NNNS: Adverse Effects (2011)
Garriga MM, Berkebile C, Metcalfe DD. A combined single-blind, double-blind, placebo-controlled study to determine the reproducibility of hypersensitivity reactions to aspartame. J Allergy Clin Immunol. 1991 Apr; 87 (4): 821-827.PubMed ID: 2013676
Determine the reproducibility of hypersensitivity reactions to aspartame.
- 18 to 65 years old
- Self-reported complaint of possible allergic nature to aspartame.
- Pregnant women
- Individuals with significant cardiovascular, neurologic, pulmonary, renal or GI disease were excluded.
- Done over 32 months; 61 screened by phone
- Advertised for individuals who thought they might be sensitive to aspartame: Four times in NIH record and five times in Washington Post Health Section
- Pooled local community of allergists and dermatologists and informed of protocol
- Alerted members of Washington, DC Allergy Society and Washington, DC Dermatology Group by direct mailing
- Announcements of protocol posted on bulletin boards at NIH and hospitals.
- Recruitment and selection process: 61 subjects were screened, 20 patients evaluated, 12 received single blind challenge
- 20 originally in aspartame sensitive group
- Patients who stated they were sensitive to aspartame
- Negative Controls: Normal and atopic volunteers who did not report sensitivity to aspartame.
Double-blinded after confirmed positive single challenge round.
- Single-bind challenge (increasing challenge from zero to 2,000mg)
- If positive response, subject had double-blind challenge (after wash-out period) with increasing aspartame dose or placebo tablets.
No statistical analysis, only subjective results reported with no data tables.
Timing of Measurements
30-minute intervals between doses (or intervals that exceeded the reaction time reported by history).
Adverse reactions included nausea, difficulty swallowing, vomiting, abdominal pain, diarrhea, abdominal distention, flatulence, urticaria, angioedema, pruritus, cutaneous flushing, eczema, rhinitis, asthma, hypotension, syncope and headache (headache only considered if reported within minutes to one hour, reproducible with each exposure). Positive challenge was defined as reproduction of historical complaint, obvious allergic reaction or increase in FEC of greater than 20%.
Aspartame challenge: Food-grade aspartame administered each 30 minutes with increasing doses (0mg, 10mg, 100mg, 500mg, 1,000mg and 2,000mg). Three subjects reported adverse reaction and returned two weeks later for double-blind, placebo-controlled challenge.
- Placebo: Lactose in opaque capsule
- Normal and Atopic individuals were challenged as control subjects
- Control N=11 (three men, eight women)
- Suspected aspartame sensitive group: N=20 (eight men, 12 women)
Attrition (Final N)
- Challenge group reduced to 12 as complaints of eight other subjects were not related to aspartame
- Control group remained N=11.
- 15 to 51 years old in suspected aspartame-sensitive patients evaluated in clinic but ages of those given challenges was not disclosed in the publication
- No age reported for 12 patients confirmed with sensitivity
- No age reported for 11 patients in control group without sensitivity.
Other Relevant Demographics
Not described except authors say participants were of similar age and education level.
Washington, DC area.
- One patient developed hives during single-blind challenge with two subsequent double-blind challenges negative
- One patient reported throat tightness during single-blind challenge
- No complaints during double-blind challenge
- Diet soda challenge: One patient reacted twice. This female patient reported feeling bloated and having abdominal distention. She did not react to regular soda but had the bloated/distention complaint at times when not exposed to aspartame.
- Nothing reproduced.
- No subject with a clearly reproducible adverse adverse reaction to aspartame was identified.
- Authors conclude that it is hard to recruit study subjects with a history of hypersensitivity reactions to aspartame in their geographical area.
- Those who think they are allergic to aspartame do not have reproducible reactions.
Severe limitations of recruiting this population in geographic area where study took place was discussed by the study authors.
Quality Criteria Checklist: Primary Research
|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|
|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?||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?||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?||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?||N/A|
|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?||N/A|
|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?||N/A|
|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?||N/A|
|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?||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?||No|
|10.2.||Was the study free from apparent conflict of interest?||Yes|