EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To evaluate the efficacy of oral copper supplementation in the treatment of Alzheimer's disease.

Inclusion Criteria:

Written informed consent, as well as caregiver consent
Diagnosis of probable Alzheimer's disease, by means of NINCDS-ADRDA criteria
Mini Mental Status Examination score below 25
Receipt of five- to 10-mg dose donezepil for at least two months; all patients continued to receive donezepil during the study
Aged 50 to 80 years
Not able to bear children
Patients taking drugs for coexistent diseases.

Exclusion Criteria:

Patients with severe and unstable somatic diseases and patients with present or known history of alcohol, drug or medication abuse
Patients taking psychotropic drugs, "nootropics" or health food supplements.

Description of Study Protocol:

Recruitment

Recruitment methods not described.

Design

Randomized, placebo-controlled phase 2 clinical trial.

Blinding Used

Double-blind.

Intervention

Copper supplementation [Cu-(II)-orotate-dihydrate; eight mg Cu daily] or placebo for 12 months.

Statistical Analysis

Demographic variables, data on the course of the disease and clinical data at baseline were compared between groups with one-way ANOVA
Pearson's product moment correlations between differences and intervening variables were calculated
For dependent variables, Kolmogorov-Smirnov tests were used to test if there were significant deviations from the normality assumption
General linear model procedure was used to perform multivariate analyses of variance with repeated measures design.

Data Collection Summary:

Timing of Measurements

Efficacy evaluations were performed and blood samples analyzed at baseline and at Months Three, Six, Nine and 12.

Dependent Variables

Cognitive performance monitored with neuropsychological tests
- Alzheimer's Disease Assessment Scale
- Cognitive subscale
- Mini Mental Status Examination.
Blood samples analyzed for copper, zinc, liver enzymes and anti-mitochondrial antibodies
Standard adverse event reporting.

Independent Variables

Copper supplementation [Cu-(II)-orotate-dihydrate; eight mg Cu daily] or placebo for 12 months.

Control Variables

Sex
Age
Disease duration
Age at onset of the disease
Duration of education.

Description of Actual Data Sample:

Initial N

120 patients screened
68 subjects randomized: 33 in the Placebo Group; 35 in the Copper Group.

Attrition (Final N)

57 completed the 12-month trial: 28 in the Placebo Group; 29 in the Copper Group
Reasons for withdrawal were similar between groups, relating to withdrawal of consent, adverse events, non-compliance, failure to return and other reasons.

Mean Age

Placebo Group: 69.4±8.1 years
Copper Group: 69.6±6.6 years.

Ethnicity

Not reported.

Other Relevant Demographics

Not reported.

Anthropometrics

There were no significant mean differences for age, disease duration, age at onset of the disease, education and clock drawing test at baseline between groups. However, the Placebo Group had higher copper levels as compared to the Copper Group at baseline.

Location

Germany.

Summary of Results:

Key Findings

There were no significant differences in primary outcome measures between the Copper and the Placebo Group
Altogether, cognitive abilities worsened progressively in both groups.

Other Findings

In both groups, mean absolute levels of copper at baseline were within the age-related normative range and no treatment effect was observed on zinc and ceruloplasmin levels
The treatment was well tolerated and the dropout rate was not statistically different between groups
There were no obvious overall trends or clinically relevant differences between the two groups in vital signs, physical examination, hematological characteristics or biochemical analyses.

Author Conclusion:

The present clinical trial demonstrates that:

Long-term oral intake of eight mg copper can be excluded as a risk factor for Alzheimer's disease
Long-term oral intake of copper is well tolerated by Alzheimer's disease patients
Copper intake has no effect on the progression of Alzheimer's disease.

Funding Source:

University/Hospital:

Saarland University Medical Faculty

Not-for-profit

International Copper Association

Foundation associated with industry:

Reviewer Comments:

Recruitment methods not described
The Placebo Group had higher copper levels as compared to the Copper Group at baseline.
Compliance with oral copper supplementation not addressed and may be an issue with Alzheimer's disease patients
Dose and duration of copper supplementation may not have been sufficient to see an effect on cognitive function.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
3.	Were study groups comparable?		???
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	???
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	???
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	N/A
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		???
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	???
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	???
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	Yes
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	No
9.	Are conclusions supported by results with biases and limitations taken into consideration?		???
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	No
10.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes