Cognitive Impairment, Dementia, Parkinson's Disease
Conditions
Keywords
Parkinson's Disease, Cognitive Impairment, Dementia, Memory
Brief summary
The purpose of this research is to evaluate the usefulness of memantine, compared to placebo (sugar pill), for the treatment of cognitive impairment in patients with idiopathic Parkinson's disease (PD) and dementia. Memantine is used as a safe and effective treatment for patients with Alzheimer's disease. Cognitive impairment includes concentration and memory difficulties. We will look at how well this medication helps your cognitive impairment, how well you tolerate this medication (including its effects on your motor symptoms of PD) your activities of daily living, your emotions, and any medical conditions you might have. We will interview a person you choose as your informant.
Detailed description
This is a randomized, placebo-controlled, parallel, double-blind 24-week prospective study of memantine at the dosage range 5-20 mg/day in 20 outpatients with idiopathic PD and dementia secondary to PD. Using the dosage escalation regimen approved for Alzheimer disease, subjects will start memantine or comparable placebo at 5 mg daily and advance 5 mg/week to 20 mg /day by week 4, with dosing at 10 mg bid. Subjects will undergo 7 clinical visits over the 6-month trial (Screen, Baseline/Week 0, and Weeks 4, 8, 14, 20, and 24). The dosage can be titrated downward in increments of 5 mg to a minimum dose of 5 mg/day in the event memantine is not tolerated at the scheduled dosages. This broad dose range is being used because 1)a favorable cognitive response may be evident at lower doses of memantine than recommended for AD and 2)adverse effects could emerge when typical AD dosing recommendations are used, as has been observed when treating PD patients with cholinesterase inhibitors. Subjects will remain on a stable dose of memantine/placebo after Week 8, unless precluded by adverse events. Ten subjects will be assigned to each treatment group. Randomization will be stratified according to whether subjects are taking a concomitant cholinesterase inhibitor. This will enable secondary group comparisons of treatment groups. Results from this initial small study will be used to evaluate the appropriateness of devising a larger-scale multi-site study of memantine for treatment of dementia in PD. The proposed assessment schedule was designed to represent use of memantine in general clinical practice and to minimize the burdens to caregivers and patients, who have impaired mobility as well as cognitive function.
Interventions
DRUGMemantine
Active memantine and placebo, taken by mouth, will be titrated from 5mg a day to 20mg a day over 4 weeks. The subject will remain on 20mg (10mg twice a day) through week 24 unless unable to tolerate. The dose will be decreased as needed.
DRUGPlacebo Oral Tablet
Placebo, taken by mouth, will be titrated from 5mg a day to 20mg a day over 4 weeks. The subject will remain on 20mg (10mg twice a day) through week 24 unless unable to tolerate. The dose will be decreased as needed.
Sponsors
Forest Laboratories
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of idiopathic PD, as defined by UK Brain Bank Criteria. 2. Age onset of PD \> 35 years old 3. Adult men and women, current age \> 50 years 4. English speaking 5. Any race or ethnic background. 6. Hoehn and Yahr Stage I-V, provided able to participate verbally in clinical assessments and travel to clinic. 7. Diagnosis of dementia secondary to PD, as defined by DSM-IV-TR. 8. Stable medical health 9. Taking stable doses for 2 months of non-excluded medications. 10. Outpatient status (may be residing in a long-term care facility). 11. Able to attend all study visits with an informed caregiver/partner who is willing to provide information on the patient's clinical status and response to treatment. 12. Presence of an informed caregiver willing to take part in weekly phone call follow-up calls for the duration of study enrollment. 13. Provision of informed consent by patient and caregiver and/or legal guardian. 14. On stable antiparkinsonian therapy for 2 months. 15. If history of major depression or anxiety disorder, must have stable symptoms and be on stable therapy for 2 months. 16. If taking antipsychotic medication, must be on stable therapy for 2 months. 17. If taking nonsteroidal anti-inflammatory medication, selegiline, or estrogen, must be on a stable dose for 30 days before study entry. 18. If taking cholinesterase inhibitors, must be on for at least 6 months and a stable dose for 2 months before randomization.
Exclusion criteria
1. History or evidence of neurodegenerative disorder other than PD. 2. Meets clinical criteria for Dementia with Lewy Bodies. 3. History or current evidence of epilepsy. 4. Participation in another investigational drug trial within 2 months of screening. 5. Treatment with memantine within 60 days of screening. 6. Current symptomatic Major Depressive Disorder, as based on Hamilton Depression Rating Scale Score \> 17. 7. Current clinically significant hepatic, kidney disease, gastrointestinal, endocrine, or cardiovascular disease, including evidence of second or third degree heart block. \[Note, patients with controlled hypertension (supine diastolic BP\<95 mm Hg), complete or partial right bundle branch block, pacemakers, or deep brain stimulators may be included.\].
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Dementia Rating Scale (DRS) Memory Subscore | change from baseline to 24 weeks | The DRS is comprised of: Attention (ATT, 8 items); Initiation-Perseveration (I-P, 11 items); Construction (CONST, 6 items); Conceptualization (CONCEPT, 6 items); and Memory (MEM, 5 items). For this study, only the memory subscore was used, with score possibilities ranging from 0-5, with 5 meaning memory was perfect, 0 being no ability to recall. A negative score indicates a decrease in memory from baseline to 24 weeks. |
| CIBIC-Plus Score | 24 weeks | CIBIC-Plus is based upon clinicians' observations of change in the patient's cognitive, functional, and behavioral performance since the beginning of a trial. It relies on both direct examination of the patient and interview of informants. It takes into account a subject's overall function in the cognitive, behavioral and functional activity domains. Scoring is based on an interview with the caregiver and examination of the patient by an independent evaluator, without consulting other information such as cognitive test results. It requires the assessor to consider a number of cognitive, functional, and behavioral areas prior to providing an overall global assessment of clinical change. 7-point categorical scale that provides a single global rating of change from baseline.A score of 1 indicates marked improvement;and a score of 7, marked worsening. |
Countries
United States
Participant flow
Recruitment details
Men and women with idiopathic Parkinson's disease (PD) and dementia due to PD recruited from outpatient clinics at Johns Hopkins and outreach to the Baltimore-Washington community through the Johns Hopkins Morris K. Udall Parkinson's Disease Research Center. Recruitment period was 2006 to 2008.
Pre-assignment details
Enrolled participants were excluded if screening assessment showed MMSE\>10 and Clinical Dementia Rating (CDR) scale score \>1, or diagnostic criteria for dementia with Lewy bodies or DSM-IV-TR substance abuse/dependence or major depressive episode, Hamilton Depression Rating Scale score\>17, or severe cardiac, vascular or renal disease.
Participants by arm
| Arm | Count |
|---|---|
| Active Memantine Memantine tablets, formulated in appearance to match the placebo comparator, were initiated at 5 mg daily and advanced by 5mg /week to 20 mg/week by week 4 with dosing at 10 mg bid over the remaining 20 weeks of the trial. Over the 6 month duration of the trial, dosage could be titrated downward in increments of 5 mg to a minimum dose of 5mg/day in the event of intolerance.
Memantine: Active memantine and placebo, taken by mouth, will be titrated from 5mg a day to 20mg a day over 4 weeks. The subject will remain on 20mg (10mg twice a day) through week 24 unless unable to tolerate. The dose will be decreased as needed. | 10 |
| Placebo Oral Tablet Placebo tablets were formulated to match active 5mg memantine tablets. Dosing same as the active comparator with initiation at 5 mg daily and advancing by 5mg /week to 20 mg/week by week 4 with dosing at 10 mg bid over the remaining 20 weeks of the trial. Over the 6 month duration of the trial, dosage could be titrated downward in increments of 5 mg to a minimum dose of 5mg/day in the event of intolerance.
Placebo Oral Tablet: Placebo, taken by mouth, will be titrated from 5mg a day to 20mg a day over 4 weeks. The subject will remain on 20mg (10mg twice a day) through week 24 unless unable to tolerate. The dose will be decreased as needed. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo Oral Tablet | Total | Active Memantine |
|---|---|---|---|
| Age, Continuous | 71.9 years STANDARD_DEVIATION 7.5 | 71.8 years STANDARD_DEVIATION 7.4 | 71.7 years STANDARD_DEVIATION 7.3 |
| Education | 16.9 years STANDARD_DEVIATION 3 | 17.1 years STANDARD_DEVIATION 3.7 | 17.2 years STANDARD_DEVIATION 4.5 |
| NART (Full Scale IQ) | 102.7 units on a scale STANDARD_DEVIATION 6.6 | 105.5 units on a scale STANDARD_DEVIATION 8.5 | 108.0 units on a scale STANDARD_DEVIATION 9.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 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 | 10 Participants | 20 Participants | 10 Participants |
| Region of Enrollment United States | 10 participants | 20 participants | 10 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 6 / 10 | 8 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Change in Dementia Rating Scale (DRS) Memory Subscore
The DRS is comprised of: Attention (ATT, 8 items); Initiation-Perseveration (I-P, 11 items); Construction (CONST, 6 items); Conceptualization (CONCEPT, 6 items); and Memory (MEM, 5 items). For this study, only the memory subscore was used, with score possibilities ranging from 0-5, with 5 meaning memory was perfect, 0 being no ability to recall. A negative score indicates a decrease in memory from baseline to 24 weeks.
Time frame: change from baseline to 24 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Active Memantine | Change in Dementia Rating Scale (DRS) Memory Subscore | 1.6 units on a scale |
| Placebo Oral Tablet | Change in Dementia Rating Scale (DRS) Memory Subscore | -1.4 units on a scale |
Primary
CIBIC-Plus Score
CIBIC-Plus is based upon clinicians' observations of change in the patient's cognitive, functional, and behavioral performance since the beginning of a trial. It relies on both direct examination of the patient and interview of informants. It takes into account a subject's overall function in the cognitive, behavioral and functional activity domains. Scoring is based on an interview with the caregiver and examination of the patient by an independent evaluator, without consulting other information such as cognitive test results. It requires the assessor to consider a number of cognitive, functional, and behavioral areas prior to providing an overall global assessment of clinical change. 7-point categorical scale that provides a single global rating of change from baseline.A score of 1 indicates marked improvement;and a score of 7, marked worsening.
Time frame: 24 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Active Memantine | CIBIC-Plus Score | No Change | 0 Participants |
| Active Memantine | CIBIC-Plus Score | Minimally Worse | 2 Participants |
| Active Memantine | CIBIC-Plus Score | Minimally Improved | 2 Participants |
| Active Memantine | CIBIC-Plus Score | Much Worse | 0 Participants |
| Active Memantine | CIBIC-Plus Score | Much Improved | 5 Participants |
| Active Memantine | CIBIC-Plus Score | Very Much Worse | 0 Participants |
| Active Memantine | CIBIC-Plus Score | Very Much Improved | 1 Participants |
| Placebo Oral Tablet | CIBIC-Plus Score | Very Much Worse | 0 Participants |
| Placebo Oral Tablet | CIBIC-Plus Score | Very Much Improved | 0 Participants |
| Placebo Oral Tablet | CIBIC-Plus Score | Much Improved | 2 Participants |
| Placebo Oral Tablet | CIBIC-Plus Score | Minimally Improved | 1 Participants |
| Placebo Oral Tablet | CIBIC-Plus Score | No Change | 3 Participants |
| Placebo Oral Tablet | CIBIC-Plus Score | Minimally Worse | 2 Participants |
| Placebo Oral Tablet | CIBIC-Plus Score | Much Worse | 2 Participants |