Endothelial Facilitation in Alzheimer's Disease

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.

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

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Simvastatin; Drug: L-Arginine; Drug: Tetrahydrobiopterin

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • UMass Medical School/ UMass Memorial Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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	Drug: Simvastatin; Simvastatin, 40 mg per day orally; Other Names: Tetrahydrobiopterin; Drug: L-Arginine; L-Arginine, 2 Gm four times per day orally; Drug: Tetrahydrobiopterin; Tetrahydrobiopterin 20 mg/kg/day orally; Other Names: Kuvan; Sapropterin

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Massachusetts, Worcester
• Collaborators: The Glass Foundation
• Investigators: Principal Investigator: Elizabeth R DeGrush, DO, UMass Medical School

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ACTUAL): November 1, 2017
• Study Completion (ACTUAL): November 1, 2017

Study Registration Dates

• First Submitted: September 16, 2011
• First Submitted That Met QC Criteria: September 21, 2011
• First Posted (ESTIMATE): September 23, 2011

Study Record Updates

• Last Update Posted (ACTUAL): July 30, 2019
• Last Update Submitted That Met QC Criteria: July 11, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Mild Cognitive Impairment; Drug treatment; Cerebral blood flow; Early Alzheimer; Endothelial facilitation; Cognitive improvement
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: 13748

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes