Showing papers on "Randomized controlled trial published in 1976"

Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design.

Abstract: The Medical Research Council has for some years encouraged collaborative clinical trials in leukaemia and other cancers, reporting the results in the medical literature. One unreported result which deserves such publication is the development of the expertise to design and analyse such trials. This report was prepared by a group of British and American statisticians, but it is intended for people without any statistical expertise. Part I, which appears in this issue, discusses the design of such trials; Part II, which will appear separately in the January 1977 issue of the Journal, gives full instructions for the statistical analysis of such trials by means of life tables and the logrank test, including a worked example, and discusses the interpretation of trial results, including brief reports of 2 particular trials. Both parts of this report are relevant to all clinical trials which study time to death, and wound be equally relevant to clinical trials which study time to other particular classes of untoward event: first stroke, perhaps, or first relapse, metastasis, disease recurrence, thrombosis, transplant rejection, or death from a particular cause. Part I, in this issue, collects together ideas that have mostly already appeared in the medical literature, but Part II, next month, is the first simple account yet published for non-statistical physicians of how to analyse efficiently data from clinical trials of survival duration. Such trials include the majority of all clinical trials of cancer therapy; in cancer trials,however, it may be preferable to use these statistical methods to study time to local recurrence of tumour, or to study time to detectable metastatic spread, in addition to studying total survival. Solid tumours can be staged at diagnosis; if this, or any other available information in some other disease is an important determinant of outcome, it can be used to make the overall logrank test for the whole heterogeneous trial population more sensitive, and more intuitively satisfactory, for it will then only be necessary to compare like with like, and not, by chance, Stage I with Stage III.

The VA cooperative randomized study of surgery for coronary arterial occlusive disease II. Subgroup with significant left main lesions.

Abstract: From a large cooperative prospective randomized study, data relating to a subgroup of 113 patients with angina pectoris and a significant lesion of the left main coronary artery were analyzed. Of these patients, 53 had been randomly allocated to a medical treatment group and 60 to a surgical treatment group. The former group received conventional medical treatment, while the surgical treatment group received one or more aortocoronary saphenous vein bypass grafts. Important risk factors were approximately uniformly distributed between the two groups. Both are being followed up to 60 months (average follow-up, 30 months). To date, 12 of 60 surgical patients (20%) and 19 of 53 medical patients (36%) died (P less than 0.06). The operative (30-day) mortality declined from a rate of 25% for the first 2 years of the study to 7% for the last 3 years. Of patients randomized in the latter 3 years of the study, 12 of 41 medical patients (29%) and three of 42 surgical patients (7%) died (P less than 0.01). The average follow-up period in this group was 24 months. The proportion surviving 24 months was clearly larger in the surgically treated group (P less than 0.02). The difference in the proportion of patients surviving after surgery as compared with medical treatment was greatest in patients with additional significant disease involving the right coronary artery, with or without left ventricular dysfunction. Relief of angina as assessed by an "anginal score" was also better in surgical patients to a significant degree. Graft-patency rates correlated well with relief of angina, but objective studies including treadmill testing are not yet available.

Randomized clinical trials. Perspectives on some recent ideas.

Abstract: In spite of the controversy over the role of randomized clinical trials in medical research, the rationale underlying such trials remains persuasive as compared to recent suggestions for alternative non-randomized studies such as those relying on the use of historical controls and adjustment technics Others have suggested that recent statistical innovations for improving clinical trials, including adaptive allocation of treatment to patients and sequential stopping procedures, are underutilized These innovations, though theoretically interesting, are not easily adapted to large-scale, complex medical trials in which there may be multiple end points and delayed response times Ethical considerations suggest that randomized trials are more suitable than uncontrolled experimentation in protecting the interests of patients Randomized clinical trials remain the most reliable method for evaluating the efficacy of therapies

Unstable angina pectoris: National cooperative study group to compare medical and surgical therapy

Abstract: A preliminary report is presented of a prospective randomized trial conducted by eight cooperative institutions under the auspices of the National Heart and Lung Institute to compare the effectiveness of medical and surgical therapy in the management of the acute stages of unstable angina pectoris. To date 150 patients have been included in the randomized trial, 80 assigned to medical and 70 to surgical therapy; the clinical presentation, coronary arterial anatomy and left ventricular function in the two groups are similar. Some physicians have been reluctant to prescribe medical or surgical therapy by a random process, and the ethical basis of the trial has been questioned. Since there are no hard data regarding the natural history and outcome of therapy for unstable angina pectoris, randomization appears to provide a rational way of selecting therapy. Furthermore, subsets of patients at high risk may emerge during the process of randomization. The design of this randomized trial is compared with that of another reported trial. Thus far, the study has shown that it is possible to conduct a randomized trial in patients with unstable angina pectoris, and that the medical and surgical groups have been similar in relation to the variables examined. The group as a whole presented with severe angina pectoris, either as a crescendo pattern or as new onset of angina at rest, and 84 percent had recurrence of pain while in the coronary care unit and receiving vigorous medical therapy. It is anticipated that sufficient patients will have been entered into the trial within the next 12 months to determine whether medical or surgical therapy is superior in the acute stages of unstable angina pectoris.

Steroid therapy in severe viral hepatitis. A double-blind, randomized trial of methyl-prednisolone versus placebo.

Abstract: The efficacy of corticosteroid therapy in severe viral hepatitis has never been demonstrated in a controlled clinical trial. For this reason, patients with severe viral hepatitis were randomly assigned to methyl-prednisolone or placebo treatment groups. The two groups were comparable in clinical findings, laboratory results and the presence of bridging necrosis on liver biopsy. Seven of the 14 patients assigned to methyl-prednisolone and two of the 15 assigned to placebo died during the 16-week study period. Although the apparent excess mortality in the steroid-treated patients is not quite statistically significant (P = 0.08), the trend persists when only patients positive for hepatitis B surface antigen (P = 0.08) or those with bridging necrosis (P = 0.04) are analyzed separately. Methyl-prednisolone does not enhance survival in patients with severe viral hepatitis, and it may be detrimental. (N Engl J Med 294:681–687, 1976)

Tranexamic acid and upper gastrointestinal haemorrhage--a double-blind trial.

Abstract: The efficacy of antifibrinolytic therapy in the management of acute upper gastrointestinal haemorrhage has been investigated in a double-blind clinical trial. Two-hundred patients were studied using tranexamic acid, a potent antifibrinolytic agent. Of these, 103 were in the treatment group and 97 in the control group. Patients were analysed to determine severity of initial blood loss, transfusion requirements, together with the incidence of recurrent bleeding, surgical intervention, and death. Final diagnosis as to the site of bleeding was arrived at using endoscopy, barium studies, and the findings at operation and necropsy. The groups were well matched as regards severity of initial haemorrhage, age, sex, aetiological diagnosis, and precipitating factors. A significant difference was observed in the requirement for surgical intervention to control continuing or recurrent haemorrhage. Twenty-three of 97 in the control group and seven of 103 in the treatment group required surgery. There appeared to be a reduction in the transfusion rate after the first three days of hospitalization in the treatment group. There were no significant differences in mortality or in side-effects between the two groups.

Unstable angina pectoris: National cooperative study group to compare medical and surgical therapy: I. Report of protocol and patient population

Abstract: A preliminary report is presented of a prospective randomized trial conducted by eight cooperative institutions under the auspices of the National Heart and Lung Institute to compare the effectiveness of medical and surgical therapy in the management of the acute stages of unstable angina pectoris. To date 150 patients have been included in the randomized trial, 80 assigned to medical and 70 to surgical therapy; the clinical presentation, coronary arterial anatomy and left ventricular function in the two groups are similar. Some physicians have been reluctant to prescribe medical or surgical therapy by a random process, and the ethical basis of the trial has been questioned. Since there are no hard data regarding the natural history and outcome of therapy for unstable angina pectoris, randomization appears to provide a rational way of selecting therapy. Furthermore, subsets of patients at high risk may emerge during the process of randomization. The design of this randomized trial is compared with that of another reported trial. Thus far, the study has shown that it is possible to conduct a randomized trial in patients with unstable angina pectoris, and that the medical and surgical groups have been similar in relation to the variables examined. The group as a whole presented with severe angina pectoris, either as a crescendo pattern or as new onset of angina at rest, and 84 percent had recurrence of pain while in the coronary care unit and receiving vigorous medical therapy. It is anticipated that sufficient patients will have been entered into the trial within the next 12 months to determine whether medical or surgical therapy is superior in the acute stages of unstable angina pectoris.

A blind controlled trial of dextran 40 in the treatment of ischæmic stroke

Abstract: A blind controlled trial of dextran 40 in ischaemic stroke is reported. In the treated group mortality in the acute stage in patients with severe strokes was significantly reduced but survivors were severely disabled and six months later no significant benefit could be detected. In less severe strokes no effect of treatment was found. It is concluded that the action of dextran 40 in reducing acute mortality probably lay in preventing or reversing cerebral swelling but no evidence of the expected action in reducing the area of infarction following improved blood flow was found. The importance of extending assessment beyond the two weeks customary in therapeutic trials in stroke is emphasized.

The Stockholm breast cancer trial: preliminary report of a randomized study concerning the value of pre-operative or post-operative radiotherapy in operable disease.

Abstract: The patterns of failure and survival data of a trial concerning the value of pre-operative or randomized clinical post-operative radiotherapy as an adjuvant to radical surgery in the management of operable breast cancer are presented. Currently, 850 patients have been entered into the trial which is expected to access eventually 1000 cases. Some preliminary short-term results are discussed. At three years, with a total of 259 patients evaluable there was no difference in survival hut a marked decrease (from 17% to 5%) in the frequency of local recurrent disease in patients receiving adjuvant radiotherapy. There was no evidence of increased metastatic disease when radiotherapy was utilized as an adjuvant to surgery. Side effects of the treatments applied, more particularly concerning theraapy were not considered of major clinical importance nor of such a nature as to warrant the discoutinuation of radiation therapy.

Very high dose fluphenazine decanoate: a controlled trial in chronic schizophrenia.

Abstract: • In a double-blind trial of six months' duration, a very high dose (VHD) regimen of fluphenazine decanoate (250 mg weekly) was compared with a standard dose (SD) regimen (12.5 mg weekly) in 50 chronic schizophrenic patients. The rating scales used included the Brief Psychiatric Rating Scale 1 and the Wing Ward Behavior Scale. 2 Both treatment groups improved during the trial, but there was no significant difference between them. The VHD regimen, however, exerted better control of the psychosis in that it had fewer patient dropouts and fewer "additional treatments" prescribed. Some of the patients receiving standard doses were probably not receiving adequate antipsychotic drug dosage. No predictors of clinical response could be defined. Extrapyramidal side effects were not significantly higher in the VHD group.

Randomised controlled trial of computer-held medical records in hypertensive patients.

Abstract: A total of 278 hypertensive patients in three clinics were randomly allocated to have their medical records held in a computer system (136) or on standard hospital notes (142). For the computer system the doctor completed a structured input form, and the information on symptoms, physical findings, and diagnoses was more complete than that in the standard notes. This resulted in certain symptoms and risk factors being recognised more often when the computer system was used. The hypertension clinics' routines were not disrupted by the introduction of a computer-held system, and follow-up consultation times were not affected by the type of records kept, although the first consultation took eight minutes longer when computer documents were completed. The patients remained in the trial for one year and clinical management was assessed from blood pressure control, drop-out rates, and the frequency of performing investigations. These estimates of management showed no significant difference between the two groups, but the attempt to tailor the computer system to help management made the system acceptable to the doctors using it. The computer system continues to be used and is providing data for research into hypertension.

A controlled trial of phenothiazine withdrawal in chronic schizophrenic patients.

Abstract: Phenothiazine drugs were withdrawn from 17 chronic schizophrenic in-patients, with a control group of 14 patients remaining on active medication. The trial was conducted under double blind conditions over a period of 42 weeks with weekly assessment of the patients by ward nurses. Of the placebo group 35% relapsed, relapse being related to the level of previous active medication.

A randomized controlled trial of vitamin C in the prevention and amelioration of the common cold.

Abstract: A randomized controlled trial of the effect of 1 g ascorbic acid per day in the prevention of the common cold was conducted on 688 adult women. There is evidence of a small reduction by vitamin C in the mean number of chest colds, but no evidence of any effect on simple colds. The existence of a subgroup of vulnerable women in the community who benefit from vitamin C was considered but further examination of the data gives no support to this conclusion.

Controlled Trial of D-Penicillamine in Rheumatoid Arthritis: Dose Effect and the Role of Zinc

Abstract: The findings are reported of a controlled clinical trial comparing in 66 rheumatoid arthritis patients 0 g (placebo), and 0.50 g a day and 1 g a day of penicillamine. Each of these groups has been subdivided into two, one part receiving 5 mg a day of zinc metal supplement, the other a placebo. The trial was planned to be double-blind, and for each patient to take part for 4 months. The results prove the effectiveness of penicillamine in rheumatoid arthritis. 0.50 g a day has the same effect as 1 g a day but gives less side effects. Zinc supplement inhibits the clinical effects of penicillamine but does not prevent the side effects.

Lithium in tardive dyskinesia

Abstract: A single blind trial and a placebo controlled double blind trial of lithium were carried out in elderly patients with tardive dyskinesia. In the pilot study, neuroleptics were continued: in the controlled trial, neuroleptics were discontinued. The results of both studies were essentially negative. Thus, the suppression effect of neuroleptics is much more dramatic than anything seen in the two studies. Several reasons for this were discussed namely, the severity and chronicity of the symptoms.

Experience with labetalol in hypertension.

Abstract: 1 The effect of labetalol has been assessed in an open clinical trial in 19 patients with sub-optimal control of blood pressure on other therapy, and in a placebo-controlled cross-over study. Most patients were taking a diuretic before the trial and they continued to do so during the trial. 2 In the open trial, labetalol successfully lowered blood pressure in most of the patients. Average daily dose was about 600 mg. The placebo-controlled trial confrimed the anti-hypertensive effect. 3 A clear postural hypotensive effect was seen. A few patients noted postural faintness as a side-effect, especially in a hot environment; but it was not troublesome. 4 There were few other side-effects. One patient experienced an increase in serum glumatic--oxalic transaminase (SGOT) and another an increasing anti-nuclear factor titre, but it is not yet certain that these were due to labetalol.

Combination chemotherapy of the malignant lymphomas: a controlled clinical trial.

Abstract: The Eastern Cooperative Oncology Group has studied 113 patients with generalized progressive malignant lymphomas in a randomized clinical trial. Pathologic diagnosis was subclassified by cell type and nodal pattern by The Pathology Panel for Lymphome Clinical Trials. Patients were randomly assigned treatment with either cyclophosphamide (C), vincristine (O), and prednisone (P) (COP) or CO without prednisone. Initial treatment was given for 8 weeks and further randomization of responders to observation or additional chemotherapy was carried out. A significant difference in complete remission rate between treatments was shown: with COP, 43%, and with CO, 17%, indicating an important role for prednisone in inducing CR. COP was also associated with longer remission durations and improved survival. Complete remission following initial chemotherapy is also associated with longer duration of disease-free time and survival. The initial pathologic cell types and nodal pattern also strongly influence survival. Extended "maintainence" CO treatment improved disease-free remission duration, but not survival.