug for patients randomized to Arm A, Arm B, and Arm C. Patients will receive a supply 
of Bupropion 150 mg XL or Matching Placebo for the entire treatment (Days 1-70). Each 
patient will receive one kit that contains 4 bottles labeled 1, 2A, 2B and 3 as well as a 
patient instruction sheet. If a patient requires additional study drug for any reason, the site 
will need to contact Clinical Research Services directly to request additional study drug. In 
addition, Clinical Research Services will ship open label bottles to the site for patients who 
were on placebo and register for the open label phase (see Appendix II for additional 
details). 
 
Upon notification of a new patient enrollment, Clinical Research Services will place an 
outbound call to the site contact to confirm that the site’s shipment is being processed. 
Clinical Research Services’  distribution team will monitor packages throughout the 
duration of transit via the FedEx web site and FedEx One Call Solution (live support). 
Real-time monitoring enables Clinical Research Services to mitigate potential delivery 
delays. 
 
Clinical Research Services will ship drug to sites in the U.S., according to the following 
schedule: 
 
NRG-CC004 Shipment Schedule 
Patient 
Randomized 
Initial e-order 
sent by NRG 
Oncology 
Initial e-order 
received by CRS 
(before  2 pm 
ET) 
Initial order 
shipped by CRS 
Initial order 
received at site 


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Version Date:  June 07, 2019 
Monday 
Monday 
Monday 
 Monday 
  Tuesday 
Tuesday 
Tuesday 
Tuesday 
 Tuesday 
 Wednesday 
Wednesday 
Wednesday 
Wednesday 
 Wednesday 
 Thursday  
Thursday 
Thursday 
Thursday 
 Thursday 
 Friday  
Friday 
Friday 
Friday 
 Friday 
Monday 
 
Drug deliveries are restricted during weekends and holidays. Clinical Research Services 
observes the following holidays: New Year’s Day, Memorial Day, Independence Day, 
Labor Day, Thanksgiving Day, the Friday following Thanksgiving Day, Christmas Eve, 
and Christmas Day. Sites should plan ahead to accommodate patients being treated during 
restricted times. 
 
Please contact the drug distributor listed in the protocol directly for shipment 
tracking information and anticipated delivery dates or if a shipment has not been 
received by the expected date.  
 
At the completion of the study, unused supplies will be destroyed at the site according to 
the institution's policy for drug destruction. A drug destruction form is available on the 
NRG website. Please complete and send the form to Clinical Research Services (see 
below for contact information). 
 
Questions about supply and delivery should be directed to: 
 
Clinical Research Services, a division of RxCrossroads by McKesson 
845 Regent Blvd. 
Suite 100B 
Irving, TX 75063 
Email: clinicalresearchservices@mckesson.com 
Toll Free: 800-693-4906 
 
10. PATHOLOGY/BIOSPECIMEN    
Not applicable for this trial. 
 
11. SPECIAL STUDIES (NON-TISSUE) 
 
11.1 Patient Reported Outcomes and Toxicity Measures (08-Jun-2018) 
All measures can be found on the NRG Oncology website under the protocol specific 
page. All scoring, including at registration, will be conducted by NRG Oncology. 
 
Female Sexual Function Index (Weigel, Meston and Rosen 2005)  
The Female Sexual Function Index is a relatively brief measure (19 items) that has been 
developed and validated to be used across the age range of women, including 
postmenopausal women. Its conceptualization came out of an evolving understanding of 
female sexual functioning in recent years. It is a multi-dimensional measure that covers 
the major domains of female sexual functioning including desire, arousal, satisfaction and 
orgasm. Additionally, it addresses lubrication and pain. Its discriminate validity is based 


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on its ability to differentiate women diagnosed with female sexual arousal disorder from 
normal controls. The FSFI looks at measures of both frequency and desire in each 
domain as well as satisfaction in most domains. The desire subscale consists of two items 
and has a range of 1.2 to 6 when scored. A cut off for less than normal desire has been 
determined to be less than 3.3. The FSFI has been used in both intervention and 
epidemiologic studies. The FSFI has been validated across a wide range of sexual 
problems, with the most recent Cronbach alpha’s being over 0.9 for internal reliability. A 
score of 26.55 (from a range of 2 to 36) was found to be the cut point to distinguish 
women with and without sexual dysfunction (lower scores indicating sexual dysfunction). 
The FSFI has also been used with female gynecologic cancer survivors and was used in 
the Alliance N10C1 study that accrued mostly women with breast cancer (Carpenter et al. 
2009). This measure will be completed at baseline, 5 and 9 weeks. For open label patients 
it will be completed in weeks 4 and 8. 
 
PROMIS Sexual Health Measure (Flynn et al. 2013) 
The PROMIS initiative or Patient Reported Outcomes Measurement Information System 
is a large effort supported by the National Institute of Health to improve measurement 
science related to self-reported health measures. There are numerous PROMIS measures 
in various stages of development and psychometric testing. To the extent possible, 
investigators are urged to use PROMIS measures to have some capability to compare 
across trials. The sexual function and satisfaction measure is one PROMIS tool that has 
good content, face, discriminant, and convergent validity, and is, therefore, ready to be 
incorporated into clinical trials. In particular, for women, it demonstrates good 
convergent validity with the FSFI, which is considered the gold standard measure in 
sexual function. However, PROMIS is shorter and easier to score. In this study, the 
following will be used: the global satisfaction domain with 6 items (correlation of 0.76 
with the FSFI satisfaction subscale) and interest domain with 4 items (correlation of 0.84 
with the FSFI desire subscale) with one question about interfering factors; fatigue, for a 
total of 11 items. PROMIS was created in such a way that investigators can use items that 
are relevant to the population and the research question while maintaining validity. This 
measure will be completed at baseline, 5 and 9 weeks.For open label patients it will be 
completed in weeks 4 and 8. 
 
PROMIS Fatigue 8  
Fatigue will be measured with the PROMIS short form 8a. This questionnaire contains 8 
questions related to severity, bother and activity interference related to fatigue.  
Responses are “not at all” to “very much” for 6 questions; and “never” to “always” for 
two questions. The perspective is in the last 7 days. The PROMIS measures have 
demonstrated good reliability and validity with a subset of 7 items correlating with the 
full fatigue item bank (95 items), with a correlation coefficient of r=0.76 and correlations 
with the FACIT-F of 0.95. Even though the vitality subscale of the SF-36 was used in the 
previous vaginal symptom study and shown to significant predict variance in sexual 
health, the PROMIS fatigue correlated with the vitality subscale of the SF-36 with a 
correlation coefficient of r=0.89, so this scale should be able to capture what is needed 
for this study (Cella et al. 2010). This will be completed at baseline, 5 and 9 weeks. For 
open label patients it will be completed in weeks 4 and 8. 


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PHQ-4  
The PHQ 4 was developed from the PHQ-9 and GAD-7 to be an ultra-brief screening 
tool for depression and anxiety disorders (Kroenke 2009). It has been validated in the 
general population and found to be comparable to the PHQ-8 (Lowe 2010). Scores on the 
PHQ-4 range from 0 to 12, with scores 0-2 being normal, 3-5 indicating mild symptoms, 
6-8 moderate symptoms and 9-12 severe.  Cronbach’s alpha for the 4 items was 0.85.  
The PHQ-4 was strongly correlated with the mental health subscale of the SF 20 (r=.80) 
and social functioning (r=.52).  These correlation coefficients were nearly identical to 
those of the PHQ-8 (Kroenke 2009). This will be completed at baseline, 5 and 9 weeks. 
For open label patients it will be completed in weeks 4 and 8. 
 
Global Impression of Change (Sloan et al. 2002, Sloan et al. 2006) 
The Subject Global Impression of Change is a 7-point item in which the participant rates 
the change in the sexual desire since beginning the study (ranging from “very much 
better,” “moderately better,” “a little better,” “about the same,” “a little worse,” 
“moderately worse,” to “very much worse”). It has been used extensively for 
determination of minimally clinically significant differences in numerous oncology 
clinical trials. Two questions will be asked using the 7-point response scale, one on 
overall sexual desire and the other on energy/fatigue level.  
 
Additional risk/benefit investigator developed questions will be included. The first is 
“How satisfied are you with the impact of the study drug on your sexual desire? “not at 
all,” “a little,” “somewhat,” “quite a bit,” “very much” and the second question will be, 
“Were the benefits of this treatment greater than any side effects you may have 
experienced?” (yes or no). This form will ONLY be completed at the end of the study, at 
9 weeks. 
 
Side effect measures  
Patients will complete PRO-CTCAE items and the Clinical Research Associates (CRAs) 
will complete CTCAE items plus the PRO-CTCAE items at phone contact points with 
the patients. This will include at the end of weeks 1, 2, 5, 7 and 9. These phone call points 
are associated with key events in the study. The end of week 1 is to evaluate the ability to 
titrate to the assigned dose. Even though the CRA will be blinded, it will be important for 
study personnel to contact patients at the end of week 1 to evaluate whether they 
experienced any unwanted effects that would result in their unwillingness to continue 
with the study. The end of week 2 coincides with being at the target dose and this contact 
is again to evaluate whether there are tolerance issues. The end of week 5 is a time when 
the primary endpoint and some secondary endpoints need to be completed so this contact 
will serve as that reminder as well as AE evaluation. The end of week 7 contact will 
encourage continued engagement in the study and the end of week 9 is the end of the 
study when the measures will also need to be completed. 
 
Impact of Treatment Scale  
This scale is a measure of body change stress and was developed by investigators at The 
Ohio State University. It was developed and tested specifically in women with breast 


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cancer and then edited and tested in women with gynecologic cancer. It has demonstrated 
good reliability and validity in both samples, with Cronbach alphas over .90 (Frierson, 
Thiel and Andersen 2006). It was able to discriminate between women with lower and 
higher satisfaction with their sexual life (Frierson, Thiel and Andersen 2006).  This 
measure is being included only at baseline, as body image is one of the known predictors 
of sexual health. 
 
Revised Dyadic Adjustment Scale  
This is a 14-item scale that measures relationship functioning and has been recently used 
in a study of breast cancer survivors. The instrument provides an overall adjustment score 
as well as subscale scores for cohesion, consensus and satisfaction. Overall scores range 
from 0 to 69, with lower scores indicating more relationship problems. Work has been 
accomplished to establish a cut off score of <41 to screen for poor relationships (Rowland 
et al. 2009). The scale has demonstrated good validity confirmed through factor analysis 
and reliability. Cronbach’s alpha coefficients are .81 for the consensus subscale, .85 for 
satisfaction and .80 for cohesion. The total scale score has a Cronbach’s alpha coefficient 
of .90 (Busby et al. 1995). The Revised Dyadic Adjustment Scale will be completed at 
baseline only. 
 
11.2 
Optional Online Completion of Patient-Reported QOL Assessments (9/8/17) 
Missing data are a significant problem, particularly for QOL assessments. Unlike data for 
traditional endpoints, such as survival, QOL data can never be obtained retrospectively if 
it is not provided by the patient at the appropriate time point. This limits researchers’ 
ability to accurately perform QOL statistical analyses and negatively impacts the clinical 
relevance of this effort. Typically, QOL forms are filled out in hardcopy (paper). To 
provide a more convenient method of completing QOL assessments, NRG Oncology is 
working with VisionTree Software, Inc., San Diego, CA. VisionTree offers patients on 
this study the option of completing their QOL forms online from any location that has a 
computer with Internet access, including the patient’s home, and provides reminders to 
patients to complete the assessments.  
 
VisionTree has developed a tool, VisionTree Optimal Care (VTOC), a HIPAA-secure, 
user friendly, web-based software system (Gorgulho 2005; Gorgulho 2007; Pedroso 
2006). The VTOC tool contains a web-based system for global patient and trial 
administration access, which allows improved compliance and accuracy of data 
collection, validation, and reporting. It is compliant with the Title 21, Code of Federal 
Regulations, Part 11 statistical process control system and provides a mobile solution for 
clinical trials. QOL data are collected with Microsoft Excel and PDF export of reports. 
VTOC also has mobile messaging and e-mail reminders. Surveys can be “pushed” to 
patients for completion at timed intervals (see http://www.visiontree.com for details). 
This technology allows consenting patients on this study to fill out their QOL forms 
online from any location and to receive e-mail reminders to complete assessments. E-
mail reminders also can be sent to research associates (RAs) at the appropriate 
institutions to remind them that a QOL time point window is about to close so that a 
patient can be contacted to fill out QOL information on time, before it becomes “missing 
data.” 


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In a pilot RTOG study (RTOG 0828), the compliance rate of patients completing QOL 
assessments at 6 months significantly improved using electronic technology. Based on 
this pilot data, NRG Oncology is offering VisionTree as an option in other studies, 
including this one. Patients preferring to complete hardcopy QOL assessments can do so. 
The QOL forms completed via VTOC are identical to the hardcopy forms; this 
technology does not add to or change the QOL assessments in this study. 
 
For this trial, the baseline QOL forms must be completed in hardcopy (on paper) prior to 
the start of treatment. In addition, should the patient cross over and continue to weeks 14 
and 18, then the Female Sexual Function Index, the PHQ-4, the pROMIS fatigue short 
form 8a, the PROMIS sexual function and satisfaction must be completed in hardcopy 
(on paper). To complete subsequent QOL forms online, patients will be asked for an e-
mail address that they consent to use so that e-mail reminders may be sent to them. The 
patient’s e-mail address also will be used for password-protected access to VTOC. 
Patients who are interested in participating but do not yet have an e-mail address can 
obtain one for free from a number of sources (e.g. Yahoo!, Hotmail, or AOL). Note: The 
site RA is responsible for setting up the patient’s account on VTOC. The RA may do so 
by logging on the VTOC portal at the following link: https://rtog.optimalcare.com - 
medical team.  RA login information will be provided by VTOC after the patient is 
randomized to the study. The patient’s VTOC account must be set up within 14 days after 
randomization.  
 
Patients will receive a login card (either printed or sent via e-mail) with which to log in 
using the secure, web-based VTOC portal. VTOC meets all HIPAA guidelines and is 
encrypted (via 128-bit SSL) for the security, privacy, and confidentiality of QOL 
information. It is similar to the secure login commonly used when performing online 
banking. The login card can then be kept and maintained by the patient. 
 
The patient’s e-mail address only will be used by NRG Oncology for this purpose. 
Patients will be sent e-mail reminders to complete QOL forms. A typical e-mail reminder 
would read: “Your Quality of Life forms for the study, NRG-xxxxx, are now due. Please 
go to http://www.optimalcare.com, use your secure login, and complete the online forms. 
If any questions make you feel uncomfortable, you may skip those questions and not give 
an answer. If you have any questions, please e-mail or call your research associate at 
[insert RA e-mail address] or [insert RA telephone number]. Thank you for participating 
in this study.” The reminders will be created by NRG Oncology and placed into a study 
template that will be sent to patients at customized intervals (at the time points when 
QOL forms are due). The first reminder will be sent at the beginning of the “window” to 
complete a QOL form, with a second reminder halfway through the window period if the 
QOL forms are not yet completed at that time point. A maximum of 3 reminders will be 
sent for each of the 7 QOL time points (following the baseline QOL forms, which are 
completed in hardcopy, and including the optional open label portion for women 
receiving placebo). After a patient has completed all forms in the VTOC portal, a 
dialogue box will appear that says “Thank you for completing your Quality of Life 
forms,” and the patient will no longer receive any remaining notices for that time point. 


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The site RA or study administrator will be informed through the VTOC “At-A-Glance” 
form management system when QOL forms have been completed. 
 
12. DATA AND RECORDS 
12.1 
Data Management/Collection (07-JUN-2019) 
Medidata Rave is a clinical data management system being used for data collection for 
this trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system 
and role assignments. To access Rave via iMedidata: 
 
Site staff will need to be registered with CTEP and have a valid and active CTEP-
IAM account; and  
 
Assigned one of the following Rave roles on the relevant Lead Protocol 
Organization (LPO) or Participating Organization roster at the enrolling site: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator. 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
o To hold Rave CRA or Rave CRA (Lab Admin) role, site staff must hold a 
minimum of an AP registration type; 
o To hold Rave Investigator role, the individual must be registered as an 
NPIVR or IVR; and 
o To hold Rave Read Only role, site staff must hold an Associates (A) 
registration type. 
Upon initial site registration approval for the study in Regulatory Support System (RSS), 
all persons with Rave roles assigned on the appropriate roster will be sent a study 
invitation e-mail from iMedidata. To accept the invitation, site staff must log in to the 
Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM username 
and password, and click on the accept link in the upper right-corner of the iMedidata 
page. Site staff will not be able to access the study in Rave until all required Medidata 
and study specific trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings), and can be accessed by clicking on the link in the upper right 
pane of the iMedidata screen. If an eLearning is required and has not yet been taken, the 
link to the eLearning will appear under the study name in iMedidata instead of the Rave 
EDC link; once the successful completion of the eLearning has been recorded, access to 
the study in Rave will be granted, and a Rave EDC link will display under the study 
name.  
Site staff that have not previously activated their iMedidata/Rave account at the time of 
initial site registration approval for the study in RSS will also receive a separate invitation 
from iMedidata to activate their account. Account activation instructions are located on 
the CTSU website in the Rave section under the Rave resource materials (Medidata 
Account Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website in the Data Management > 
Rave section at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-888-
823-5923 or by e-mail at ctsucontact@westat.com.   


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Collection of Quality of Life Questionnaires 
Patients will be permitted to complete questionnaires at the study site or at home.  For 
convenience, patients can be given stamped, self-addressed envelopes in which to mail 
completed questionnaires back at 5 and 9 weeks.  
 
12.2 
Summary of Data Submission 
Patients will complete PRO-CTCAE items and the Clinical Research Associates (CRAs) 
will complete CTCAE items at phone contact points with patients. This will include at 
the end of weeks 1, 2, 5, 7 and 9. These phone call points are associated with key events 
in the study. The end of week 1 is to evaluate the ability to titrate to the assigned dose. 
Even though providers will be blinded, it will be important for study personnel to contact 
patients at the end of week 1 to evaluate whether they experienced any unwanted effects 
that would result in their unwillingness to continue with the study. The end of week 2 
coincides with being at the target dose and this contact is again to evaluate whether there 
are tolerance issues. The end of week 5 is a time some secondary endpoints need to be 
completed so this contact will serve as that reminder as well as AE evaluation. The end of 
week 7 contact will encourage continued engagement in the study and the end of week 9 
is the end of the study when the measures will also need to be completed including the 
primary endpoint. 
 
The AE data will be entered into the RAVE using the standard RAVE AE form.  Keep a 
source documentation for the AE collection in the patient’s record. 
Summary of Data Submission: Refer to the NRG website  
 
12.3 
Data Quality Portal (07-JUN-2019) 
The Data Quality Portal (DQP) provides a central location for site staff to manage 
unanswered queries and form delinquencies, monitor data quality and timeliness, 
generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data Management. 
The Rave Home section displays a table providing summary counts of Total 
Delinquencies and Total Queries. DQP Queries, DQP Delinquent Forms and the 
DQP Reports modules are available to access details and reports of unanswered 
queries, delinquent forms, and timeliness reports. Review the DQP modules on a 
regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and have access to 
the CTSU website. Staff that have Rave study access can access the Rave study 
data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon displayed on the 
Rave Home, DQP Queries, and DQP Delinquent Forms modules. 
Note: Some Rave protocols may not have delinquent form details or reports specified on 
the DQP. A protocol must have the Calendar functionality implemented in Rave by the 
Lead Protocol Organization (LPO) for delinquent form details and reports to be available 
on the DQP. Site staff should contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality.   


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12.4 
Global Reporting/Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means. 
Reports are due January 31, April 30, July 31, and October 31. 
 
13. STATISTICAL CONSIDERATIONS 
13.1 
Study Design 
 
This is a prospective, randomized, double-blinded, placebo-controlled phase II trial will 
determine which Bupropion dose, if any, will move to a phase III trial.  Patients will be 
stratified by current SSRI use (yes vs. no), prior pelvic treatment (none vs. pelvic surgery 
and/or pelvic RT), and aromatase inhibitor use (yes vs. no) and then randomized 1:1:1 to 
receive a150XL target dose of Bupropion, a 300 XL target dose of Buproprion, or 
placebo.  The target accrual is 234 patients and patients will be analyzed according to the 
intent-to-treat principle using all enrolled at-risk patients. 
13.2 
Study Endpoints 
13.2.1 Primary Endpoint 
 
Change in sexual desire, as measured by the desire subscale of the Female FSFI, from 
baseline to 9 weeks 
13.2.2 Secondary Endpoints 
 Adverse events, including PRO-CTCAE 
 Fatigue, as measured by PROMIS fatigue scale 
 Sexual desire, as measured by the desire subscale of the FSFI at 5 weeks and 
PROMIS sexual desire and satisfaction measure at 5 and 9 weeks 
 Sexual functioning, as measured by the FSFI total score 
 Depressive mood, as measured by the PHQ-4 
 Patient’s perception of change, as measured by the Global Impression of Change 
scale, and risk vs. benefit 
 
13.3 
Primary Objectives Study Design 
13.3.1 Primary Hypothesis and Endpoints 
The primary hypothesis is the intervention (Bupropion 150 XL or 300XL ) will result in 
improved sexual desire, as measured by the sexual desire subscale of the FSFI, greater 
than that of the placebo. 
13.3.2 How Primary Endpoints Will Be Analyzed 
The primary endpoint, change from baseline to 9 weeks in FSFI desire subscale (sum of 
questions 1 and 2 on the FSFI), will be tested between both bupropion arms and the 
control arm using a t-test with each comparison having a 1-sided significance level of 
0.05.  Effect sizes between placebo and each treatment arm will be reported.  The desire 
subscale will be scored at each data point according to the scoring guidelines.  The 
change score will be calculated as baseline subtracted from follow-up score.  
Longitudinal trends in FSFI desire subscalewill be assessed using a mixed effects model 
with maximum likelihood estimation on the mean scores with treatment arm, treatment 
by time interaction, baseline FSFI desire subscale score,  and PROMIS fatigue score as 
covariates to assess the impact of treatment and fatigue. Other covariates of interest are 
stratification factors (SSRI use, prior pelvic treatment and aromatase inhibitor use), 


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sociodemographic variables [age, race, disease type, current treatment, partner status, 
time since diagnosis, (<5 years, 5-10 years, >1 year) and BMI], baseline impact of 
treatment scale score, and baseline revised dyadic adjustment scale score.  Since the 
revised dyadic adjustment scale is to be completed only by patients with a partner, 
separate models will be run with and without this covariate as the sample size will be 
decreased when this variable is included.  Inclusion of the impact of treatment scale 
allows for controlling the influence of body image on sexual desire.  Inclusion of the 
revised dyadic adjustment scale score will allow control of potential confounding of 
effect of partner issues.  
 
Each FSFI subscale score will be assessed for confounding the treatment effect of on 
desire.  General linear models (GLMs) will be used to assess this with FSFI desire 
subscale change score as the dependent variable separately at 5 and 9 weeks with other 
relevant subscale scores (arousal, lubrication, orgasm, and pain) at the corresponding 
time point as an independent variable along with baseline FSFI desire subscale score and 
treatment arm.  For the model with pain, whether the patient has clitoral and labial pain 
and an interaction between clitoral or labial pain and FSFI pain subscale score will also 
be included as independent variables.  If any of these subscales shows evidence of 
confounding, they will be incorporated into the main FSFI desire subscale model 
described above. 
 
Missing data will be assessed. If ≥15% of the data is missing at any time point for the 
FSFI desire subscale score, patient characteristics will be compared between patients with 
completed assessments and those with missing assessments. Graphical methods may also 
be used to determine the type of missingness.  If the missingness is determined to be 
ignorable, no additional analyses need to occur. If the missingness is determined to be 
non-ignorable, other methods, such as imputation and pattern mixture models, may be 
performed.   
 
Since the FSFI desire subscale consists of only 2 items, an assessment of floor and effects 
will be performed.  Counts and frequencies of patients who experienced floor effects will 
be provided by arm for each time point of FSFI collection.  This will be done to inform 
the phase III trial if bupropion appears to be helpful. Due to the eligibility criteria of 
patients scoring < 3.3 on the desire subscale at baseline, ceiling effects will not occur. 
 
In order to move forward with a phase III study evaluating bupropion for sexual desire, at 
least one dose of bupropion would need to result in statistically significant improvement 
over placebo as measured by the desire subscale of FSFI. This bupropion dose would 
need to meet the following criteria: 
 be absent of grade 4+ SAE’s attributable to treatment  
 ≤ 20% of patients on the bupropion arm of interest would not have stopped 
protocol treatment based on AE’s 
If both doses equally improve sexual desire as measured by the FSFI desire subscale, the 
dose that meets the above criteria would move forward. If both doses meet the above 
criteria, then the lower dose will move forward to the phase III trial.  
 


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If neither dose meets the desired effect size but less than or equal to 20% of patients have 
not terminated treatment early and there are no grade 4 SAE’s attributable to study 
treatment, then an analysis will be conducted to determine the effect of the assigned 
treatment in those patients who score in the “normal” range of the dyspareunia subscale, 
dyspareunia subscale score > 3.  Specifically, a general linear model will be performed 
with desire subscale change score at 9 weeks as the dependent variable and treatment 
arm, dyspareunia (as a binary variable) at 9 weeks, and a treatment by dyspareunia 
interaction as independent variables.  If there is a clear signal that a bupropion dose has a 
positive impact when vaginal atrophy symptoms are less severe, it can be argued that 
bupropion should be studied further.  In other words, a lack of effect in the entire 
population could be confounded too much by vaginal atrophy symptoms.  To make 
vaginal atrophy an exclusion, however, would make the study nearly impossible to recruit 
to.  The overall plan for this research is to identify effective interventions for various 
components of sexual health.  In clinical practice, as these treatments are implemented, it 
would be expected that if a woman had low desire and vaginal atrophy symptoms, that 
both would be treated, which would be the plan for the phase III trial.     
 
13.3.3 Sample Size and Power Calculations 
The primary endpoint of this trial is the change in FSFI desire subscale score from 
baseline to 9 weeks.  The FSFI is the current gold standard for the measurement of 
female sexual health and it contains a validated subscale specific to sexual desire. This 
was one of the outcomes used in the FDA approved drug, flibanserin, for Hypoactive 
Sexual Desire Disorder (HSDD). Since there is limited data using this drug in this patient 
population, an effect size will be used to calculate the sample size.  Cohen’s widely used 
guidelines for interpreting the magnitude of difference define 0.8 standard deviation (SD) 
as a “large” effect size, 0.5 SD as a “medium” effect size, and 0.2 SD as a “ small” effect 
size (Cohen 1988).  In this trial looking for a signal to move forward to a phase III trial, a 
small to moderate effect size of 0.45 will be used.  Studies in different patient populations 
and those using different interventions, such as flibanserin, have shown similar effect 
sizes (DeRogatis 2012) with recent meta-analysis demonstrating an effect size of 0.4 
(Jaspers 2016).  Using a two sample t-test with a one-sided type I error of 0.05 (overall 
type I error of 0.1 after a Bonferroni correction) and an effect size of 0.45, 62 
patients/arm will be needed to achieve 80% statistical power.  After adjusting for 20% 
non-compliance, 234 patients will be enrolled in this trial. 
 
13.4 
Study Monitoring of Primary Objectives 
Interim Analysis for the DMC 
The NRG Oncology Data Monitoring Committee (DMC) will review the study twice a 
year with respect to patient accrual and morbidity. The DMC also will review the study 
on an “as needed” basis.  
 
13.5 
Accrual/Study Duration Considerations 
 
 
This study will only be open to NRG Oncology NCORP sites. Previous randomized 
controlled trials for vaginal symptoms and sexual desire have been completed in a timely 
fashion in the NCORP mechanism [NCCTG now Alliance] trials N10C1 DHEA for 
vaginal symptoms and N02C3 Evaluation of transdermal testosterone for libido). The 


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DHEA study recruited 464 women from 82 NCORP sites between July, 2011 and May, 
2013. The transdermal testosterone for libido study recruited 150 women in just 8 
months. 
    
 
 
It is expected that due to regulatory processes at the site, the first 6 months after study 
activation will result in negligible accrual. Once sites have the study active, it is projected 
to accrue 10 patients/month after the initial 6 month period which results in a total study 
duration of approximately 2 years. During months 6-8 after activation, accrual will be 
monitored. If the accrual rate during this period is < 50% of the expected monthly accrual 
rate, the study team, with input from the NRG Oncology, DMC will evaluate whether the 
trial should be opened to the entire NRG Oncology membership. 
 
13.6 
Secondary or Exploratory Endpoints (including correlative science aims) 
13.6.1 Secondary Hypotheses and Endpoints:  
 Evaluation of adverse events, including PRO-CTCAE, specifically it is hypothesized 
that there will not be any grade 4+ AEs related to treatment 
 Comparison of fatigue, as measured by the PROMIS fatigue at baseline, 5 and 9 
weeks, between the placebo and each intervention arm and determine it’s impact and 
association on sexual desire and sexual functioning 
 Comparison of sexual desire, as measured by the desire subscale of the FSFI at 
baseline and 5 weeks and PROMIS sexual desire and satisfaction measure at baseline, 
5 and 9 weeks, between the placebo and each intervention arm 
 Comparison of sexual functioning, as measured by the FSFI total score at baseline, 5 
and 9 weeks, between the placebo and each intervention arm 
 Evaluation of depressive mood, as measured by the PHQ-4 at baseline, 5 and 9 weeks 
 Patient’s perception of change, as measured by the Global Impression of Change 
scale at 9 weeks,  and risk vs. benefit, measured at 9 weeks, between the placebo and 
each intervention arm 
13.6.2 Definitions of Secondary Endpoints and How These Will Be Analyzed 
 
 
Adverse events 
 
Adverse events (AEs) will be graded according to the NCI’s Common Terminology 
Criteria for Adverse Events  (CTCAE) v. 5.0.  Adverse events will also be assessed using 
PRO-CTCAE items.  PRO-CTCAE items of Interest that are associated with potential 
drug side effects, based on the well-documented AEs of bupropion, include: tremors, 
dizziness, insomnia, headache, dry mouth, decreased appetite, nausea, and constipation. 
Counts of all AEs by grade will be provided by treatment arm. Nasopharyngeal effects will 
be graded using the CTCAE, two items from the Respiratory category: nasal congestion 
and pharyngeal pain (dryness). Patients will complete PRO-CTCAE items and providers 
will complete CTCAE items at the end of weeks 1, 2, 5, 7 and 9.   
 
 
Counts and frequencies will be provided for the worst grade AE experienced by the patient 
by treatment arm.  The distribution of AE grade and PRO-CTCAE score in each 
intervention arm will be compared to the placebo arm using a chi-square test, or Fisher’s 
exact test if cell frequencies are < 5, at the one-sided 0.05 significance level. Missing data 
will be assessed as described in Section 13.3.2. 
 


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Fatigue 
Fatigue, which is believed to be a potential mediator,  will be measured by the PROMIS 
fatigue at baseline and 5 and 9 weeks from the start of treatment.  The change from 
baseline to 5 and 9 weeks will be compared between the placebo and each intervention 
arm using a t-test, or Wilcoxon test if the data is non-normal, and compared at the one-
sided 0.05 significance level.  Spearman correlation coefficients will be used to assess the 
association between fatigue and sexual desire, as measured by both the sexual desire 
subscale of the FSFI and the PROMIS sexual desire and satisfaction measure, and sexual 
functioning, as measured by the FSFI total score, at each time point.  Missing data will be 
assessed as described in Section 13.3.2.   
 
 
Dyspareunia 
Dyspareunia will be measured using the FSFI dyspareunia subscale score at baseline, 5 
and 9 weeks.  It will be assessed using a cutpoint of ≤3 (painful intercourse) vs. >3 (not 
painful intercourse; Wiegel 2005).  The percent of patients with and without painful 
intercourse at each follow-up time point will be compared between the placebo and each 
intervention arm using a chi-square test, or Fisher’s exact test if cell frequencies are < 5.  
In order to also assess the effect clitoral or labial pain have on painful intercourse, logistic 
regression will be used at each follow-up time point (ref).  If one of the groups has a very 
small frequency of events (<5%), Firth’s penalized likliehood will be used as maximum 
likelihood estimation may be biased (Firth 1993).  Stratification factors, baseline 
dyspareunia (defined using the cutpoint), and other sociodemographic variables may also 
be considered for inclusion in the model.  Missing data will be assessed as described in 
Section 13.3.2.   
 
 
 
Sexual Desire 
 
Sexual desire will be measured by the sexual desire subscale of the FSFI and the 
PROMIS sexual desire and satisfaction measure at baseline, 5 and 9 weeks from the start 
of treatment.  The primary endpoint compares the change from baseline to 9 weeks using 
the sexual desire subscale of the FSFI.  The PROMIS sexual desire and satisfaction 
measure was chosen to be a secondary endpoint, as it is a relatively newly validated 
measure for sexual health.  This endpoint will include comparison of the placebo and 
intervention arms of the change from baseline to 5 weeks for both sexual desire tools as 
well as the change from baseline to 9 weeks using the PROMIS sexual desire and 
satisfaction measure using a t-test, or Wilcoxon test if the data is non-normal, and 
compared at the one-sided 0.05 significance level.  A longitudinal model for the FSFI 
desire subscale is described in Section 13.3.2.  Similarly, longitudinal trends in PROMIS 
sexual desire and satisfaction measure will be assessed using a mixed effects model with 
maximum likelihood estimation on the mean scores with treatment arm, baseline 
PROMIS sexual desire score, and PROMIS fatigue score as covariates to assess the 
impact of treatment and fatigue. Other covariates of interest are stratification factors 
(SSRI use and aromatase inhibitor use), sociodemographic variables (age, race, disease 
type, current treatment, partner status, and BMI), baseline impact of treatment scale 
score, and baseline revised dyadic adjustment scale score.  Inclusion of the impact of 
treatment scale allows for controlling the influence of body image on sexual desire.  
Inclusion of the revised dyadic adjustment scale score will allow control of potential 


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confounding of effect of partner issues. Missing data will be assessed as described in 
13.3.2.   
 
 
 
Sexual Functioning 
 
Sexual functioning will be measured using the FSFI total score at baseline, 5 and 9 
weeks. The change from baseline to 5 and 9 weeks will be compared between the placebo 
and each intervention arm using a t-test, or Wilcoxon test if the data is non-normal, and 
compared at the one-sided 0.05 significance level. Longitudinal trends in FSFI total score 
will be assessed using a mixed effects model with maximum likelihood estimation on the 
mean scores with treatment arm and PROMIS fatigue score as covariates to assess the 
impact of treatment and fatigue. Other covariates of interest are stratification factors 
(SSRI use and aromatase inhibitor use), sociodemographic variables (age, race, disease 
type, current treatment, partner status, and BMI), baseline impact of treatment scale 
score, and baseline revised dyadic adjustment scale score.  Inclusion of the impact of 
treatment scale allows for controlling the influence of body image on sexual desire.  
Inclusion of the revised dyadic adjustment scale score will allow control of potential 
confounding of effect of partner issues. Missing data will be assessed as described in 
Section 13.3.2.   
 
Depressive Mood 
Depressive mood will be measured using the PHQ-4 at baseline, 5 and 9 weeks.  
Depressive mood at each time point will be compared between the placebo and each 
intervention arm using a t-test, or Wilcoxon test if the data is non-normal, and compared 
at the one-sided 0.05 significance level.  Since bupropion is an anti-depressant, it is 
expected that patients on the bupropion arms will have improved mood as compared to 
those on placebo.  Spearman correlation coefficients will be used to assess the association 
between depressive mood and sexual desire, as measured by both the sexual desire 
subscale of the FSFI and the PROMIS sexual desire and satisfaction measure, sexual 
functioning, as measured by the FSFI total score, and fatigue, as measured by the 
PROMIS fatigue, at each time point.  If depressive mood is found to be associated with 
sexual desire, it will be considered in the longitudinal model for sexual desire using the 
FSFI desire subscale.  Missing data will be assessed as described in Section 13.3.2.   
 
 
 
Patient’s perception of change and risk vs. benefit 
The Global Impression of Change will be assessed by dividing responses into two 
categories: positive response (patients reporting “a little better to very much better”) and 
negative response (patients reporting “the same to very much worse”).  This is measure 
will be used assess the degree of perceived benefit patients had from the study agent. This 
will help to explore the clinical significance of the statistical changes on the primary and 
secondary endpoints such as sexual desire and sexual functioning. Assessment of the 
patient’s perception of risk vs. benefit will be performed after determining the percentage 
of women responding “yes” to the question about benefits being greater than the side 
effects and the percentage responding “somewhat” or better to the question about 
satisfaction with treatment.  These questions will be used in the decision rule for a phase 
III trial. Differences between treatment arms will be tested using the chi-square test, or 
Fisher’s exact test if cell frequencies are < 5, for these comparisons at the one-sided 0.05 


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significance level. 
 
13.7 
Gender/Ethnicity/Race Distribution 
Since this trial is only open to NRG NCORP members, there will be no international 
accrual. No differences across the patient subsets below are anticipated. 
 
 
Racial Categories 
DOMESTIC PLANNED ENROLLMENT REPORT 
Ethnic Categories 
Not Hispanic or 
Latino 
Hispanic or Latino 
 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
2 
0 
0 
0 
2 
Asian 
19 
0 
0 
0 
19 
Native Hawaiian or Other 
Pacific Islander 
1 
0 
0 
0 
1 
Black or African American 
21 
0 
2 
0 
23 
White  
175 
0 
14 
0 
189 
More Than One Race 
0 
0 
0 
0 
0 
Total 
218 
0 
16 
0 
234 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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recurrence. J Clin Oncol, 2007. 25(21): p. 3151-7. 
 
Arnow, B.A., et al., Women with hypoactive sexual desire disorder compared to normal females: 
a functional magnetic resonance imaging study. Neuroscience, 2009. 158(2): p. 484-502. 
Bancroft, J., The endocrinology of sexual arousal. J Endocrinol, 2005. 186(3): p. 411-27. 
 
Barton, D., Loprinzi CL, Atherton P, Sloan J, Dalton R, Balcueva E, Carpenter P, The 
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Davis, S.R., et al., Testosterone for low libido in postmenopausal women not taking estrogen. N 
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Derogatis, L.R., et al., Treatment of hypoactive sexual desire disorder in premenopausal women: 
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bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry, 2005. 7(3): p. 106-13. 
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Neuropsychopharmacology, 2013. 38(11): p. 2179-87. 
 
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Flibanserin [package insert]. Sprout Pharmaceuticals, Raleigh, NC; June 4, 2015. 
 
Flynn, K.E., et al., Construct validity of the PROMIS(R) sexual function and satisfaction measures 
in patients with cancer. Health Qual Life Outcomes, 2013. 11: p. 40. 
 
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the Breast-Impact of Treatment Scale. Ann Behav Med, 2006. 32(1): p. 77-81. 
 
Frohlich, J., et al., Hormones, genes and the structure of sexual arousal. Behav Brain Res, 1999. 
105(1): p. 5-27. 
 
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Ganz, P.A., et al., Life after breast cancer: understanding women's health-related quality of life 
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Maturitas, 2011. 70(1): p. 42-57. 
 
Gitlin, M.J., et al., Bupropion-sustained release as a treatment for SSRI-induced sexual side 
effects. J Sex Marital Ther, 2002. 28(2): p. 131-8. 
 
Goldstat, R., et al., Transdermal testosterone therapy improves well-being, mood, and sexual 
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Cancer, 2011. 117(12): p. 2643-51. 
 
Hull, E.M., et al., Hormone-neurotransmitter interactions in the control of sexual behavior. 


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Katz, M., et al., Efficacy of flibanserin in women with hypoactive sexual desire disorder: results 
from the BEGONIA trial. J Sex Med, 2013. 10(7): p. 1807-15. 
 
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10 Suppl 1: p. 5-15. 
 
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chemotherapy for high-risk breast cancer. Br J Cancer, 2006. 95(12): p. 1626-31. 
 
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quality of life of mixed-site cancer patients and their partners. Psychooncology, 2006. 15(3): p. 
259-67. 
 
Nathorst-Boos, J., et al., Treatment with percutanous testosterone gel in postmenopausal women 
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Safarinejad, M.R., Reversal of SSRI-induced female sexual dysfunction by adjunctive bupropion 
in menstruating women: a double-blind, placebo-controlled and randomized study. J 
Psychopharmacol, 2011. 25(3): p. 370-8. 
 
Segraves, R.T., et al., Bupropion sustained release for the treatment of hypoactive sexual desire 
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Shifren, J.L., et al., Transdermal testosterone treatment in women with impaired sexual function 
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Shifren, J.L., et al., Testosterone patch for the treatment of hypoactive sexual desire disorder in 
naturally menopausal women: results from the INTIMATE NM1 Study. Menopause, 2006. 13(5): 
p. 770-9. 
 
Simon, J., et al., Testosterone patch increases sexual activity and desire in surgically menopausal 
women with hypoactive sexual desire disorder. J Clin Endocrinol Metab, 2005. 90(9): p. 5226-33. 
 
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Speer, J.J., et al., Study of sexual functioning determinants in breast cancer survivors. Breast J, 
2005. 11(6): p. 440-7. 
 
Thorp, J., et al., Treatment of hypoactive sexual desire disorder in premenopausal women: 
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Versace, F., et al., Brain responses to erotic and other emotional stimuli in breast cancer survivors 
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Wilmoth, M.C., et al., Fatigue, weight gain, and altered sexuality in patients with breast cancer: 
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Zyban [package insert]. GlaxoSmithKline, Research Triangle Park, NC; January 2015. 


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APPENDIX I (08-JUN-2018) 
Bupropion is a strong CYP 2D6 inhibitor.  That means that if another drug is primarily metabolized by 
CYP2D6 (called a CYP2D6 substrate) then taking that drug with bupropion may impact the effect or 
toxicity of the drug.  Therefore, it is important that you look up each participant’s usual drugs to make sure 
they are not taking any CYP2D6 substrates.   Some of the main ones are listed below but this is not a all-
inclusive or comprehensive list.  If you don’t see a drug, nutrition or herbal supplement on this list, that 
doesn’t mean it is ok to take with bupropion.  
 
Please consult with a pharmacist for complete drug/drug interaction screening review.  
Drugs Metabolized by CYP2D6 Enzyme 
ANALGESICS 
CHOLINESTERASE INHIBITORS 
codeine 
donepezil 
hydrocodone 
oxycodone 
COUGH SUPPRESSANT 
phenacetin 
dextromethorphan 
tramadol 
PSYCHOTROPICS 
ANESTHETICS 
amitriptyline 
lidocaine 
amphetamine 
aripiprazole 
ANORECTICS 
atomoxetine 
dexfenfluramine 
chlorpromazine 
clomipramine 
ANTIEMETIC/PROKINETICS 
desipramine 
metoclopramide 
duloxetine 
ondansetron 
fluoxetine 
 
fluvoxamine 
ANTIHISTAMINES 
chlorpheniramine 
haloperidol 
iloperidone 
promethazine 
imipramine 
methamphetamine 
ANTINEOPLASTICS 
methoxyamphetamine 
tamoxifen 
minaprine 
nortriptyline 
CARDIOVASCULAR 
paroxetine 
carvedilol 
perphenazine 
clonidine 
pimozide 
 diltiazem 
risperidone 
 disopyramide 
 flecainide 
sertraline 
thioridazine 
S-metoprolol 
zuclopenthixol 
mexiletine 
 
nebivolol 
propafenone 
propranolol 
sparteine 
timolol 


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APPENDIX II (07-JUN-2019) 
 
 
Provisions for Unblinded (Open-Label) Bupropion for Patient Enrolled in Placebo Only 
Arm 
 
1.0 
Summary 
Patients receiving Arm C (placebo only) may choose to receive bupropion for 8 weeks.   
1.1 
Buproion will be supplied to the patient free of charge and distributed by Biologics, Inc 
(see Section 9.1.2 of the protocol). 
1.2 
Steps to receive open-label bupropion  
1.2.1 Code breaking is completed by NRG Oncology for patients enrolled on the placebo arm 
only. 
1.2.2 The treatment code will be supplied to the treating institution via the Patient Crossover 
Form in Medidata Rave by NRG Oncology immediately after all study data has been 
submitted to NRG Oncology. If the Patient Crossover Form appears in the Week 10 
folder, then the patient was randomized to the placebo arm.  If this form does not appear, 
then the patient was randomized to one of the two experimental arms and will not be 
unblinded. 
1.2.3 Once the treatment code has been received by the institution, the decision to receive 
open-label bupropion will be made by the patient and treating physician  
1.2.4 The treating institution will complete the Patient Crossover Form in the 10 week folder in 
Medidata Rave which will trigger an auto-generated email message to request drug be 
shipped by Clinical Research Services, a division of RxCrossroads by McKesson. Drug 
will not be provided until this form has been submitted.  
 
Note:  Treating institutions should complete the patient crossover form in Medidata Rave 
for all patients who received placebo. For patients who do not wish to receive bupropion 
the treating site should answer “no” to the question on the Patient Crossover Form.  
 
For patients who wish to receive bupropion the treating institution should answer “yes” to 
the question on the Form.  
 
If the patient decides to crossover and has previously consented to participate in Vision 
Tree, the RA must go back into the patient’s Vision Tree account and activate the  
placebo template . 
 
2.0 
Treatment Plan 
Patients will receive bupropion 150 or 300 mg XL for a total of 8 weeks.  This includes a 
week to titrate up and a week to titrate down if the desired dose is 300 mg XL. 
2.1 
Patients choosing to receive bupropion will complete QOL assessments at weeks 4 and 8. 
See Section 4.0 of the Protocol “Assessments for Participants Continuing on Bupropion.” 
2.2 
Drug Information 
 
See Section 9 of the protocol 
2.3 
Supply 
 
Bupropion will be supplied free of charge to the patient and distributed by Clinical 
Research Services, a division of RxCrossroads by McKesson. See protocol Section 9.1.2.   
3.0 
Adverse Event Reporting: See Section 7.0 of the protocol for further details. 


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APPENDIX III 
 
SAFETY PLAN 
 
PHQ-4 Assessment of Depression/Anxiety 
The PHQ-4 is a screening questionnaire evaluating depression and anxiety and is included in this 
protocol related to eligibility, and is repeated at weeks 5 and 9.  The Stage I Screening 
assessment will be done in person and the Stage II Follow-Up assessment will be done according 
to site procedures, either by phone or in person. This Safety Plan provides detailed instructions 
on reporting severe depression or anxiety based on the PHQ-4 screening tool. The healthcare 
team will be required to respond in accordance with this Safety Plan in the event that the 
participant scores either 6 to 8 or 9 or higher. 
 
PHQ-4 Emergent Risk:  further assessment for elevated anxiety or depression requiring 
intervention will be presumed with a score of 9 or higher.  
 
PHQ-4 Non-emergent risk:  Participants who score 6 to 8 will be offered a referral for further 
assessment and help. 
 
Emergent Risk Policy 
Participants who score 9 or higher on the PHQ-4 are required to undergo evaluation by a 
clinician in the patient’s cancer care setting to assess degree of risk. If a participant meets criteria 
for this, notify clinical staff immediately that the patient requires a risk assessment prior to 
leaving the clinic.  
 
Inform the participant that you are required by protocol to request further assessment based on 
the total score on the questionnaire.  
 
If the participant refuses or denies acute distress, suicidality or acute anxiety, let the participant 
know you are required to complete a report and to notify their health care provider about the 
assessment result.  Council the patient to contact their health care provider if they feel acute 
distress and to call 911. 
 
The Informed Consent gives us permission and it is not a breech of confidentialit. Once clinical 
staff have been notified, your responsibility has been discharged. 
 
The CRA must complete an Emergent Risk Incident Report (see Appendix IV) and submit it to 
NRG Oncology by uploading the form in Rave. 
 
Non-Emergent Risk Policy 
Staff at NRG member institutions will be required to review completed questionnaires and 
respond in accordance with this Safety Plan in the event that the participant scores 6-8 on the 
PHQ- 4. Telephone interviewers will be required to respond in accordance with this Safety Plan 
in the event that  the PHQ-4 is scored at 6 to 8. 
 
This policy requires the site CRA to offer referral information to the participant, to offer 
assistance to the participant in obtaining further evaluation and treatment, and completion of a  


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APPENDIX III, CONT’D 
 
Non-Emergent Risk Incident Report. Participants should be offered resources at the site where 
they are receiving cancer care (if available) or elsewhere as well as community resources. 
 
The CRA must complete the Non-Emergent Risk Incident Report (see Appendix V) and submit 
it to NRG Oncology by uploading the form in Rave. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX IV 
Emergent Risk Incident Report 
 
Note: This form must be submitted within 1 business day after completion of the questionnaire 
and/or interview. 
 
Case Number:                                            
 
Date:                                      
 
What triggers Emergent Risk? 
 
Score on PHQ-4  of 9 or greater requires completion of the Emergent Risk Incident Report and 
following the safety plan outlined in appendix III. 
Did participant agree to contact with clinical staff for further assessment?     
 Yes               No  
On-Site Clinical Personnel Contacted: 
 
Name of On-Site Clinical Staff:                                                   
   Yes         ______Time         of         contact                                              
  No 
 
 
Did participant desire contact information for counseling or other mental health treatment? 
 Yes             No 
 
 
Was information provided?                                             Yes               No 
 
 
 
Signature of Site CRA:                                                                        Date:                                        
 
Check one: 
 
 Pre-randomization 
 
 Week 5 
 
 Week 9 
 
Upload the completed form in Rave. 


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APPENDIX V  
Non-Emergent Risk Incident 
Report 
 
Note: This form must be submitted within 2 business days after completion of the questionnaire 
and/or interview. 
 
Case Number:                                            
 
Date:                                      
 
Participant scored 6 to 8 on PHQ-4: 
 
 
Did participant desire contact information for counseling or other mental health treatment? 
 Yes             No 
 
Was information provided?                                             Yes              No 
 
 
 
Signature of Site CRA:                                                                        Date:                                        
 
Check one: 
 
 Pre-randomization 
 
 Week 5 
 
 Week 9 
 
Upload completed form in Rave. 
 
 

ICF_001.pdf: 
NRG ONCOLOGY 
 
NRG-CC004 
 
(ClinicalTrials.gov NCT #: 03180294) 
 
 
PHASE III DOUBLE BLIND DOSE FINDING TRIAL OF BUPROPION VERSUS 
PLACEBO FOR SEXUAL DESIRE IN WOMEN WITH BREAST OR GYNECOLOGIC 
CANCER 
 
 
 
Amendment 3:  June 7, 2019 


Protocol Version Date: 07-JUN-2019 
 
  NRG-CC004 
                                                                                                                                                                 
Page 1 of 7 
 
 
NRG-CC004 Consent Form 
Study Title for Study Participants: Comparing Two Dose Levels of Bupropion Versus 
Placebo for Sexual Desire  
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: NRG-CC004 
Phase II Double Blind Dose Finding Trial of Bupropion Versus Placebo for Sexual Desire in 
Women with Breast or Gynecologic Cancer (NCT #NCT03180294) 
 
What is the usual approach for sexual health in women who have been treated for 
gynecologic and breast cancers? 
Long term consequences of the cancer experience can include unwanted changes in sexual health.  People who 
do not take part in this study may receive counseling or use topical lubricants to improve aspects of their sexual 
health.  
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual approach described above 
• you may choose to take part in a different study, if one is available 
 
Why is this study being done? 
Sexual health after treatment for cancer is an important survivorship issue. This study will address the common 
side effect of decreased sexual health in women who have been treated for breast or gynecologic cancer. The 
study will test whether bupropion, a medication that is approved for depression and smoking cessation can 
improve sexual desire compared to placebo.  
 
A placebo is a pill that looks like the bupropion but contains no medication.  
 
There will be about 234 people taking part in this study. 
 
What are the study groups? (08-Jun-2018) 
This study has three study groups. Two different doses of bupropion, 150 mg extended release (XL) and 300 mg 
extended release (XL), will be compared to a placebo.  Participants will be randomized into one of three study 
groups described below. A computer will by chance assign you to treatment groups in the study.  This is done 
by chance because no one knows if one study group is better or worse than the others. You will have an equal 
chance of being placed in any of the three groups. Neither the research team nor you will know which group 
you are assigned to. 
 
Each group will be supplied with 4 bottles of pills which will come in a kit with an instruction sheet. 
 
You will take 1 pill each morning for 1 week, then take 2 pills each morning for 8 weeks, and then take 1 pill 
each morning for 1 week.  
 
 


Protocol Version Date: 07-JUN-2019 
 
  NRG-CC004 
                                                                                                                                                                 
Page 2 of 7 
 
 
 
Another way to find out what will happen to you during this study is to read the chart below. Start reading at the 
left side and read across to the right, following the lines and arrows. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
How long will I be in this study? 
You will receive bupropion, or placebo or a combination of bupropion and placebo for a total of 10 weeks.   
 
Do not crush, chew or cut the capsules as that will change the way the medicine is delivered and can be 
harmful.  You may take the capsules with our without food.  Take them with a full glass of water. Do not stop 
this medicine suddenly before talking with your provider.  If you start any new medicine including over the 
counter medicine, please let your provider know as some medicine can interact with this medicine.   
 
If you are assigned to the group that gets only placebo, you will be given the option to try the study drug, 
provided by the study.  If you choose to participate you will take bupropion for a total of 8 additional weeks 
after you have completed the first 10 weeks of study treatment and returned all of the study materials.  
 
What extra tests and procedures will I have if I take part in this study? (9/8/17) 
There are no extra medical tests or medical procedures that are required to take part in this study.  You will be 
asked to complete questionnaires that ask about your sexual desire, your sexual health, fatigue, mood and your 
quality of life.  You will be asked to complete these questionnaires 3 times during the study; before you start 
taking bupropion and during treatment at 5 weeks and 9 weeks.  Two questionnaires will only be completed at 
the beginning of the study, one that asks about your relationship with your partner and one that asks about your 
self image.  You will also be asked to fill out a questionnaire about any side effects or negative effects you feel 
you are experiencing from the medication.  This information will be filled out at the end of weeks 1, 2, 5, 7 and 
9 during treatment. All study related questionnaires can be completed during an office visit, by phone or filling 
it out at home using paper and pen. 
 
You agree 
to take part 
in the study 
Randomize 
(The 
computer 
will 
randomly put 
you in a 
study group) 
• 1 pill (placebo) each morning for 1 week 
• 2 pills (placebo) each morning for 8 weeks 
• 1 pill (placebo) each morning for 1 week 
 
• 1 pill (150mg bupropion XL) each morning for 1 week 
• 2 pills (150mg bupropion XL for a total dose of 300 mg 
bupropion XL) each morning for 8 weeks 
• 1 pill (bupropion 150 mg XL) each morning for 1 week 
• 1 pill (150mg bupropion XL) each morning for 1 week 
• 2 pills (150mg bupropion XL and placebo for total dose of 
150 mg bupropion XL) each morning for 8 weeks 
• 1 pill each morning (placebo) for 1 week 


Protocol Version Date: 07-JUN-2019 
 
  NRG-CC004 
                                                                                                                                                                 
Page 3 of 7 
 
 
If you are in the placebo group and choose to try bupropion for 8 extra weeks you will be asked to complete 
questionnaires at weeks 4 and 8 after starting the buproprion.  
 
At the end of the study, all participants will be asked about the overall level of satisfaction and how much you 
feel you benefited from the study medication. 
 
In the past, patients often have filled out these quality of life forms on paper. NRG Oncology is working with a 
company, VisionTree Software, Inc., that has a web site where patients can fill out these forms anywhere there 
is a computer with Internet access.  This option is being offered as some patients may find it more convenient to 
fill out the forms electronically from any location, including home. When you log on to the web site, it will take 
you through the process of completing the forms step by step. You will need an e-mail address that you agree to 
use for this purpose. The e-mail address is needed to identify you on the VisionTree web site and for e-mail 
reminders that will be sent to you when the forms are due. Your e-mail address will only be used for the 
purpose of this study, not for mail or marketing purposes. If you are interested in filling out quality of life forms 
electronically but do not have an e-mail address, you may obtain one (quickly and for no charge at web sites 
such as Yahoo!, Hotmail, or AOL). You will only be sent e-mail reminders at the time that the forms are due (a 
maximum of 3 e-mail reminders per time point). Your access to the VisionTree web site is password protected 
and secure. You can use your e-mail address to retrieve your password if you forget it or lose your login card. 
You will receive a login card either by regular mail or e-mail, and it will include the information you need to 
log in to the VisionTree web site the first time. All patients will complete the forms before treatment on paper. 
After that, you can choose to complete the remaining forms online or on paper. The choice is up to you. 
 
Please circle your answer: I choose to use the VisionTree Software. I agree to fill out the Quality of Life forms 
electronically (after treatment has started) using the VisionTree web site.  
 
YES                                       NO 
 
What possible risks can I expect from taking part in this study? (08-Jun-2018) 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s office than usual 
• You may be asked sensitive or private questions which you normally do not discuss 
• Bupropion may not be better, and could possibly be worse, than the usual approach of counseling for 
sexual health. 
 
There is also a risk that you could have side effects from bupropion. 
 
Here are important points about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go away. 
• Some side effects may be serious and may even result in death. 
 
Here are important points about how you and the study doctor can make side effects less of a problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are having a side 
effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust bupropion to try to reduce side effects, if you choose to participate in the 
open-label portion of the study. 


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The tables below show the most common and the most serious side effects that researchers know about. There 
might be other side effects that researchers do not yet know about. If important new side effects are found, the 
study doctor will discuss these with you. 
 
Possible side effects of bupropion 
 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving bupropion, more than 20 and up to 100 may have: 
• Headache 
• Nausea 
• Dry mouth 
• Difficulty sleeping 
• Loss of appetite 
• Weight loss 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving bupropion, from 4 to 20 may have: 
• Constipation 
• Dizziness 
• Abnormal body movement 
• Restlessness, Worry 
• Infection 
• Stomach, muscle, bone pain 
• Abnormal heartbeat 
• Diarrhea 
• Mood changes, irritability 
• Sweating, rash,itching 
• Runny nose, sore throat 
• Ringing/buzzing in the ear 
 
RARE, AND SERIOUS 
In 100 people receiving bupropion, 3 or fewer may have: 
• Severe allergic reactions 
• mood problems  
• psychiatric problems (such as hallucination, psychosis, agitation, confusion) 
• Seizure 
• High blood pressure 
 
 
In patients taking bupropion for depression and other mental health disorders, increased depression and/or 
suicidal thoughts and behaviors is a rare and serious side effect. In addition, patients taking bupropion for 
smoking cessation have experienced serious changes in mood and behavior. Although patients in this study are 
not being treated for depression and the formulation of bupropion is different than that approved for smoking 
cessation, it is important to be aware of these additional rare and serious side effects. Tell your doctor if you 
experience any side effects, including changes in mood and behavior. 


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One of the questionnaires asks about depression and anxiety.  If you score 9 or more on this questionnaire, 
study personnel will be required to let your provider know and a health care provider will talk to you further to 
determine whether you need emotional support or treatment more urgently.   
 
Let your study doctor know of any questions you have about possible side effects. You can ask the study doctor 
questions about side effects at any time. 
 
What possible benefits can I expect from taking part in this study? 
It is not possible to know at this time if bupropion is better than the usual approach so this study may or may not 
help you. This study will help researchers learn things that will help people in the future. 
 
Can I stop taking part in this study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study 
doctor know as soon as possible so you can stop safely. You should not stop the study medication without 
talking to your study team.  If you stop, you can decide whether or not to let the study doctor continue to 
provide your medical information to the organization running the study. 
 
The study doctor will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow the study rules 
• If the study is stopped by the sponsor, IRB or FDA. 
 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your decision changes, 
there will be no penalty to you. You will not lose medical care or any legal rights. 
 
For questions about your rights while in this study, call the ________________________ (insert name of 
center) Institutional Review Board at __________________ (insert telephone number). (Note to Local 
Investigator: Contact information for patient representatives or other individuals at a local institution who are 
not on the IRB or research team but take calls regarding clinical trial questions can also be listed here.) 
 
What are the costs of taking part in this study? 
Bupropion will be supplied at no charge while you take part in this study.  You and/or your health 
plan/insurance company will need to pay for all of the costs of  your usual health care while in this study, 
including the cost of tests, procedures, or medicines to manage any side effects, unless you are told that certain 
tests are supplied at no charge. Before you decide to be in the study, you should check with your health plan or 
insurance company to find out exactly what they will pay for. 
 
You will not be paid for taking part in this study. 
 


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What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please tell your 
study doctor. The study sponsors will not offer to pay for medical treatment for injury.  Your insurance 
company may not be willing to pay for study-related injury.  If you have no insurance, you would be 
responsible for any costs. 
 
If you feel this injury was a result of medical error, you keep all your legal rights to receive  payment for this 
even though you are in a study. 
 
Who will see my medical information? (08-Jun-2018) 
Your privacy is very important to us.  The study doctors will make every effort to protect it.  The study doctors 
have a privacy permit to help protect your records if there is a court case.  However, some of your medical 
information may be given out if required by law.  If this should happen, the study doctors will do their best to 
make sure that any information that goes out to others will not identify who you are.  
 
Some of your health information, such as results of study tests, and medicines you took, will be kept by the 
study sponsor in a central research database.  However, your name and contact information will not be put in 
the database.  If information from this study is published or presented at scientific meetings, your name and 
other personal information will not be used.  
 
There are organizations that may inspect your records. These organizations are required to make sure your 
information is kept private, unless required by law to provide information. Some of these organizations are: 
• NRG Oncology 
• The Institutional Review Board, IRB, is a group of people who review the research with the goal of 
protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S., and similar ones if 
other countries are involved in the study. 
• VisionTree Software, Inc. 
 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general information 
about cancer. You may also call the NCI Cancer Information Service to get the same information at: 1-800-4-
CANCER (1-800-422-6237). 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. 
This Web site will not include information that can identify you. At most, the Web site will include a summary 
of the results. You can search this Web site at any time. 
 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to report side 
effects or injuries. Contact the study doctor __________________ (insert name of study doctor[s]) at 
__________________ (insert telephone number). 
 


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My Signature Agreeing to Take Part in the Main Study 
 
I have read this consent form or had it read to me. I have discussed it with the study doctor and my questions 
have been answered. I will be given a signed copy of this form. I agree to take part in the study. 
 
Participant’s signature________________________________ 
 
Date of signature_____________________________________ 
 
 
Signature of person(s) conducting the informed consent discussion___________________________________ 
 
Date of signature_____________________________________