Cognitive Impairment, RRSO
Conditions
Keywords
Cognitive complaints, RRSO, Oophorectomy, Memory, Cognition, Early menopause
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.
Interventions
DRUGLisdexamfetamine
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.
DRUGPlacebo oral capsule
The placebo capsule will be filled with microcellulose.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
35 Years to 58 Years
Healthy volunteers
Yes
Inclusion criteria
* Female; * Age 35-58; * Have undergone risk-reducing bilateral salpingo-oophorectomy (RRSO) within the previous 15 years AND were premenopausal at the time of RRSO; * Score of ≥ 20 on the Brown Attention Deficit Disorder Scale (BADDS); * Onset of executive function difficulties occurred post RRSO; * Clean urine drug screen (nicotine and marijuana are permissible); * Are fluent in written and spoken English; * Are able to give written informed consent (obtained at screening visit); * Have a high school diploma or equivalent degree (i.e., GED), as per subject report; * If using aromatase inhibitors or tamoxifen: Must have been on a stable dose for at least 6 months; * 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.
Exclusion criteria
* Current, untreated psychiatric disorder; * Substance use disorder within the previous 3 years; * Lifetime history of ADHD or psychotic disorder including bipolar disorder, schizoaffective disorder, and schizophrenia; * Lifetime history of stimulant abuse or dependence; * Regular use of psychotropic medications except selective serotonin reuptake inhibitors (SSRI), serotonin noradrenergic reuptake inhibitors (SNRI), bupropion, zolpidem, gabapentin, or buspirone; * Chemotherapy within the past year; * Previous history of sensitivity or adverse reaction to lisdexamfetamine (LDX); * History of seizures or unstable medical condition; * Known heart disease or clinically significant abnormal electrocardiogram during screening as determined by the study MD; * Uncontrolled hypertension; * Presence of a metallic implant contraindicative to scanning at the 7T level; * Claustrophobia. * Consistent systolic blood pressure of \>145mm Hg or diastolic blood pressure \>90 mm Hg after three readings at time of screening; * Known renal impairment and End Stage Renal Disease (ESRD).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brown Attention Deficit Disorder Scale (BADDS) Change Score (End of Trial Minus Baseline). | Outcome measure change score represents end of trial (6 weeks) minus baseline. | The Brown Attention Deficit Disorder Scale (BADDS) (Brown, 1996) is a 40-item questionnaire that assesses five subscales of executive functioning. For each item in the questionnaire, participants reported the extent to which it had been a problem over the last six months (0 = never, 1 = once a week or less, 2 = twice a week, or 3 = almost daily). Total BADDS scores can range from 0-120, with higher scores indicating more self-reported difficulties with executive functioning. Outcome measures are reported as change scores for end of trial (6 weeks) minus baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Brain Activation (Glutamate Contrast) | 6 weeks | To measure the effects of Lisdexamfetamine on objective report of executive function difficulties proton magnetic resonance spectroscopy (1H-MRS) was utilized to assess the relative importance of dorsolateral prefrontal cortex (DLPFC) glutamate (Glut) contrast levels during working memory task performance. Measurement of glutamate contrast range from 0 to 15% with higher levels associated with optimal performance. Glutamate contrast is calculated by: GluCEST contrast (%) = \[(Msat(-3ppm) - Msat(+3ppm))/Msat(-3ppm)\]\*100. |
| Brain Activation (BOLD Percent Signal Change) | 6 weeks | To measure the effects of Lisdexamfetamine on objective report of executive function difficulties functional magnetic resonance imaging (fMRI) were utilized to assess the relative importance of dorsolateral prefrontal cortex (DLPFC) blood oxygen dependent (BOLD) signals during working memory task performance and the effect of LDX on the executive system activation. Measurement of BOLD perecent signal change range is 0 to 2%. Percent signal change is the difference in fMRI signal between the baseline condition (B) and the task condition (T) and calculated here as: percent signal change = (T-B)/B×100%. Higher percent signal change in the DLPFC is generally associated with better executive function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lisdexamfetamine, Then Placebo 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. | 36 |
| Placebo, Then Lisdexamfetamine 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. | 33 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (6 Weeks) | Adverse Event | 3 | 2 |
| First Intervention (6 Weeks) | Withdrawal by Subject | 0 | 1 |
| Second Intervention (6 Weeks) | Adverse Event | 1 | 0 |
| Washout (2 Weeks) | Adverse Event | 2 | 0 |
| Washout (2 Weeks) | Lost to Follow-up | 1 | 0 |
| Washout (2 Weeks) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo, Then Lisdexamfetamine | Total | Lisdexamfetamine, Then Placebo |
|---|---|---|---|
| Age, Continuous | 47.3 years STANDARD_DEVIATION 5.8 | 47.0 years STANDARD_DEVIATION 5.5 | 46.8 years STANDARD_DEVIATION 5.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 62 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 66 Participants | 34 Participants |
| Sex: Female, Male Female | 33 Participants | 69 Participants | 36 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 64 | 0 / 59 | 0 / 43 | 0 / 58 |
| other Total, other adverse events | 2 / 64 | 3 / 59 | 12 / 43 | 4 / 58 |
| serious Total, serious adverse events | 0 / 64 | 0 / 59 | 0 / 43 | 0 / 58 |
Outcome results
Primary
Brown Attention Deficit Disorder Scale (BADDS) Change Score (End of Trial Minus Baseline).
The Brown Attention Deficit Disorder Scale (BADDS) (Brown, 1996) is a 40-item questionnaire that assesses five subscales of executive functioning. For each item in the questionnaire, participants reported the extent to which it had been a problem over the last six months (0 = never, 1 = once a week or less, 2 = twice a week, or 3 = almost daily). Total BADDS scores can range from 0-120, with higher scores indicating more self-reported difficulties with executive functioning. Outcome measures are reported as change scores for end of trial (6 weeks) minus baseline.
Time frame: Outcome measure change score represents end of trial (6 weeks) minus baseline.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Lisdexamfetamine (Per Intervention) | Brown Attention Deficit Disorder Scale (BADDS) Change Score (End of Trial Minus Baseline). | -19.68 score on a scale |
| Placebo (Per Intervention) | Brown Attention Deficit Disorder Scale (BADDS) Change Score (End of Trial Minus Baseline). | -4.31 score on a scale |
Secondary
Brain Activation (BOLD Percent Signal Change)
To measure the effects of Lisdexamfetamine on objective report of executive function difficulties functional magnetic resonance imaging (fMRI) were utilized to assess the relative importance of dorsolateral prefrontal cortex (DLPFC) blood oxygen dependent (BOLD) signals during working memory task performance and the effect of LDX on the executive system activation. Measurement of BOLD perecent signal change range is 0 to 2%. Percent signal change is the difference in fMRI signal between the baseline condition (B) and the task condition (T) and calculated here as: percent signal change = (T-B)/B×100%. Higher percent signal change in the DLPFC is generally associated with better executive function.
Time frame: 6 weeks
Population: In response to the COVID -19 pandemic baseline neuroimaging data was only collected and analyzed on a subset of study participant (n=14).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine (Per Intervention) | Brain Activation (BOLD Percent Signal Change) | .42 percentage of signal change | Standard Deviation 0.229 |
| Placebo (Per Intervention) | Brain Activation (BOLD Percent Signal Change) | .21 percentage of signal change | Standard Deviation 0.223 |
Secondary
Brain Activation (Glutamate Contrast)
To measure the effects of Lisdexamfetamine on objective report of executive function difficulties proton magnetic resonance spectroscopy (1H-MRS) was utilized to assess the relative importance of dorsolateral prefrontal cortex (DLPFC) glutamate (Glut) contrast levels during working memory task performance. Measurement of glutamate contrast range from 0 to 15% with higher levels associated with optimal performance. Glutamate contrast is calculated by: GluCEST contrast (%) = \[(Msat(-3ppm) - Msat(+3ppm))/Msat(-3ppm)\]\*100.
Time frame: 6 weeks
Population: In response to the COVID -19 pandemic baseline neuroimaging data was only collected and analyzed on a subset of study participant (n=14).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lisdexamfetamine (Per Intervention) | Brain Activation (Glutamate Contrast) | 8.4 percentage of Glutmate Contrast | Standard Deviation 1.03 |
| Placebo (Per Intervention) | Brain Activation (Glutamate Contrast) | 8.91 percentage of Glutmate Contrast | Standard Deviation 0.86 |