Alzheimer's Disease
Conditions
Keywords
Early Alzheimer, Mild Cognitive Impairment, Drug treatment, Cerebral blood flow, Endothelial facilitation, Cognitive improvement
Brief summary
Purpose of the study: Patients with mild Alzheimer's Disease will be given three different drugs over a 4-month period to try to increase the blood flow to their brains, and improve blood vessel and brain function. Each drug can help to open the blood vessels in the brain, and together they may be more effective than each drug alone. The hypothesis is that small blood vessels secrete substances that maintain the integrity of the brain, and may prevent loss of nerve cells leading to Alzheimer's Disease
Interventions
DRUGSimvastatin
Simvastatin, 40 mg per day orally
DRUGL-Arginine
L-Arginine, 2 Gm four times per day orally;
Tetrahydrobiopterin 20 mg/kg/day orally
Sponsors
The Glass Foundation
University of Massachusetts, Worcester
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Subjects must have mild Alzheimer's Disease or Mild Cognitive Impairment (MCI); * age between 55-85; * Mini Mental Status Exam (MMSE) between 15-26; * a caregiver who can provide information, and bring patient to the sessions; * no known allergies to any of the medications to be used; * normal renal function; willingness of patient and spouse/responsible caregiver to participate.
Exclusion criteria
* Significant Psychiatric disorder; * stroke; current use of any of the test medications (e.g., statin, L-Arginine, Kuvan); * phenylketonuria (PKU) ; * elevated serum phenylalanine level (\>10 mg/dL); * allergy to any of the medications; current active malignancy; * renal insufficiency (elevated creatinine above 1.3mg/dl); * abnormal liver function (Alanine Aminotransferase (ALT) or Aspartate Transaminase (AST) 2x normal); * other serious disease including coronary insufficiency or congestive heart failure, carotid stenosis greater than 50%, active peptic ulcer, urinary tract or other active infection, cancer (except skin cancer, or 5 years inactive breast or prostate cancer )etc.; * pregnancy; or * inability to come to UMass for follow-up. Subjects may continue to take anticholinesterase drugs for Alzheimer's Disease (Aricept, Exelon, Razadyne) and/or Namenda, if they have been on the drug(s) for at least 3 months. Subjects on levodopa and male subjects taking drugs for erectile dysfunction (Viagra, Cialis, Levitra) are cautioned regarding hypotension.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI) | Baseline to 16 weeks | Measurement of changes to cerebral blood flow (ml/110g/min) in regions of interest as measured using Magnetic Resonance Imaging (MRI) |
| Change in Cerebral Blood Flow as Measured by Arterial Spin Labeling During Magnetic Resonance Imaging (MRI) | Baseline to week 16 | Data not available as files corrupted and could not be analyzed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Dementia Rating Scale (CDR) | Baseline to 16 weeks post-baseline | This outcome measures Clinical Dementia Rating Scale (CDR) scores at baseline (enrollment) and 16 weeks post-enrollment. The Clinical Dementia Rating Scale is scored with a composite scale of 0 to 3, with higher scores indicating lower functional status and lower scores indicating better functional status. |
| Mini Mental State Examination (MMSE) Scores | Baseline to 4 weeks, 8 weeks and 16 weeks post-baseline | Change in mental state as reflected by changes to mean Mini Mental State Examination (MMSE) score as measured 4 weeks, 8 weeks and 16 weeks post-baseline. The MMSE uses a 30 point questionnaire to measure cognitive impairment. The MMSE is scored from 0 to 30,with a score equal to or greater than 24 points indicating normal cognition, a score of 19-23 points indicating mild cognitive impairment, 10-18 points indicating moderate impairment and a score equal to or below 9 indicating severe impairment. |
| Clinical Interview Based Impression of Change + Caregiver Input (CIBIC Plus) | Baseline to 4 weeks, 8 weeks and 16 weeks post-baseline | The Clinical Interview Based Impression of Change + Caregiver Input (CIBIC Plus) is a semi-structured instrument to examine four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It is scored from 1 to 7. A score of 1 indicates marked improvement, 4 indicates no change and 7 indicates marked worsening. |
| Alzheimer's Disease Assessment Scale: Cognitive and Modified Version (ADAS-COG) | Baseline to 16 weeks post-baseline | Mean Alzheimer's Disease Assessment Scale: Cognitive Subscale (ADAS-COG) score at baseline and at 16 weeks post-enrollment. The ADAS-COG consists of 11 tasks measuring disturbances of memory, language, praxis, attention and other cognitive abilities. Total scores range from 0 to 70, with higher scores (18 and above) indicating greater cognitive impairment. |
| Cognitive Assessment Screening Test (CAST) | Baseline to 16 weeks post-baseline | This outcome measured the change in average Cognitive Assessment Screening Test (CAST) scores for the participant group. The CAST is scored from 0 to 40. A higher score indicates better performance, and a lower score indicates worse performance. The participants were given the CAST at baseline, 4 weeks, 8 weeks and 16 weeks post-baseline. The outcome reports on the averaged change for the averaged CAST scores from baseline to 16 weeks. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Simvastatin + L-Arginine + Tetrahydrobiopterin Simvastatin, 40 mg per day orally; L-Arginine, 2 Gm four times per day orally; Tetrahydrobiopterin 20 mg/kg/day orally
Simvastatin: Simvastatin, 40 mg per day orally
L-Arginine: L-Arginine, 2 Gm four times per day orally;
Tetrahydrobiopterin: Tetrahydrobiopterin 20 mg/kg/day orally | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
Baseline characteristics
| Characteristic | Simvastatin + L-Arginine + Tetrahydrobiopterin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 67.1 Years of Age STANDARD_DEVIATION 6.84 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
Change in Cerebral Blood Flow as Measured by Arterial Spin Labeling During Magnetic Resonance Imaging (MRI)
Data not available as files corrupted and could not be analyzed
Time frame: Baseline to week 16
Population: Data files corrupted, analysis not possible
Primary
Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI)
Measurement of changes to cerebral blood flow (ml/110g/min) in regions of interest as measured using Magnetic Resonance Imaging (MRI)
Time frame: Baseline to 16 weeks
Population: Data for 6 participants available. Data file for remaining participants corrupted and could not be retrieved for analysis/reporting.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI) | Baseline | 0.621528 ml/110g/min | Standard Deviation 0.116513988 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI) | Week 4 | 0.6447692 ml/110g/min | Standard Deviation 0.070388324 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI) | Week 8 | 0.654822667 ml/110g/min | Standard Deviation 0.024032403 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI) | Week 16 | 0.579838667 ml/110g/min | Standard Deviation 0.091658076 |
Secondary
Alzheimer's Disease Assessment Scale: Cognitive and Modified Version (ADAS-COG)
Mean Alzheimer's Disease Assessment Scale: Cognitive Subscale (ADAS-COG) score at baseline and at 16 weeks post-enrollment. The ADAS-COG consists of 11 tasks measuring disturbances of memory, language, praxis, attention and other cognitive abilities. Total scores range from 0 to 70, with higher scores (18 and above) indicating greater cognitive impairment.
Time frame: Baseline to 16 weeks post-baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Alzheimer's Disease Assessment Scale: Cognitive and Modified Version (ADAS-COG) | ADAS-COG Baseline | 21.6 score on a scale | Standard Deviation 5.65 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Alzheimer's Disease Assessment Scale: Cognitive and Modified Version (ADAS-COG) | ADAS-COG 16 weeks | 21.9 score on a scale | Standard Deviation 8.9 |
Secondary
Clinical Dementia Rating Scale (CDR)
This outcome measures Clinical Dementia Rating Scale (CDR) scores at baseline (enrollment) and 16 weeks post-enrollment. The Clinical Dementia Rating Scale is scored with a composite scale of 0 to 3, with higher scores indicating lower functional status and lower scores indicating better functional status.
Time frame: Baseline to 16 weeks post-baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Clinical Dementia Rating Scale (CDR) | CDR Score at Baseline | 0.9 score on a scale | Standard Deviation 0.47 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Clinical Dementia Rating Scale (CDR) | CDR Score at 16 weeks | 0.9 score on a scale | Standard Deviation 0.47 |
Secondary
Clinical Interview Based Impression of Change + Caregiver Input (CIBIC Plus)
The Clinical Interview Based Impression of Change + Caregiver Input (CIBIC Plus) is a semi-structured instrument to examine four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It is scored from 1 to 7. A score of 1 indicates marked improvement, 4 indicates no change and 7 indicates marked worsening.
Time frame: Baseline to 4 weeks, 8 weeks and 16 weeks post-baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Clinical Interview Based Impression of Change + Caregiver Input (CIBIC Plus) | Change in CIBIC score from baseline to 4 weeks | -.1 score on a scale | Standard Deviation 0.32 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Clinical Interview Based Impression of Change + Caregiver Input (CIBIC Plus) | Change in CIBIC Score from 4 weeks to 8 weeks | .6 score on a scale | Standard Deviation 0.84 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Clinical Interview Based Impression of Change + Caregiver Input (CIBIC Plus) | Change in CIBIC Score from 8 weeks to 16 weeks | -.1 score on a scale | Standard Deviation 1.29 |
Secondary
Cognitive Assessment Screening Test (CAST)
This outcome measured the change in average Cognitive Assessment Screening Test (CAST) scores for the participant group. The CAST is scored from 0 to 40. A higher score indicates better performance, and a lower score indicates worse performance. The participants were given the CAST at baseline, 4 weeks, 8 weeks and 16 weeks post-baseline. The outcome reports on the averaged change for the averaged CAST scores from baseline to 16 weeks.
Time frame: Baseline to 16 weeks post-baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Cognitive Assessment Screening Test (CAST) | 31.4 score on a scale | Standard Deviation 5.46 |
Secondary
Mini Mental State Examination (MMSE) Scores
Change in mental state as reflected by changes to mean Mini Mental State Examination (MMSE) score as measured 4 weeks, 8 weeks and 16 weeks post-baseline. The MMSE uses a 30 point questionnaire to measure cognitive impairment. The MMSE is scored from 0 to 30,with a score equal to or greater than 24 points indicating normal cognition, a score of 19-23 points indicating mild cognitive impairment, 10-18 points indicating moderate impairment and a score equal to or below 9 indicating severe impairment.
Time frame: Baseline to 4 weeks, 8 weeks and 16 weeks post-baseline
Population: Patients were sequentially treated with the HMC-CoA reductase synthesis inhibitor simvastatin (weeks 0-16); L-Arginine (weeks 4-16); and tetrahydrobiopterin (weeks 8-16). The investigators assessed cognitive function with a psychometric battery including the MMSE at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Mini Mental State Examination (MMSE) Scores | Week 8 | 26 score on a scale | Standard Deviation 3.13 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Mini Mental State Examination (MMSE) Scores | Baseline | 24.2 score on a scale | Standard Deviation 3.155 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Mini Mental State Examination (MMSE) Scores | Week 4 | 25.33 score on a scale | Standard Deviation 2.21 |
| Simvastatin + L-Arginine + Tetrahydrobiopterin | Mini Mental State Examination (MMSE) Scores | Week 16 | 25.55 score on a scale | Standard Deviation 2.51 |