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D DeMets

Publications and source records attributed to D DeMets.

9 recordsLinked to original sources
PubMed1996

Approached to monitoring the results of long-term disease prevention trials: examples from the Women's Health Initiative.

We contrast monitoring therapeutic trials with monitoring prevention trails. We argue that in monitoring prevention trials one should place more emphasis on formally defined global measures of health, not simply on a single targeted disease, particularly when an intervention may reduce the incidence of some diseases but increase the incidence of others. We describe one approach, illustrated by the Women's Health Initiative. For each of several sets of hypothetical interim results ("scenarios"), members of the Data and Safety Monitoring Committee (DSMC) were asked whether they would continue or stop the trial. In parallel with this exercise, various statistical methods of monitoring that are based on (1) the primary targeted disease, (2) a combination of various disease outcomes, or (3) a mixture of both were applied to these scenarios. One objective was to find a statistical approach that mirrors the majority view of the DSMC. A second objective was to stimulate discussion among DSMC members in preparation for their task of monitoring the trial as the real data become available. We found that no single method fully matched the majority vote of the DSMC. However, a mixed approach requiring the primary outcome to be significant and the global index to be "supportive," with separate monitoring of adverse effects, corresponded with the majority vote quite well. This approach maintains the emphasis on the primary hypothesis while assuring that broader safety and ethical issues of multiple diseases are incorporated.

Bayes Theorem↗
PubMed1993

Data monitoring in the cardiac arrhythmia suppression trial.

OBJECTIVE: This report discusses practical aspects of data monitoring in a clinical trial which stopped ahead of schedule due to adverse findings. DESIGN: A review of the considerations and decisions made by the data-monitoring committee of the Cardiac Arrhythmia Suppression Trial (CAST), a randomized, double-blind clinical trial. PATIENTS: CAST consisted of men and women with a recent myocardial infarction, asymptomatic or minimally symptomatic ventricular arrhythmias, and reduced left ventricular ejection fraction. INTERVENTIONS: In CAST, 3 antiarrhythmic agents, encainide, flecainide, and moricizine, were compared against placebo. MAIN OUTCOME MEASURES: The main outcome measures in CAST were arrhythmic death and total mortality. RESULTS: CAST found the 3 agents to be harmful. Encainide and flecainide were stopped first. Subsequently, moricizine was discontinued ahead of schedule. CONCLUSIONS: The complexity of the study design and a midcourse protocol modification raise several data-monitoring issues not previously discussed. These include how to handle apparently dramatic yet unexpected results, the need for flexibility in modifying study design and goals, and the conflict between existing study data and both conventional wisdom and medical practice.

Anti-Arrhythmia Agents↗
PubMed1992

The Monitored Atherosclerosis Regression Study (MARS). Design, methods and baseline results.

OBJECTIVE: The Monitored Atherosclerosis Regression Study (MARS) was designed to evaluate the effect of cholesterol lowering by monotherapy with an HMG-CoA reductase inhibitor on progression/regression of atherosclerosis in subjects with angiographically documented coronary artery disease. The purpose of this paper is to present the design, methods, and baseline results of MARS. DESIGN: MARS is a prospective, randomized, double-blind, placebo-controlled trial with baseline, 2-year, and 4-year coronary angiography as well as carotid, brachial, and popliteal ultrasonography. SETTING: Outpatient clinics at the University of Southern California School of Medicine and the University of Wisconsin School of Medicine. SUBJECTS: Two hundred seventy participants of both sexes were recruited directly from the cardiac catheterization laboratory or by chart review of patients having undergone cardiac catheterization in the past. Subjects were considered eligible if they had angiographically demonstrable atherosclerosis in 2 or more coronary artery segments, unaltered by angioplasty, with at least 1 lesion > or = 50% but < 100% diameter stenosis (%S). The inclusion range for total cholesterol (TC) was between 190 and 295 mg/dL. Exclusion factors were: triglycerides > or = 500 mg/dL; premenopausal females; uncontrolled hypertension; diabetes mellitus; untreated thyroid disease; liver dysfunction; renal insufficiency; congestive heart failure; major arrhythmia; left ventricular conduction defects; or any life-threatening disease. INTERVENTION: Subjects were placed on a low-fat, low-cholesterol diet and either 40 mg b.i.d. lovastatin (Mevacor) or placebo. Randomization was stratified by sex, smoking status, and TC. MAIN OUTCOME MEASURES: Per-subject average change in %S as determined by quantitative coronary angiography (QCA) is the primary angiographic endpoint. Secondary endpoints are: categorical analyses of the proportion of subjects with progression; human panel reading of coronary angiograms; and change in minimum lumen diameter (MLD) in mm by QCA. Carotid, brachial, and popliteal ultrasonography is also being performed. RESULTS: The subjects randomized into MARS are 91.5% male with an age range of 37 to 67 years (mean age 57.9 years). For the cohort, baseline lipids are (mean +/- SD): TC, 231 +/- 24 mg/dL; low-density lipoprotein cholesterol (LDL-C) by ultracentrifugation, 153 +/- 24 mg/dL; LDL-C, by calculation, 157 +/- 23 mg/dL; high-density lipoprotein cholesterol (HDL-C), 43 +/- 10 mg/dL; and triglycerides, 160 +/- 73 mg/dL. There were no significant differences between treatment groups in baseline lipid levels or baseline angiographic characteristics. CONCLUSIONS: MARS baseline data show adequacy of randomization with comparability of lovastatin and placebo groups in demographic, lipid, and angiographic characteristics.

Adult↗
PubMed1988

Essential fatty acid deficiency in premature infants.

To better characterize essential fatty acid (EFA) deficiency in neonates, we assessed 63 premature infants by serial determinations of plasma fatty acids for the level of linoleic acid, the presence of an abnormal trienoic acid (5,8,11-eicosatrienoic acid [20:3 omega 9]), and the ratio of this compound to arachidonic acid, ie, the triene-tetraene ratio. The data indicated that at age 7 d, 67% of these infants had low plasma linoleic acid levels, 62% showed readily detectable 20:3 omega 9, and 44% had a high triene-tetraene ratio. Infants fed by age 2 d had a normal mean linoleate level at 7 d and none showed detectable 20:3 omega 9 by 10 d. In contrast, infants who were not fed until 7 d showed a very high incidence of abnormal fatty acid status. By maintaining a daily record of linoleate intake, we calculated from regression models that the average amount required to achieve normal fatty acid nutrition was 1.19 g.kg-1.d-1.

8,11,14-Eicosatrienoic Acid↗
PubMed1985

Phase I evaluation of a synthetic mutant of beta-interferon.

A synthetic mutant of beta-interferon, produced by recombinant DNA technology, was prepared with serine substituted for the naturally occurring cysteine at amino acid 17. This molecule, after purification to homogeneity, was evaluated in 23 patients with cancer for tolerated doses, safety, and pharmacokinetics. Each patient was begun on twice weekly administration, one dose i.m., then an identical dose i.v. Doses, escalated weekly, were tolerated by 9 of 12 patients at 100 X 10(6) units i.m., 11 of 14 patients at 100 X 10(6) units i.v., and 8 of 10 patients receiving i.v. doses of 200 X 10(6) units. Fever (greater than or equal to 38.9 degrees C), the commonest cause for ceasing dose escalation, occurred in 11 of 13 patients who developed limiting i.v. toxicity and 6 of 11 who developed limiting i.m. toxicity. Patients who did not have progressive cancer after completion of dose escalation received five consecutive daily doses at their maximum tolerated single dose by each route, i.m. and i.v. These two 5-day treatments were given without difficulty. All patients treated with 300 X 10(6) units or less, i.m. (n = 13) or i.v. (n = 10), were able to receive five daily doses without limiting toxicity. Peak serum titers occurred immediately after i.v. administration and declined in an exponential manner thereafter. Despite absence of measurable titers in serum after i.m. injection, fever and significant (P less than 0.05) depression of WBC and platelet counts, serum calcium, and serum cholesterol occurred (prestudy to maximum tolerated dose). An immunoglobulin antibody to beta-interferon, detected by enzyme-linked immunoabsorbent assay, developed in 17 of 23 patients. Neutralizing activity (titer 10(2] was found in only 1 of 23 patients. No immune-mediated sequelae (symptomatic or renal) were identified. Further Phase I and II trials with this molecule will determine whether it will prove to have a better therapeutic index or different spectrum of therapeutic activity from alpha-interferon or gamma-interferon.

Adult↗
PubMed1983

Inter-observer variation in refraction and visual acuity measurement using a standardized protocol.

Reproducible measures of refraction and visual acuity are necessary in clinical and population studies of eye diseases. Inter-observer differences in measurements of these parameters were evaluated using the Early Treatment of Diabetic Retinopathy Study (ETDRS) protocol. No clinically significant interobserver variation was found for refraction or visual acuity measurements between three observers. This study confirms that when standardized measurement procedures are used, observer differences as a source of variability in the data can be minimized.

Evaluation Studies as Topic↗
PubMed1981

How informed is informed consent? The BHAT experience.

In the Beta-blocker Heart Attack Trial (BHAT) a number of strategies were implemented to increase the probability of informed voluntary consent among survivors of an acute myocardial infarction. To evaluate the subjects' comprehension of the study, a bioethicist conducted in-depth home interviews with a random sample of 64 participants from 11 geographic areas. The great majority of respondents proved to be well informed about the study design, its scientific logic, and possible risks of the experimental drug. However, five subjects (8% of the sample) appeared to believe they were involved in a therapeutic program rather than a research project. The analysis of predictor variables indicates that education, race, and age were associated with the degree of respondent awareness of fundamental aspects of the trial.

Adrenergic beta-Antagonists↗
PubMed1980

Sample sizes for long-term medical trial with time-dependent dropout and event rates.

A general model is formulated that allows for time-dependent dropout and event rates in the determination of sample sizes for long-term medical trials when a therapy group and a control group are to be compared. The need for time-dependent event (dropout) rate is illustrated by using the Framingham Heart Study Mortality data to estimate sample size for the NHLBI (National Heart, Lung, and Blood Institute) Multiple Risk Factor Intervention Trial (MRFIT). A further generalization of the model allows for participants who drop out of the control group (e.g., because of therapeutic measures prescribed by their own physicians) to return (or not return) to the control group at a later date. The question of unequal sample sizes for the therapy and the control groups is also discussed.

Clinical Trials as Topic↗