EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To test the hypothesis that daily use of zinc-monocysteine (ZMC) supplement will be well tolerated and result in improved macular function in persons with dry age-related macular degeneration (AMD).

Inclusion Criteria:

Eligibility criteria included the presence of macular drusen with or without pigment changes as documented by dilated slit lamp biomicroscopy (90 diopter moncontact lens) and fluorescein angiography. Chronic open angle glaucoma with stable intraocular pressures and visual fields was allowed.

Exclusion Criteria:

Choroidal neovascular activity was an exclusion criterion along with any condition preventing a satisfactory view of the fundus. Diabetics and those who had any eye surgery other than cataract removal and intraocular lens implantation or any potentially confounding eye diseases were also excluded.

Description of Study Protocol:

Recruitment

All volunteer subjects gave informed consent after listening to a verbal presentation of the project, reading the description and consent form, having all questions answered and signing that form.

Design

Randomized, placebo-controlled clinical trial

Subjects were randomized using a 50% likelihood scheme with one group receiving the ZMC supplement and the other group receiving a placebo.

Blinding used

Masked trained examiners conducted the functional assessments.

Intervention

ZMC supplement or a placebo

Statistical Analysis

Functional analysis difference between follow-up and baseline were computed for acuity, contrast sensitivity and photorecovery times.
The primary analytic strategy tested right eyes and left eyes as separate groups which provided non-independent replication. This was warranted since the intervention was systematic.
To test for functional improvement, differences between placebo and ZMC treatment were analyzed by a one-sided unpaired t-test of paired differences between baseline and evaluation time-points of three and six months.

Data Collection Summary:

Timing of Measurements

Subjects were examined at baseline enrollment, a three-month follow-up and a six-month final exam.

Dependent Variables

Acuity
Contrast sensitivity
Photo recovery time.

Independent Variables

Zinc-monocysteine (ZMC) supplement or Placebo

Control Variables

Age
Ethnicity: White or African American
Gender: Male or female
Macular drusen: Small <75 microns, medium <125 microns or RPE detachment >250 microns
Geographic atrophy: Any within one disc diameter of fovea.

Description of Actual Data Sample:

Initial N: 80, with 40 in each group
Attrition (final N): 74 with 37 in each group
Age:
- Placebo Group: 73.3+9.5
- ZMC Group: 72.1+11.7
Ethnicity:
- Placebo Group: 31 White and six African American
- ZMC Group: 29 White and eight African American
Other relevant demographics:
- Placebo Group: Eight male, 29 female
- ZMC Group: Seven male and 30 female
Anthropometrics:

	Placebo Group	ZMC Group
Macular drusen
Small <75 microns	37	37
Medium <125 microns	6	5
RPE detachment >250 microns	4	2
Geographic atrophy (any) within one disc diameter of fovea	7	4

Location: New Orleans, LA.

Summary of Results:

The ZMC supplement group showed significantly improved functional scores in each category in comparison with the placebo group. The following charts show the results for the ZMC supplement group:

Increase in Visual Acuity

	Left Eye	P Value	Right Eye	P Value
3 Months	No Improvement	N/A	Improvement	P=0.0024
6 Months	Improvement	P<0.0001	Improvement	P<0.0001

Improvement in Contrast Sensitivity

	Left Eye	P Value	Right Eye	P Value
3 Months	No Improvement	N/A	Improvement	P=0.0239
6 Months	Improvement	P<0.0001	Improvement	P<0.0001

Shortened Photorecovery Time

	Left Eye	P Value	Right Eye	P Value
3 Months	Improvement	P=0.0001	Improvement	P<0.0001
6 Months	Improvement	P<0.0001	Improvement	P<0.0001

The placebo group showed no functional loss
ZMC appeared to be well tolerated as only one of the of the 40 originally enrolled subjects experienced gastrointestinal complaints definitely attributable to ZMC consumption.

Author Conclusion:

ZMC administration was well tolerated by mouth and in comparison with the effects of placebo, conferred significant improvement in macular function in persons with vision loss from AMD. Other studies in progress suggest that ZMC is beneficial compared to zinc alone. Considering the challenges posed by the nature of our food supply in the 21st century, improved therapeutic supplements will likely play important roles in treating chronic neurodegenerative diseases such as AMD, as well as supporting general health.

Funding Source:

Not-for-profit

Retinal Disease Research Foundation, Inc.

Foundation associated with industry:

Other:

Reviewer Comments:

The subjects may not have been a representative sample of the relevant population, as there were more women than men in the study
Although, multivitamin (MVI) usage was addressed (co-intervention), extra or unplanned treatments were not described, other factors were not accounted for that could affect outcomes and multivariate analysis was not used to account for confounding factors. All subjects in the study except three in Group 1 and four in Group 2 were taking a daily MVI prior to starting the study. Those taking an MVI continued its use throughout the study.
There was not a discussion of the study limitations; although it was mentioned that it was unknown whether maximal improvement in the efficacy variables was achieved since the current study was for six months. The steepness of the measurements between time-points suggests further improvement may be realized if treatment duration is extended, but additional intervention studies would be needed.
Conflict of interest likely exists as the study author, David A. Newsome co-owns the US patents on ZMC, licensed to Pipex pharmaceuticals.

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?	???
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.)	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%.)	Yes
	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?		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)?	No
	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?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		No
	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?		No
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	No