Endothelial Facilitation in Alzheimer's Disease

• Sponsor: University of Massachusetts, Worcester (Other)
• Overall Status: Completed
• CT.gov ID: NCT01439555
• Collaborator: The Glass Foundation (Other)
• Enrollment: 11
• Location: 1
• Arm: 1
• Duration (Months): 72
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Simvastatin; Drug: L-Arginine; Drug: Tetrahydrobiopterin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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.
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Nov 1, 2017
• Actual Study Completion Date: Nov 1, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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)

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UMass Medical School/ UMass Memorial Medical Center	Worcester	Massachusetts	United States	01655

Sponsors and Collaborators

• University of Massachusetts, Worcester
• The Glass Foundation

Investigators

• Principal Investigator: Elizabeth R DeGrush, DO, UMass Medical School

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 11, 2017

More Information

Publications

None provided.

• Responsible Party: Elizabeth Degrush, Assistant Professor, Psychiatry, University of Massachusetts, Worcester
• ClinicalTrials.gov Identifier: NCT01439555
• Other Study ID Numbers: 13748
• First Posted: Sep 23, 2011
• Last Update Posted: Jul 30, 2019
• Last Verified: Jul 1, 2019

• 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
• Keywords provided by Elizabeth Degrush, Assistant Professor, Psychiatry, University of Massachusetts, Worcester: Early Alzheimer; Mild Cognitive Impairment; Drug treatment; Cerebral blood flow; Endothelial facilitation; Cognitive improvement
• Additional relevant MeSH terms: Alzheimer Disease; Simvastatin

Study Results

Participant Flow

Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Period Title: Overall Study
STARTED	11
COMPLETED	10
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 10%
>=65 years	9 90%
Age (Years of Age) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years of Age]	67.1 (6.84)
Sex: Female, Male (Count of Participants)
Female	6 60%
Male	4 40%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	10 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Mean Change in Cerebral Blood Flow as Measured by Magnetic Resonance Imaging (MRI)
Description	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

Outcome Measure Data

Analysis Population Description

Data for 6 participants available. Data file for remaining participants corrupted and could not be retrieved for analysis/reporting.

Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Measure Participants	6
Baseline	0.621528 (0.116513988)
Week 4	0.6447692 (0.070388324)
Week 8	0.654822667 (0.024032403)
Week 16	0.579838667 (0.091658076)

2. Primary Outcome

Title	Change in Cerebral Blood Flow as Measured by Arterial Spin Labeling During Magnetic Resonance Imaging (MRI)
Description	Data not available as files corrupted and could not be analyzed
Time Frame	Baseline to week 16

Outcome Measure Data

Analysis Population Description

Data files corrupted, analysis not possible

Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Measure Participants	0

3. Secondary Outcome

Title	Mini Mental State Examination (MMSE) Scores
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Measure Participants	10
Baseline	24.2 (3.155)
Week 4	25.33 (2.21)
Week 8	26 (3.13)
Week 16	25.55 (2.51)

4. Secondary Outcome

Title	Cognitive Assessment Screening Test (CAST)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Measure Participants	10
Mean (Standard Deviation) [score on a scale]	31.4 (5.46)

5. Secondary Outcome

Title	Clinical Dementia Rating Scale (CDR)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Measure Participants	10
CDR Score at Baseline	0.9 (.47)
CDR Score at 16 weeks	0.9 (.47)

6. Secondary Outcome

Title	Alzheimer's Disease Assessment Scale: Cognitive and Modified Version (ADAS-COG)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Measure Participants	10
ADAS-COG Baseline	21.6 (5.65)
ADAS-COG 16 weeks	21.9 (8.9)

7. Secondary Outcome

Title	Clinical Interview Based Impression of Change + Caregiver Input (CIBIC Plus)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
Measure Participants	10
Change in CIBIC score from baseline to 4 weeks	-.1 (0.32)
Change in CIBIC Score from 4 weeks to 8 weeks	.6 (.84)
Change in CIBIC Score from 8 weeks to 16 weeks	-.1 (1.29)

Adverse Events

Time Frame	6 Years.
Arm/Group Title	Simvastatin + L-Arginine + Tetrahydrobiopterin
Arm/Group Description	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
All Cause Mortality
	Simvastatin + L-Arginine + Tetrahydrobiopterin
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Serious Adverse Events
	Simvastatin + L-Arginine + Tetrahydrobiopterin
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Other (Not Including Serious) Adverse Events
	Simvastatin + L-Arginine + Tetrahydrobiopterin
	Affected / at Risk (%)	# Events
Total	0/10 (0%)

Limitations/Caveats

The data for the MRI measurements (cerebral blood flow) experienced file corruption, rendering segments of data irretrievable and the whole set non-analyzable.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.