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

NCT ID: NCT02878538

Last Updated: 2018-02-06

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

WITHDRAWN

Clinical Phase

EARLY_PHASE1

Study Classification

INTERVENTIONAL

Study Start Date

2018-01-31

Study Completion Date

2023-04-30

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.

Conditions

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Mild Cognitive Impairment

Study Design

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Allocation Method

NON_RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

OTHER

Blinding Strategy

SINGLE

Participants

Study Groups

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deferiprone

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.

Group Type ACTIVE_COMPARATOR

Deferiprone

Intervention Type DRUG

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).

Placebo Phase

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.

Group Type PLACEBO_COMPARATOR

Placebo phase

Intervention Type OTHER

Placebo tablets with inactive substance will be provided to subjects for two, 3 month blocks during the study.

Interventions

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Deferiprone

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).

Intervention Type DRUG

Placebo phase

Placebo tablets with inactive substance will be provided to subjects for two, 3 month blocks during the study.

Intervention Type OTHER

Other Intervention Names

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Ferriprox, ATC Code V03AC02

Eligibility Criteria

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Inclusion Criteria

1. MA (Mexican Americans) or NHW TARCC participants with competent informants;
2. TARCC diagnosis of "MCI" (any subtype);
3. Incident MCI or conversion to MCI from control in the two previous TARCC waves;
4. 65-80 yrs of age;
5. Non-institutionalized level of care;
6. Capacity to give informed consent
7. GDS (Geriatric Depression Screen) score (15 item) ≤ 6;
8. TARCC MMSE (Mini-Mental State Examination) ≥ 26 /30;
9. HIS (Hachinski Ischemic Scale) ≤ 05/15;
10. Most recent TARCC dEQ-score = 0 ± 0.25.

Exclusion Criteria

1. A clinical diagnosis of "Diabetes Mellitus" and current treatment with insulin;
2. A self-reported diagnosis of "Major Depression" (treatment with "antidepressants" not exclusionary);
3. A history of psychosis, including visual hallucinations;
4. History or treatment for Parkinson's, or tremor, or Rapid Eye Movement (REM) behavior disorder;
5. History or treatment for atrial fibrillation;
6. Treatment for cancer in the last 5 years (exc. skin cancers);
7. Major surgery in the last year;
8. History of craniotomy;
9. Serum Ferritin \< 500mcg/ml, Hgb \< 14g/dl♂ /12g/dl♀,, HCT \< 45%♂ /40%♀, recent blood transfusion (last 5 years), FeSO4 supplementation, erythromycin therapy;
10. ANC (absolute neutrophil count) \< 500 cells/µL, platelet count \< 150 × 106 /ml;
11. Treatment with anti-convulsants, mood stabilizers, neuroleptics, opiates, muscle relaxants, systemic steroids, or AD-indicated agents.
Minimum Eligible Age

65 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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The University of Texas Health Science Center at San Antonio

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Donald R Royall, MD

Role: PRINCIPAL_INVESTIGATOR

The University of Texas Health Science Center at San Antonio

Dean Kellogg, MD, PHD

Role: PRINCIPAL_INVESTIGATOR

The University of Texas Health Science Center at San Antonio

Locations

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University of Texas Health Science Center

San Antonio, Texas, United States

Site Status

Countries

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United States

References

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Becerril-Ortega J, Bordji K, Freret T, Rush T, Buisson A. Iron overload accelerates neuronal amyloid-beta production and cognitive impairment in transgenic mice model of Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2288-301. doi: 10.1016/j.neurobiolaging.2014.04.019. Epub 2014 May 1.

Reference Type BACKGROUND
PMID: 24863668 (View on PubMed)

De Chiara G, Marcocci ME, Sgarbanti R, Civitelli L, Ripoli C, Piacentini R, Garaci E, Grassi C, Palamara AT. Infectious agents and neurodegeneration. Mol Neurobiol. 2012 Dec;46(3):614-38. doi: 10.1007/s12035-012-8320-7. Epub 2012 Aug 17.

Reference Type BACKGROUND
PMID: 22899188 (View on PubMed)

Fine JM, Renner DB, Forsberg AC, Cameron RA, Galick BT, Le C, Conway PM, Stroebel BM, Frey WH 2nd, Hanson LR. Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation. Neurosci Lett. 2015 Jan 1;584:362-7. doi: 10.1016/j.neulet.2014.11.013. Epub 2014 Nov 13.

Reference Type BACKGROUND
PMID: 25445365 (View on PubMed)

Gavett BE, Vudy V, Jeffrey M, John SE, Gurnani AS, Adams JW. The delta latent dementia phenotype in the uniform data set: Cross-validation and extension. Neuropsychology. 2015 May;29(3):344-52. doi: 10.1037/neu0000128. Epub 2014 Aug 25.

Reference Type BACKGROUND
PMID: 25151112 (View on PubMed)

Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry. 1982 Jun;140:566-72. doi: 10.1192/bjp.140.6.566.

Reference Type BACKGROUND
PMID: 7104545 (View on PubMed)

Nairz M, Schroll A, Sonnweber T, Weiss G. The struggle for iron - a metal at the host-pathogen interface. Cell Microbiol. 2010 Dec;12(12):1691-702. doi: 10.1111/j.1462-5822.2010.01529.x. Epub 2010 Oct 21.

Reference Type BACKGROUND
PMID: 20964797 (View on PubMed)

Peters DG, Connor JR, Meadowcroft MD. The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer's disease: Two sides of the same coin. Neurobiol Dis. 2015 Sep;81:49-65. doi: 10.1016/j.nbd.2015.08.007. Epub 2015 Aug 22.

Reference Type BACKGROUND
PMID: 26303889 (View on PubMed)

Royall DR, Palmer RF, Markides KS. Exportation and Validation of Latent Constructs for Dementia Case Finding in a Mexican American Population-based Cohort. J Gerontol B Psychol Sci Soc Sci. 2017 Oct 1;72(6):947-955. doi: 10.1093/geronb/gbw004.

Reference Type BACKGROUND
PMID: 26968639 (View on PubMed)

Royall DR, Palmer RF; Texas Alzheimer's Research and Care. Validation of a latent construct for dementia case-finding in Mexican-Americans. J Alzheimers Dis. 2013;37(1):89-97. doi: 10.3233/JAD-130353.

Reference Type BACKGROUND
PMID: 23800829 (View on PubMed)

Royall DR, Palmer RF. Ethnicity moderates dementia's biomarkers. J Alzheimers Dis. 2015;43(1):275-87. doi: 10.3233/JAD-140264.

Reference Type BACKGROUND
PMID: 25079802 (View on PubMed)

Royall DR, Palmer RF. Thrombopoietin is associated with delta's intercept, and only in Non-Hispanic Whites. Alzheimers Dement (Amst). 2016 Feb 26;3:35-42. doi: 10.1016/j.dadm.2016.02.003. eCollection 2016.

Reference Type BACKGROUND
PMID: 27239547 (View on PubMed)

Royall DR, Palmer RF, O'Bryant SE; Texas Alzheimer's Research and Care Consortium. Validation of a latent variable representing the dementing process. J Alzheimers Dis. 2012;30(3):639-49. doi: 10.3233/JAD-2012-120055.

Reference Type BACKGROUND
PMID: 22451315 (View on PubMed)

Salkovic-Petrisic M, Knezovic A, Osmanovic-Barilar J, Smailovic U, Trkulja V, Riederer P, Amit T, Mandel S, Youdim MB. Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease. Life Sci. 2015 Sep 1;136:108-19. doi: 10.1016/j.lfs.2015.06.026. Epub 2015 Jul 6.

Reference Type BACKGROUND
PMID: 26159898 (View on PubMed)

Other Identifiers

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HSC20160395H

Identifier Type: OTHER

Identifier Source: secondary_id

P30AG044271

Identifier Type: NIH

Identifier Source: org_study_id

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