New statistical approach shows that hydroxy-methionine is noninferior to DL-Methionine in 35-day-old broiler chickens.

The efficacy of a new molecule is assessed in the pharmaceutical industry through noninferiority tests to establish that it is not unacceptably less efficient than the reference. This method was proposed to compare DL-Methionine (DL-Met) as reference and DL-Hydroxy-Methionine (OH-Met) as alternative, in broiler chickens. The research hypothesized that OH-Met is inferior to DL-Met. Noninferiority margins were determined using 7 datasets comparing broiler growth response between a sulfur amino acid deficient and adequate diet from 0 to 35 d. The datasets were selected from the literature and internal records of the company. The noninferiority margins were then fixed as the largest loss of effect (inferiority) acceptable when OH-Met is compared to DL-Met. Three corn/soybean meal-based experimental treatments were offered to 4,200 chicks (35 replicates of 40 birds). Birds received from 0 to 35 d 1) a negative control diet deficient in Met and Cys; the negative control treatment supplemented on equimolar basis with 2) DL-Met or 3) OH-Met in amounts allowing to reach Aviagen Met+Cys recommendations. The three treatments were adequate in all other nutrients. Growth performance, which was analysed with one-way ANOVA, showed no significant difference between DL-Met and OH-Met. The supplemented treatments improved (P < 0.0001) the performance parameters compared to the negative control. The lower limits of the confidence intervals of the difference between means for the feed intake [-1.34; 1.41], body weight [-57.3; 9.8] and daily growth [-1.64; 0.28], did not exceed the noninferiority margins. This demonstrates that OH-Met was non-inferior to DL-Met.

The treatment of missing data in a large cardiovascular clinical outcomes study.

BACKGROUND: The potential impact of missing data on the results of clinical trials has received heightened attention recently. A National Research Council study provides recommendations for limiting missing data in clinical trial design and conduct, and principles for analysis, including the need for sensitivity analyses to assess robustness of findings to alternative assumptions about the missing data. A Food and Drug Administration advisory committee raised missing data as a serious concern in their review of results from the ATLAS ACS 2 TIMI 51 study, a large clinical trial that assessed rivaroxaban for its ability to reduce the risk of cardiovascular death, myocardial infarction or stroke in patients with acute coronary syndrome. This case study describes a variety of measures that were taken to address concerns about the missing data. METHODS: A range of analyses are described to assess the potential impact of missing data on conclusions. In particular, measures of the amount of missing data are discussed, and the fraction of missing information from multiple imputation is proposed as an alternative measure. The sensitivity analysis in the National Research Council study is modified in the context of survival analysis where some individuals are lost to follow-up. The impact of deviations from ignorable censoring is assessed by differentially increasing the hazard of the primary outcome in the treatment groups and multiply imputing events between dropout and the end of the study. Tipping-point analyses are described, where the deviation from ignorable censoring that results in a reversal of significance of the treatment effect is determined. A study to determine the vital status of participants lost to follow-up was also conducted, and the results of including this additional information are assessed. RESULTS: Sensitivity analyses suggest that findings of the ATLAS ACS 2 TIMI 51 study are robust to missing data; this robustness is reinforced by the follow-up study, since inclusion of data from this study had little impact on the study conclusions. CONCLUSION: Missing data are a serious problem in clinical trials. The methods presented here, namely, the sensitivity analyses, the follow-up study to determine survival of missing cases, and the proposed measurement of missing data via the fraction of missing information, have potential application in other studies involving survival analysis where missing data are a concern.

Monitoring the randomized trials of the Women's Health Initiative: the experience of the Data and Safety Monitoring Board.

Data Safety Monitoring Committees (DSMB) for large, long-term randomized trials of agents in common use face challenging problems especially when the emerging data indicate unanticipated effects. The DSMB for the Women's Health Initiative Clinical Trials, on observing early indication of a surprising adverse cardiovascular effect of post-menopausal hormones, spent several years deliberating what recommendations it should make. This paper describes the dilemmas faced by the DSMB and the considerations it made over the course of its existence. The paper concludes with some recommendations for other DSMBs.

Glucose and insulin responses to dietary chromium supplements: a meta-analysis.

BACKGROUND: Several authors, mostly on the basis of nonrandomized studies, have suggested dietary trivalent chromium supplementation as an attractive option for the management of type 2 diabetes and for glycemic control in persons at high risk of type 2 diabetes. OBJECTIVE: The study aimed to determine the effect of chromium on glucose and insulin responses in healthy subjects and in individuals with glucose intolerance or type 2 diabetes. DESIGN: The study design was a systematic review and meta-analysis of randomized clinical trials (RCTs). RESULTS: The authors identified 20 reports of RCTs assessing the effect of chromium on glucose, insulin, or glycated hemoglobin (Hb A(1c)). This review summarizes data on 618 participants from the 15 trials that reported adequate data: 193 participants had type 2 diabetes and 425 were in good health or had impaired glucose tolerance. The meta-analysis showed no association between chromium and glucose or insulin concentrations among nondiabetic subjects. A study of 155 diabetic subjects in China showed that chromium reduced glucose and insulin concentrations; the combined data from the 38 diabetic subjects in the other studies did not. Three trials reported data on Hb A(1c): one study each of persons with type 2 diabetes, persons with impaired glucose tolerance, and healthy subjects. The study of diabetic subjects in China was the only one to report that chromium significantly reduced Hb A(1c). CONCLUSIONS: Data from RCTs show no effect of chromium on glucose or insulin concentrations in nondiabetic subjects. The data for persons with diabetes are inconclusive. RCTs in well-characterized, at-risk populations are necessary to determine the effects of chromium on glucose, insulin, and Hb A(1c).