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

The University of Texas System (UT)

Status and phase: Completed; Phase 2

Conditions: MCI; Aging; Alzheimer's Disease; AD; Mild Cognitive Impairment

Treatments: Drug: Methylene Blue; Drug: FD&C Blue # 2; Drug: Phenazopyridine hydrochloride

Study type: Interventional

Funder types: Other

Identifiers

NCT02380573

HSC20150410H

Details and patient eligibility

About

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.

Full 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.

Enrollment: 117 patients

Sex: All

Ages: 45 to 89 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Single Group Assignment

Masking: Quadruple Blind

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117 participants in 8 patient groups, including a placebo group

Healthy Aging MB

Experimental group

Description:

Methylene Blue (USP grade, 282mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Treatment:

Drug: Phenazopyridine hydrochloride

Drug: Methylene Blue

Healthy Aging Placebo

Placebo Comparator group

Description:

Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Treatment:

Drug: Phenazopyridine hydrochloride

Drug: FD&C Blue # 2

Mild Cognitive Impairment (MCI) MB

Experimental group

Description:

Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Treatment:

Drug: Phenazopyridine hydrochloride

Drug: Methylene Blue

Mild Cognitive Impairment (MCI) Placebo

Placebo Comparator group

Description:

Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Treatment:

Drug: Phenazopyridine hydrochloride

Drug: FD&C Blue # 2

Mild Alzheimer's Disease (AD) MB

Experimental group

Description:

Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Treatment:

Drug: Phenazopyridine hydrochloride

Drug: Methylene Blue

Mild Alzheimer's Disease (AD) Placebo

Placebo Comparator group

Description:

Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Treatment:

Drug: Phenazopyridine hydrochloride

Drug: FD&C Blue # 2

Healthy Middle Age MB

Experimental group

Description:

Methylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Treatment:

Drug: Phenazopyridine hydrochloride

Drug: Methylene Blue

Healthy Middle Age Placebo

Placebo Comparator group

Description:

Drug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Treatment:

Drug: Phenazopyridine hydrochloride

Drug: FD&C Blue # 2