Trial of Novel Oral Zinc Cysteine Preparation in Alzheimer's Disease

Study Overview
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Brief Summary
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This trial aims to test the hypothesis that 1) a single dose of zinc cysteine in a proprietary gastro-retentive form will produce sustained blood levels of zinc giving a larger bioavailable amount of zinc than an FDA approved preparation of inorganic zinc acetate; and 2) that the zinc cysteine gastro-retentive, sustained-release preparation will be better tolerated with significantly less gastrointestinal side effects than the zinc acetate capsules. The trial also tests the hypothesis that, after 6 months of once daily administration, the zinc cysteine subjects will show reduced serum non-ceruloplasmin copper. Additionally, subjects will perform tests of mental function,including the dementia rating scale, the Mini Mental Status Examination and the ADAS-cognitive performance test aimed at Alzheimer's status assessment. Tests will be administered at baseline, 3 and 6 months, and the performance results compared. Care-giver assessments will also be noted.

Detailed Description
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This multi-center study aims to determine the pharmacokinetics and pharmacodynamics of a novel gastro-retentive, sustained-release zinc cysteine preparation on the blood and urine measures of copper and zinc balance in Alzheimer's disease and mild cognitive impairment. Data expected to be derived include tolerability of the novel preparation in comparison with oral inorganic zinc salt, and long-term effects on primarily blood-measured copper-zinc balance. The study design is that of a prospective, randomized, double blind placebo-controlled clinical trial, with a duration for individual subjects of 6 months. The study will be performed at a total of 3 sites, under the direction of a single principal investigator, with a sub-investigator. The statistical plan calls for a comparison of data from the two long-term parallel groups using ANOVA and other applicable techniques. In addition to blood parameters, mental function assessments obtained at baseline, 3 and 6 months will be evaluated statistically.

Official Title
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CopperProof-2: Prospective, Randomized, Double-Blind Placebo-Controlled Clinical Trial Comparing the Effects of a Novel Once-Daily Oral Zinc Cysteine Preparation on Zinc and Copper Parameters in Mild Cognitive Impairment and Alzheimer's Disease

Conditions
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Alzheimer's Disease, Mild Cognitive Impairment

Intervention / Treatment
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* Other: Gastro-retentive zinc cysteine tablet
* Other: Tablet identical physically to active comparator containing some lactose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Alzheimer's disease mild to moderate as diagnosed by standard clinical, functional and NINDA-ADRDA criteria Mild cognitive impairment diagnosed by standard clinical, functional and NINDA-ADRDA criteria All subjects able to swallow Tablets Subjects taking copper or zinc containing supplements must have a 30-day wash out before starting study materials Screening laboratory values either within normal limits or deemed not clinically significant by investigator Exclusion Criteria: Subjects or their study companions/care givers unable to give adequate informed consent Presence of a disease or condition known to affect biometal homeostasis Presence of psychosis, substance abuse or other major medical or neurological issues Presence of vascular dementia Clinically significant anemia at the time of the screening visit Current use of a decoppering drug such as trientine or penicillamine

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 90 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Gastro-retentive zinc cysteine tablet<br>Once daily administration by mouth of a gastro-retentive, sustained-release preparation of zinc cysteine with excipients, all G.R.A.S., with adequate water. | Other: Gastro-retentive zinc cysteine tablet<br>* Oral, one tablet, once daily with water for 6 months.<br>* Other names: Zinthionein ZC;|
| Placebo Comparator: Identical appearance of placebo with active comparator<br>Once daily administration of placebo of identical physical appearance to that of active comparator with similar amount of water. | Other: Tablet identical physically to active comparator containing some lactose<br>* Oral, once daily, with water, 6 months.<br>* Other names: Placebo Tablet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biometal levels will be measured in serum by atomic absorption spectrometry | Active comparator material orally administered will be associated with better tolerability than oral zinc acetate, and will produce a reduction in serum non-ceruloplasmin bound copper levels and an elevation in serum zinc levels | 6 to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum zinc levels after oral administration of two different zinc-containing compounds and placebo will be determined by atomic absorption spectrometry | The change in serum zinc levels over time after oral administration of the active comparator of the study as well as the placebo and for certain subjects an inorganic zinc salt will be compared | 3 months | 
| Comparison of mental status functions at baseline, 3 and 6 months in active comparator versus placebo groups. | All subjects will perform standard and standardized tests of mental function, ranging from a general dementia rating scale (Mini Mental Status Exam) to more Alzheimer's specific tests (ADAS-cognitive). Daily living and caregiver assessments of overall daily functioning will be noted. Test results will be compared statistically in a two-point fashion, and correlated with biometal ststus. | 6 to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, Mild Cognitive Impairment, Copper metabolism, Zinc metabolism, Ceruloplasmin