A Pilot of the Feasibility of Using the Iron-Chelator Deferiprone on Mild Cognitive Impairment

Study Overview
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Brief Summary
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The investigators propose to conduct a series of N of One (No1) single blinded clinical trials to pilot the feasibility of using the iron-chelator deferiprone on Mild Cognitive Impairment (MCI). Chelation therapy has previously been reported to slow the rate of cognitive decline in Alzheimer's Disease (AD) by 50% in a single human randomized clinical trial.

Detailed Description
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Iron chelation's mechanism of action (MOA) in Alzheimer's disease (AD) is uncertain. Potential MOA include reversal of aluminum (AL) toxicity, the prevention of a-beta aggregation, β-amyloid disaggregation, and the obstruction of microbacterial and viral parasitism. The latter mechanism involves augmentation of innate immunity, and disruption of microbacterial iron metabolism. Infectious models of AD's pathophysiology have been recently proposed. Iron blocks toll-like receptor (TLR) initiated anti-microbial actions mediated via gamma-interferon (IFN-γ) tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-10 (IL-10). These biomarkers are of interest because they have also been associated with our novel latent dementia phenotype (i.e., d for dementia) in the Texas Alzheimer's Research and Care Consortium (TARCC). d is a continuous measure of dementia severity that can be constructed from any cognitive battery that also includes a measure of Instrumental Activities of Daily Living (IADL). Serum biomarkers might trigger dementing processes without participating in their later stages. Thus, the investigators have indications as to who might benefit from iron-chelation and when the intervention might be best applied. This knowledge may help them detect an effect of deferiprone on prospective change in d and even on MCI conversion in TARCC NHW (Non Hispanic White) subjects.

Official Title
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An N of One Clinical Trial to Pilot the Feasibility of Using the Iron-Chelator Deferiprone on Mild Cognitive Impairment

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Drug: Deferiprone
* Other: Placebo phase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: MA (Mexican Americans) or NHW TARCC participants with competent informants; TARCC diagnosis of MCI (any subtype); Incident MCI or conversion to MCI from control in the two previous TARCC waves; 65-80 yrs of age; Non-institutionalized level of care; Capacity to give informed consent GDS (Geriatric Depression Screen) score (15 item) ≤ 6; TARCC MMSE (Mini-Mental State Examination) ≥ 26 /30; HIS (Hachinski Ischemic Scale) ≤ 05/15; Most recent TARCC dEQ-score = 0 ± 0.25. Exclusion Criteria: A clinical diagnosis of Diabetes Mellitus and current treatment with insulin; A self-reported diagnosis of Major Depression (treatment with antidepressants not exclusionary); A history of psychosis, including visual hallucinations; History or treatment for Parkinson's, or tremor, or Rapid Eye Movement (REM) behavior disorder; History or treatment for atrial fibrillation; Treatment for cancer in the last 5 years (exc. skin cancers); Major surgery in the last year; History of craniotomy; Serum Ferritin < 500mcg/ml, Hgb < 14g/dl♂ /12g/dl♀,, HCT < 45%♂ /40%♀, recent blood transfusion (last 5 years), FeSO4 supplementation, erythromycin therapy; ANC (absolute neutrophil count) < 500 cells/µL, platelet count < 150 × 106 /ml; Treatment with anti-convulsants, mood stabilizers, neuroleptics, opiates, muscle relaxants, systemic steroids, or AD-indicated agents.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: deferiprone<br>Deferiprone will be administered three times a day (25mg/kg). Total dose per day will depend on participants' body weight for one, three month block. | Drug: Deferiprone<br>* Subjects will then begin an experimental No1 design: placebo-deferiprone-placebo. Study drug will be administered in three 3 month blocks. All subjects will receive 30 days of active study drug. The placebo-deferiprone contrast compares placebo to active drug initiation. The deferiprone-placebo contrast tests active drug withdrawal. All will be given placebo in months 1-3, and 6-12. This will allow the investigators to examine active drug exposure on d score up to one year and prospective time to MCI conversion. Dosing: Participants will be treated 25 mg/kg po tid (75mg /kg /d total) The dose will be rounded by the prescriber to the nearest 250 mg (half-tablet).<br>* Other names: Ferriprox, ATC Code V03AC02;|
| Placebo Comparator: Placebo Phase<br>Placebo tablets with inactive substance will be used. Total number of placebo tablets will be equivalent to the active tablets administered depending on participants' body weight for two, three month blocks. | Other: Placebo phase<br>* Placebo tablets with inactive substance will be provided to subjects for two, 3 month blocks during the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of deferiprone therapy on d scores in Mild Cognitive Impairment (MCI) | Using N of 1 trial design in small number of MCI cases to compare within subject response to placebo and deferiprone in a A1-A-A1 design | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Explore deferiprone's longitudinal effect on d and dementia conversion | We want to survey the effect of deferiprone on d to see If serum biomarkers trigger dementing processes in non Hispanic whites and if deferiprone exposure in MCI may terminate progression and conversion to dementia. | 12 months |