Endothelial Facilitation in Alzheimer's Disease

Study Overview
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Brief Summary
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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

Official Title
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Endothelial Facilitation in Alzheimer's Disease. An Open Label Pilot Study of the Sequential and Cumulative Effects of Simvastatin, L-Arginine, and Sapropterin (Kuvan) on Cerebral Blood Flow and Cognitive Function in Patients With Alzheimer's Disease.

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Simvastatin
* Drug: L-Arginine
* Drug: Tetrahydrobiopterin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simvastatin + L-Arginine + Tetrahydrobiopterin<br>Simvastatin, 40 mg per day orally; L-Arginine, 2 Gm four times per day orally; Tetrahydrobiopterin 20 mg/kg/day orally | Drug: Simvastatin<br>* Simvastatin, 40 mg per day orally<br>* Other names: Tetrahydrobiopterin;Drug: L-Arginine<br>* L-Arginine, 2 Gm four times per day orally;<br>Drug: Tetrahydrobiopterin<br>* Tetrahydrobiopterin 20 mg/kg/day orally<br>* Other names: Sapropterin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | Baseline to 16 weeks | 
| 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 | Baseline to week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline to 4 weeks, 8 weeks and 16 weeks post-baseline | 
| 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. | Baseline to 16 weeks post-baseline | 
| 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. | Baseline to 16 weeks post-baseline | 
| 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. | Baseline to 16 weeks post-baseline | 
| 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. | Baseline to 4 weeks, 8 weeks and 16 weeks post-baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early Alzheimer, Mild Cognitive Impairment, Drug treatment, Cerebral blood flow, Endothelial facilitation, Cognitive improvement