Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer's Disease (MB2)

August 25, 2022 updated by: The University of Texas Health Science Center at San Antonio

Cognitive and Functional Connectivity Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer's Disease

A double-blind, placebo-controlled study that aims to investigate the effect of 2-week and 12-week administration of USP methylene blue (MB) on cerebral blood flow, functional connectivity, memory and attention cognitive abilities using fMRI and behavioral measures in healthy aging, mild cognitive impairment (MCI) and mild Alzheimer's disease (AD) subjects.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Healthy aging and aging human subjects with mild cognitive impairment and mild Alzheimer's disease from the TARCC cohort and South Texas will be studied using a double-blind, placebo-controlled design. After informed consent and familiarity with the tasks and the MRI environment, the subject will enter an MRI scanner and perform the following 6 tasks.

fMRI and behavioral data will be collected simultaneously while inside the scanner.

Delayed match-to-sample task: The subject views a pattern for a few seconds and then is prompted to recall the memorized pattern using a response system (approx. 10 mins).

Face-name task: The subject is shown blocks of stimuli where a novel or familiar face is paired with a name. In a later run, the subjects are asked whether the correct name is matched with the correct face. (approx. 10 mins).

Psychomotor vigilance task: The subject receives a visual cue that alerts them to press a button as fast as possible. (approx. 10 mins).

Cerebral Blood Flow and Resting State fMRI: Subject scanned with eyes closed and told to not think about a particular topic, each lasting about 10 minutes.

fMRI data acquisition: fMRI and neuropsychological battery measurements will be made before the intervention. These measurements will then be repeated after 2 weeks and 12 weeks.

fMRI will image changes in regional brain activity associated with these tasks. The MRI pulse sequences include diffusion tensor imaging, standard and non-invasive anatomical and quantitative MRI for coregistration and blood-oxygen-level dependent (BOLD) fMRI.

CO2 challenge: Cerebral blood flow measurements will be obtained while the subject rests in the scanner after administration of medical-grade 5% CO2 in air for 3-5 minutes. This will be repeated on weeks 2 and 12.

Data analysis: Standard fMRI analysis will be analyzed using established fMRI software. Statistical parametric analysis will be performed to generate activation maps. fMRI data will be corrected for multiple comparisons using a false discovery rate (q < 0.05) and threshold for cluster values to conservatively control for type I error. Behavioral data will be analyzed with paired t-test and ANOVA calculations used for group comparison with p < 0.05 (with Bonferroni correction) considered statistically significant.

Expected results: The investigators predict that, compared to placebo, MB will: i) improve working memory retention in a delayed match-to-sample task by memory performance and enhanced fMRI responses in the prefrontal cortex and parietal lobes, ii) improve episodic memory as determined by fMRI activation in the hippocampus, medial temporal lobes and prefrontal cortex iii) reduce reaction time in a psychomotor vigilance test and enhance fMRI responses within a cortical sustained attention network iv) improve CBF and v) improve fMRI connectivity in default mode and visuospatial and memory networks/subnetworks. The fMRI and behavioral performance effects on memory will be greater in the MCI and mild AD groups than in the healthy aging group. The effects will be greater in the MCI and AD groups than in the control groups.

Power analysis: Sample sizes were calculated using an fMRI power tool based on pilot data from the current study for a power of 80%, alpha = 0.05, False Discovery Rate < 0.05, to detect statistical difference between MB and placebo23. The investigators estimate they will need 20-25 subjects per arm of group (complete studies) and thus will recruit 200-240 subjects to account for potential failed studies.

Study Type

Interventional

Enrollment (Actual)

117

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • San Antonio, Texas, United States, 78229
        • Research Imaging Institute, The University of Texas Health Science Center at San Antonio

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

43 years to 87 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria for all subjects:

  1. 45-89 years old
  2. All genders
  3. All minorities
  4. English, Spanish, or multilingual speakers
  5. Postmenopausal or surgically sterile females only.
  6. Inclusion for MCI group only: participants will meet the criteria for amnestic and non-amnestic MCI such as those currently used by Texas Alzheimer's Research and Care Consortium (TARCC) consensus diagnosis
  7. Inclusion for AD group only: Alzheimer's Early-stage, sporadic-type

Exclusion Criteria:

  1. Pregnancy or breastfeeding
  2. Contraindication for MRI (Claustrophobia and magnetic metal implants)
  3. Glucose-6-phosphate deficiency, methemoglobinemia
  4. Allergy to MB
  5. Color-blindness
  6. Craniotomy, craniectomy or endovascular neurosurgery
  7. A current diagnosis of stroke, transient ischemic attack (TIA), any primary neurodegenerative disorder, or any other causes of neuropsychologic disturbances or secondary dementia (MCI or AD does not exclude subject)
  8. A serious intercurrent illness likely to cause death within the next 5 years, such as terminal cancer
  9. Alcohol and/or drug abuse
  10. Any detection of an unknown disease process (eg. new tumor) on the study's neuroimaging at the discretion of the investigators
  11. A systolic blood pressure ≥180 mmHg and/or a diastolic blood pressure ≥105 mmHg
  12. Severe difficulty or an inability to perform any one of the 6 Katz Activities of Daily Living
  13. Patients who are unlikely to comply with trial visit schedule or with trial medication,
  14. On any psychiatric serotonergic antidepressant medication or psychotropic medication within the last 5 weeks
  15. Diagnosis of epilepsy, traumatic brain injury with loss of consciousness, psychosis, panic attacks,
  16. Chronic kidney disease, cirrhosis, liver or renal transplants
  17. Known hypersensitivity to thiazide diuretics and phenothiazines
  18. Any other condition, which in the opinion of the investigator, would put the participant at risk and warrant exclusion from the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Single Group Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Healthy Aging MB
Methylene Blue (USP grade, 282mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Drug: Methylene Blue
Other Names:
  • Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate
Drug: Phenazopyridine hydrochloride
Other Names:
  • Azo
Placebo Comparator: Healthy Aging Placebo
Drug: FD&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Drug: Phenazopyridine hydrochloride
Other Names:
  • Azo
Drug: FD&C Blue # 2
Other Names:
  • Placebo
Experimental: Mild Cognitive Impairment (MCI) MB
Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Drug: Methylene Blue
Other Names:
  • Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate
Drug: Phenazopyridine hydrochloride
Other Names:
  • Azo
Placebo Comparator: Mild Cognitive Impairment (MCI) Placebo
Drug: FD&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Drug: Phenazopyridine hydrochloride
Other Names:
  • Azo
Drug: FD&C Blue # 2
Other Names:
  • Placebo
Experimental: Mild Alzheimer's Disease (AD) MB
Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Drug: Methylene Blue
Other Names:
  • Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate
Drug: Phenazopyridine hydrochloride
Other Names:
  • Azo
Placebo Comparator: Mild Alzheimer's Disease (AD) Placebo
Drug: FD&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Drug: Phenazopyridine hydrochloride
Other Names:
  • Azo
Drug: FD&C Blue # 2
Other Names:
  • Placebo
Experimental: Healthy Middle Age MB
Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Drug: Methylene Blue
Other Names:
  • Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate
Drug: Phenazopyridine hydrochloride
Other Names:
  • Azo
Placebo Comparator: Healthy Middle Age Placebo
Drug: FD&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Drug: Phenazopyridine hydrochloride
Other Names:
  • Azo
Drug: FD&C Blue # 2
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Working memory task
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
fMRI measurement of task blocked activation
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Working memory task response
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Working memory task behavioral measures (ie. correct number of responses)
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Episodic memory task
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
fMRI measurement of task blocked activation
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Episodic memory task response
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Face-Name Task behavioral measures (ie. correct recalls)
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Sustained attention task
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
fMRI measurement of task blocked activation
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Sustained attention task reaction time
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Psychomotor vigilance task (PVT) behavioral measures (ie. reaction time)
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Neuropsychological battery composite score
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
TARCC designed neurocognitive tests
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cerebral blood flow measures
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Resting measurements will be used to assess response and CBF using fMRI
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Functional Connectivity measures
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
fMRI measurements will be obtained while the subject rests in the scanner
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
CO2 challenge
Time Frame: baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days
Cerebral blood flow measurements will be acquired during a brief (3-5 minutes) inhalation of medical-grade 5% CO2 in air.
baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

Texas Alzheimer's Research and Care Consortium (TARCC)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2015

Primary Completion (Actual)

April 21, 2022

Study Completion (Anticipated)

July 1, 2023

Study Registration Dates

First Submitted

February 24, 2015

First Submitted That Met QC Criteria

February 27, 2015

First Posted (Estimate)

March 5, 2015

Study Record Updates

Last Update Posted (Actual)

August 26, 2022

Last Update Submitted That Met QC Criteria

August 25, 2022

Last Verified

August 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HSC20150410H

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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