Clinical trial NCT04263519: A Pilot Open Labeled Study of Tacrolimus in Alzheimer's Disease.
Official title: A Pilot Open Labeled Study of Tacrolimus to Assess it's Effects on Bio-markers of Mild Cognitive Impairment and Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Alzheimer Disease
Mild Cognitive Impairment
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
First posted: 2020-02-10
Enrollment: 0
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A Pilot open labeled study of Tacrolimus in Alzheimer's Disease.

Detailed description: This study will investigate the neurobiological effect of tacrolimus in persons with MCI and dementia due to AD by measuring biomarkers of target engagement in immune response, amyloid-b, tau and neurodegeneration in CSF, functional connectivity with MRI and EEG, and cognition. Study objectives include:

Eligibility criteria: Inclusion Criteria:

Study subjects meeting all of the following criteria will be allowed to enroll in the study:

1. Age 55-85 inclusive, male or female.
2. Diagnosis of MCI or dementia due to AD as shown by positive AD biomarker (CSF or neuroimaging).
3. Education level, English language skills and literacy indicates subject will be able to complete all assessments.
4. Willing and able to complete all assessment and study procedures, including phlebotomies, lumbar punctures, MRIs, neurocognitive testing.
5. Subject has a study partner with at least two days of contact per week and willingness to assist with subject's research activities.
6. If on cholinesterase inhibitor and/or memantine, doses are stable for 3 months prior to baseline.

Exclusion Criteria:

Subjects meeting any of the following criteria during the screening evaluation will be excluded:

1. Allergy or hypersensitivity to tacrolimus.
2. Any specific CNS disease other than suspected AD, such as major clinical stroke, brain tumor, normal pressure hydrocephalus, multiple sclerosis, significant head trauma with persistent neurological of cognitive deficits or complaints, Parkinson's disease, frontotemporal dementia, and/or other neurodegenerative diseases.
3. Any significant systemic illness or clinically significant unstable medical condition that could affect subject safety or compliance with the study; including but not limited to any active infection, active malignancy except non-melanomatous skin cancers, cirrhosis, active hepatitis, uncontrolled diabetes (A1c \>8), AIDS, common variable immunodeficiency, conditions treated with biologics, uncontrolled hypertension, chronic kidney disease with an eGFR \<45 ml/min, Platelets \< 100K, Hgb \<9.
4. History of alcohol or other substance abuse or dependence with the past two years.
5. Major active psychiatric illness (e.g. depression, bipolar disorder, obsessive compulsive disorder, schizophrenia) within the previous year.
6. Current suicidal ideation or history of suicide attempt.
7. Contraindications to undergo MRI studies:

   1. History of a cardiac pacemaker or pacemaker wires,
   2. Metallic particles in the body,
   3. Vascular clips in the head,
   4. Prosthetic heart valves, or
   5. Severe claustrophobia impeding ability to participate in an imaging study.
8. MRI findings that show one or more of the following:

   1. More than 4 incidental microhemorrhages,
   2. Incidental lacunar infarcts with attributable signs or symptoms and with history of stroke,
   3. Incidental meningiomas with attributable signs or symptoms, or
   4. Newly recognized meningioma.
9. Laboratory abnormalities in B12, TSH, or other common laboratory parameters that may contribute to cognitive dysfunction.
10. Laboratory abnormalities in PT-INR, CBC, electrolytes, magnesium, LFTs, BUN, Cr or others, or abnormalities in ECG posing risk to treatment with tacrolimus.
11. Current use of medications with psychoactive properties (e.g., anticholinergics, antihistamines, antipsychotics, sedative hypnotics, anxiolytics) that may deleteriously affect cognition in the judgement of the investigator.
12. Current use of medications that interact with tacrolimus (protease inhibitors, macrolides, rifampin, barbiturates, phenytoin, or azoles).
13. Inability to avoid any dietary supplements that could interact with tacrolimus metabolism.
14. Inability to avoid grapefruit and grapefruit juice.
15. Use of other small molecule or device-based investigational agents one month prior to entry and for the duration of the trial; or participation in any immunotherapy clinical trial within three months prior to baseline visit.
16. Discontinuation of cholinesterase inhibitor or memantine within one month (28 days) prior to baseline visit.
17. Females who are pregnant, lactating or of child-bearing potential

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Primary outcomes:
measure: CSF biomarkers of target engagement, AD pathology, and neurodegeneration
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Blood biomarkers of target engagement, AD pathology, and neurodegeneration.
timeFrame: Baseline and 12 weeks
measure: Structural neuroimaging of Hippocampal volume.
timeFrame: Baseline and 12 weeks
measure: Functional neuroimaging of default mode network connectivity.
timeFrame: Baseline and 12 weeks
measure: Electroencephalograms (EEG) spectral power
timeFrame: Baseline and 12 weeks
measure: Montreal Cognitive Assessment (MoCA)
timeFrame: Baseline and 12 weeks
measure: Neuropsychiatric Inventory Questionnaire (NPIQ)
timeFrame: Baseline, 4 weeks, 8 weeks and 12 weeks
measure: Functional Activities Questionnaire (FAQ)
timeFrame: Baseline, 4 weeks, 8 weeks and 12 weeks
measure: Repeated Battery for the Assessment of Neuropsychological Status
timeFrame: Baseline, 4 weeks, 8 weeks and 12 weeks
Other outcomes:
Locations:
Study officials:
References: