Omalizumab for the Treatment of Multiple Food Allergies
BACKGROUND: Food allergies are common and are associated with substantial morbidity; the only approved treatment is oral immunotherapy for peanut allergy. METHODS: In this trial, we assessed whether omalizumab, a monoclonal anti-IgE antibody, would be effective and safe as monotherapy in patients with multiple food allergies. Persons 1 to 55 years of age who were allergic to peanuts and at least two other trial-specified foods (cashew, milk, egg, walnut, wheat, and hazelnut) were screened. Inclusion required a reaction to a food challenge of 100 mg or less of peanut protein and 300 mg or less of the two other foods. Participants were randomly assigned, in a 2:1 ratio, to receive omalizumab or placebo administered subcutaneously (with the dose based on weight and IgE levels) every 2 to 4 weeks for 16 to 20 weeks, after which the challenges were repeated. The primary end point was ingestion of peanut protein in a single dose of 600 mg or more without dose-limiting symptoms. The three key secondary end points were the consumption of cashew, of milk, and of egg in single doses of at least 1000 mg each without dose-limiting symptoms. The first 60 participants (59 of whom were children or adolescents) who completed this first stage were enrolled in a 24-week open-label extension. RESULTS: Of the 462 persons who were screened, 180 underwent randomization. The analysis population consisted of the 177 children and adolescents (1 to 17 years of age). A total of 79 of the 118 participants (67%) receiving omalizumab met the primary end-point criteria, as compared with 4 of the 59 participants (7%) receiving placebo (P<0.001). Results for the key secondary end points were consistent with those of the primary end point (cashew, 41% vs. 3%; milk, 66% vs. 10%; egg, 67% vs. 0%; P<0.001 for all comparisons). Safety end points did not differ between the groups, aside from more injection-site reactions in the omalizumab group. CONCLUSIONS: In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT03881696. opens in new tab.) https://doi.org/10.1056/NEJMoa2312382
Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy
Background: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. Methods: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. Results: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. Conclusions: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).
https://doi.org/10.1056/NEJMoa2212895
Primary prevention of cardiovascular disease with a mediterranean diet supplemented with extra-virgin olive oil or nuts.
BACKGROUND: Observational cohort studies and a secondary prevention trial have shown inverse associations between adherence to the Mediterranean diet and cardiovascular risk. METHODS: In a multicenter trial in Spain, we assigned 7447 participants (55 to 80 years of age, 57% women) who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was a major cardiovascular event (myocardial infarction, stroke, or death from cardiovascular causes). After a median follow-up of 4.8 years, the trial was stopped on the basis of a prespecified interim analysis. In 2013, we reported the results for the primary end point in the Journal. We subsequently identified protocol deviations, including enrollment of household members without randomization, assignment to a study group without randomization of some participants at 1 of 11 study sites, and apparent inconsistent use of randomization tables at another site. We have withdrawn our previously published report and now report revised effect estimates based on analyses that do not rely exclusively on the assumption that all the participants were randomly assigned. RESULTS: A primary end-point event occurred in 288 participants; there were 96 events in the group assigned to a Mediterranean diet with extra-virgin olive oil (3.8%), 83 in the group assigned to a Mediterranean diet with nuts (3.4%), and 109 in the control group (4.4%). In the intention-to-treat analysis including all the participants and adjusting for baseline characteristics and propensity scores, the hazard ratio was 0.69 (95% confidence interval [CI], 0.53 to 0.91) for a Mediterranean diet with extra-virgin olive oil and 0.72 (95% CI, 0.54 to 0.95) for a Mediterranean diet with nuts, as compared with the control diet. Results were similar after the omission of 1588 participants whose study-group assignments were known or suspected to have departed from the protocol. CONCLUSIONS: In this study involving persons at high cardiovascular risk, the incidence of major cardiovascular events was lower among those assigned to a Mediterranean diet supplemented with extra-virgin olive oil or nuts than among those assigned to a reduced-fat diet. (Funded by Instituto de Salud Carlos III, Spanish Ministry of Health, and others; Current Controlled Trials number, ISRCTN35739639 .).
Primary Prevention of Cardiovascular Disease with a Mediterranean Diet
Background Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events. Methods In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years. Results A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported. Conclusions Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government's Instituto de Salud Carlos III and others; Controlled-Trials.com number, ISRCTN35739639 .).
Vitamin E Consumption and the risk of coronary heart disease in women.
BACKGROUND. Interest in the antioxidant vitamin E as a possible protective nutrient against coronary disease has intensified with the recognition that oxidized low-density lipoprotein may be involved in atherogenesis. METHODS. In 1980; 87;245 female nurses 34 to 59 years of age who were free of diagnosed cardiovascular disease and cancer completed dietary questionnaires that assessed their consumption of a wide range of nutrients; including vitamin E. During follow-up of up to eight years (679;485 person-years) that was 97 percent complete; we documented 552 cases of major coronary disease (437 nonfatal myocardial infarctions and 115 deaths due to coronary disease). RESULTS. As compared with women in the lowest fifth of the cohort with respect to vitamin E intake; those in the top fifth had a relative risk of major coronary disease of 0.66 (95 percent confidence interval; 0.50 to 0.87) after adjustment for age and smoking. Further adjustment for a variety of other coronary risk factors and nutrients; including other antioxidants; had little effect on the results. Most of the variability in intake and reduction in risk was attributable to vitamin E consumed as supplements. Women who took vitamin E supplements for short periods had little apparent benefit; but those who took them for more than two years had a relative risk of major coronary disease of 0.59 (95 percent confidence interval; 0.38 to 0.91) after adjustment for age; smoking status; risk factors for coronary disease; and use of other antioxidant nutrients (including multi-vitamins). CONCLUSIONS. Although these prospective data do not prove a cause-and-effect relation; they suggest that among middle-aged women the use of vitamin E supplements is associated with a reduced risk of coronary heart disease. Randomized trials of vitamin E in the primary and secondary prevention of coronary disease are being conducted; public policy recommendations about the widespread use of vitamin E should await the results of these trials.
Effect of walnuts on serum lipid levels and blood pressure in normal men.
BACKGROUND. In a recent six-year follow-up study; we found that frequent consumption of nuts was associated with a reduced risk of ischemic heart disease. To explore possible explanations for this finding; we studied the effects of nut consumption on serum lipids and blood pressure. METHODS. We randomly placed 18 healthy men on two mixed natural diets; each diet to be followed for four weeks. Both diets conformed to the National Cholesterol Education Program Step 1 diet and contained identical foods and macronutrients; except that 20 percent of the calories of one diet (the walnut diet) were derived from walnuts (offset by lesser amounts of fatty foods; meat; and visible fat [oils; margarine; and butter]). RESULTS. With the reference diet; the mean (+/- SD) serum values for total; low-density lipoprotein (LDL); and high-density lipoprotein (HDL) cholesterol were; respectively; 182 +/- 23; 112 +/- 16; and 47 +/- 11 mg per deciliter (4.71 +/- 0.59; 2.90 +/- 0.41; and 1.22 +/- 0.28 mmol per liter). With the walnut diet; the mean total cholesterol level was 22.4 mg per deciliter (0.58 mmol per liter) lower than the mean level with the reference diet (95 percent confidence interval; 28 to 17 mg per deciliter [0.72 to 0.44 mmol per liter]); the LDL and HDL cholesterol levels were; respectively; 18.2 mg per deciliter (0.47 mmol per liter) (P < 0.001) and 2.3 mg per deciliter (0.06 mmol per liter) (P = 0.01) lower. These lower values represented reductions of 12.4; 16.3; and 4.9 percent in the levels of total; LDL; and HDL cholesterol; respectively. The ratio of LDL cholesterol to HDL cholesterol was also lowered (P < 0.001) by the walnut diet. Mean blood-pressure values did not change during either dietary period. CONCLUSIONS. Incorporating moderate quantities of walnuts into the recommended cholesterol-lowering diet while maintaining the intake of total dietary fat and calories decreases serum levels of total cholesterol and favorably modifies the lipoprotein profile in normal men. The long-term effects of walnut consumption and the extension of this finding to other population groups deserve further study.
Vitamin E consumption and the risk of coronary heart disease in men.
BACKGROUND. The oxidative modification of low-density lipoproteins increases their incorporation into the arterial intima; an essential step in atherogenesis. Although dietary antioxidants; such as vitamin C; carotene; and vitamin E; have been hypothesized to prevent coronary heart disease; prospective epidemiologic data are sparse. METHODS. In 1986; 39;910 U.S. male health professionals 40 to 75 years of age who were free of diagnosed coronary heart disease; diabetes; and hypercholesterolemia completed detailed dietary questionnaires that assessed their usual intake of vitamin C; carotene; and vitamin E in addition to other nutrients. During four years of follow-up; we documented 667 cases of coronary disease. RESULTS. After controlling for age and several coronary risk factors; we observed a lower risk of coronary disease among men with higher intakes of vitamin E (P for trend = 0.003). For men consuming more than 60 IU per day of vitamin E; the multivariate relative risk was 0.64 (95 percent confidence interval; 0.49 to 0.83) as compared with those consuming less than 7.5 IU per day. As compared with men who did not take vitamin E supplements; men who took at least 100 IU per day for at least two years had a multivariate relative risk of coronary disease of 0.63 (95 percent confidence interval; 0.47 to 0.84). Carotene intake was not associated with a lower risk of coronary disease among those who had never smoked; but it was inversely associated with the risk among current smokers (relative risk; 0.30; 95 percent confidence interval; 0.11 to 0.82) and former smokers (relative risk; 0.60; 95 percent confidence interval; 0.38 to 0.94). In contrast; a high intake of vitamin C was not associated with a lower risk of coronary disease. CONCLUSIONS. These data do not prove a causal relation; but they provide evidence of an association between a high intake of vitamin E and a lower risk of coronary heart disease in men. Public policy recommendations with regard to the use of vitamin E supplements should await the results of additional studies.