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J Wittes

Publications and source records attributed to J Wittes.

At least 37 records · Page 2Linked to original sources
PubMed1999

Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. European Pediatric Meningococcal Septic Shock Trial Study Group.

Meningococcal septic shock has a rapid onset and characteristic skin hemorrhages that allow bedside diagnosis. Initial plasma endotoxin levels are high and correlate closely with clinical outcome. In a double-blind, randomized, placebo-controlled trial (planned, n = 270; actual, n = 269), we compared the effectiveness of HA-1A (6 mg/kg of body weight iv; maximum, 100 mg), a human monoclonal antibody to endotoxin, and placebo in reducing the 28-day all-cause mortality rate among children with a presumptive clinical diagnosis of meningococcal septic shock. Treatment groups were well balanced for baseline characteristics and prespecified prognostic variables. In this trial no significant benefit of HA-1A could be demonstrated. The 28-day mortality rates in the intention-to-treat analysis were as follows: placebo, 28%; HA-1A, 18%; reduction in mortality, 33% (P = .11, per Fisher's exact test, two-tailed; odds ratio = 0.59; 95% confidence interval for the difference, 0.31-1.05). All patients tolerated HA-1A well, and no antibodies to HA-1A were detected.

Antibodies, Monoclonal↗
PubMed1998

Rationale and design for the Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial.

The Controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial is a randomized, prospective, double-blind, parallel-group, two-arm, actively controlled, multicenter, international 5-year clinical trial involving 15,000 patients. CONVINCE will compare the incidence of fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, or cardiovascular-disease-related death in two antihypertensive treatment regimens. One treatment arm begins with controlled onset-extended release (COER)-verapamil, which has its major antihypertensive effect 6-12 hours after administration. The other arm (standard of care (SOC)) begins with either hydrochlorothiazide (HCTZ) or atenolol, one of which is preselected by the investigator for an individual patient prior to randomization. Secondary objectives include comparisons of the regimens for each of the components of the primary endpoint (separately), death or hospitalization related to cardiovascular disease, efficacy in lowering blood pressure to goal, primary events occurring between 6 am and noon, all-cause mortality, withdrawals from blinded therapy, cancer, and hospitalizations due to bleeding. Patients may be enrolled if they are hypertensive and at least 55 years of age and have an established second risk factor for cardiovascular disease. Initial medications include COER-verapamil (180 mg/d), HCTZ (12.5 mg/d), or atenolol (50 mg/d). Initial doses are doubled if blood pressure (BP) does not reach goal (systolic BP < 140 mm and diastolic BP < 90 mm Hg). If BP is not controlled by the higher dose of the initial medication, HCTZ is added to COER-verapamil, or the SOC choice not initially selected is added in the SOC arm. An ACE-inhibitor is recommended (although nearly any open-label medication is allowed) as the third step for patients whose BP is not adequately controlled or who have a contraindication to one of the two SOC medications. Patients take two sets of tablets daily, one in the morning and one in the evening. Although most patients switch from an established antihypertensive medication to randomized treatment, untreated patients with stages I-III hypertension (SBP between 140 and 190 or DBP between 90 and 110 mm Hg) are eligible. Outcomes are monitored by an independent Data and Safety Monitoring Board. Enrollment began during the third quarter of 1996, and follow-up is to be completed in the third quarter of 2002.

Aged↗
PubMed1998

Effects of margarine compared with those of butter on blood lipid profiles related to cardiovascular disease risk factors in normolipemic adults fed controlled diets.

Effects of butter and 2 types of margarine on blood lipid and lipoprotein concentrations were compared in a controlled diet study with 23 men and 23 women. Table spreads, added to a common basal diet, provided 8.3% of energy as fat. Diets averaged 34.6% of energy as fat and 15.5% as protein. Each diet was fed for 5 wk in a 3 x 3 Latin-square design. One margarine (TFA-M) approximated the average trans monoene content of trans fatty acid-containing margarines in the United States (17% trans fatty acids by dry wt). The other margarine (PUFA-M) was free of trans unsaturated fatty acids; it contained approximately twice the polyunsaturated fatty acid content of TFA-M (49% compared with 27% polyunsaturated fatty acids). The tub-type margarines had similar physical properties at ambient temperature. Fasting blood lipids and lipoproteins were determined in 2 samples taken from the subjects during the fifth week of each dietary treatment. Compared with butter, total cholesterol was 3.5% lower (P=0.009) after consumption of TFA-M and 5.4% lower (P< 0.001) after consumption of PUFA-M. Similarly, LDL cholesterol was 4.9% lower (P=0.005) and 6.7% lower (P< 0.001) after consumption of TFA-M and PUFA-M, respectively. Neither margarine differed from butter in its effect on HDL cholesterol or triacylglycerols. Thus, consumption of TFA-M or PUFA-M improved blood lipid profiles for the major lipoproteins associated with cardiovascular risk when compared with butter, with a greater improvement with PUFA-M than with TFA-M.

Adult↗
PubMed1997

Blinded subjective rankings as a method of assessing treatment effect: a large sample example from the Systolic Hypertension in the Elderly Program (SHEP).

Because many randomized clinical trials study more than one important outcome variable, evaluation of efficacy is often difficult and not completely satisfactory. This paper considers the use of a procedure for endpoint determination described by Follmann et al., that allows raters to integrate subjectively all relevant information about an individual's clinical course into a single univariate assessment. To explore the method's feasibility, we tested the procedure with data from a completed clinical trial, the Systolic Hypertension in the Elderly Program (SHEP). We provided raters blinded to treatment assignment with cards that schematically represent the clinical trajectories of SHEP study participants. The raters independently ranked these trajectories. The method combined ranks across raters to determine a single rank for each study participant; we used a rank procedure to test treatment effect. The major findings were: (i) the raters showed a high level of concordance of rankings; (ii) tests of treatment effect were highly statistically significant; (iii) three statistical methods were effective for implementing the ranking in the large study size case. These methods were use of: (a) scoring rules; (b) incomplete block designs, and (c) categorical ranking.

Data Interpretation, Statistical↗
PubMed1997

Plasma lipoprotein (a) levels in men and women consuming diets enriched in saturated, cis-, or trans-monounsaturated fatty acids.

Studies that have shown adverse effects of trans-unsaturated fatty acids on plasma lipoprotein (a) [Lp(a)] levels have used levels of trans-fatty acid that are higher than those in the average U.S. diet. This study was conducted to clarify the effects on Lp(a) of trans-fatty acids levels commonly found in U.S. diets. Lp(a) levels were measured in a double-blind study of 29 men and 29 women who ate 4 controlled diets in random order for 6 weeks each. Fatty acids represented 39% to 40% of energy. The diets were: (1) Oleic (16.7% of energy as oleic acid); (2) Moderate trans (3.8% of energy as trans-monoenes, approximately the trans content of the U.S. diet); (3) High trans (6.6% of energy as trans-monoenes); (4) Saturated (16.2% of energy as lauric plus myristic plus palmitic acids). The Saturated diet lowered Lp(a) levels significantly (by 8% to 11%). Compared to the Oleic diet, the trans diets had no adverse effect on Lp(a) levels when all subjects were considered collectively. A subset with initially high levels of Lp(a) (> or = 30 mg/dL), however, responded to the High trans diet with a slight (5%) increase in Lp(a) levels relative to the Oleic and Moderate trans diets. Thus, in amounts commonly found in the typical U.S. diet, saturated fatty acids consistently decrease Lp(a) concentrations. The adverse effects of replacing cis- with trans-fatty acids are only suggestive and are restricted to high trans intakes in subjects with high Lp(a) levels.

Adult↗
PubMed1996

Randomised double-blind placebo-controlled trial of SPf66 malaria vaccine in children in northwestern Thailand. Shoklo SPf66 Malaria Vaccine Trial Group.

BACKGROUND: Previous efficacy trials of SPf66 malaria vaccine have produced conflicting results in different populations. We report a randomised double-blind trial of the SPf66 vaccine conducted in Karen children aged 2-15 living in a malarious region of northwestern Thailand. Recombinant hepatitis B vaccine was used as a comparator. METHODS: The study had a power of 90% to detect an efficacy of 30%, defined as a reduction in the incidence of first cases of symptomatic falciparum malaria after three doses of vaccine. 1221 children received three immunisations and were eligible for the primary efficacy analysis. Intense active and passive case detection continued over 15 months of follow-up. FINDINGS: The SPf66 vaccine was well tolerated, although 26 children had mild or moderately severe local or systemic allergic reactions, compared with none in the comparator group. The vaccine was immunogenic; after three doses, 73% of recipients had seroconverted. There were no deaths due to malaria during the study. During the 15-month period of evaluation there were 379 first cases of symptomatic falciparum malaria (195 in the SPf66 recipients, 184 in the comparator group); an SPf66 efficacy of -9% (95% CI -33 to 14, p = 0.41). No significant differences between the two study groups in parasite density or any other measure of malaria-related morbidity were detected. INTERPRETATION: These findings are consistent with a recent study showing lack of efficacy of SPf66 among Gambian infants and differ from earlier positive reports from South America and evidence of borderline efficacy from Tanzania. We conclude that SPf66 does not protect against clinical falciparum malaria and that further efficacy trials are not warranted.

Adolescent↗
PubMed1996

Plasmodium falciparum circumsporozoite vaccine immunogenicity and efficacy trial with natural challenge quantitation in an area of endemic human malaria of Kenya.

It has been hypothesized that antibody induced by Plasmodium falciparum circumsporozoite protein vaccine would be effective against endemic human malaria. In a malaria endemic region of Kenya, 76 volunteers, in 38 pairs sleeping adjacently, were immunized with subunit circumsporozoite protein Asn-Ala-Asn-Pro tetrapeptide repeat-pseudomonas toxin A, or hepatitis B vaccine. After quinine and doxcycycline, volunteers were followed for illness daily, parasitemia weekly, antibody, T-lymphocyte responses, and treated if indicated. Anopheles mosquitoes resting in houses were collected, and tested for P. falciparum antigen, or dissected for sporozoites and tested for blood meal ABO type and P. falciparum antigen. Vaccine was safe, with side-effects similar in both groups, and immunogenic, engendering IgG antibody as high as 600 micrograms ml-1, but did not increase the proportion of volunteers with T-lymphocyte responses. Estimation of P. falciparum challenge averaged 0.194 potentially infective Anopheles bites/volunteer/ day. Mosquito blood meals showed no difference in biting intensity between vaccine and control groups. Both groups had similar malaria-free survival curves, cumulative positive blood slides, cumulative parasites mm-3, and numbers of parasites mm-3 on first positive blood slide, during three post-vaccination observation periods. Every volunteer had P. falciparum parastemia at least once. Vaccinees had 82% and controls 89% incidences of symptomatic parasitemia (P = 0.514, efficacy 9%, statistical power 95% probability of efficacy < 50%). Vaccine-induced anti-sporozoite antibody was not protective in this study. Within designed statistical precisions the present study is in agreement with efficacy studies in Colombia, Venezuela and Tanzania.

Animals↗
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↗
PubMed1994

Impact of the treatment of isolated systolic hypertension on behavioral variables. Results from the systolic hypertension in the elderly program.

BACKGROUND: Little information has been published on the impact of antihypertensive medications on quality of life in older persons. Particular concern has existed that lowering systolic blood pressure in older persons might have adverse consequences on cognition, mood, or leisure activities. METHODS: A multicenter double-blind randomized controlled trial was conducted over an average of 5 years' followup involving 16 academic clinical trial clinics. Participants consisted of 4736 persons (1.06%) selected from 447,921 screenees aged 60 years and older. Systolic blood pressure at baseline ranged from 160 to 219 mm Hg, while diastolic blood pressure was less than 90 mm Hg. Participants were randomized to active antihypertensive drug therapy or matching placebo. Active treatment consisted of 12.5 to 25 mg of chlorthalidone for step 1, while step 2 consisted of 25 to 50 mg of atenolol. If atenolol was contraindicated, 0.05 to 0.10 mg of reserpine could be used for the second-step drug. The impact of drug treatment on measures of cognitive, emotional, and physical function and leisure activities was assessed. RESULTS: Our analyses demonstrate that active treatment of isolated systolic hypertension in the Systolic Hypertension in the Elderly Program cohort had no measured negative effects and, for some measures, a slight positive effect on cognitive, physical, and leisure function. The positive findings in favor of the treatment group were small. There was no effect on measures related to emotional state. Measures of cognitive and emotional function were stable in both groups for the duration of the study. Both treatment groups showed a modest trend toward deterioration of some measures of physical and leisure function over the study period. CONCLUSIONS: The overall study cohort exhibited decline over time in activities of daily living, particularly the more strenuous ones, and some decline in certain leisure activities. However, mood, cognitive function, basic self-care, and moderate leisure activity were remarkably stable for both the active and the placebo groups throughout the entire study. Results of this study support the inference that medical treatment of isolated systolic hypertension does not cause deterioration in measures of cognition, emotional state, physical function, or leisure activities.

Activities of Daily Living↗
PubMed1994

Intercept studies, clinical trials, and cluster experiments: to whom can we extrapolate?

While sample surveys rely on an explicit theory of the relationship between a sample and its reference population, many nonsurvey-based designs lack a clear relationship to the population to which inferences are to be drawn. For example, in order to be applicable to large populations, intercept studies--which include observational studies of migrant populations and randomized studies such as mall intercepts--must make implicit or explicit assumptions about the probability of finding members of the population. In conducting clinical trials, constraints imposed by the research often lead large segments of the population to have zero probability of observation. Although such experiments generally conduct research at only a few sites, investigators usually intend to apply their results quite broadly. This paper compares intercept studies and clinical trials with particular emphasis on inference to a population for which the probabilities of being observed are unknown, unreliable, or very small.

Adult↗
PubMed1994

Dietary trans fatty acids: effects on plasma lipids and lipoproteins of healthy men and women.

Effects of cis and trans monounsaturated fatty acids (TFA) and saturated fatty acids were assessed in 29 men and 29 women consuming controlled diets. Subjects ate each diet for 6 wk in a Latin square design. The diets, each with 39-40% of energy as fat were: 1) high oleic (16.7% of energy as oleic acid), 2) moderate TFA (3.8% of energy as TFA), 3) high TFA (6.6% of energy as TFA), 4) and saturated (16.2% of energy as lauric+myristic+palmitic acids). Compared with the oleic diet, LDL cholesterol increased 6.0%, 7.8%, and 9.0% after moderate TFA, high TFA, and saturated diets, respectively. HDL cholesterol was unchanged after moderate TFA, but was slightly lower (2.8%) after high TFA. HDL cholesterol after the saturated diet was 3.5% higher than after the oleic diet. Changes in apolipoproteins B and A-I corresponded with changes in the lipoprotein cholesterols. Thus, compared with oleic acid, dietary TFAs raise LDL cholesterol, but to a slightly lesser degree than do saturates, and high TFA concentrations may result in minor reductions of HDL cholesterol.

Adult↗
PubMed1993

Analysis as-randomized and the problem of non-adherence: an example from the Veterans Affairs Randomized Trial of Coronary Artery Bypass Surgery.

In most randomized clinical trials not all patients adhere to the therapy to which they were randomly assigned. Instead, they may receive the therapy assigned to another treatment group, or a therapy different from any prescribed in the protocol. When non-adherence occurs, problems occur with the analysis comparing the treatments under study. Rigorous statistical principles require attributing outcome events to the original random treatment assignment ('intent-to-treat' analysis). Using data from the Veterans Administration Cooperative Study of Coronary Artery Bypass Surgery, we report the intent-to-treat analysis and apply four other methods of analysis for analysing non-adherers: 1. exclude non-adherers from analysis; 2. transfer them to the alternative treatment group at the time of randomization; 3. censor them at the time of treatment change, and 4. transfer them to the alternative treatment group at the time of treatment change. Inherent problems and biases of these four other methods are discussed.

Angina Pectoris↗
PubMed1993

Behind closed doors: the data monitoring board in randomized clinical trials.

Many randomized clinical trials include a data and safety monitoring board (DSMB) that is responsible for reviewing accruing data, monitoring performance of the trial, assuring safety of the participants in the trial, and assessing the efficacy of treatment. The DSMB often makes recommendations about continuation of the trial or alteration of the protocol. Although such boards are very influential in both the conduct and interpretation of randomized clinical trials, there is no standard mode in which DSMBs operate nor do they routinely report publicly about their deliberations. This paper describes the composition of DSMBs as well as their functions. It concludes with a series of questions that needs to be addressed to ensure that the DSMBs operate effectively.

Aged↗
PubMed1993

Statistical considerations in monitoring the Systolic Hypertension in the Elderly Program (SHEP).

The Systolic Hypertension in the Elderly Program (SHEP), a randomized, double-masked, placebo-controlled trial of 4736 persons, was designed to assess the efficacy of antihypertensive drug treatment to reduce the risk of fatal and nonfatal strokes among people age 60 and over with isolated systolic hypertension. The statistical method used in interim monitoring of results was conditional power (or stochastic curtailment). The findings did not become conclusive until near the completion of the trial, and therefore SHEP was continued to its scheduled closing date. The trial demonstrated a 36% reduction in the incidence of stroke in the active treatment group (P = .0003). In addition to evaluating overall efficacy of treatment, the monitoring process considered such other issues as nonstroke outcomes, lag time between first report of stroke and final confirmation of stroke diagnosis, consistency of results across subgroups, and completeness of follow-up. The purpose of this article is to review these factors with primary emphasis on the statistical aspects.

Aged↗
PubMed1993

The power of the Mantel-Haenszel test for grouped failure time data.

The Mantel-Haenszel test for grouped failure time data (MHF test) compares the distribution of failure times in two cohorts followed for an interval of time when the data are collected in discrete subintervals. This paper derives approximations to the power of the Mantel-Haenszel test for arbitrary failure time distributions in the presence of censoring. The approximations are appropriate for both equal and nonequal odds ratios in the constituent tables, and can be used for arbitrary subdivisions of time. Four approximations are proposed. They differ from each other according to whether the parameter measuring treatment effect is an odds ratio or a difference in proportions, and whether the survival distributions are calculated under the null or alternative hypothesis. In addition, we demonstrate that when the hazards are constant, increasing the number of subintervals often produces only a negligible increase in the power of the MHF test. On the other hand, for arbitrary hazards and nonconstant hazard ratios, the choice of frequency and actual times of measurement can have important effects on power. Finally, the paper presents simple expressions for power under exponential failure and censoring models.

Biometry↗
PubMed1992

The use of subjective rankings in clinical trials with an application to cardiovascular disease.

Evaluating a clinical trial can be problematic if the studied treatments affect patients in many ways. A possible method for evaluating treatments is to have raters rank all the patients' trial experiences and then test whether the distribution of ranks differ between treatments. Before one can advocate such a procedure, however, one would like to be assured that raters agree fairly well with one another. As a first step in examining whether raters tend to agree, we conducted a small study with 20 raters evaluating 43 trial experiences from an imaginary cardiovascular clinical trial. Raters showed a high degree of consensus. Moreover, the average ranks agreed fairly well with two quantitative ranking rules. On the other hand, the average ranks did not agree very well with weightings usually selected in cardiovascular trials. These results suggest ranking may be a feasible approach to analysing certain clinical trials with multiple outcomes.

Cardiovascular Diseases↗