Cognitive Impairment
Conditions
Brief summary
This study is designed to test if megestrol acetate induces changes in declarative memory in healthy controls and if pre-administration of phenytoin can ameliorate any induced cognitive impairments.
Detailed description
Healthy adults (n=20) will be recruited and informed consent will be obtained. Participants will agree to a number of visits, a Baseline Visit, 6 Study Visits, and a follow-up Safety Visit. Each course of study drug will be followed by a washout, but allowed preexisting medications will not be stopped for study participation. A small subset (n=4) of participants will also undergo MRI scanning as a component of their visits following drug administration. Baseline Visit: Cognition will be assessed by a variety of measures, which will determine baseline declarative memory and working memory. Mood will be assessed by a psychiatric interview, self-assessments, and a review of any standing physical symptoms will be completed for comparison to any side effects which develop after medication administration. Vital signs will be recorded and women will be screened for pregnancy. Blood will be collected for complete blood count (CBC) and comprehensive metabolic panel (CMP). Visit 1: Participants will be randomized to one of three treatment possibilities: 1) phenytoin with megestrol, 2) placebo with megestrol, 3) placebo with placebo. Participants will receive phenytoin (200 mg BID) or placebo and will be instructed to take this medication for one full day (two doses) before starting their megestrol. They will take this medication for a total of 3.5 days. Visit 2: After the participants have completed their medication course on the morning of this visit day, they will return to have cognition and mood reassessed. Vital signs will be taken and blood will be drawn to assess CMP, CBC, cortisol and phenytoin levels. Participants will now enter a washout period of this medicine combination (approximately 3 weeks) before returning for their next visit. For those participants offered the MRI scans, their visit will extend to approximately 3 hours. Visit 3: Participants will return and be randomized to one of remaining two treatment possibilities as detailed above. Participants will again be instructed to start the first medication and take for one full day before taking the second medication, and will be instructed to take their second medication at starting the following day after starting the first medication at 0900 hours and continue taking the drugs for 3 consecutive days. Visit 4: After the participants have completed their medication course on the morning of this visit day, they will return to have cognition and mood reassessed; completing all previously administered assessments excepting the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (SCID). Vital signs will be taken and blood will be drawn to assess CMP, CBC, cortisol and phenytoin levels. Participants will now enter a washout period of this medicine combination (approximately 3 weeks) before returning for their next visit. For those participants offered the MRI scans, their visit will extend to approximately 3 hours. Visit 5: Participants will return and receive the remaining treatment possibility, detailed above. Participants will again be instructed to start the first medication and take for one full day before taking the second medication and will be instructed to take their second medication at starting the following day after starting the first medication at 0900 hours and continue taking the drugs for 3 consecutive days. Visit 6: After the participants have completed their medication course on the morning of this visit day, they will return to have cognition and mood reassessed. Vital signs will be taken and blood will be drawn to assess CMP, CBC, cortisol and phenytoin levels. Participants will now enter a washout period of this medicine combination (approximately 3 weeks) before returning for their final visit. For those participants offered the MRI scans, their visit will extend to approximately 3 hours. Safety Visit: Participants will return for a final safety visit which will evaluate any remaining side effects, take vital signs, and include a final urinary pregnancy test (for women).
Interventions
DRUGPhenytoin 200 mg capsule
Phenytoin oral capsule was initiated on Day 1 and administered at 200 mg twice/day for four consecutive days (Days 1 - 4).
DRUGMegestrol 800 mg liquid
Liquid megestrol 800 mg/was initiated on Day 2 and administered at 09:00 for three consecutive days (Days 2 - 4).
DRUGPhenytoin-matched Placebo capsule
Phenytoin-matched oral Placebo capsule was initiated on Day 1 and administered for four consecutive days (Days 1 - 4).
DRUGMegestrol-matched liquid Placebo
Megestrol-matched liquid placebo was initiated on Day 2 and administered at 09:00 for three consecutive days (Days 2 - 4).
Sponsors
The Rogosin Institute
University of Texas Southwestern Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Each participant receives three treatments: phenytoin + megestrol, placebo + megestrol, or placebo + placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy men and women age 18-50 years * Education of ≥ 12 years and baseline Rey Auditory Verbal Learning Test (RAVLT) total words recalled score ≥ 40 (normal baseline memory) * Body mass index (BMI) between 18.5-35 * The ability to read and speak English as not all neurocognitive assessments have been translated and validated in other languages.
Exclusion criteria
* History (lifetime) of Bipolar Disorder, Major Depressive Disorder, psychotic depressive, schizophrenic, schizoaffective, or other Axis I psychotic disorders * Has an unstable general medical condition (GMC) or significant medical condition, including but not limited to myocardial infarction, cancer, diabetes (hypertension is allowed if condition is being treated and is stable) * Vulnerable populations including pregnant or nursing women, the incarcerated, or those with severe cognitive disorders * Education history that includes Special Education or history of mental disability * History of psychotropic medication therapy in the past 30 days * Baseline Quick Inventory of Depressive Symptoms-Clinician Rated (QIDS-C) \> 5 * Initiation of new medications within 14 days of the baseline visit, with the exception of over-the-counter (OTC) as needed medications (e.g. Tylenol, Advil, Motrin, etc.) * Significant hypertensive blood pressure at baseline, defined as either systolic pressure \> 150 or diastolic pressure \> 95 * Febrile at baseline, defined as body temperature ≥ 100.5°F (38°C) * Baseline heart rate \> 100 bpm or \< 50 bpm * Medical history of diseases with central nervous system (CNS)-involvement, including but not limited to stroke, traumatic brain injury, and loss of consciousness \> 1 minute * History of allergic reaction or medical contraindication to megestrol or phenytoin * Clinically significant abnormalities on baseline labs (e.g. hypokalemia, hypernatremia, anemia) * Lifetime history of an immunosuppressive disorder or immunosuppressive therapy with within the past 6 months * History of blood clots such as myocardial infarction (MI), stroke, deep vein thromboses (DVTs), pulmonary embolism (PE) or blood clotting disorder * Currently actively suicidal or considered a high suicide risk (e.g. more than one lifetime suicide attempt or any attempt in the past 12 months) * Any reason not listed which, as determined by the principle investigator (PI), would affect participant safety in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rey Auditory Verbal Learning Test (RAVLT) | 4 days after intervention administration | Rey Auditory Verbal Learning Test (RAVLT) is a test of verbal learning and declarative memory. During the test, 15 nouns that are read aloud for 5 consecutive trials. Each trial is followed by a free recall test (participant is asked to recall the words that were just read to them). The sum of correctly recalled words across 5 trials is called the total raw score. The raw scores on the total recall (number of words correct across trials 1-5) are converted to standardized T-scores (Mean=50; SD=10; range 20-100) based on participant age and gender. The scores below are presented as T-scores, with higher scores indicative of better performance. |
Countries
United States
Participant flow
Recruitment details
35 patients were screened for eligibility between July 2015 and September 2016.
Pre-assignment details
21 of 35 participants were randomized. Of those not randomized, 14 did not meet inclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Ph + Meg, Then Pl + Meg, Then Pl + Pl Participants first received pretreatment with Phenytoin 200 mg capsule twice/day for one day. Participants then received both Phenytoin (200 mg capsule twice/day) and liquid Megestrol (800 mg/day) for three consecutive days.
Following first 21-day washout, participants then received both Placebo (matching Phenytoin 200 mg capsule) twice/day and liquid Megestrol (800 mg/day) for three consecutive days.
Following second 21-day washout, participants then received both Placebo (matching Phenytoin 200 mg capsule) twice/day and liquid Placebo (matching liquid Megestrol 800 mg/day) for three consecutive days. | 8 |
| Pl + Meg, Then Pl + Pl, Then Ph + Meg Participants first received pretreatment with Placebo (matching Phenytoin 200 mg capsule) twice/day for one day. Participants then received both Placebo (matching Phenytoin 200 mg capsule) twice/day and liquid Megestrol (800 mg/day) for three consecutive days.
Following first 21-day washout, participants then received both Placebo (matching Phenytoin 200 mg capsule) twice/day and liquid Placebo (matching liquid Megestrol 800 mg/day) for three consecutive days.
Following second 21-day washout, participants then received both Phenytoin (200 mg capsule twice/day) and liquid Megestrol (800 mg/day) for three consecutive days. | 6 |
| Pl + Pl, Then Ph + Meg, Then Pl + Meg Participants first received pretreatment with Placebo (matching Phenytoin 200 mg capsule) twice/day for one day. Participants then received both Placebo (matching Phenytoin 200 mg capsule) twice/day and liquid Placebo (matching liquid Megestrol 800 mg/day) for three consecutive days.
Following first 21-day washout, participants then received both Phenytoin (200 mg capsule twice/day) and liquid Megestrol (800 mg/day) for three consecutive days.
Following second 21-day washout, participants then received both Placebo (matching Phenytoin 200 mg capsule) twice/day and liquid Megestrol (800 mg/day) for three consecutive days. | 7 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| First Washout (21 Days) | Lost to Follow-up | 1 | 0 | 0 |
| First Washout (21 Days) | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Ph + Meg, Then Pl + Meg, Then Pl + Pl | Pl + Meg, Then Pl + Pl, Then Ph + Meg | Pl + Pl, Then Ph + Meg, Then Pl + Meg | Total |
|---|---|---|---|---|
| Age, Continuous | 27.63 years STANDARD_DEVIATION 3.97 | 30.50 years STANDARD_DEVIATION 7.94 | 30.71 years STANDARD_DEVIATION 9.2 | 29.48 years STANDARD_DEVIATION 7.05 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 5 Participants | 12 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 5 Participants | 14 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 20 | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 5 / 20 | 0 / 19 | 5 / 19 |
| serious Total, serious adverse events | 0 / 20 | 0 / 19 | 0 / 19 |
Outcome results
Primary
Rey Auditory Verbal Learning Test (RAVLT)
Rey Auditory Verbal Learning Test (RAVLT) is a test of verbal learning and declarative memory. During the test, 15 nouns that are read aloud for 5 consecutive trials. Each trial is followed by a free recall test (participant is asked to recall the words that were just read to them). The sum of correctly recalled words across 5 trials is called the total raw score. The raw scores on the total recall (number of words correct across trials 1-5) are converted to standardized T-scores (Mean=50; SD=10; range 20-100) based on participant age and gender. The scores below are presented as T-scores, with higher scores indicative of better performance.
Time frame: 4 days after intervention administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phenytoin, Then Megestrol | Rey Auditory Verbal Learning Test (RAVLT) | 51.89 T-scores | Standard Deviation 8.08 |
| Placebo, Then Megestrol | Rey Auditory Verbal Learning Test (RAVLT) | 45.90 T-scores | Standard Deviation 10.4 |
| Placebo, Then Placebo | Rey Auditory Verbal Learning Test (RAVLT) | 48.37 T-scores | Standard Deviation 10.42 |
p-value: 0.003Mixed Models Analysis