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S S Ellenberg

Publications and source records attributed to S S Ellenberg.

At least 37 records · Page 2Linked to original sources
PubMed1993

The use of external monitoring committees in clinical trials of the National Institute of Allergy and Infectious Diseases.

Randomized clinical trials are being conducted and/or sponsored by all scientific divisions of the National Institute of Allergy and Infectious Diseases (NIAID). External committees to review the progress of ongoing trials and to make recommendations to the Institute concerning continuation or termination are an integral part of many of these trials. These committees have evolved considerably from the ad hoc committees, called together when a need arose, which were used beginning in the mid 1970s. Currently, there are many monitoring committees operating for NIAID-sponsored trials. They function in a variety of ways, based partially on historical precedent and partially on the specialized requirements of the particular trial; there is no 'standard operating procedure' for the Institute, or even for divisions within the Institute. One of the major issues faced in establishing the data and safety monitoring board for AIDS treatment trials was access to the meetings of this board and to the reports of interim data that the board reviewed. After much discussion, procedures were established that restrict such access to a very limited group of programme and statistical centre staff. These procedures, while remaining controversial, appear necessary to ensure confidentiality and the integrity of the clinical trials process.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Do large, simple trials have a place in the evaluation of AIDS therapies?

Would trials enrolling large numbers of patients and that would require the collection of a relatively small amount of baseline and follow-up data be useful in evaluating treatments for AIDS? It seems worth considering whether widely available large, simple trials, especially those focused on optimizing dosage regimens of existing drugs, could serve the dual purpose of answering important patient management questions and improving the access of indigent populations to marketed therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials.

About a third of patients with ovarian cancer present with localized disease; despite surgical resection, up to half the tumors recur. Since it has not been established whether adjuvant treatment can benefit such patients, we conducted two prospective, randomized national cooperative trials of adjuvant therapy in patients with localized ovarian carcinoma (International Federation of Gynecology and Obstetrics Stages Ia to IIc). All patients underwent surgical resection plus comprehensive staging and, 18 months later, surgical re-exploration. In the first trial, 81 patients with well-differentiated or moderately well differentiated cancers confined to the ovaries (Stages Iai and Ibi) were assigned to receive either no chemotherapy or melphalan (0.2 mg per kilogram of body weight per day for five days, repeated every four to six weeks for up to 12 cycles). After a median follow-up of more than six years, there were no significant differences between the patients given no chemotherapy and those treated with melphalan with respect to either five-year disease-free survival (91 vs. 98 percent; P = 0.41) or overall survival (94 vs. 98 percent; P = 0.43). In the second trial, 141 patients with poorly differentiated Stage I tumors or with cancer outside the ovaries but limited to the pelvis (Stage II) were randomly assigned to treatment with either melphalan (in the same regimen as above) or a single intraperitoneal dose of 32P (15 mCi) at the time of surgery. In this trial (median follow-up, greater than 6 years) the outcomes for the two treatment groups were similar with respect to five-year disease-free survival (80 percent in both groups) and overall survival (81 percent with melphalan vs. 78 percent with 32P; P = 0.48). We conclude that in patients with localized ovarian cancer, comprehensive staging at the time of surgical resection can serve to identify those patients (as defined by the first trial) who can be followed without adjuvant chemotherapy. The remaining patients with localized ovarian cancer should receive adjuvant therapy, and with adjuvant melphalan or intraperitoneal 32P should have a five-year disease-free survival of about 80 percent.

Adult↗
PubMed1990

Issues in the design of drug trials for AIDS.

Although the fundamental principles that drive the design, conduct, and analysis of clinical trials are as applicable to AIDS as to other diseases, there is no question that we have been confronted with unusually difficult challenges in studying therapeutic approaches in this disease area. Treatments are being developed that show great promise, but when investigated further some may be seen to offer no clinical benefit and others may do active harm through toxicity. A group of biostatisticians, meeting in association with the AIDS Clinical Trials Group (ACTG), has discussed and written a report on a number of issues, primarily related to principles of study design, with the goal of stimulating thought on new study designs and the timely implementation of well-designed trials to identify effective treatment strategies for HIV-infected populations. These issues include (1) progression of clinical trials through phases, (2) choices of outcomes, (3) breadth and complexity of clinical trials (eligibility criteria and "low-tech" trials, (4) alternative designs to be used in randomized trials, and (5) the concept of randomized clinical trials as a desirable option, both for patients and for science. The current HIV epidemic makes the requirements of obtaining valid scientific comparisons more important, not less so, but the challenge is to expedite this process.

Acquired Immunodeficiency Syndrome↗
PubMed1990

On the use of laboratory markers as surrogates for clinical endpoints in the evaluation of treatment for HIV infection.

There are strong ethical and practical reasons for hastening decision-making about the efficacy of new treatments for human immunodeficiency virus (HIV) infection. One strategy is to use early markers of disease progression, such as CD4+ lymphocyte levels, as surrogates for ultimate clinical endpoints, such as the development of acquired immune deficiency syndrome (AIDS) or death, in the evaluation of new therapies. We used a simple model of transitions among three health states (well; alive but with an adverse marker; and having experienced a definitive clinical endpoint) to examine the extent to which treatment comparisons based on the surrogate endpoint predict ultimate clinical benefits. With parameters chosen to model the treatment of HIV infection, computer simulations of clinical trials demonstrated substantial time savings by use of the surrogate endpoint. However, reliance on the surrogate led to serious overestimates of ultimate clinical benefit if treatment entailed delayed toxicity or had only transient beneficial effects. Likewise, reliance on the surrogate led to serious underestimates of ultimate clinical benefit when the treatment had no effect on the transition from well to the marker state but did reduce the rates of transition from the marker state to the ultimate clinical endpoint and directly from the well state to the ultimate clinical endpoint.

Antiviral Agents↗
PubMed1989

Biostatistics in clinical trials: Part 2. Determining sample sizes for clinical trials.

The appropriate sample size for a clinical trial depends on the objectives of the trial. For Phase II trials, the recommended sample size is generally in the neighborhood of 25-40 patients, regardless of the choice of design. Sample sizes for Phase III trials are much more variable, ranging from less than a hundred to thousands of patients. The methodology of sample size determination for Phase III trials depends on the type of endpoint that is to be the primary focus of analysis. Tables of sample sizes for a variety of situations are presented. Use of sequential designs may reduce the required sample size by permitting early termination of trials whose results become definitive prior to completion of patient entry.

Clinical Trials as Topic↗
PubMed1989

A two-stage design for choosing among several experimental treatments and a control in clinical trials.

In clinical trials where several experimental treatments are of interest, the goal may be viewed as identification of the best of these and comparison of that treatment to a standard control therapy. However, it is undesirable to commit patients to a large-scale comparative trial of a new regimen without evidence that its therapeutic success rate is acceptably high. We propose a two-stage design in which patients are first randomized among the experimental treatments, and the single treatment having the highest observed success rate is identified. If this highest rate falls below a fixed cutoff then the trial is terminated. Otherwise, the "best" new treatment is compared to the control at a second stage. Locally optimal values of the cutoff and the stage-1 and stage-2 sample sizes are derived by minimizing expected total sample size. The design has both high power and high probability of terminating early when no experimental treatment is superior to the control. Numerical results for implementing the design are presented, and comparison to Dunnett's (1984, in Design of Experiments: Ranking and Selection, T. J. Santner and A. C. Tamhane (eds), 47-66; New York: Marcel Dekker) optimal one-stage procedure is made.

Biometry↗
PubMed1988

Correlates of severe or life-threatening toxic effects from trimetrexate.

Trimetrexate, an investigational antifol, has been associated with marked variability in drug tolerance among patients. The agent is extensively protein bound, and hepatic biotransformation plays a major role in its elimination. In early phase II testing, nine of 15 patients who experienced life-threatening or fatal toxic effects from trimetrexate had albumin levels less than or equal to 3.5 g/dL prior to treatment. This prompted a review of the data base on 272 patients entered in phase I clinical trails. The incidence of severe or life-threatening anemia, leukopenia, neutropenia, thrombocytopenia, mucositis, and hepatic toxic effects during the first course of trimetrexate was analyzed according to dose, schedule, prior treatment, and baseline protein and albumin levels. The schedules using doses given by short infusions of 30-60 minutes daily for 5 days or weekly for 3 weeks were generally associated with higher incidence of toxic effects than the schedules using doses given every other week by short infusions or those using continuous infusion. The occurrence of leukopenia and mucositis was dose related. Patients with baseline albumin levels less than or equal to 3.5 g/dL had higher incidence of all types of severe or life-threatening toxic effects than those with albumin levels greater than or equal to 3.6 g/dL, and the differences were significant for the development of anemia, thrombocytopenia, and mucositis. Similar correlations were noted for pretreatment protein levels less than or equal to 6.0 g/dL. The small cohort of patients with leukemia experienced substantial toxic effects and tended to have low protein and albumin levels. Performance status and prior therapy did not emerge as strong predictors of severe toxic effects in the univariate analysis. Multivariate analysis confirmed that the type of cancer (leukemia vs. solid tumor), dose, schedule, and baseline albumin level were significant and independent predictors of severe and life-threatening toxic effects in the phase I patient population. Multivariate analysis including only patients with solid tumors indicated that albumin level, dose, and schedule remained significant predictors of toxic effects. Since normal liver function as reflected by bilirubin and transaminase values were a requirement for eligibility, the results suggest that albumin and protein levels may provide a more sensitive index of hepatic function. Patients with hypoalbuminemia and hypoproteinemia are at increased risk of experiencing severe or life-threatening toxic effects from trimetrexate and should be treated cautiously.

Adult↗
PubMed1988

Optimal two-stage designs for clinical trials with binary response.

We present a simple two-stage design for a randomized clinical trial with dichotomous outcomes. It is based on a design of Ellenberg and Eisenberger which permits early acceptance of the null hypothesis after the first stage. We have optimized the design by minimizing the average expected sample size subject to constraints on the type 1 and type 2 errors. The resulting designs have maximum sample size only slightly larger than that of single stage trial, with 40-45 per cent of this maximum allocated to the first stage, and null hypothesis probability of early acceptance in excess of 0.60.

Clinical Trials as Topic↗
PubMed1987

A randomized study of oral nutritional support versus ad lib nutritional intake during chemotherapy for advanced colorectal and non-small-cell lung cancer.

One hundred ninety-two patients with previously untreated metastatic cancer (102 non-small-cell lung cancer [NSCLC]; 90 colorectal cancer) were randomized to receive either ad lib nutritional intake (control group) or specific nutritional intervention during a 12-week study period when chemotherapy was administered. Those patients randomized to nutritional interventions were counselled to take oral nutrients with caloric intake equal to 1.7 to 1.95 times their basal energy expenditure, depending on their pretreatment nutritional status ("standard" group). An augmented group was counselled to have a caloric intake equivalent to that of the standard group but with 25% of calories provided as protein and additional supplements of zinc and magnesium. Counselling increased caloric intake in both tumor types but reduced weight loss in the short term only for lung cancer patients. Ninety-three NSCLC patients were evaluable for tumor response to vindesine and cisplatin. Overall, only 20.4% of the patients responded, and there were no significant differences in response rates, median time to progression, or overall duration of survival between the nutrition intervention groups and the control group. The tumor response rate to time-sequenced 5-fluorouracil (5-FU) and methotrexate in the 81 evaluable patients with colorectal cancer was only 14.8%, and no significant differences in tumor response rates were noted between the three groups. Furthermore, the median time to progression and overall duration of survival were not different for the control, standard, and augmented groups. Nutritional interventions using dietary counselling had no impact on the percent of planned chemotherapy dose administered, the degree of toxicity experienced by patients, or the frequency of treatment delays. A multivariate prognostic factor analysis demonstrated that for lung cancer, the percent of weight loss, serum albumin concentration, and presence of liver metastases were significant (P less than .05) and independent prognostic variables for survival duration. For colorectal cancer, serum albumin, alkaline phosphatase, lactic dehydrogenase (LDH) levels, and percent targeted caloric intake (TCI) were significant independent predictors of survival duration.

Adult↗
PubMed1987

Results of second-look laparotomy in patients with early-stage ovarian carcinoma.

One hundred twelve patients with early (FIGO stage I and II) ovarian carcinoma had a second-look laparotomy performed after comprehensive surgical staging and randomization into clinical protocols. Of the 95 patients who were asymptomatic before second-look laparotomy, only 5% had positive findings. In contrast, 53% of the 17 patients with findings that suggested recurrence or bowel obstruction had disease at second-look laparotomy. Overall, only 13% of the entire group of 112 patients had recurrent disease at second-look laparotomy. Asymptomatic patients with early ovarian carcinoma who have undergone careful initial surgical staging followed by appropriate adjuvant therapy can be spared a routine second-look operation.

Female↗