EAL

NNNS: Behavior Changes, Cognitive Function and Moods (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine aspartame's effect at two dose levels over several months on cognitive function, EEGs and biochemical parameters in PKUH (heterozygotes for PKU).

Inclusion Criteria:

Heterozygotes for PKU whose carrier status had been proven by DNA analysis.

Exclusion Criteria:

Subjects with PKU
Concomitant illness and medication that would interfere with results
Taking of an investigational medication within 30 days prior to the study
Positive pregnancy test.

Description of Study Protocol:

Recruitment

Subjects were known to research group.
Methods not identified.

Design

Randomized controlled crossover trial.

Blinding Used

Double-blind.

Intervention

Aspartame ingestion at low and high doses and placebo.

Statistical Analysis

Quantitative variables, including error rate and response time variables from the SVAT tests, EEG spectral data, organic acids in urine and amino acid levels in plasma, were subjected to ANOVA appropriate for a crossover study.
No adjustment was made for the large number of statistical tests.
Statistical significance as assumed at a P-value of 0.05.
All pairwise tests are two-tailed.
Statistical tests for within-subject differences in the clinical EEG evaluations and the occurrence of adverse effects were done by the exact form of McNemar's test.

Data Collection Summary:

Timing of Measurements

Aspartame or placebo ingested for 12 weeks.
Computerized battery of neuropsychological tests administered and samples for plasma amino acids and urinary organic acids collected at Baseline Weeks -2 and -1 and during treatment at Weeks Six, 12, 18 and 24.

Dependent Variables

Cognitive function through computerized cognitive test battery
Electroencephalograms (EEGs) evaluated by conventional and spectral analysis at Baseline Week -1 and treatment Weeks 12 and 24
Biochemical parameters from blood and urine samples.

Independent Variables

Aspartame at either 15mg/kg or 45mg per kg body weight or placebo as capsules for 12 weeks
Compliance checked through phone calls and capsule counting.

Description of Actual Data Sample:

Initial N

49 adults (22 men and 27 women).
24 subjects (nine men and 15 women) randomized to receive 45mg/kg dose and 25 subjects (13 men and 12 women) randomized to receive 15mg/kg dose.

Attrition (Final N)

48 adults (21 men and 27 women).
One subject dropped out due to inability to complete the neuropsychological tests successfully.

Age

15mg/kg group: Mean age 37±1.77 years
45mg/kg group: Mean age 36.7±1.94 years.

Ethnicity

Not mentioned.

Other Relevant Demographics

Not mentioned.

Location

Germany.

Summary of Results:

	Aspartame 15mg/kg	Placebo	P-Value	Aspartame 45mg/kg	Placebo	P-Value
Phenylalanine: One hour post-dose	95.4±21.01	95.6±30.48	0.97	116.9±29.48	90.4±21.23	<0.01
Phenylalanine: Three hours post-dose	94.1±26.38	95.4±30.15	0.84	112.5±40.30	88.7±22.36	<0.01
Phe/LNAA: One hour post-dose	0.166±0.023	0.154±0.030	0.06	0.207±0.034	0.162±0.026	<0.01
Phe/LNAA: Three hours post-dose	0.168±0.027	0.162±0.033	0.32	0.207±0.039	0.158±0.022	<0.01
Tyrosine/LNAA: One hour post-dose	0.107±0.022	0.106±0.025	0.75	0.107±0.021	0.106±0.019	0.75
Tyrosine/LNAA: Three hours post-dose	0.095±0.039	0.087±0.030	0.59	0.097±0.052	0.094±0.036	0.59

Other Findings

There were no significant differences in mild adverse effects when aspartame was compared with placebo
Regular phone calls and capsule-counting revealed excellent compliance (mean>96%, range 88-102%)
The results of the neuropsychological tests demonstrated that aspartame had no effect on cognitive function
Plasma phenylalanine significantly increased, within the normal range for PKUH, at one and three hours following the morning dose of 45mg per kg of body weight (aspartame only)
There were no significant differences in the conventional or spectral EEG analyses, urinary organic acid concentrations and adverse experiences when aspartame was compared with placebo
Statistical analysis of the neuropsychological data resulted in 230 significance tests of treatment and only eight of them (3%) revealed significant differences, which is less than might be expected by chance. Since all significant results were found in the low-dose group, a lack of treatment effect is further supported.

Author Conclusion:

In conclusion, this study reaffirms the safety of aspartame or corresponding phenylalanine loads from any dietary source in PKU heterozygotes and refutes the speculation that aspartame affects cognitive performance, EEGs and urinary organic acids when ingested in doses up to 20 times the current level of aspartame consumption.

Funding Source:

Reviewer Comments:

96% compliance checked with phone calls and capsule-counting.

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.)	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?	Yes
	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)?	N/A
	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?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
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