Anti-Oxidant Treatment of Alzheimer's Disease

Evaluation of the Safety, Tolerability and Impact on Biomarkers of Anti-Oxidant Treatment of Mild to Moderate Alzheimer's Disease

The purpose of this study is to examine the safety and effectiveness of two anti-oxidant treatment regimens in patients with mild to moderate Alzheimer's disease. The anti-oxidant treatments include vitamin E + C + alpha-lipoic acid, and Coenzyme Q (CoQ).

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Vitamin E, Vitamin C, and Alpha-lipoic Acid; Drug: Placebo wafers; Drug: Coenzyme Q; Drug: Placebo capsules

Detailed Description

Oxidative damage has been shown to be a factor in Alzheimer's disease (AD), and some studies have suggested that supplemental anti-oxidants can decrease the risk of AD or slow its progression. There are many candidate antioxidants, including combinations, which could be neuroprotective in established AD or could have efficacy in the prevention of AD. However, testing each of the possibilities in standard clinical trials is prohibitively expensive. This study will examine antioxidant supplements or vitamins which target specific cellular compartments, and look for evidence of biologically relevant effects in AD by measurement of biomarkers in CSF.

Two general cellular compartments where antioxidant supplements may act are the cytosol and mitochondria. The study will examine a combination of antioxidants that act primarily at cytosolic sites (vitamin E + C + α-lipoic acid) and a single mitochondrial antioxidant, coenzyme Q10.

This multicenter trial will recruit 75 participants who will be randomized into three groups:

1. 25 participants will be given a combination of vitamin E 800 IU, vitamin C 200 mg, and alpha-lipoic acid 600 mg formulated into three capsules, one capsule given three times per day with meals, plus two placebo wafers three times per day with meals;
2. 25 participants will be given CoQ 400 mg, compounded as a wafer, two wafers three times per day with meals, plus one placebo capsule three times per day with meals;
3. 25 participants will be given both the placebo wafers, two wafers three times per day with meals, plus one placebo capsule three times per day with meals.

The treatment period will last four months. The effects of the two anti-oxidant treatments will be evaluated by measuring biomarkers in blood and cerebrospinal fluid (CSF) at the beginning and end of the 4-month period.

• Study Type: Interventional
• Enrollment (Anticipated): 75
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Irvine, California, United States, 92697
      • University of California- Irvine
    • La Jolla, California, United States, 92037
      • University of California, San Diego
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
  • Florida
    • Miami Beach, Florida, United States, 33140
      • Wien Center, Mount Sinai Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • New Jersey
    • Piscataway, New Jersey, United States, 08855
      • University of Medicine and Dentistry of New Jersey
  • New York
    • Syracuse, New York, United States, 13210
      • Neurological Care of CNY
  • Ohio
    • Cleveland, Ohio, United States, 44120
      • Case Western Reserve University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • South Carolina
    • North Charleston, South Carolina, United States, 29406
      • Medical University of South Carolina
  • Washington
    • Seattle, Washington, United States, 98108
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women aged 60-85, inclusive
• Diagnosis of probable Alzheimer's disease
• English-speaking; Spanish-speaking if individual site allows
• Study partner or caregiver to assure compliance
• Mini-Mental State Examination score at screening visit greater than 14
• Female participants either surgically sterile or postmenopausal for over 1 year
• Stable medical condition for 3 months prior to screening, with no significant abnormal liver, kidney, or blood studies
• Stable medications for 4 weeks prior to screening
• Able to take oral medications
• Modified Hachinski Ischemic Index less than or equal to 4
• CT or MRI since onset of memory impairment demonstrating the absence of a clinically significant focal lesion
• Physically acceptable for this study as confirmed by medical history, physical exam, neurological exam, and clinical tests

Exclusion Criteria:

• Significant neurologic disease such as Parkinson's disease, stroke, brain tumor, multiple sclerosis, or seizure disorder
• Major depression in the past 12 months, major mental illness such as schizophrenia, or recent (in past 12 months) alcohol or substance abuse
• History of invasive cancer within the past two years (excluding non-melanoma skin cancer)
• Contra-indications to lumbar puncture
• Use of any investigational agents within 30 days prior to screening
• Major surgery within 8 weeks prior to the Baseline Visit
• Uncontrolled cardiac conditions or severe unstable medical illnesses
• Antiretroviral therapy for human immunodeficiency virus (HIV)
• Conditions that will contribute to oxidative stress: current cigarette or cigar smokers (within past month), diabetics on insulin or poorly controlled on oral hypoglycemics
• Residence in skilled nursing facility
• Blindness, deafness, language difficulties or any other disability which may prevent the participant from participating or cooperating in the protocol

Note: Exceptions to these criteria may be considered on a case-by-case basis, at the discretion of the Project Director.

Excluded Medications:

• Experimental drugs
• Coumadin
• Insulin
• Immunosuppressive agents: prednisone and other corticosteroids (taken orally or by injection), methotrexate, cyclophosphamide, cyclosporin, tacrolimus, etc.
• HIV protease inhibitors
• Neuroleptics and lithium
• Anti-cancer agents (exception: stable doses of hormonal therapy, e.g. Lupron, estrogen, are permitted)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; vitamin E 800 IU, vitamin C 200 mg, and alpha-lipoic acid 600 mg formulated into three capsules, one capsule given three times per day with meals, plus two placebo wafers three times per day with meals	Drug: Vitamin E, Vitamin C, and Alpha-lipoic Acid; vitamin E 800 IU, vitamin C 200 mg, and alpha-lipoic acid 600 mg formulated into three capsules, one capsule given three times per day with meals; Drug: Placebo wafers; two placebo wafers three times per day with meals
Experimental: 2; CoQ 400 mg, compounded as a wafer, two wafers three times per day with meals, plus one placebo capsule three times per day with meals	Drug: Coenzyme Q; 400 mg, compounded as a wafer, two wafers three times per day with meals; Drug: Placebo capsules; one placebo capsule three times per day with meals
Placebo Comparator: 3; two placebo wafers three times per day with meals, plus one placebo capsule three times per day with meals	Drug: Placebo wafers; two placebo wafers three times per day with meals; Drug: Placebo capsules; one placebo capsule three times per day with meals

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
effect on cerebrospinal fluid (CSF) biomarkers related to oxidative damage	baseline and 4 months

Secondary Outcome Measures

Outcome Measure	Time Frame
change in plasma and CSF concentrations of a-beta42 and a-beta40	baseline and 4 months

Collaborators and Investigators

• Sponsor: National Institute on Aging (NIA)
• Collaborators: Alzheimer's Disease Cooperative Study (ADCS)
• Investigators: Principal Investigator: Douglas Galasko, MD, University of California, San Diego

Publications and helpful links

General Publications

• Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, Norton MC, Welsh-Bohmer KA, Breitner JC; Cache County Study Group. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol. 2004 Jan;61(1):82-8. doi: 10.1001/archneur.61.1.82.
• Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997 Apr 24;336(17):1216-22. doi: 10.1056/NEJM199704243361704.
• Behl C. Alzheimer's disease and oxidative stress: implications for novel therapeutic approaches. Prog Neurobiol. 1999 Feb;57(3):301-23. doi: 10.1016/s0301-0082(98)00055-0.
• Galasko DR, Peskind E, Clark CM, Quinn JF, Ringman JM, Jicha GA, Cotman C, Cottrell B, Montine TJ, Thomas RG, Aisen P; Alzheimer's Disease Cooperative Study. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol. 2012 Jul;69(7):836-41. doi: 10.1001/archneurol.2012.85.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): September 1, 2007
• Study Completion (Actual): September 1, 2007

Study Registration Dates

• First Submitted: June 30, 2005
• First Submitted That Met QC Criteria: June 30, 2005
• First Posted (Estimate): July 6, 2005

Study Record Updates

• Last Update Posted (Estimate): April 3, 2009
• Last Update Submitted That Met QC Criteria: April 1, 2009
• Last Verified: April 1, 2008

More Information

Terms related to this study

• Keywords: dementia; biomarkers; anti-oxidant; CoQ; alpha-tocopherol
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Antioxidants; Vitamin B Complex; Vitamin E; Vitamins; Thioctic Acid; Ubiquinone
• Other Study ID Numbers: IA0067