EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To measure the change from baseline in visual function-Best-Corrected Visual Acuity (BCVA) via the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, contrast sensitivity, central 10 degree visual fields and retinal imaging (angiograms and photographs) at six months in subjects with atrophic (dry) age-related macular degeneration (AMD) treated with a targeted nutritional supplement.

Inclusion Criteria:

Have signed a written consent
Between ages 50 to 90
Inclusive of any race or gender
Have a diagnosis of nonexudative (dry) AMD in at least one eye having >10 large soft drusen 63μm in diameter within 3,000um of the fovea center documented on macular exam, retinal angiography and fundus photographs
Able to understand and comply with the requirements of the trial
BCVA in the trial eye(s) of 20/32 to 20/125 inclusive as measured by ETDRS (logMAR)
Must not have conditions that limit the view to the fundus and undergo Potential Acuity Meter testing if deemed necessary to determine study inclusion
Must agree to take only the nutritional supplement that is provided during the study
Be available for a minimum trial duration of approximately six months.

Exclusion Criteria:

Those currently enrolled in an ophthalmic clinical trial
Those with eyes with concomitant macular or choroidial disorders other than AMD with indefinite signs of AMD
Those with a diagnosis of exudative (wet) AMD with active subretinal neovascularization (SRNV) or CNV lesions requiring laser photocoagulation in the study eye
Those with significant ocular lens opacities causing vision decrease
Those with amblyopia, optic nerve disease, unstable glaucoma, history of retina-vitreous surgery, degenerative myopia, active posterior intraocular inflammatory disease, chronic use of topical ocular steroid medications, vasoproliferative retinopathies, rhegmatogenous retinal detachment and inherited macular dystropies
Those with demand type pacemakers or epilepsy
Those with uncontrolled hypertension
Those with a recent history of cerebral vascular disease
Those manifested with transient ischemic attacks or cerebral vascular accidents
Those with a history of AIDS
Those who have had an experimental procedure in either eye or used any investigational drug or treatment within 30 days prior to enrolling in the trial
Those who have had intraocular surgery in trial eye within three months prior to enrolling in the trial
Smoker or those using any tobacco.

Description of Study Protocol:

Recruitment

Conducted at five independent study sites

Design

Case-Control Study, Non-randomized Trial

Prospective, double blind, six-month trial where patients received a nutritional supplement and results were compared to a placebo cohort constructed from the literature that was matched for inclusion and exclusion criteria.

Blinding used

Double blind study

Intervention

Self-administered microcurrent treatment and nutritional supplementation. The microcurrent treatment (n=36) was found to have little significant effect on any of the efficacy endpoints and was abandoned. Only the results from the nutritional supplement aspect (n=37) of the study were reported.
Nutritional supplement contained 573% of the daily value for vitamin A, 753% for vitamin C, 667% for vitamin E, 464% for zinc oxide, and 80% for copper, as well as taurine, EPA and DHA omega-3 fatty acids, lutein and zeaxanthin.

Statistical Analysis

Sample size and power calculations were based on the primary efficacy endpoint
A paired t-test was used to test the null hypothesis with the average visual acuity (VA) score the same at baseline and follow-up
A two-sided alpha level of 0.05 was used to determine statistical significance.

Data Collection Summary:

Timing of Measurements

Each subject was scheduled for five visits between baseline and six months.

Dependent Variables

Primary objective: Change in BCVA from baseline to six months
Secondary efficacy variable: Objective signs of improved macular function
Primary safety variables: Unexpected ocular or systemic findings, adverse event rate, temporary and permanent discontinuation.

Independent Variables

Nutritional supplementation

Control Variables

Gender
Age
Ethnicity
Current smoker or former smoker
Family history of macular degeneration
Diabetes
Hypertension
Heart Disease
Cataract surgery
Refractive surgery
Glaucoma
Diabetic retinopathy
Mean baseline BCVA (log MAR).

Description of Actual Data Sample:

Initial N:
- Treatment group with microcurrent stimulation and nutritional supplementation: n=36,
- Treatment group with nutritional supplementation only: n=37
- Placebo Group n=15
Attrition (final N):
- Treatment group with nutritional supplementation only: n=37
- Placebo Group n=15
- Treatment group with microcurrent stimulation and nutritional supplementation was abandoned, since it had little significant effect on any of the efficacy endpoints
Age:
- Treatment group: 76.3±7.8
- Placebo Group 74.7±5.9
Ethnicity:
- Treatment group: 91.9% Caucasian, 2.7% African American, 2.7% Asian, 2.7% Hispanic
- Placebo Group: 100% Caucasian
Other relevant demographics:
Anthropometrics: Controls were matched for inclusion and exclusion criteria. Subjects in both groups were similar across age, gender, ethnicity and mean baseline BCVA.
Location: Five independent study sites, location not specified.

Summary of Results:

The mean change from baseline in ETDRS BCVA (logMAR) was calculated at three and six months:

While the placebo arm experienced a negative mean ETDRS line change of 1.49 lines at six months (loss of VA), the treatment group demonstrated a positive mean ETDRS line change of 0.54 lines at six months (gain in VA)
The mean logMAR line difference between the treatment and placebo-control groups was 2.03 lines at six months postbaseline
A continual improvement in BCVA (logMAR) over time was demonstrated in the treatment group, while overall, the placebo arm continued to lose VA over time
At six months, of those in the treatment arm, 56.7% experienced improved BCVA (logMAR), 20% maintained their BCVA (logMAR) and 23.3% experienced worsened BCVA (logMAR). Overall, 76.7% of patients improved or maintained their BCVA (logMAR) with the TOZAL nutritional supplementation.

Statistical findings:

The average (SD) VA score was 0.409 (0.196) vs. 0.355 (0.184) for baseline and follow-up respectively, t= -2.09; df=33; P=0.045
The average increase in VA was 0.0541 and the 95% confidence interval increase was (-0.107, -0.0013).

Other Findings

The following secondary outcomes were found:

Fluorescein angiogram, retinal photographs, contrast sensitivity, full-threshold visual fields, macular testing (central 10° threshold visual field) and the Visual Function Questionnaire-25 (VFQ-25) were found to have little significant change at six months.

Author Conclusion:

This study confirms previously published reports on the direction and magnitude of improved visual acuity in dry AMD. Improvement in other visual function parameters was not found likely due to the short duration of the study. The Age-Related Eye Disease Study (AREDS) II trial will follow a qualitatively similar supplement as TOZAL. The results of this study support the potential for positive visual outcomes in the AREDS II trial. Microcurrent stimulation cannot be completely dismissed with or without supplementation as all available methods of stimulation were not evaluated. Treatment based on dietary manipulation should continue to be pursued and refined as a simple, low-cost, effective therapy for AMD.

Funding Source:

Industry:

Atlantic Medical, Inc.

Other:

Reviewer Comments:

The author noted the following issues for specific nutrients regarding nutritional supplementation and AMD, but did not discuss limitations of this particular study, such as the fact that dietary intake was not measured.

Several studies have suggested that supplement beta-carotene increases lung cancer risks in heavy smokers. Increased intake of foods rich in beta-carotene has not been shown to increase this risk.
Data links high doses of vitamin E with an increase in heart failure and also the chance of early death
In the AREDS study, participants receiving high dose zinc reported urinary tract problems and increased rates of anemia
One study found that lutein negatively affected beta-carotene absorption when the two are given together.

The TOZAL study supplement was designed to address these risks and issues.

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?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	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.)	Yes
	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?	N/A
	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?	Yes
	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?		Yes
	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?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments described?	No
	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?	No
	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?	Yes
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	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