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

NCT02380573 | Completed Phase 2 Results DMC

• 1 other identifier: HSC20150410H
• Study Type: interventional
• Target: 117
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Keywords

methylene blue; fMRI

Outcome Measures

Primary Outcomes (9)

• fMRI Measurement

  fMRI measurement of task blocked activation during Wechsler Memory Scale III

  baseline, 2 weeks and 12 weeks

• Wechsler Memory Scale, Third Edition

  Working memory task behavioral measures (ie. correct number of responses) Score is 0-104, with higher scores being better.

  baseline, 2 weeks ± 3 days, 12 weeks ± 3 days

• fMRI During FNAME

  Functional Magnetic Resonance Imaging (fMRI) measurement of task blocked activation. Measure reflects blood flow counts, and is not a scale with a high or low score.

  baseline, 2 weeks ± 3 days,12 weeks ± 3 days

• FNAME

  Face-Name Task behavioral measures (ie. correct recalls). The FNAME is a cross-modal associative memory test which includes 16 face-name pairs and 16 face-occupation pairs, with a total of 32 pairs to remember. Scores range from 0-32, higher scores are better

  baseline, 2 weeks ± 3 days,12 weeks ± 3 days

• fMRI During Psychomotor Vigilance Task

  fMRI measurement of task blocked activation

  baseline,2 weeks ± 3 days,12 weeks ± 3 days

• Psychomotor Vigilance Task

  Psychomotor vigilance task (PVT) behavioral measures (ie. reaction time). The primary outcome measures of PVT performance, lapses, are defined as reaction times exceeding 500 msec or failure to react. The PVT lapses are believed to represent perceptual, processing, or executive failures in the central nervous system (CNS) Lower scores are better, as they indicate quicker reaction times.

  baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days

• Wechsler Memory Scale III, Logical Memory Subset

  The patient is read two stories, out loud, by the test administrator. After each story is read, the patient is then asked to tell the story back to the administrator, as well as possible. Scores range from 0-75, with higher scores indicating better outcome.

  baseline, then 12 weeks ± 3 days

• Mini-Mental State Exam (MMSE)

  Short screening tool for providing an overall measure of cognitive impairment in clinical, research and community settings. The MMSE contains 11 questions with scores ranging from 1-5 depending on how many responses are required for each question. One point is assigned for each correct answer. The total score can range from 0-30 with a higher score indicating better cognitive skills.

  baseline, 2 weeks ± 3 days,12 weeks ± 3 days

• CLOX: An Executive Clock Drawing Test

  The subject draws a clock that says 1:45. Performance is rated according to the CLOX directions, and scored as "CLOX1" with scores ranging from 0-15 with a lower score indicating greater impairment. CLOX1 reflects performance in a novel and ambiguous situation. The CLOX's second step is a simple copying task. The examiner allows the patient to observe him or her drawing a clock in the circle provided on the scoring sheet. The examiner sets the hands again to "1:45", places the 12, 6, 3, and 9 first, and makes the hands into arrows. The patient is allowed to copy the examiner's clock. This clock is scored as "CLOX2" with scores ranging from 0-15 with a lower score indicating greater impairment. Participants can earn up to 15 points for each test, this is summed to give a possible score out of 30 with a higher score indicating less cognitive impairment. Scores reported are from inter-rater reliability

  baseline, 2 weeks ± 3 days, 12 weeks ± 3 days

Secondary Outcomes (1)

• Cerebral Blood Flow Measures

  baseline, 2 weeks ± 3 days, 12 weeks ± 3 days

Other Outcomes (2)

• Functional Connectivity Measures

  baseline, 2 weeks ± 3 days, 12 weeks ± 3 days

• CO2 Challenge

  baseline, change from baseline at 2 weeks ± 3 days, change from baseline at 12 weeks ± 3 days

Study Arms (8)

Healthy Aging MB

EXPERIMENTAL

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

Drug: Methylene Blue; Drug: Phenazopyridine hydrochloride

Healthy Aging Placebo

PLACEBO COMPARATOR

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

Mild Cognitive Impairment (MCI) MB

EXPERIMENTAL

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; Drug: Phenazopyridine hydrochloride

Mild Cognitive Impairment (MCI) Placebo

PLACEBO COMPARATOR

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

Mild Alzheimer's Disease (AD) MB

EXPERIMENTAL

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; Drug: Phenazopyridine hydrochloride

Mild Alzheimer's Disease (AD) Placebo

PLACEBO COMPARATOR

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

Healthy Middle Age MB

EXPERIMENTAL

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; Drug: Phenazopyridine hydrochloride

Healthy Middle Age Placebo

PLACEBO COMPARATOR

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

Interventions

Methylene Blue DRUG

Also known as: Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate

Healthy Aging MB; Healthy Middle Age MB; Mild Alzheimer's Disease (AD) MB; Mild Cognitive Impairment (MCI) MB

FD&C Blue # 2 DRUG

Also known as: Placebo

Healthy Aging Placebo; Healthy Middle Age Placebo; Mild Alzheimer's Disease (AD) Placebo; Mild Cognitive Impairment (MCI) Placebo

Phenazopyridine hydrochloride DRUG

Also known as: Azo

Healthy Aging MB; Healthy Aging Placebo; Healthy Middle Age MB; Healthy Middle Age Placebo; Mild Alzheimer's Disease (AD) MB; Mild Alzheimer's Disease (AD) Placebo; Mild Cognitive Impairment (MCI) MB; Mild Cognitive Impairment (MCI) Placebo

Eligibility Criteria

• Age: 45 Years - 89 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years old
• All genders
• All minorities
• English, Spanish, or multilingual speakers
• Postmenopausal or surgically sterile females only.

You may not qualify if:

• Pregnancy or breastfeeding
• Contraindication for MRI (Claustrophobia and magnetic metal implants)
• Glucose-6-phosphate deficiency, methemoglobinemia
• Allergy to MB
• Color-blindness
• Craniotomy, craniectomy or endovascular neurosurgery
• 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)
• A serious intercurrent illness likely to cause death within the next 5 years, such as terminal cancer
• Alcohol and/or drug abuse
• Any detection of an unknown disease process (eg. new tumor) on the study's neuroimaging at the discretion of the investigators
• A systolic blood pressure ≥180 mmHg and/or a diastolic blood pressure ≥105 mmHg
• Severe difficulty or an inability to perform any one of the 6 Katz Activities of Daily Living
• Patients who are unlikely to comply with trial visit schedule or with trial medication,
• On any psychiatric serotonergic antidepressant medication or psychotropic medication within the last 5 weeks
• Diagnosis of epilepsy, traumatic brain injury with loss of consciousness, psychosis, panic attacks,

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead
• Texas Alzheimer's Research and Care Consortium: collaborator

Study Sites (1)

Research Imaging Institute, The University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Related Publications (15)

• Bruchey AK, Gonzalez-Lima F. Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue. Am J Pharmacol Toxicol. 2008 Jan 1;3(1):72-79. doi: 10.3844/ajptsp.2008.72.79.

  PMID: 20463863 BACKGROUND

• Rojas JC, Bruchey AK, Gonzalez-Lima F. Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue. Prog Neurobiol. 2012 Jan;96(1):32-45. doi: 10.1016/j.pneurobio.2011.10.007. Epub 2011 Nov 3.

  PMID: 22067440 BACKGROUND

• Telch MJ, Bruchey AK, Rosenfield D, Cobb AR, Smits J, Pahl S, Gonzalez-Lima F. Effects of post-session administration of methylene blue on fear extinction and contextual memory in adults with claustrophobia. Am J Psychiatry. 2014 Oct;171(10):1091-8. doi: 10.1176/appi.ajp.2014.13101407.

  PMID: 25018057 BACKGROUND

• Lin AL, Poteet E, Du F, Gourav RC, Liu R, Wen Y, Bresnen A, Huang S, Fox PT, Yang SH, Duong TQ. Methylene blue as a cerebral metabolic and hemodynamic enhancer. PLoS One. 2012;7(10):e46585. doi: 10.1371/journal.pone.0046585. Epub 2012 Oct 9.

  PMID: 23056355 BACKGROUND

• Huang S, Du F, Shih YY, Shen Q, Gonzalez-Lima F, Duong TQ. Methylene blue potentiates stimulus-evoked fMRI responses and cerebral oxygen consumption during normoxia and hypoxia. Neuroimage. 2013 May 15;72:237-42. doi: 10.1016/j.neuroimage.2013.01.027. Epub 2013 Jan 26.

  PMID: 23357077 BACKGROUND

• Talley Watts L, Long JA, Chemello J, Van Koughnet S, Fernandez A, Huang S, Shen Q, Duong TQ. Methylene blue is neuroprotective against mild traumatic brain injury. J Neurotrauma. 2014 Jun 1;31(11):1063-71. doi: 10.1089/neu.2013.3193. Epub 2014 Apr 8.

  PMID: 24479842 BACKGROUND

• Long JA, Watts LT, Chemello J, Huang S, Shen Q, Duong TQ. Multiparametric and longitudinal MRI characterization of mild traumatic brain injury in rats. J Neurotrauma. 2015 Apr 15;32(8):598-607. doi: 10.1089/neu.2014.3563. Epub 2015 Jan 22.

  PMID: 25203249 BACKGROUND

• Rodriguez P, Jiang Z, Huang S, Shen Q, Duong TQ. Methylene blue treatment delays progression of perfusion-diffusion mismatch to infarct in permanent ischemic stroke. Brain Res. 2014 Nov 7;1588:144-9. doi: 10.1016/j.brainres.2014.09.007. Epub 2014 Sep 8.

  PMID: 25218555 BACKGROUND

• Shen Q, Du F, Huang S, Rodriguez P, Watts LT, Duong TQ. Neuroprotective efficacy of methylene blue in ischemic stroke: an MRI study. PLoS One. 2013 Nov 21;8(11):e79833. doi: 10.1371/journal.pone.0079833. eCollection 2013.

  PMID: 24278191 BACKGROUND

• Peter C, Hongwan D, Kupfer A, Lauterburg BH. Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol. 2000 Jun;56(3):247-50. doi: 10.1007/s002280000124.

  PMID: 10952480 BACKGROUND

• Gonzalez-Lima F, Bruchey AK. Extinction memory improvement by the metabolic enhancer methylene blue. Learn Mem. 2004 Sep-Oct;11(5):633-40. doi: 10.1101/lm.82404.

  PMID: 15466319 BACKGROUND

• Naylor GJ, Martin B, Hopwood SE, Watson Y. A two-year double-blind crossover trial of the prophylactic effect of methylene blue in manic-depressive psychosis. Biol Psychiatry. 1986 Aug;21(10):915-20. doi: 10.1016/0006-3223(86)90265-9.

  PMID: 3091097 BACKGROUND

• Mackworth JF. Vigilance, arousal, and habituation. Psychol Rev. 1968 Jul;75(4):308-22. doi: 10.1037/h0025896. No abstract available.

  PMID: 4875885 BACKGROUND

• Rombouts SA, Barkhof F, Goekoop R, Stam CJ, Scheltens P. Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study. Hum Brain Mapp. 2005 Dec;26(4):231-9. doi: 10.1002/hbm.20160.

  PMID: 15954139 BACKGROUND

• Wang L, Li H, Liang Y, Zhang J, Li X, Shu N, Wang YY, Zhang Z. Amnestic mild cognitive impairment: topological reorganization of the default-mode network. Radiology. 2013 Aug;268(2):501-14. doi: 10.1148/radiol.13121573. Epub 2013 Mar 12.

  PMID: 23481166 BACKGROUND

Related Links

• Texas Alzheimer's Research and Care Consortium
• Research Imaging Institute

MeSH Terms

Conditions

Cognitive Dysfunction; Alzheimer Disease

Interventions

Methylene Blue; Indigo Carmine; Phenazopyridine

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases

Intervention Hierarchy (Ancestors)

Phenothiazines; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Aminopyridines; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr. Peter Fox
• Organization: University of Texas Health Science Center at San Antonio

fox@uthscsa.edu

210-567-8150

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2015
• First Posted: March 5, 2015
• Study Start: July 1, 2015
• Primary Completion: April 21, 2022
• Study Completion: July 1, 2023
• Last Updated: September 19, 2024
• Results First Posted: September 19, 2024

Record last verified: 2024-08

Locations

US (1)