Clinical trial NCT03187353
Conditions: Cognitive Impairment RRSO
Keywords: Cognitive complaints RRSO Oophorectomy Memory Cognition Early menopause
Sponsor: University of Pennsylvania
Start date: 2017-09-22; Completion date: 2022-04-30
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a double-blind, placebo-controlled, crossover study testing whether Vyvanse (lisdexamfetamine; LDX) improves executive functioning (EF) in 100 postmenopausal women who report onset of EF difficulties after oophorectomy. This study involves magnetic resonance imaging (MRI) to see how LDX affects brain chemistry while undergoing two 6-week trials of the study drug and placebo capsules.

UPDATE: We have recently updated this protocol (09/2020) to offer a remote version of the study that can be completed entirely from the participant's home. This alternate version of the study eliminates travel, the MRI, and blood draws.

Detailed description:
Following a medically induced menopause, many women report difficulty in remembering things, focusing and concentrating. The purpose of this study is to examine the effects of a stimulant medication called Vyvanse® (lisdexamfetamine; LDX) on executive functioning, such as attention, processing, organization, and memory, in women who are experiencing executive functioning difficulties after having undergone a risk-reducing bilateral salpingo-oophorectomy (RRSO). This study involves magnetic resonance imaging (MRI) to see how LDX affects brain chemistry while undergoing two 6-week trials of the study drug and placebo capsules.

Individuals wishing to participate in this study are medically healthy women between the ages of 35-58 years old who have undergone a risk-reducing bilateral salpingo-oophorectomy (RRSO) within the previous 15 years. Participants must have been premenopausal before undergoing RRSO (meaning they were having regular periods). They also must not have undergone radiation or chemotherapy in the past year.

Furthermore, participants must not suffer from a mental illness, including Attention Deficit Hyperactivity Disorder (ADHD), and must not have a recent history of drug abuse. Additionally, participants must not suffer from a fear of small, enclosed spaces (claustrophobia), and not have any implanted medical devices such as a pacemaker, orthodontic braces, or shrapnel. They must not have a history of seizures, uncontrolled hypertension or known renal impairment.

Arms: arm 1: Participants will have a 50% chance of first receiving the active study medication. They will begin at 20 mg/d and will increase up to 60 mg/d after 4 weeks, if well tolerated. Total time on the study drug is up to 6 weeks. After a washout period of 2 weeks they will begin with 1 sugar pill and will increase up to 3 pills after 4 weeks. Maximum time for taking the placebo is 6 weeks. arm 2: Participants will have a 50% chance of first receiving the placebo, beginning with 1 sugar pill and increasing up to 3 pills after 4 weeks. Maximum time for taking the placebo is 6 weeks. After a washout period of 2 weeks, they will begin active study medication at 20 mg/d and will increase up to 60 mg/d after 4 weeks, if well tolerated. Total time on the study drug is up to 6 weeks.
Interventions: intervention 1: Lisdexamfetamine intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Stimulant medications are used to reduce interruptive behavior, fidgeting, and other hyperactive symptoms, as well as help a person finish tasks and improve his or her relationships for adults who have ADHD. Please note that the FDA has not approved the use of Vyvanse® for the treatment of memory and concentration difficulties related to medically induced menopause. intervention 2: The placebo capsule will be filled with microcellulose.

Protocol documents:
Prot_SAP_000.pdf: 
Investigator’s Protocol IRB #826981 
 
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University of Pennsylvania Perelman School of Medicine 
 
IMPRES: IMProving Executive function Study 
IRB #826981 
 
Principal Investigator 
 
 
Neill Epperson, M.D. 
 
 
 
 
 
 
Department of Psychiatry 
 
 
 
 
 
 
3535 Market Street, Suite 3001 
 
 
 
 
 
 
Philadelphia, PA 19104 
 
 
 
 
 
 
215-573-8871 
 
Co-Principal Investigator 
 
 
James Loughead, Ph.D. 
 
Co-Investigators 
 
 
 
Mary Sammel, Sc.D. 
Ravi Prakash Reddy Nanga, Ph.D. 
Susan Domchek, M.D. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the University of Pennsylvania. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written authorization from the 
study sponsor. 


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ABSTRACT  
Risk-reduction bilateral salpingo-oophorectomy (RRSO) after completion of childbearing has 
become the standard-of-care for prevention of gynecologic and breast cancer in BRCA1 or BRCA2 
gene mutation carriers. Although surgery reduces the risk of death due to cancer by over 75%, 
knowledge regarding the impact of this procedure and subsequent hypogonadism on brain 
structure, function and neurotransmitter systems is limited. Menopause before the age of 40 is 
associated with significant cognitive decline in the years that follow and an almost 2-fold increased 
risk of dementia if a woman does not supplement with estradiol (E2). However, E2 is not an option 
for many post-RRSO women due to enhanced risk of cancer. Systematic assessment of a large 
group of women who underwent RRSO suggests subjective deficits in executive functions (EF), 
with severity inversely correlated with age at RRSO. As the prefrontal cortex is impacted by loss 
of E2 and is critical for working memory and other EFs, we propose to examine the biological and 
behavioral impact of the psychostimulant lisdexamfetamine (LDX) in 100 women between the 
ages of 35 and 58 with post-RRSO EF complaints. LDX is FDA approved for the treatment of 
attention deficit hyperactivity disorder which is characterized by many of the symptoms reported 
by some peri- and postmenopausal women. Participants in this study will undergo multi-modal 
imaging (functional magnetic resonance spectroscopy, fMRI; and proton magnetic resonance 
spectroscopy, 1H-MRS) using the ultrahigh magnetic field strength of 7 Tesla pre- and post- a 6-
week course of the psychostimulant lisdexamfetamine (LDX; Vyvanse®) or placebo followed by 
an approximate 2-week washout before crossing over to the other condition. Our overarching aim 
is to determine the impact of LDX treatment on brain function (neural activation and chemistry) 
as it relates to subjective and objective measures of EFs such as 1) organization and activation for 
work, 2) attention and concentration, 3) alertness, effort, processing speed, 4) managing affective 
interference, and 5) working memory, accessing recall. LDX has already demonstrated the 
potential to improve new-onset EF difficulties among women who underwent a natural menopause 
and has provided important information regarding a potential mechanism of therapeutic action, 
specifically LDX-induced changes in dorsolateral prefrontal cortex (dlPFC) glutamate (GLUT) 
levels. 
 
Background 
It is becoming standard of care to recommend that premenopausal women who carry BRCA 1/2 
gene mutation(s) undergo risk-reducing bilateral salpingo-oophorectomy (RRSO) upon 
completion of child bearing. Though RRSO before the age of 40 is associated with an 80% 
reduction risk of ovarian, fallopian tube, and peritoneal cancer, premature menopause is associated 
with significant cognitive decline in the short-term and an almost 2-fold increase risk for dementia 
in the long-term if subsequent intervention is not utilized (Finch et al., 2014; Domchek et al., 2010; 
Ryan et al., 2014). Preliminary data suggest varying degrees of executive function difficulties 
occur in 30% to 50% of women post-RRSO. Cognitive domains particularly affected by early 
menopause include verbal memory (Sherwin & Henry, 2008), verbal fluency and processing speed 
(Ryan et al., 2014), and executive functions such as attention, organization, and working memory 
in some women (Epperson, et al., 2011).  
 
Treatment of executive function difficulties with estradiol therapy (ET) after surgery is relatively 
contraindicated for some women who undergo RRSO. Overall rates of ET use after RRSO are 
between 25% and 47% (Madalinska et al., 2006). Moreover, longer periods of time without ET 
after RRSO may diminish the potential positive impact of ET (Maki, 2013; Rocca et al, 2011, 


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2012). Women who experience cognitive difficulties after RRSO may put off use of ET due to fear 
of breast cancer, diminishing the potential benefits of ET should they reconsider treatment to 
mitigate cognitive changes. However, ET is only partially protective even if utilized within the 
first month of surgical menopause as certain domains of cognitive function such as spatial memory 
may not be amenable to ET (Ryan et al., 2014). Hence women and their oncologists must conduct 
a cost benefit analysis between a potential life-saving procedure and preservation of quality of life. 
Given that premature menopause has adverse effects on cognitive function at a time in a woman’s 
life when she is experiencing the greatest demands professionally and personally, it is imperative 
to seek alternative interventions. 
 
Our group has explored the use of other pharmacologic strategies to target executive systems with 
the goal of improving symptoms of executive function difficulties. We have conducted two RCTs 
with medication marketed for the treatment of attention deficit hyperactivity disorder (ADHD), 
one with the non-psychostimulant atomoxetine (ATX, Straterra®) and two with the pro-drug and 
psychostimulant lisdexamfetamine (LDX, Vyvanse®) in the treatment of executive function 
difficulties in perimenopausal and menopausal women. Women who participated in the ATX study 
reported a significant improvement in concentration/attention and working memory domains of 
the Brown Attention Deficit Disorder Scale (BADDS) (Epperson et al., 2011). Participants in both 
LDX studies were also invited to undergo the brain-imaging paradigm that is described for the 
current study.  
 
Figure 1 shows the main outcome of the published results, specifically that LDX was more 
effective than placebo at decreasing scores in 4 of the 5 BADDS subscales (Epperson et al., 2015). 
Findings from the imaging sub-study indicated that baseline glutamate (Glut) levels were 
correlated with baseline severity of total BADDS scores, meaning that individuals presenting at 
baseline with higher severity of executive function difficulties also had higher Glut levels within 
the left dorsolateral prefrontal cortex (DLPFC) at baseline. Additionally, the decline in BADDS 
subscale 1 (Organization and Activation) scores during LDX vs. placebo treatment was negatively 
associated with increase in left DLPFC blood oxygen dependent (BOLD) signal during a working 
memory task (N-Back). That is, the increase in left DLPFC BOLD signal to active drug compared 
to placebo was greater in people who had greater improvement in BADDS score on LDX vs. 
placebo. These findings provide important evidence of co-occurring behavioral and brain changes 
with LDX treatment. Applying this paradigm in a larger sample of women from whom we will 
also acquire neurocognitive data to assess objective changes in function will provide important 
information regarding the mechanism of therapeutic action of LDX in this unique population.  
 
1 Study Objectives 
 
1.1 Overall Objectives 
The overarching aim of this study is to determine the 
impact of LDX treatment on brain function (neural 
activation and chemistry) as it relates to subjective 
and objective measures of executive functioning.  
 
1.2 Primary Outcome Variable(s) 


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LDX effects on subjective report of executive function difficulties. Brown Attention Deficit 
Disorder Scale (BADDS) is a clinically administered 40-item questionnaire that assess the 
frequency and severity of five clusters of symptoms: 1) organization and activating for work, 2) 
sustaining attention, 3) sustaining alertness, 4) managing affective interference, and 5) using 
working memory and accessing recall. The total BADDS score will serve as the primary outcome 
variable, while sub-scale scores will be examined to more fully determine the impact of LDX 
treatment on various domains of executive function and to determine whether any sub-categories 
of executive difficulty are more responsive to LDX treatment in this particular population. 
 
1.3 Secondary Outcome Variable(s) 
LDX effects on objective report of executive function difficulties. Proton magnetic resonance 
spectroscopy (1H-MRS) and functional magnetic resonance imaging (fMRI) will be utilized to 
assess the relative importance of dorsolateral prefrontal cortex (DLPFC) glutamate (Glut) levels 
and blood oxygen dependent (BOLD) signals during working memory task performance and the 
effect of LDX on the executive system activation.  
 
2 Study Design  
 
2.1 General Design 
To further our understanding of the mechanism of LDX treatment in women with executive 
function complaints after risk-reducing bilateral salpingo-oophorectomy (RRSO), participants will 
undergo multi-modal imaging (fMRI and 1H-MTS at 7 Tesla) pre- and post- a 6-week course of 
LDX (20-60mg/d) or placebo followed by an approximate 2-week washout before crossing over 
to the other condition. This study utilizes a double-blind, placebo-controlled, cross-over design. 
We will recruit 100 women who are between the ages of 35 and 58 years old. Subjects will be 
recruited from flyers posted around campus, paid advertisements, referrals from collaborators at 
FORCE (Facing Our Risk of Cancer Empowered), the Basser Center, and other medical settings 
where women who have undergone RRSO may seek treatment. Study subjects will be screened by 
a member of the research staff who can gauge whether the individuals are likely to meet study 
criteria. Potential participants who appear to meet criteria and express an interest in the study will 
have the option of completing the screening visit remotely or completing the visit in-office. 
Participants will also have the option to complete a remote version of the study.  
 
In-Office Screening: Participants who report for an in-office screening will be presented with the 
full, written ICF where they will have the chance to review and sign it with the study CRC. After 
giving full, written informed consent, subjects will undergo screening for past and current 
psychiatric disorders with the Mini International Neuropsychiatric Interview (M.I.N.I) and 
complete several behavioral ratings and questionnaires concerning personal history. A urine 
sample will be collected from participants to do a urine drug screen. Subjects will then undergo a 
brief medical evaluation and electrocardiogram (EKG) conducted by the study PI (Epperson, 
M.D.) or key study personnel. Vital signs including blood pressure and pulse will be recorded. 
Women with a consistent systolic blood pressure of >145mm Hg or diastolic blood pressure >90 
mm Hg after three readings at screening will not be enrolled and referred to their primary care 
doctors for further evaluation. Routine laboratory studies will include TSH, FSH and estrogen 
assays. If potential subjects have had these tests performed within the previous 6 months and can 
present their results, they will forgo additional blood work except that for genetics studies (4 mL) 


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to examine genes related to estrogen metabolism and various neurotransmitter systems involved 
in cognition. These tests will assess general health and confirm postmenopausal status. The study 
PI will be responsible for the final decisions regarding enrollment.  
 
Remote Screening: Participants who decide to complete the screening visit remotely must have 
access to telecommunication applications (i.e., Skype) that would enable the research team and 
participants to communicate via video chat in real-time. Furthermore, participants must have 
access to a scanner/fax machine so that they can send documents to the study CRC during the 
screening visit. Subjects who meet these stipulations will be presented with the full, written 
informed consent form via email and will have the opportunity to review the document in its 
entirety with the study CRC in real-time. After providing consent, subjects are expected to scan/fax 
the ICF document with their signatures to the CRC before completing other study-related 
procedures. The CRC will sign the document, attesting that she obtained consent, and scan/fax the 
document back to the subjects so that they have a copy for their records. Subjects will then undergo 
screening for past and current psychiatric disorders with the Mini International Neuropsychiatric 
Interview (M.I.N.I) and complete several behavioral ratings and questionnaires concerning 
personal history. Subjects will have the option of completing the brief medical evaluation, 
electrocardiogram (EKG), and routine laboratories studies (TSH, FSH, and estrogen levels) with 
their physician of choice or with key study personnel before their baseline visit. If applicable, 
participants will not proceed to the MRI portion of the visit until they have received medical 
clearance from study personnel. If potential subjects have had the blood work performed within 
the previous 6 months and can present their results, they will forgo additional blood work except 
that for genetics studies (4 mL). The study PI will be responsible for the final decisions regarding 
enrollment. 
 
Participants will also review a supplemental informed consent form with a study physician, 
pertaining to the purpose, procedures and risks/benefits of using both of the study medications. 
This form will be reviewed and signed in anticipation of the participant’s first dose of study 
medication.   
 
Participants either unable to travel or unable to complete an MRI will be offered a remote non-
imaging alternative which removes the MRI and blood draws from the required study procedures.  
 
Baseline MRI Scan (Visit 2): Upon completion of the screening visit, subjects will be scheduled 
to undergo their baseline 1H-MRS and fMRI scan session, which will take approximately 75 
minutes. Subjects will be instructed to present to the Penn Center for Women’s Behavioral 
Wellness approximately 2.5 hours before their scheduled scan to complete behavioral 
assessments regarding their mood and emotions and to complete out-of-scanner cognitive testing. 
Subjects will then be escorted to the Center for Magnetic Resonance and Optical Imaging 
(CMROI) by the study CRC where they will be scanned and asked to perform a series of tasks 
assessing their memory and attention. Subjects will then be given the study drug for the entirety 
of Trial A (either placebo or LDX) and instructed to begin taking the medication as directed by 
the study provider. If the participant needs additional study drug in order to complete the trial an 
additional script will be submitted to IDS for dispensation. Upon completion of the visit, the 
subject will be given a scale and blood pressure cuff for future remote vital sign collections. In 
total, the baseline scan visit will require approximately 4 hours to complete. 


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Additional Study Procedures for MRI eligible Subjects who Completed Screening 
Remotely: All subjects who completed the screening visit remotely will be reminded to 
bring the original version of the ICF to their Baseline MRI Scan (Visit 2) so that the original 
copy can be stored at PCWBW. A urine sample will be collected from all subjects to do a 
urine drug screen and an additional tube of blood will be collected for those who consented 
to genetics studies (4 mL) on the ICF before they start their scan. Subjects who indicated 
that they prefer research personnel to complete their required EKG and medical evaluation 
will be instructed to present to the Penn Center for Women’s Behavioral Wellness 
approximately 3.5 hours before their scheduled scan to complete said procedures in 
addition to the assessments stipulated by Visit 2. In total, the baseline scan visit will require 
approximately 5 hours to complete for those that still need medical clearance. 
 
Remote Baseline (Visit 2): Upon completion of the screening process, subjects will be scheduled 
for the baseline visit which will require approximately two hours. Medication will be mailed 
directly to the patient’s home through appropriate and approved direct-to-patient services. Subjects 
will be prescribed study drug for the entirety of Trial A (either placebo or LDX) and instructed to 
begin taking the medication as directed by the study provider. If the participant needs additional 
study drug in order to complete the trial an additional script will be submitted to IDS for 
dispensation. The subject will be sent a scale (if needed) and blood pressure cuff for future remote 
vital sign collections. On the day of the remote baseline visit, subjects will meet remotely with a 
member of the study team to complete behavioral assessments regarding their mood and emotions 
and complete cognitive testing. 
 
Week 2 Phone Check-In: At the end of week 2 of medication use, the CRC will check in with the 
participant by phone to assess for side effects. Subjects who are having more than mild side effects 
will be instructed to reduce their dose back to one pill per day.  
 
Week 3 Mid-Trial Check-In: Halfway through Trial A, during their third week, subjects will be 
scheduled for a remote follow-up visit where they will be monitored by the CRC for potential side 
effects of the medication and medication compliance. If no or mild side effects are reported, 
subjects will be instructed to increase the study drug to three pills per day. Subjects who are having 
more than mild side effects will be instructed to reduce their dose back to one pill per day. The 
study CRC can exercise her discretion regarding medical personnel involvement at this check-in. 
Subjects will be instructed to complete various mood and symptoms ratings during the visit. In 
total, the visit will require approximately 60 minutes and will include measures of blood pressure, 
pulse, and weight.  
 
Week 4 Phone Check-In: During week 4, the CRC will check in with the participant by phone to 
assess for side effects.  Subjects who are having more than mild side effects will be instructed to 
reduce their dose back to 2 pills per day for the remainder of the trial.   
 
End of Trial Scan: After the 6-week period, subjects will be scheduled to undergo their end of 
Trial A 1H-MRS and fMRI scan session, which will take approximately 75 minutes. Subjects will 
be instructed to present to the Penn Center for Women’s Behavioral Wellness approximately 2.5 
hours before their scheduled scan to complete cognitive testing and behavioral assessments 


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regarding their mood and emotions. Subjects will then be escorted to the CMROI by the study 
CRC where they will be scanned and asked to perform a series of tasks assessing their memory 
and attention. In total, the end of Trial A scan will require approximately 4 hours to complete. The 
completion of this visit concludes all visits for Trial A. Upon completion of the visit and Trial A, 
subjects will be given the study drug for the entirety of Trial B (either placebo or LDX) and 
instructed to begin taking the medication after the washout period, as directed by the study 
provider. 
 
Following an approximate 2-week washout period, subjects will complete their Trial B Baseline 
Visit, initiating the start of Trial B and medication usage. With the exception of the first baseline 
scan and cognitive testing, subjects will undergo the same study procedures for Trial B as they did 
for Trial A. Subsequent to their last scan, subjects will be required to bring their scales, blood 
pressure cuffs and unused capsules/empty bottles back to the study team so that they can be 
returned to Penn Investigational Drug Service (IDS). 
 
The primary investigator and research staff will unblind themselves to the drug treatment that was 
administered in each trial upon each participant’s completion or discharge from the study. 
 
Remote End of Trial Visit: After the 6-week period, subjects will be scheduled to undergo their 
end of trial visit which will require approximately two hours. On the day of the remote end of trial 
visit, subjects will meet remotely with a member of the study team to complete behavioral 
assessments regarding their mood and emotions and complete cognitive testing. The completion 
of this visit concludes all visits for Trial A. Upon completion of the visit and Trial A, subjects will 
return the prescription bottle and any remaining study drug from Trial A so that they can be 
returned to Penn Investigational Drug Service (IDS). At this point, all subjects will be instructed 
to complete an approximate 2-week wash out period before continuing to Trial B. 
 
Following an approximate 2-week washout period, subjects will be mailed their prescription for 
Trial B and complete their Trial B Baseline Visit remotely, initiating the start of Trial B and 
medication usage. Subjects will undergo the same study procedures for Trial B as they did for Trial 
A.  
 
At the completion of the remote End of Trial B visit, subjects will be required to bring return the 
scale (if applicable), blood pressure cuffs and unused capsules/empty bottles back to the study 
team so that they can be returned to Penn Investigational Drug Service (IDS). 
 
The primary investigator and research staff will unblind themselves to the drug treatment that was 
administered in each trial upon each participant’s completion or discharge from the study. 
 
 
2.2 1H-MRS Methods 
All the single-voxel 1H-MRS experiments to measure glutamate will be performed on a 7.0T whole 
body MRI scanner (Siemens Medical Systems, Erlangen, Germany) with a vendor supplied 
volume coil transmit/32 channel receive proton head phased array coil. BOLD signal change will 
be measured during performance of cognitive task and during rest.  
 


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2.3 Medical Administration 
Subjects will be prescribed lisdexamfetamine (LDX) 20mg capsules or a look-alike placebo 
(microcellulose) by the study PI (Epperson, M.D.) or her designee. Subjects will be instructed to 
take one pill (LDX = 20 mg) each morning for 7 days and then will be asked to increase to two 
pills (LDX = 40 mg) each morning for 14 days. If the study drug is well tolerated by the end of 
week 3 (as per medication monitoring by the CRC), participants will be asked to increase to three 
pills (LDX = 60 mg) each morning until the completion of the trial. Participants will be instructed 
to contact the study team if they experience any side effects and may decrease their medication as 
instructed. At the end of week 6, which is the end of the trial, participants will be evaluated and 
instructed to stop their study drug. After an approximate 2-week washout, participants will be 
crossed over to the other condition and the procedure will repeat. See table below for dosing 
instructions when the substance is well tolerated.  
 
Week 
1 
2 
3 
4 
5 
6 
Dosage 
20mg 
40mg 
40mg 
60mg 
60mg 
60mg 
 
2.4 Medication Dispensation 
Subjects will receive one medication bottle at their Trial A Baseline MRI Scan (Visit 2), which 
should last through the entirety of Trial A (6 weeks). Upon completion of their End of Trial A 
MRI Scan (Visit 4), subjects will receive their second medication bottle for Trial B. Subjects will 
be instructed to begin taking the medication after their Trial B Baseline Visit.  
 
In the event that a subject would require additional capsules, another prescription will be submitted 
on her behalf for the exact number of capsules needed to get her through the remainder of her trial.  
 
2.5 Compensation 
Participants will be compensated for their participation in all study visits. If the participant 
completes all parts of the study, is on time for appointments, and takes her medication, total 
payment for participants is $650.  
 
The breakdown of subject payment by visit is as follows: 
 
Visit Name 
Visit Number 
Amount 
Screening Visit* 
Visit 1 
$50 
Trial A 
Baseline (with Scan) 
Visit 2 
$150 
Week 3* 
Visit 3 
$50 
End of Trial A (with Scan) 
Visit 4 
$150 
Trial B 
Baseline (without Scan)* 
Visit 5 
$50 
Week 3* 
Visit 6 
$50 
End of Trial B (with Scan) 
Visit 7 
$150 
Note: “*” indicates that study visit can be complete remotely. 
 
Subject reimbursement is available for: 
• Transportation to and from required in-office visits (Visits 2, 4, and 7). 


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• Hotel accommodations provided by the research team for up to two nights for required in-
office visits (Visits 2, 4, and 7) 
• Study-related procedures completed with the subject’s physician that were NOT covered 
by the subject’s insurance (i.e., EKG, blood work, and physical exam). 
 
2.6 Study Duration 
We anticipate completion of recruitment within 5 years of study inception. Each subject will spend 
approximately 4-5 months completing all study related procedures. 
 
3. Subject Selection and Withdrawal 
 
3.1 Target Population 
We will recruit 100 women, aged 35 to 58 years old, who have undergone a RRSO within the 
previous 15 years and are currently reporting impairment in some aspect of their daily function. 
We anticipate a drop-out rate of 10%. Given that the composition of the proposed study population 
will reflect the Greater Philadelphia referral base, we will make attempts to enhance the 
recruitment of minorities, but we are limited by the racial and ethnic make-up of women who 
typically seek oophorectomy for prevention of breast and ovarian cancer.  
 
3.2 Accrual 
We anticipate that we will meet our recruitment goals by working with our longstanding 
collaborators in the Department of Oncology at Penn and the support group: Facing Our Risk of 
Cancer Empowered (FORCE) for women who are at genetic risk for breast and ovarian cancer 
and/or gynecologic cancer survivors. Based on previous recruitment efforts, the organization could 
provide 30% of our participants from the FORCE membership of 25,000 women. Also, 500 
BRCA-1/2 gene carriers are followed yearly at the Basser Center for BRCA at the Abramson 
Cancer Center and the Basser registry of post-RRSO women includes 1800 individuals. Another 
50-60 women undergo RRSO each year at one of the University of Pennsylvania Health System 
hospitals. Additionally, Philadelphia has several other nationally ranked cancer centers from which 
we can recruit. 
 
We have found advertisements on the local Philadelphia public radio station (WHYY) to be 
enormously productive for our menopause studies, yielding 1-2 new qualifying participants with 
each run. Hence, we plan to advertise on WHYY at least twice a month. Also, we have already 
conducted an online evaluation of the severity of executive function difficulties among post-RRSO 
women in the greater tri-state area and were granted IRB approval to re-contact these women to 
inform them about the proposed study. With access to clinical samples and referrals from FORCE 
and the Basser Center, we could complete our study enrollment if even 5% of the genetically at- 
risk population in the area were to meet study criteria and agree to participate.  
 
3.3 Key inclusion criteria 
1. Females aged 35 to 58 years; 
2. Have undergone risk-reducing bilateral salpingo-oophorectomy (RRSO) within the 
previous 15 years AND were premenopausal at the time of RRSO; 
3. Score of ≥ 20 on the Brown Attention Deficit Disorder Scale (BADDS); 
4. Onset of executive function difficulties occurred post RRSO; 


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5. Clean urine drug screen (nicotine and marijuana are permissible). Potential false positive 
screenings will be reviewed and exclusionary based on PI discretion; 
6. Are fluent in written and spoken English; 
7. Are able to give written informed consent (obtained at screening visit); 
8. Have  a high school diploma or equivalent degree (i.e., GED), as per subject report; 
9. If using aromatase inhibitors or tamoxifen: Must have been on a stable dose for at least 6 
months; 
10. If completing visits remotely: Must have access to a telecommunications application (i.e., 
Skype), email, scanner/fax machine, and a private area that enables the protection of 
participant confidentiality.  
 
3.4 Key exclusion criteria 
1. Current untreated psychiatric disorder; 
2. Substance use disorder within the previous 3 years;  
3. Lifetime history of ADHD or psychotic disorder including bipolar disorder, schizoaffective 
disorder, and schizophrenia; 
4. Lifetime history of stimulant abuse or dependence;  
5. Regular use of psychotropic medications except selective serotonin reuptake inhibitors 
(SSRI), serotonin noradrenergic reuptake inhibitors (SNRI), bupropion, zolpidem, 
gabapentin, or buspirone; 
6. Chemotherapy within the past year;  
7. Previous history of sensitivity or adverse reaction to lisdexamfetamine (LDX); 
8. History of seizures or unstable medical condition; 
9. Known heart disease or clinically significant abnormal electrocardiogram during 
screening as determined by the study MD; 
10. Uncontrolled hypertension; 
11. Presence of a metallic implant contraindicative to scanning at the 7T level; 
11. Claustrophobia; 
12. Consistent systolic blood pressure of >145mm Hg or diastolic blood pressure >90 mm Hg 
after three readings at time of screening; 
13. Known renal impairment and End Stage Renal Disease (ESRD). 
 
Note: Chemotherapy and RRSO are commonly paired as a treatment plan for feminine 
cancers. Participants who underwent relatively concurrent treatments of chemotherapy and 
RRSO, such as when chemotherapy immediately precedes RRSO, will be considered by the 
principal investigator and be included at the PI’s discretion. 
 
3.5 Populations vulnerable to undue influence or coercion 
University of Pennsylvania students and employees (both of appropriate age and study criteria) 
and economically disadvantaged persons are welcome to participate in this study. Potential 
subjects will be provided with information about the study and will have the opportunity to ask 
questions of study staff prior to signing consent. They will be informed that their decision to 
participate or decline will not affect their care, or their employment or education (if an employee 
or student of UPenn). The participants will be appropriately consented and their information will 
be kept in a locked cabinet, filed by code, in a locked room that only the research study personnel 
has access to. 


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3.6 Subject Recruitment 
Subjects will be recruited by word of mouth, referrals by collaborators at FORCE, the Basser 
Center, and other medical practices, flyers/brochures, paid advertisements, and direct calling of 
qualified, prescreened women who agreed to future contact for the proposed study.  
 
3.7 Non-Imaging Subsection of Participants 
Subjects will be evaluated for their eligibility to participate in the full list of protocol procedures. 
However, there may be some subjects that are not eligible due to MRI incompatibility. Therefore, 
we will have a subsection of participants who are not eligible to complete the MRI due to having 
metal in their body, claustrophobia, or handedness, but are still eligible to complete all other study 
procedures at the PIs discretion. The non-imaging subsection will serve as an alternative for 
anyone unable or not interested in completing the MRI. This subsection of participants will have 
to meet all other study criteria in order to be included in this subsection and will be reviewed by 
the PI. Participants eligible for the non-imaging subsection of this study will receive a separate 
consent form that details the study procedures, risks/benefits, and compensation.  
 
4 Analysis Plan 
4.1 Statistical Analysis 
Summaries of each outcome (BADDS scores, performance on the cognitive tasks, Glut, and BOLD 
signal) under each treatment condition (baseline, LDX, and placebo) will be examined using 
histograms, boxplots, and normal probability plots. Transformations of the outcomes will be 
considered as necessary to meet modeling assumptions. General linear regression (mixed models) 
will be employed to estimate the association between each outcome, treatment condition and cross-
over sequence while accounting for the nonzero correlation among the repeated observations 
within individuals.  
 
Aim 1: Total BADDS score at each time point will be examined for an interaction effect between 
time (pre vs. post) and treatment (LDX vs. placebo) to assess whether within-subject total BADDS 
score is significantly reduced post LDX treatment rather than post placebo. Baseline BADDS 
scores will be dichotomized at the median score and considered as a covariate in the mixed effects 
models. Additional interaction terms for baseline group by time (pre vs. post) and baseline group 
by treatment (LDX vs. placebo) will be added to the model to test whether treatment effects 
differentially affect those with higher baseline scores. 
 
Aim 2: Similar models will evaluate BADDS subscores, cognitive task performance, and L-
DLPFC Glut levels. Similar mixed models will assess associations between change in specific 
BADDS domains with identified deficits in executive function and change in DLPFC Glut levels.  
 
Aim 3: We will quantify associations between baseline percentage BOLD signal change during 
performance of the n-back (3-back) and L-DLPFC Glut. 
 
Current methods for fMRI analyses are as follows: Functional scans will be realigned, 
normalized, time-corrected, and spatially smoothed by an 8 mm FWHW Gaussian kernel. The time 
series will be high-pass filtered to correct for drift across the scan. For blocked designed 
experiments (3-back), regressors will represent trial conditions; for the event-related design 


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experiments regresses will represent individual trials and trial outcomes. At the individual level, 
voxel-wise fixed-effects contrast analyses will be performed for each subject to assess the 
magnitude of pair wise difference in blood oxygen dependent (BOLD) signal between the 
emotional and the neutral control condition. At the group-level, a second stage of the process will 
use a random effects model to create spatial parametric maps (SPM) depicting loci that are active 
across subjects. Movements parameters derived from the realignment correction (for all six 
possible directions) will be entered into the design matrix as covariates of no interest. For a priori 
regions of interests, clusters will be reported if they are significant at P=0.05 corrected, using a 
small volume correction (SVC). Clusters will also be reported if they are significant at a threshold 
of P=0.001, uncorrected, with an extend threshold of 10 voxels. Repeated measures analysis of 
variance (ANOVA) will then be performed to test the effect of LDX on brain activation patterns 
and simple effects analyses will reveal overall effects of LDX treatment. 
 
fMRI/MRS Analysis: Percent BOLD signal changes in the left DLPFC will be entered in a 
correlational analysis with corresponding Glut concentrations. Size and orientation of regions 
included for analysis of BOLD signal and Glut concentration will be identical. Percent BOLD 
signal change will be calculated for each regressor of interest and correlation coefficients will be 
obtained. Voxel wise regression of BOLD signal vs. mean Glut concentration will be performed 
for each functional voxel. 
 
4.2 Rationale for sample size 
Sample size is estimated for the 3 primary outcome measures: BADDS scores, DLPFC Glut levels, 
BOLD signal activation during the N-Back Task. 
 
Assuming a type I, alpha, error of 5%, and 80% power, we anticipate being able to detect a 0.3 SD 
difference between within subject change under active LDX and placebo conditions with 88 
participants. Based on our pilot data for total BADDS score, we will have 80% power to detect as 
small as an 8.4% difference in BADDS total score when comparing placebo to LDX 
administration. Given our pilot data from naturally menopausal women, this effect size 
corresponds to a 19% difference between active LSX and placebo in organization and activation 
for work, and 15% for attention/concentration BADDS subscales. We are conservatively powered 
for an effect size of 0.3 SD, meaning that we have sufficient power to examine a number of 
different covariates and possible predictors of outcome in this study.  
 
Given our pilot data for levels of Glut in the left DLPFC, we will have 80% power to detect as 
small as a 2.6% reduction in Glut for active LDX administration compared to placebo. A similar 
0.3 SD can be detected for BOLD signal in left DLPFC. This corresponds to a 25% difference in 
BOLD signal change between placebo and LDX for 3-back task. 
 
5 Safety and Adverse Events 
 
5.1 Potential Risks 
Risk of Vyvanse® (LDX): The reported adverse reactions to LDX treatment include: constipation, 
decreased appetite, diarrhea, dizziness, dry mouth, headache, increased sweating, mild irritability, 
nervousness, or restlessness, nausea, trouble sleeping, unpleasant taste, upper stomach pain, 
vomiting and weight loss.  


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The most common side effects reported by adults are decreased appetite, difficulty falling asleep, 
and dry mouth. LDX can cause an increase in blood pressure and heart rate, although it is not 
contraindicated in the treatment of individuals with stable hypertension (Huffman & Stern, 2004). 
While the likelihood that individuals will develop peripheral vasculopathy is very small, subjects 
will be monitored at each assessment for tingling and numbing sensations in their extremities. 
Sudden death has been reported in adults using stimulant medications within the normal dosing 
range. This type of serious event has not occurred with Vyvanse® but will be discussed with 
subjects as a potential adverse event of this class of medication. Although rare, the risk of serotonin 
syndrome increases when co-administered with other serotonergic agents (i.e., SSRIs, SNRIs, 
triptans). Women taking serotonergic medications will be briefed on potential symptoms and 
monitored at each visit for any side effects. Serious side effects will be minimized by short-term 
treatment, exclusion of women who would be at heightened risk for participation, and careful 
monitoring of the treatment.  
 
Risk of 1H-MRS operating at 7T: To date, no persistent adverse effects have been reported by 
facilities with magnetic field strengths at 7.0T. A metallic taste in the mouth, dizziness or nausea 
upon being moved into the magnetic field is not uncommon. This dizziness and nausea typically 
last less than 10 minutes and can be reduced by reducing the speed at which the subject is placed 
into the magnet. If experienced, the metallic taste usually goes away within minutes.  In rare cases 
individuals may experience brief, intermittent sensations such as tingling in parts of their body 
during the scan.  The FDA has authorized the use of the 7.0T magnets in humans. Some of the 
pulse sequences and/or RF coils are not FDA authorized but are considered non-significant risk 
investigational devices. All subjects will be informed of the possibility of having these sensations 
during the informed consent process. The 7.0T scanners are not approved in pregnant women and 
they are to be excluded from trials utilizing the 7.0T magnet. As the women in this study are not 
of child bearing potential, they will not be subjected to a urine pregnancy test before scans. All 
subjects will be screened for the presence of any metallic objects that they may be holding or have 
implanted in their bodies, and all potential subjects with metallic implants contraindicative to 
scanning at the 7.0T level will be excluded.  
 
Experimental Device Clause: Some of the pulse sequences and/or RF coils are not FDA 
approved but are considered non-significant risk investigational devices. 
 
Pregnancy Clause: Women in this study will be postmenopausal and are therefore unable 
to conceive. 
 
Use of venipuncture for blood sampling: Inserting a needle into a vein is safe when done by 
professionals under clean conditions. Sometimes a bruise will occur at the puncture site and on 
rare occasions fainting, a blood clot, or an infection may form in the vein. If this occurs, appropriate 
treatment will be instituted immediately. 
 
Clinical Assessments: Subjects will be administered a number of cognitive and behavioral 
assessments during the screening process and at follow-up visits. However, there is no risk 
associated with administering these assessments. Knowing the outcome of the assessments should 


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not make the subject feel any differently about themselves. We will not be sharing the results with 
anyone besides the subjects and the research team.  
 
Genetics: In the laboratory, genetic samples will be labeled with a number only. Subject name or 
any other identifying information will not be attached to the samples in the research laboratory. 
This measure is taken to protect confidentiality, in addition to the following specific measures: 
 
 
a.) The genetic testing of all samples will be used for research purposes only. No results 
 
of genetic testing from this study will appear in any subject’s medical record. 
 
b.) Genetic test results will not be made available to subjects, to their doctors, or to the 
 
other clinicians or any other clinical staff. 
 
c.) To protect confidentiality as much as possible, no computer records will be created 
 
that could be used to identify a subject’s genetic or medical information individually. 
 
Thus, even if a “hacker” breaks into the laboratory computer system, there will be no 
 
information stored there that can identify any individual subject. 
 
d.) Information about genes will only be stored in Dr. Epperson’s laboratory, using 
 
procedures described above to protect your confidentiality, unless the information has 
 
become completely stripped of information that could identify an individual subject. 
 
In our experience at a previous academic institution, in which many hundreds of samples have 
been collected, no outside agency has ever tried to gain access to any research subject’s genetics 
samples. Dr. Epperson believes that the risk of this happening to any sample collected as part of 
this study is extremely small. 
 
The goal of the genetic testing for the study is exploratory, not predictive. 
 
5.2 Potential Study Benefits 
There are no intended direct benefits for subjects in this study however participants may experience 
an improvement in their perceived cognitive functioning during the course of the study trials.  
Results from this clinical trial may help add to our understanding of treatment options for 
individuals experiencing executive function difficulties as a result of RRSO.  
 
5.3 Risk/Benefit Assessment 
This study represents more than minimal risk to the subject, as individuals will undergo 
neuroimaging and treatment with LDX, which they may never have otherwise taken. Should this 
study show that LDX administration improves executive function outcomes of interest and is 
correlated with changes in left DLPFC glut concentrations and BOLD signal, we will have 
additional evidence that psychostimulant –related changes in brain neurochemistry and neuronal 
function are clinically relevant.  
 
5.4 Data Safety and Monitoring 
The Principal Investigatory (Dr. C. Neill Epperson) will be the primary source for data and subject 
safety monitoring. The research staff will meet weekly to discuss recruitment, retention, breaches 
of confidentiality, adverse events, and collected data. Subjects will be instructed to call study 
personnel as soon as possible in the event of side effects. If we have concerns about their physical 
and emotional health, we will share these concerns with the subjects’ primary care physicians. 


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5.5 Resources Necessary for Human Research Protection 
Dr. Epperson, the study Principal Investigator has had more than 20 years of experience 
conducting translational neuroscience research in human subjects focusing on the impact of sex 
hormones and neurosteriods on behavior and cognition in women. Dr. Epperson is the recipient of 
3 RO1 grants from the NIMH, NIDA, and NIA. She is also the recipient of several K awards from 
the NIH. Dr. Epperson has extensive experience overseeing the conduct of research in her 
laboratory. She is personally responsible for all aspects of the study or delegation of duties to 
individuals she has trained over the years. 
 
If an individual were to demonstrate the need for mental health services, they would first be 
referred to the Penn Center for Women’s Behavioral Wellness (PCWBW) for evaluation by one 
of the Center’s psychologists or psychiatrists. An appropriate treatment plan and/or referral would 
be developed as necessary. The PCWBW is housed in a large office building with 24-hour security. 
The Center’s main offices at 3535 Market St. are comprised of 8 clinical offices, one laboratory 
space, copy, fax and mail room, reception area and kitchen. In addition, there is both clinical and 
administrative space at Pennsylvania Hospital in the same area as Maternal Fetal Medicine 
outpatient services. 
 
6 Data Handling and Record Keeping 
 
6.1 Subject Confidentiality 
This study will utilize directly-identifiable protected health information (PHI). PHI, as defined by 
HIPAA, means individually identifiable health information about an individual that is transmitted 
or maintained by electronic media or in any other form or medium. PHI includes demographic 
information that is created or received by a health care provider, health plan, employer, or health 
clearinghouse. PHI relates to the past, present, or future physical or mental health or condition of 
an individual; the provisions of health care to an individual; or the past, present, or future payment 
for the provision of health care to an individual; and identifies the individual or can reasonably be 
used as a basis to identify an individual. The following PHI will be collected for this study: 
 
• Name 
• Postal address information 
• All elements of dates, such as birthdate and date of visit, (except year) for dates directly 
related to an individual and all ages over 89) 
• Telephone and fax number 
• Electronic mail addresses 
• Social security numbers (for study compensation) 
• Medical record numbers (for ordering MRIs and medications) 
 
In accordance to University of Pennsylvania’s policy regarding how PHI is handled, managed, and 
disseminated, study personnel will utilize an institutionally secured and managed network drive.  
 
Institutionally secured and managed network drive: The PCWBW utilizes a departmental shared 
drive to securely store PHI. The PCWBW shared drive is managed and secured by The Penn 
Medicine Academic Computing Services (PMACS). Access to the shared drive requires password 


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access to a departmental device (PCWBW desktop or laptop) then additional password access to 
the departmental shared drive. After being granted access to the shared drive, one must have an 
encryption code to access the files storing PHI. Therefore, the only PCWBW employees that will 
have access to the PHI connected to this study will be the approved study personnel (Principal 
Investigator, Project Supervisor, Clinical Research Coordinators).  
 
Any paperwork that includes PHI (such as SSN on subject compensation forms) will be kept in a 
locked draw within a locked office. To reduce the possibility of breaches in subject confidentiality, 
subjects will be given a unique identifier to place on their demographic information, 
questionnaires, behavioral ratings, and data from scan sessions. Only the study personnel will have 
access to the code. Five years after completion of the study, the subject code will be destroyed.  
Data will be destroyed 8 years after study completion. 
 
6.2 Subject Privacy 
The study personnel will maintain a high level of privacy for this research study. To respect those 
boundaries, several safeguards will be in place. Subjects will be screened and interviewed in a 
private office at the PCWBW offices located at 3535 Market Street. When contacting subjects, 
information about mental and physical health will not be disclosed; telephone messages or 
voicemails will be worded so as to not reveal the subjects study status, diagnoses, or any other 
confidential information. 
 
7 Investigational Agent 
7.1 Investigational Agent 
– 
Drug name: Vyvanse® (lisdexamfetamine; LDX) 
– 
Pharmacological class: STIMULANT 
– 
Structural formula (if known): C15H25N3O(CH4O3S)2 
– 
Formulation and dose: Capsules 20 mg, 30 mg, 40 mg, 50 mg, 60 mg and 70 mg 
– 
Route of Administration: Oral 
 
Planned exposure (e.g. duration of study drug administration):  One hundred, otherwise healthy, 
adult women (age range 35 to 55 years) who have undergone RRSO and are currently reporting 
some impairment in daily functioning will be enrolled in this study to determine the impact of 
LDX treatment on brain function as it relates to subjective and objective measures of executive 
function such as 1) organization and memory, 2) attention and concentration, 3) alertness, effort, 
processing speed, 4) managing affective interference, 5) working memory, accessing recall. 
Participants will undergo multi-modal imaging-fMRI and 1H-MRS pre and post a 6-week course 
of LDX or placebo followed by a 2-week washout before crossing over to the other condition. 
 
7.2 Overview of Previous Human Experience  
Please see section 10 of this protocol for data regarding human experience with LDX. 
 
7.2.1 Reference to previously submitted IND application(s) 
Please see section 10 of this protocol for information regarding IND applications for LDX. 
 
7.3 Overview of Preclinical Data 
Please see FDA Labeling for Protocol 812470. 


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8 Investigational Agent: Chemistry and Manufacturing 
8.1 General Method of Preparation and packaging 
Vyvanse® (LDX) is designed as a capsule for once-a-day oral administration. LDX is 
commercially available from the manufacturer. 
 
All study drugs used n this study will be obtained directly from the manufacturer and dispensed 
by the Penn Investigational Drug Service (IDS). 
 
8.2 Drug Components and Drug Product 
Vyvanse® capsules contain LDX as the active ingredient in dosages of 20mg, 30mg, 40mg, 50mg, 
60mg, and 70mg. Each capsule contains the following inactive ingredients; microcrystalline 
cellulose, coscamellose sodium and magnesium stearate. The capsule shells contain gelatin, 
titanium dioxide and one or more of the following: D&C Red #28, D&C Yellow #10, FD&C Blue 
#1, FD&C Green #3, and FD&C Red #40. 
 
8.3 Placebo Product 
Capsules will be filled with microcellulose. The placebo capsules will also be administered by 
IDS. 
 
8.4 Labeling 
The drug used for this study will be placed in a bottle labeled with the subject’s name, instructing 
them to take the capsule(s) by mouth. The capsules will be ordered through the IDS at UPenn and 
brought to the PCWBW by research staff and then distributed to the subject. 
 
8.5 Environmental Analysis Requirements 
As LDX is a marketed medication we believe an environmental analysis is not required. 
 
9 Pharmacology and Toxicology 
LDX is a product of dextroamphetamine. After oral administration, LDX is rapidly absorbed from 
the GI tract and converted to dextroamphetamine, which is responsible for the drug’s activity. 
Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. The 
mode of therapeutic action in ADHD is not known. Amphetamines are thought to block the 
reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of 
these monamines into the neural space. The parent drug, LDX does not bind to the sites responsible 
for the reuptake of norepinephrine and dopamine in vitro. 
 
Pharmacokinetic studies of dextroamphetamine after oral administration id LDX have been 
conducted in healthy adults 
 
10 Previous Human Experience with Investigational Agent 
10.1 Marketed experience  
The study investigator has received an IND exemption from FDA for IRB #812470 and IRB 
#817628 and therefore would be expected to receive an exemption for this protocol as well. Shire’s 
IND, #67,482, provides important information about LDX, including marketing experience with 
humans.  


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10.2 Prior Clinical Research Experience 
Shire’s IND, #67,482, provides important information about LDX, including clinical research 
experience with human subjects. In addition, the FDA approved prescribing information includes 
a brief summary of clinical trials of LDX in both children and adults. Pertinent to the present 
project, the information regarding adults from IND#67,482 is presented here. 
 
A double blind, randomized, placebo-controlled, parallel-group, study was conducted in adults 
(N=420) who met DSM-IV criteria for ADHD. In this four-week study, patients were randomized 
to fixed dose treatment groups receiving final doses of 30, 50, or 70 mg of Vyvanse® or placebo. 
All subjects receiving Vyvanse® were initiated on 30mg for the first week of treatment. Subjects 
assigned to the 50 and 70 mg dose groups were titrated by 20 mg per week until they achieved 
their assigned dose. Significant improvements in ADHD symptoms, based upon investigator rating 
on the ADHD Rating Scale (ADHD-RS), were observed at endpoint for all Vyvanse® doses 
compared to placebo. 
 
A second study was a multi-center randomized double-blind, placebo-controlled, cross-over 
design, modified analog classroom study of Vyvanse® to simulate a workplace environment in 
142 adults who met DSM-IV TR criteria for ADHD. There was a 4-week open-label, dose 
optimization phase with Vyvanse (30, 50, or 70 mg/d in the morning). Subjects were then 
randomized to one of two treatment sequences: 1) Vyvanse® (optimized dose) followed by 
placebo, each for one week or 2) placebo followed by Vyvanse®, each for one week. Efficacy 
assessments occurred at the end of each week, using the Permanent Product Measure of 
Performance (PERMP). The PERMP is a skill-adjusted math test that measures attention in 
improvement in attention across all post-dose time points, as measured by average PERMP total 
scores over the course of one assessment day, as well as at each time point measured. The PERMP 
assessments were administered at pre-dose (-0.5 hours) and at 2,4,8,10,12, and 14 hours post-dose. 
 
10.3 Clinical Care Experience 
While psychostimulants have been used to manage cancer related fatigue with variable success 
(Minton et al., 2010), there have been no controlled studies of psychostimulants in the treatment 
of new onset executive function difficulties after RRSO. Several placebo-controlled studies of 
psychostimulants have been conducted in children who experience cognitive deficits after surgery, 
chemotherapy and/or radiation, particularly for head and neck cancers. Benefits of active drug over 
placebo have been shown for domains such as attention, vigilance, working memory and 
processing speed (Castellino et al., 2014). Likewise, use of psychostimulants in adults with cancer 
treatment related to neurocognitive impairment has been met with variable success (Prommer, 
2012), possibly due to the advanced age of the individuals studied. To our knowledge, there are 
no controlled studies examining the efficacy of psychostimulants in treatment of subjective or 
objective cognitive decline in young women after RRSO or other forms of premature menopause.  
 
Of the few 1H-MRS studies of psychostimulant effects on brain neurochemistry most have been 
performed in pediatric populations with ADHD. A recent study in adults with ADHD found no 
difference in baseline GLX (glutamate+glutamine) levels in the DLPFC between adults with and 
without ADHD (Maltezos et al., 2014)  
 


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11 Additional Information 
11.1 Drug dependence and abuse potential 
Amphetamines have been extensively abused. Tolerance, extreme psychological dependence and 
severe social disability have occurred. There are reports of patients who have increased the dosage 
to levels many times higher than recommended. Abrupt cessation following prolonged high-
dosage administration results in extreme fatigue and mental depression; changes are also noted on 
the sleep EEG. Manifestations of chronic intoxication with amphetamines may include severe 
dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe 
manifestation of chronic intoxication is psychosis, often clinically indistinguishable from 
schizophrenia. 
 
In a human abuse liability study, when equivalent oral doses of 100 mg lisdexamfetamine 
dismesylate and 40 mg immediate-release d-amphetamine sulfate were administered to individual 
with a history of drug abuse, lisdexamfetamine dismesylate 100 mg produced subjective responses 
on a scale of “Drug Liking Effects” (primary endpoint) that were significantly less than d-
amphetamine immediate-release 40 mg. However, oral administration of 100 mg 
lisdexamfetamine dismesylate produced increases in positive subjective responses that were 
statistically indistinguishable from the positive subjective responses produced by the 40 mg of oral 
immediate-release d-amphetamine and 200 mg of diethpropion (C-IV) Intravenous administration 
of 50 mg lisdexamfetamine dismesylate to individuals with a history of drug abuse produced 
positive subjective response on scales measuring “Drug Liking Euphoria,” “Amphetamine 
Effects,” and “Benzedrine Effects” that were greater than placebo but less than those produced by 
an equivalent dose (20 mg) of intravenous d-amphetamine. 
 
11.2 Radioactive drugs- Not applicable to this study. 
 
11.3 Pediatric studies- not applicable for this study. 
 
11.4 Direct-to-Patient Services 
Participants who complete the remote option for this study will have the medication appropriately 
and legally shipped directly to their home for each trial. After the completion of each study trial, 
the participants will ship back their prescription bottle and any unused medication for return and 
destruction to Penn’s IDS.  
 
 
 
 
 
 
 
 
 
 
 


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12. Bibliography 
Castellino, S.M., Ullrich, N.J., Whelen, M.J., & Lange, B.J. (2014). Developing interventions for       
 
cancer-related cognitive dysfunction in childhood cancer survivors. Journal for the 
 
National Cancer Institute 106(8), 1-16. 
 
Domchek, S.M., Friebel, T.M., Singer, C.F., Evans, D.G., Lynch, H.T., Isaacs, C., Garber, J.E.,                           
 
Neuhausen, S.L., Matloff, E., Eeles, R., Pichert, G., Van t’veer, L., Tung, N., Weitzel, 
 
J.N., Couch, F.J., Rubinstein, W.S., Ganz, P.A., Daly, M.B., Olopade, O.I., Tomlinson, 
 
G., Schildkraut, J., Blum, J.L., & Rebbeck, T.R. (2010). Association of risk-reducing 
 
surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. Journal of 
 
American Medical Association (9), 967-975.  
 
Epperson, C.N., Pittman, B., Czarkowski, K.A., Bradley, J., Quinlan, D.M., & Brown T.E.  
(2011).  Impact of atomoxetine on subjective attention and memory difficulties in 
perimenopausal and postmenopausal women. Menopause (18), 542-548. 
 
Epperson, C.N., Shanmugan, S., Kim, D.R., Mathews, S., Czarkowski, K.A., Bradley, J., 
 
Appleby D.H., Iannelli, C., Sammuel, M.D., & Brown, T.E. (2015). New onset executive 
 
function difficulties at menopause: A possible role for lisdexamfetamine. 
 
Psychopharmacology, 232 (16), 3091-3100. 
 
Finch, A.P.M., Lubinski, J., Møller, P., Singer, C.F., Karlan, B., Senter, L., Rosen, B., Maehle, 
 
L., Ghadirian, P., Cybulski, C., Huzarski, T., Eisen, A., Foulkes, W.D., Kim-Sing, C., 
 
Ainsworth, P., Tung, N., Lynch, H.T., Neuhausen, S., Metcalfe, K.A., Thompson, I., 
 
Murphy, J., Sun, P., & Narod, S.A. (2014). Impact of oophorectomy on cancer incidence 
 
and mortality in women with a BRCA1 or BRCA 2 mutation. American Society of 
 
Clinical Oncology (32), 1547-1554). 
 
Madalinska, J.B., van Beurden, M., Bleiker, E.M.A., Valdimarsdottir, H.B., Hollenstein, J., 
 
Massuger, L.F., Gaarenstroom, K.N., Mourits, M.J., Verheijen, R.H., van Dorst, E.B.L., 
 
van der Putten, H., Boonstra, H., & Aaronson, N.K. (2006). The impact of hormone 
 
replacement therapy on menopausal symptoms in younger high-risk women after 
 
prophylactic salpingo-oophorectomy. Journal of Clinical Oncology 24(22), 3576-3582. 
 
Maltezos, S., Horder, J., Coghlan, S., Skirrow, C., O’Gorman, R., Lavender, T.J., Mendez, M.A., 
 
Mehta, M., Daly, E., Xenitidis, K., Paliokossta, E., Spain, D., Pitts, M., Asherson, P., 
 
Lythgoe, D.J., Barker, G.J., & Murphy, D.G. (2014). Glutamate/glutamine and neuronal 
 
integrity in adults with ADHD: A proton MRS study. Translational Psychology (4), 1-8. 
 
Maki. P.M. (2013). The critical window hypothesis of hormone therapy and cognition: A 
 
scientific update on clinical studies. Menopause 20(6), 695-709. 
 
Minton, O., Richardson, A., Sharpe, M., Hotopf, M., & Stone, P. (2010). Drug therapy for the 
 
management of cancer-related fatigue. Cochrane Database of Systematic Reviews (7), 
 
DOI: 10.1002/14651858.CD006704. 
 


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Prommer, E. (2012). Methylphenidate: Established and expanding roles in symptom 
 
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