Mild Cognitive ImpairmentPhase 2MB2NCT02380573

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

A Phase 2 study testing Methylene Blue, FD&C Blue # 2 and Phenazopyridine hydrochloride in people with Mild Cognitive Impairment and MCI, run by The University of Texas Health Science Center at San Antonio at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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… Read more about this study

Who is it for?: Ages 45 to 89 yearsHealthy volunteers can take part
Conditions the study is for: Mild Cognitive Impairment, MCI, Aging
What is being tested?: Methylene Blue, FD&C Blue # 2 and Phenazopyridine hydrochloride
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 117 participants
Where: 1 siteUnited States
Study dates: Jul 2015to Jul 2023
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 45 to 89 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

45-89 years old
All genders
All minorities
English, Spanish, or multilingual speakers
Postmenopausal or surgically sterile females only.
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
Inclusion for AD group only: Alzheimer's Early-stage, sporadic-type

Who cannot join

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

Show all 18Show fewer

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,
Chronic kidney disease, cirrhosis, liver or renal transplants
Known hypersensitivity to thiazide diuretics and phenothiazines
Any other condition, which in the opinion of the investigator, would put the participant at risk and warrant exclusion from the study

Trial locations and contacts

1 site in 1 country.

United States1 site

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

Other trials in United States

About this study

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

Read the 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.

Conditions: Mild Cognitive Impairment, MCI, Aging, Alzheimer's Disease, AD
Being tested: Methylene Blue, FD&C Blue # 2, Phenazopyridine hydrochloride
Keywords: methylene blue, fMRI
Medical subject headings: Cognitive Dysfunction, Alzheimer Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Methylene BlueDrug
Also called Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate
FD&C Blue # 2Drug
Also called Placebo
Phenazopyridine hydrochlorideDrug
Also called Azo

Study groups in NCT02380573
Study group	Role	What they receive
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) Receives: 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) Receives: 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) Receives: 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) Receives: 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) Receives: 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) Receives: 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) Receives: 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) Receives: Drug: FD&C Blue # 2; Drug: Phenazopyridine hydrochloride

What is being measured

The primary outcome is the main question the study is designed to answer.

fMRI Measurement
fMRI measurement of task blocked activation during Wechsler Memory Scale III
Measured: 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.
Measured: 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.
Measured: 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
Measured: baseline, 2 weeks ± 3 days,12 weeks ± 3 days
fMRI During Psychomotor Vigilance Task
fMRI measurement of task blocked activation
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: baseline, 2 weeks ± 3 days, 12 weeks ± 3 days

Secondary outcomes (1)

Cerebral Blood Flow Measures
Resting measurements will be used to assess response and CBF using fMRI. Scores are baseline, percent change between baseline and 2 weeks, baseline and 12 weeks
Measured: baseline, 2 weeks ± 3 days, 12 weeks ± 3 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jul 2015Jul 2023

First posted5 Mar 2015 (estimated)
Study startJul 2015
Primary completion21 Apr 2022
Study completionJul 2023

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (15)Papers the sponsor has linked to this study.
Other trials for Mild Cognitive ImpairmentStudies of the same condition, open and under way.
More trials run by The University of Texas Health Science Center at San AntonioThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Single group
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 117 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02380573
Sponsor's protocol ID: HSC20150410H
Acronym: MB2
Status last verified: Aug 2024
First submitted: 24 Feb 2015
Last updated: 19 Sep 2024
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 20463863
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.
PubMed 22067440
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.
PubMed 25018057
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.
PubMed 23056355
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.
PubMed 23357077
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.
PubMed 24479842
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.
PubMed 25203249
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.
PubMed 25218555
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.
PubMed 24278191
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.
PubMed 10952480
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.
PubMed 15466319
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.
PubMed 3091097
Mackworth JF. Vigilance, arousal, and habituation. Psychol Rev. 1968 Jul;75(4):308-22. doi: 10.1037/h0025896. No abstract available.
PubMed 4875885
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.
PubMed 15954139
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.
PubMed 23481166

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Cognitive and Functional Connectivity Effects of Methylene Blue in Healthy Aging, Mild Cognitive Impairment and Alzheimer's Disease
ClinicalTrials.gov ID: NCT02380573
Acronym / sponsor ID: MB2 / HSC20150410H
Conditions: Mild Cognitive Impairment, MCI, Aging, Alzheimer's Disease, AD
Keywords: methylene blue, fMRI
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 117 participants (actual)
Lead sponsor: The University of Texas Health Science Center at San AntonioUniversity, hospital or other
Collaborators: Texas Alzheimer's Research and Care Consortium
Study start: Jul 2015
Primary completion: 21 Apr 2022 (actual)
Study completion: Jul 2023 (actual)
First posted: 5 Mar 2015 (estimated)
Results: Posted 19 Sep 2024

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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).

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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Single group
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 8

Arm	Type	Receives
Healthy Aging MB	Experimental	Drug: Methylene Blue, Drug: Phenazopyridine hydrochlorideMethylene Blue (USP grade, 282mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Healthy Aging Placebo	Placebo comparator	Drug: FD&C Blue # 2, Drug: Phenazopyridine hydrochlorideDrug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Mild Cognitive Impairment (MCI) MB	Experimental	Drug: Methylene Blue, Drug: Phenazopyridine hydrochlorideMethylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Mild Cognitive Impairment (MCI) Placebo	Placebo comparator	Drug: FD&C Blue # 2, Drug: Phenazopyridine hydrochlorideDrug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Mild Alzheimer's Disease (AD) MB	Experimental	Drug: Methylene Blue, Drug: Phenazopyridine hydrochlorideMethylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Mild Alzheimer's Disease (AD) Placebo	Placebo comparator	Drug: FD&C Blue # 2, Drug: Phenazopyridine hydrochlorideDrug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Healthy Middle Age MB	Experimental	Drug: Methylene Blue, Drug: Phenazopyridine hydrochlorideMethylene Blue (USP grade, 282 mg oral, daily, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)
Healthy Middle Age Placebo	Placebo comparator	Drug: FD&C Blue # 2, Drug: Phenazopyridine hydrochlorideDrug: FD\&C Blue # 2 (USP grade, 282 mg oral, 2 weeks, 12 weeks) Phenazopyridine hydrochloride (97.5 mg oral, 2 weeks, 12 weeks)

Who may qualify

Ages: 45 to 89 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

45-89 years old
All genders
All minorities
English, Spanish, or multilingual speakers
Postmenopausal or surgically sterile females only.

Key exclusion criteria (18 listed)

Pregnancy or breastfeeding
Contraindication for MRI (Claustrophobia and magnetic metal implants)
Glucose-6-phosphate deficiency, methemoglobinemia
Allergy to MB
Color-blindness

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Methylene BlueAlso: Phenothiazin-5-ium, 3, 7-bis (dimethylamino)-chloride, trihydrate	Drug	Healthy Aging MB, Healthy Middle Age MB, Mild Alzheimer's Disease (AD) MB, Mild Cognitive Impairment (MCI) MB
FD&C Blue # 2Also: Placebo	Drug	Healthy Aging Placebo, Healthy Middle Age Placebo, Mild Alzheimer's Disease (AD) Placebo, Mild Cognitive Impairment (MCI) Placebo
Phenazopyridine hydrochlorideAlso: Azo	Drug	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

Primary outcome

fMRI Measurement
Time frame: baseline, 2 weeks and 12 weeks
fMRI measurement of task blocked activation during Wechsler Memory Scale III
Wechsler Memory Scale, Third Edition
Time frame: baseline, 2 weeks ± 3 days, 12 weeks ± 3 days
Working memory task behavioral measures (ie. correct number of responses) Score is 0-104, with higher scores being better.
fMRI During FNAME
Time frame: baseline, 2 weeks ± 3 days,12 weeks ± 3 days
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.
FNAME
Time frame: baseline, 2 weeks ± 3 days,12 weeks ± 3 days
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
fMRI During Psychomotor Vigilance Task
Time frame: baseline,2 weeks ± 3 days,12 weeks ± 3 days
fMRI measurement of task blocked activation
Psychomotor Vigilance Task
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). 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.
Wechsler Memory Scale III, Logical Memory Subset
Time frame: baseline, then 12 weeks ± 3 days
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.
Mini-Mental State Exam (MMSE)
Time frame: baseline, 2 weeks ± 3 days,12 weeks ± 3 days
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.
CLOX: An Executive Clock Drawing Test
Time frame: baseline, 2 weeks ± 3 days, 12 weeks ± 3 days
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

1 secondary outcome

Cerebral Blood Flow Measures
Time frame: baseline, 2 weeks ± 3 days, 12 weeks ± 3 days

Results and safety

Results posted to the registry on 19 Sep 2024, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Healthy Aging MB	22	12
Healthy Aging Placebo	21	13
Mild Cognitive Impairment (MCI) MB	28	12
Mild Cognitive Impairment (MCI) Placebo	24	16
Mild Alzheimer's Disease (AD) MB	1	1
Mild Alzheimer's Disease (AD) Placebo	2	1
Healthy Middle Age MB	0	0
Healthy Middle Age Placebo	0	0

Primary outcome: fMRI Measurement

Time frame: baseline, 2 weeks and 12 weeks. Mean (Standard Deviation). Unit: voxels

Measure	Healthy Aging MB n = 12	Healthy Aging Placebo n = 13	Mild Cognitive Impairment (MCI) MB n = 12	Mild Cognitive Impairment (MCI) Placebo n = 16	Mild Alzheimer's Disease MB n = 0	Mild Alzheimer's Disease Placebo n = 0
Baseline	2267.0 (2428.23)	1491.23 (1343.81)	673.31 (1366.69)	989.19 (1651.97)	–	–
2 weeks	1719.00 (1377.02)	962.69 (843.93)	12270.59 (1955.60)	930.25 (1157.55)	–	–
12 weeks	1451.83 (1623.84)	1623.84 (919.08)	1238.58 (1743.67)	1334.38 (2341.44)	–	–

Population analysed: There was not sufficient data collected to be analyzed for Mild Alzheimer's disease MB or placebo, only the scale score was measured, as reported in the Wechsler Memory Scale outcome.

Primary outcome: Wechsler Memory Scale, Third Edition

Time frame: baseline, 2 weeks ± 3 days, 12 weeks ± 3 days. Mean (Standard Deviation). Unit: score on a scale

Measure	Healthy Aging MB n = 12	Healthy Aging Placebo n = 14	Mild Cognitive Impairment (MCI) MB n = 13	Mild Cognitive Impairment (MCI) Placebo n = 15	Mild Alzheimer's Disease (AD) MB n = 1	Mild Alzheimer's Disease (AD) Placebo n = 1
baseline	14.58 (2.35)	15.43 (2.85)	15.23 (2.5)	13.06 (3.23)	4 (0)	15 (0)
2 weeks	16 (2.3)	17.29 (1.33)	15.23 (2.68)	15.31 (2.94)	5 (0)	17 (0)
12 weeks	15.58 (2.11)	15.93 (2.13)	14.69 (1.55)	13.2 (3.17)	11 (0)	13 (0)

Primary outcome: fMRI During FNAME

Time frame: baseline, 2 weeks ± 3 days,12 weeks ± 3 days. Mean (Standard Deviation). Unit: voxels activated over a threshold

Measure	Healthy Aging MB n = 12	Healthy Aging Placebo n = 13	Mild Cognitive Impairment (MCI) MB n = 12	Mild Cognitive Impairment (MCI) Placebo n = 16	Mild Alzheimer's Disease (AD) MB n = 1	Mild Alzheimer's Disease (AD) Placebo n = 1	Healthy Middle Age MB n = 0	Healthy Middle Age Placebo n = 0
baseline	16881.03 (8823.60)	17382.29 (6401.56)	13166.23 (4796.32)	13777.75 (8955.52)	2211.00 (0)	3938.00 (0)	–	–
2 weeks	18146.92 (7075.66)	19748.86 (8221.18)	12935.15 (7042.78)	15617.31 (7519.81)	4939.00 (0)	4140.00 (0)	–	–
12 weeks	16893.83 (6689.61)	18342.57 (8230.30)	13973.56 (10759.77)	14466.56 (9944.16)	2240.00 (0)	1355.00 (0)	–	–

Population analysed: There was not sufficient data collected to be analyzed for Mild Alzheimer's disease MB or placebo, only the scale measure was obtained in the next outcome.

Primary outcome: FNAME

Time frame: baseline, 2 weeks ± 3 days,12 weeks ± 3 days. Mean (Standard Deviation). Unit: score on a scale

Measure	Healthy Aging MB n = 12	Healthy Aging Placebo n = 14	Mild Cognitive Impairment (MCI) MB n = 13	Mild Cognitive Impairment (MCI) Placebo n = 16	Mild Alzheimer's Disease (AD) MB n = 1	Mild Alzheimer's Disease (AD) Placebo n = 1
baseline	14.5 (4.83)	14.36 (4.86)	10.54 (3.71)	11.19 (4.23)	8 (0)	6 (0)
2 weeks	16.08 (4.7)	15.36 (6.1)	12.54 (4.52)	11.5 (4.62)	2 (0)	9 (0)
12 weeks	16.67 (4.16)	16 (6.24)	14 (3.96)	12.69 (5.62)	6 (0)	1 (0)

1 secondary outcome is reported in the full results.

Adverse events

Time frame: Adverse events were collected from the time of randomization to 12 weeks. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Healthy Aging MB	0 of 22 (0%)	22 of 22 (100%)	0 of 22
Healthy Aging Placebo	0 of 21 (0%)	19 of 21 (90.5%)	0 of 21
Mild Cognitive Impairment (MCI) MB	0 of 28 (0%)	27 of 28 (96.4%)	0 of 28
Mild Cognitive Impairment (MCI) Placebo	0 of 24 (0%)	21 of 24 (87.5%)	0 of 24
Mild Alzheimer's Disease (AD) MB	0 of 1 (0%)	0 of 1 (0%)	0 of 1
Mild Alzheimer's Disease (AD) Placebo	0 of 1 (0%)	0 of 1 (0%)	0 of 1

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 20463863Bruchey 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.
Background: PubMed 22067440Rojas 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.
Background: PubMed 25018057Telch 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.
Background: PubMed 23056355Lin 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.
Background: PubMed 23357077Huang 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.
Background: PubMed 24479842Talley 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.
Background: PubMed 25203249Long 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.
Background: PubMed 25218555Rodriguez 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.
Background: PubMed 24278191Shen 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.
Background: PubMed 10952480Peter 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.
Background: PubMed 15466319Gonzalez-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.
Background: PubMed 3091097Naylor 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.
Texas Alzheimer's Research and Care ConsortiumLink provided by the sponsor.
Research Imaging InstituteLink provided by the sponsor.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

The record lists no contact. Use the official record to reach the sponsor.

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

fMRI Measurement (time frame: baseline, 2 weeks and 12 weeks). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02380573, which also lists 15 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.