EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The primary objective of this research was to examine the effects of oral supplementation with three different doses of lutein (2.5, 5 and 10mg) on the serum lutein concentration in patients with Age-Related Macular Degeneration (AMD) of various severities.

The secondary objective was to investigate the relationship between lutein absorption, AMD severity and macular pigment density.

Inclusion Criteria:

Participants with no AMD, large drusen or advanced AMD
Over aged 60.

Exclusion Criteria:

No exclusion criteria was specified.

Description of Study Protocol:

Recruitment

No information on recruitment of participants was provided

Design

Randomized clinical trial

Participants were equally stratified at baseline into three categories based on the level of AMD severity: small or no drusen, large drusen, and advanced AMD in at least one eye. Within each stratum, 15 participants were randomized into three groups of five each, with each group receiving one of three doses of lutein for a six-month supplementation period. Participants were observed for an additional six months after supplementation was stopped. Participants returned at one week, one month, and three months, six months, nine months, and 12 months after baseline. Fasting blood samples were drawn at each study visit. Information on dietary sources of lutein were collected from a food frequency questionnaire at each visit based on the Minnesota Nutritional Coordinating Center. Complete opthalmic exams were performed at each visit, including manifest refraction, visual acuity measurements, and visual field, and optical densities were measured.

Data about adverse effects of supplementation were measured by visual acuity, comprehensive opthalmic exams, fundus photography, liver function tests, visual field tests, and the Age-Related Eye Disease Study (AREDS) side-effects questionnaire.

Blinding used

Blood samples were blinded at the CDC lab so those analyzing the results did not know which group the samples were from.

Intervention

Lutein supplements in one of three doses: 2.5mg per day, 5mg per day, and 10mg per day for six months.

Statistical Analysis

The generalized estimating equation method was applied to investigate the trends and variations of serum concentrations of lutein measured over the six-month supplementation period. The analysis of variance method was used for testing whether mean changes in visual acuities differed among the three dose arms. Models for each outcome was searched by a backward variable selection of disease severity, age, gender, smoking history, alcohol status, and other sources of lutein and zeaxanthin intakes, body mass index, and duration of supplementation.

Data Collection Summary:

Timing of Measurements

Supplementation with lutein began one week after the baseline visit and continued for six months. Participants returned for follow-up visits at one, three, six, nine and 12 months.

Dependent Variables

Serum lutein concentration as measured using a modification of a routine HPLC method
Serum carotenoids as measured using a modification of a routine HPLC method
Serum zeaxanthin as measured using a modification of a routine HPLC method
Macular pigment density as measured by heterochromatic flicker photometry
AMD severity as measured by a complete ophthalmic exam that included manifest refraction, visual acuity measurements and visual field.

Independent Variables

Supplemental lutein (dose of 2.5mg per day, 5mg per day or 10mg per day).

Control Variables

Description of Actual Data Sample:

Initial N: 45 adults over 60 years of age
- 33 women
- 12 men
Attrition (final N): One participant was lost due to meningioma, making the final n=44
Age: Participants ranged in age from 60 to 91 years (mean=71 years)
Ethnicity:
- 40 participants were Caucasian
- Two Asian
- Two African American
Other relevant demographics: No data was collected on education level or SES
Anthropometrics: BMI was collected at baseline and mean BMI ranged from a low of 25.3±3.6 (those who received 5.0mg of lutein) to a high of 27.1±5.4 (those who received 10mg of lutein). The range of BMI for the entire group at baseline was not reported.
Location: United States.

Summary of Results:

Key Findings

During the six-month period of lutein supplementation, serum concentrations of lutein in all participants rose with increasing doses of lutein, regardless of AMD severity status
The highest lutein dose (10mg) led to a four-fold increase in serum lutein concentration
The authors were unable to demonstrate increases in macular pigment corresponding to increases in serum lutein concentrations because the measurements of macular pigments were not reproducible.

Summary Statistics of Serum Concentrations of Lutein

	Dose 2.5mg	Dose 5.0mg	Dose 10.0mg	AMD Small or no drusen	AMD Large drusen	AMD Advanced AMD
Baseline	20.0±5.8	9.0±7.4	19.0±9.2	20.6±9.0	20.5±7.5	16.9±5.0
Month 1	34.1±11.8	48.9±16.5	75.8±18	51.5±26.3	55.0±15.0	53.6±28.4
Month 3	41.0±15.5	54.2±15.7	84.3±25.0	60.6±30.3	59.5±16.8	59.5±31.0
Month 6	37.1±12.6	56.9±22.7	80.3±48.5	64.8±52.0	55.2± 20.6	52.4±25.8
Month 9	20.9±7.9	24.9±13.9	21.9±10.0	20.2±7.4	28.2±15.1	18.9±4.7
Year 1	19.6±7.4	19.3±8.0	21.8±11.7	21.7±8.1	23.0±11.5	15.5±5.8

Comparison of Increases in Serum Concentrations Adjusted for Age and Duration of Oral Supplementation

Relative Increase	Estimate	95% CI Lower Limit	95% CI Upper Limit	P
10mg vs. 2.5mg	2.366	1.877	2.984	<0.0001
5mg vs. 2.5mg	1.554	1.232	1.959	0.0002
10mg vs. 5mg	1.523	1.177	1.971	0.0014

Visual Acuity by Dose Group

Dose	2.5mg	5mg	10mg	P
Baseline (mean/median)	75.5/80	68.7/83	70.6/81	0.56
Changes (letters) from baseline
Month 1	1.0/0	0.8/1	0.8/0	0.98
Month 6	0.5/2	0.9/1	1.7/1	0.65
Month 9	0.6/1	-1.2/0	0.4/0	0.37

Other Findings

Disease severity, age, gender, smoking history, alcohol status, other sources of lutein and zeaxanthin intakes and BMI were not significantly associated with the increase in serum lutein concentration
No adverse effects of lutein supplementation were noted based on an AREDS side-effects questionnaire, tests of visual function, and liver function tests.

Author Conclusion:

The authors conclude that increasing doses of lutein supplements significantly increased the serum levels of lutein and zeaxanthin. However, they were unable to draw a conclusion about increases in macular pigmentations corresponding to increases in serum lutein concentrations.

Funding Source:

Government:

National Eye Institute, National Institutes of Health, Centers for Disease Control and Prevention

Industry:

Pfizer Pharmaceuticals

University/Hospital:

Florida International University, University of Maryland

Reviewer Comments:

Small numbers of subjects in groups; the target population and setting were not specified
Recruitment of participants was not described
Exclusion factors were not described
It is unclear if the participants had risk factors, family history of vision problems, or other vision problems such as cataracts or glaucoma
The method of randomization was not described.

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?		No
	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?	No
	2.2.	Were criteria applied equally to all study groups?	???
	2.3.	Were health, demographics, and other characteristics of subjects described?	No
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
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)	No
	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.)	No
	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?	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?	No
	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?	No
	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?	No
	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?		???
	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