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Methods used in the evaluation of therapeutic results in clinical oncology are criticized on the basis of recent examples of studies including the most-used antitumor agents. The need for random allocation of patients in comparative studies is underlined and the practical, statistical, and ethical limitations on randomization procedures are reviewed.
In a prospective study, women who were hypertensive before the 28th wk of gestation were randomly allocated into two groups: those who received specific hypotensive therapy (Ht) and those who did not (Hu). The outcome was compared with a random sample of the hospital population (S) ascertained after delivery. In both hypertensive groups there was a higher incidence of clinical signs of possible fetal distress and instrumental delivery. Although there was no difference between the groups in the distribution of birthweight above and below the mean for gestational age, the treated hypertensive group had an excess of infants with relatively smaller head circumferences for their gestational age compared with both the untreated hypertensive group and the hospital sample. Tube-feeding was also more frequent in the treated hypertensive group. In the untreated hypertensive group there were more infants whose neurological status was categorized as questionable or abnormal in the neonatal period, compared with the sample. The different problems encountered by infants in the two hypertensive groups emphasized the need for further study of these babies. Their development during the first year of life will be examined in a subsequent paper.
The influence of ciamexone on the activity and course of endocrine orbitopathy was investigated. Fifty-one patients with active orbitopathy classes II-VI were allocated randomly to two groups: over a period of six months, 26 patients received 300 mg/day ciamexone and 25 patients received placebo tablets. In both groups, prednisolone was administered in addition in the first four weeks. Ophthalmological investigations and clinical tests as well as orbit sonography were carried out before as well as one, three and six months after the beginning of therapy. Before and after treatment, computer tomography of the orbit was performed. Symptoms and signs did not show any significant improvement one and six months after therapy. No differences between the two therapy groups were observed. Detailed examination did not reveal any preferential action of the product on individual parameters. Sonography and computer tomography showed no significant alterations of the thickness of the oculomotor muscles. Thus administration of 300 mg ciamexone once a day as compared with placebo did not show any effect on the course and activity of endocrine orbitopathy.
The Helsinki Heart Study is a coronary primary prevention trial in a group of middle aged men with lipid abnormalities. Its aim is to investigate the effects on the incidence of coronary heart disease of simultaneously lowering serum total and low density lipoprotein (LDL)-cholesterol and elevating high density lipoprotein (HDL)-cholesterol with gemfibrozil, over a period of 5 years. Participants were selected from a population of 23 531 men between 40 and 55 years of age. The mean serum total cholesterol among 18 966 screened subjects was 6.3 mmol l-1 (245 mg dl-1) and the mean HDL-cholesterol 1.3 mmol l-1 (50.3 mg dl-1). All subjects meeting the lipid acceptance criterion of non-HDL-cholesterol (i.e. total cholesterol minus HDL-cholesterol) greater than 5.2 mmol l-1 (200 mg dl-1) on two separate occasions two to three months apart, who were free from coronary heart disease or other major illness, were invited to participate. The total cholesterol level for the final 4081 study participants was 7.5 mmol l-1 (290 mg dl-1) and HDL-cholesterol was 1.23 mmol l-1 (47.6 mg dl-1). Mean systolic and diastolic blood pressures were 141.7 and 91.3 mmHg. About 15% of participants were hypertensive and 36% were smokers. A total of 2051 men were randomly allocated to receive gemfibrozil 600 mg twice daily and 2030 matching placebo capsules. A cholesterol-lowering diet was also prescribed for all participants. The randomized treatment groups were well balanced. Equal distribution of major risk factors was achieved in relevant sub-groups. This report describes the procedures involved in setting up the study, summarizes the baseline data obtained and reviews the success of the randomization procedure. Finally, it compares the design of this study with that of some other major preventive trials.
A controlled clinical study with random allocation of method of rehabilitation (lens implant or contact lenses) was designed for comparative outcome assessments. Sixty-one patients were included in the study: 31 patients randomized to lens implantation and 30 patients to extended-wear contact lens rehabilitation with early post-operative fitting. Complication rates were low in both groups with slight accumulation of intraocular complications in the implant group and of external complications in the contact lens group. We found no significant differences between the groups in final visual acuity, in vision dependent practical functioning, or in patients' contentment. Two main points summarize our results and impressions from this study: At the expense of a slightly higher risk the lens implant patients get the most convenient and comfortable rehabilitation and at the expense of frequent visits for follow-up and lens cleaning the contact lens patients get the safest rehabilitation. The patient offered contact lens rehabilitation should be capable of alert cooperation, fairly mobile and living within easy access to ophthalmic service, while the patient offered lens implant does not need to fulfill these criteria.
Nizatidine, a new H2-receptor antagonist for the treatment of duodenal ulcer disease, was compared with placebo in a dose-response, double-blind, parallel, multicenter clinical trial. Patients were randomly allocated to receive either nizatidine (25 mg b.i.d., 150 mg b.i.d., or 300 mg at bedtime) or placebo. At the end of 4 weeks, patients whose ulcer had not healed were randomly reallocated to receive either the nizatidine 150 mg b.i.d. dosage regime or placebo for an additional 4 weeks. Nizatidine doses of 300 mg at bedtime and 150 mg b.i.d. demonstrated similar healing frequencies. Both of these doses were statistically significantly superior in ulcer healing to the nizatidine 25 mg b.i.d. dose and to placebo at the end of 4 weeks. Patients randomly reallocated to receive nizatidine had significantly greater healing rates than patients randomly reallocated to receive placebo. In summary, nizatidine given as a single evening dose of 300 mg or as 150 mg b.i.d. proved to be equally safe and effective in the healing of active duodenal ulcers.
One hundred and twelve consecutive Child Class A and B cirrhotic patients were included in a prospective controlled trial aimed at investigating the efficacy and safety of endoscopic sclerotherapy vs. distal splenorenal shunt in the elective treatment of hemorrhage from esophagogastric varices. Fifty-seven patients were randomly allocated to splenorenal shunt and 55 to endoscopic sclerotherapy. Since only 4 of the 55 patients assigned to endoscopic sclerotherapy had to be excluded after randomization and before treatment as compared to 14 of the 57 patients assigned to splenorenal shunt, it is suggested that the applicability of endoscopic sclerotherapy is greater than that of splenorenal shunt. One patient in each group died within 30 days of the procedure and two in the endoscopic sclerotherapy group were lost to follow-up just after discharge. Variceal rebleeding during follow-up occurred in 37.5% (18/48) of patients in the endoscopic sclerotherapy group and in 14.3% of those in the splenorenal shunt group (6/42) (p less than 0.02), whereas hepatic encephalopathy was more frequent in patients submitted to splenorenal shunt (10/42, 24%) than in those treated by endoscopic sclerotherapy (4/48, 8%) (p less than 0.05). The therapeutic modality was the only variable with independent predictive value for rebleeding during follow-up, whereas for hepatic encephalopathy, the therapeutic modality, and the presence of encephalopathy related to the bleeding episode each showed independent predictive value. Early and long-term mortality, did not differ between the two therapeutic groups, being the 2-year survival was 71% for splenorenal shunt and 68% for endoscopic sclerotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Between 1972 and 1975 the Children's Cancer Study Group conducted two clinical trials for the treatment of newly diagnosed patients with acute lymphoblastic leukemia. Upon achieving 3 yr of continuous complete remission, 316 children and young adults were randomly allocated either to discontinue chemotherapy or to continue chemotherapy for an additional 24 mo. With a median follow-up from the time of randomization of 50 mo, those patients who received 3 yr of therapy have demonstrated a statistically non-significant yet higher incidence of bone marrow relapse as compared to those patients treated for 5 yr (p = 0.09). However, the proportion of patients surviving 5 yr from randomization is 93% for the 3-yr treatment group and 89% for the 5-yr treatment group (p = 0.27). No significant difference was observed between the randomized groups for the occurrence of testicular relapse (p = 0.12), central nervous system relapse (p = 0.17), or first occurrence of relapse or death (p = 0.24). The relapse-free survival of patients treated for 5 yr as compared to those treated for 3 yr was not significantly higher in males (81% versus 75%, p = 0.14) or females (89% versus 89%, p = 0.95). This randomized study did not demonstrate a significant difference between treatment for either 3 or 5 yr.
The effect of tampon use on cervicovaginal immunoglobulins, complement, fibronectin, and antistaphylococcal opsonic activity was determined in a study of 35 healthy women randomly allocated to either tampon or napkin use for three consecutive menstrual cycles. Sequential cervicovaginal washings were collected on days 3 (+/- 2), 15 (+/- 2), and 25 (+/- 2) of the menstrual cycle before randomization and that 3 months afterward. Prior to randomization, no statistically significant differences were noted for any parameter (with correction for total protein content) between regular tampon users and exclusive napkin users. Following randomization, total opsonic activity during tampon use increased significantly over that in the same women during napkin use (P = .04, Wilcoxon matched-pairs signed-ranks test, two-tailed). This difference was observed only in menstrual samples and not at other sampling times. These data indicate that tampon use has minimal effects on cervicovaginal mucosal immunity and is not associated with aberrations of opsonophagocytosis in the lower female genital tract.
The effect of tampon usage on the vaginal microflora of 35 healthy women was determined following their random allocation to either tampon or napkin use for three consecutive menstrual cycles. Sequential and semiquantitative vaginal cultures were obtained on days 3 +/- 2, 15 +/- 2, and 25 +/- 2 of the menstrual cycle (day 1, first day of menses) before and after randomization. Before randomization, the rate of isolation and median counts of facultative lactobacilli were significantly higher (P less than .05) and that of eubacteria was significantly lower (P = .026) among regular tampon users than among exclusive napkin users. After randomization, only median counts of coagulase-negative staphylococci were significantly increased (P = .025) during tampon use compared with the rates for the same women during napkin use. These shifts in vaginal microflora occurred only in samples obtained during menstruation and not in those obtained at other sampling times. The data presented here support the notion that the use of tampons may result in alterations in the autochthonous vaginal microflora. It remains to be determined if these ecologic shifts in the vaginal microflora may adversely affect resistance to colonization by potential pathogens in the lower female genital tract.
This was a random double-blind study versus placebo designed to assess the effectiveness and tolerability of defibrotide in patients with chronic peripheral vascular disease (PVD), Leriche stage II. A total of 20 male outpatients (mean age 58.8 years) were selected and treated with placebo for 2 weeks (run-in period), and then allocated randomly to treatment with defibrotide (200 mg/day, intramuscular, n = 10) or matched placebo (n = 10) for 90 days. Before intake and at 15, 30, 60, and 90 days of treatment, each patient received a Doppler ultrasound examination of the lower limbs, and the residual perfusion index (Winsor) was calculated at rest and immediately after a symptom-limited treadmill test. Absolute walking distance was measured in addition. Blood samples were taken for routine laboratory tests before intake and at 30 and 90 days of treatment. All patients completed the trial without adverse effects; no meaningful alterations of laboratory test returns were detected. Patients receiving defibrotide showed a significant increase of the Winsor index after exercise at 90 days versus basal (mean 0.47 +/- 0.04 vs. 0.43 +/- 0.05, p less than 0.05), and a parallel increase of walking distance (basal 288 +/- 42.3 m vs. 368 +/- 46.6 at 60 days, p less than 0.05, and 407 +/- 64.3 m at 90 days, p less than 0.01). No improvement was seen in the placebo group. These preliminary results suggest that defibrotide may prove beneficial to patients with PVD; further studies are needed to find the most appropriate dosage regime.
To assess the efficacy of low dose praziquantel regimens in comparison with standard 40 mg/kg dosing in the treatment of urinary schistosomiasis, a random allocation dose-finding trial was performed in children and adults from a Schistosoma haematobium endemic region in Coast Province, Kenya. Following an initial screening, 280 individuals with greater than or equal to 50 eggs/10 ml urine were randomly assigned to receive either 10, 20, 30, or 40 mg/kg of the drug in a single oral dose. Two to three months later, cure rates of 26%, 68%, 78%, and 84% were found for the 10, 20, 30, and 40 mg/kg doses, respectively. The results of 10 mg/kg oral dosing were significantly worse than for all other doses in terms of cure rate and of post-treatment prevalence of morbidity. The 40 mg/kg dosing resulted in a significantly higher cure rate than the 20 mg/kg doses; nevertheless, there was no significant difference between 20 mg/kg and 40 mg/kg doses in terms of mean post-treatment intensity of infection or post-treatment prevalence of hematuria or proteinuria. For large-scale control programs, oral 20 mg/kg praziquantel therapy for urinary schistosomiasis may prove as effective as the standard oral 40 mg/kg dosing for control of infection-associated morbidity and reduction of parasite transmission.
Betaxolol is a cardioselective beta-blocker, which has a bioavailability of 90% and a T 1/2 of 20 h. A four group, cross-over double-blind trial was conducted to select between betaxolol 20 mg and 40 mg for long term trials. 60 patients were allocated randomly to one of the sequences placebo-20 mg, 20 mg-placebo, placebo-40 mg and 40 mg-placebo, each treatment lasting for 2 weeks. Groups were homogenous for baseline diastolic blood pressure (DBP), age and male/female ratio, and were slightly unbalanced for weight. A two-way ANOVA (3 treatments, 2 sequences) showed no treatment-sequence interaction nor sequence effect. The mean reduction in DBP was 14.2 +/- 1.8 mm Hg following 20 mg and 18.0 +/- 1.8 following 40 mg betaxolol, and 4.0 +/- 1.2 mm Hg during placebo (p less than 0.001). Age, weight, baseline DBP and duration of hypertension did not influence the treatment effect. The 95% confidence intervals of the reduction in DBP were 10.4 - 17.9 for 20 mg and 14.3 - 21.6 mm Hg for betaxolol 40 mg. Aiming at a mean reduction to 90 mm Hg, betaxolol 20 mg would appear to be adequate in similar patient populations.
Two experiments were performed in order to study how weaning and post-weaning dietary zinc level affect serum IGF-I. Further, whether the growth-enhancing effect of 2500 ppm of dietary zinc (Zn2500) and/or 175 ppm of dietary copper (Cu175) in post-weaning diets is associated with elevated serum IGF-I levels in piglets was studied. Experiment 1 included 54 piglets (six litters of nine piglets). One piglet from every litter was assigned to a control group (blood sampled 1 day before weaning). At weaning the remaining eight piglets from every litter were allocated randomly to four dietary treatments with increasing zinc inclusions (Zn100, Zn250, Zn1000, Zn2500). In exp. 2, 48 piglets (six litters of eight piglets) were allocated to four dietary treatments (Zn100, Zn100Cu175, Zn2500, Zn2500Cu175). All piglets in exp. 1 were blood sampled at -1, 1-2, 5-6 or 14-15 days after weaning and in exp. 2 blood samples were taken from all pigs 5-7 days after weaning. Feed intake was recorded per pen (two piglets) and weight gain was recorded for every piglet. Just after weaning feed intake was very low, piglets lost weight and serum IGF-I decreased in exp. 1. However, the piglets fed 2500 ppm of zinc reached pre-weaning levels of serum IGF-I at 14-15 days post-weaning, whereas piglets receiving lower zinc levels showed no changes in serum IGF-I. In exp. 2, additional dietary zinc in weaning diets for piglets was found to be associated with increased feed intake, improved growth rate and increased serum IGF-I. High levels of dietary copper did not affect any of these measurements. Zinc-induced rise in serum IGF-I was partly due to increased feed intake. After correcting for differences in feed intake, zinc significantly increased serum IGF-I. However, to completely separate effects of feed intake from effects of zinc status, pair-feeding should be considered in future studies.
The combined spinal-epidural technique (CSE) has been associated with prolonged motor recovery and more frequent arterial hypotension as compared with a single-shot spinal (SSS) technique. We determined the median effective dose (MED) of intrathecal hyperbaric bupivacaine for CSE and SSS by using the up-down sequential allocation technique. Sixty male patients were randomly allocated to receive intrathecal administration through an SSS or CSE technique. Needle insertion occurred at the L3-4 interspace in all patients. In SSS, 9.5 mg of hyperbaric bupivacaine was administered through a 27-gauge Whitacre spinal needle. In CSE, a 17-gauge Tuohy needle with 4 mL of air was used to locate the epidural space, through which a 27-gauge Whitacre spinal needle was introduced and 7.0 mg of hyperbaric bupivacaine was administered. The dosing adjustment was 0.5 mg. A "successful" outcome was arbitrarily defined as sensory anesthesia at or above the T6 dermatome lasting for 60 min. A "success" resulted in a 0.5-mg decrement, whereas a "failure" resulted in a 0.5-mg increment in the next patient. There were 13 successes in both groups. The MED of bupivacaine was 9.18 mg (95% confidence interval, 8.89-9.47 mg) for CSE as compared with 11.37 mg (95% confidence interval, 10.88-11.86 mg) for SSS (P < 0.001). CSE required 19.3% (95% confidence interval, 14.9%-23.6%) less local anesthetic to achieve the defined clinical target. We found significant discrepancies in the MED of hyperbaric bupivacaine between the two techniques. Under similar clinical conditions, a 20% decrement in the dose of bupivacaine may be warranted whenever CSE is intended in place of SSS.
One hundred and eighty children admitted with measles were randomly allocated to receive routine treatment alone or with additional large doses of vitamin A (200,000 IU orally immediately and again the next day). Baseline characteristics of the two groups were virtually identical for age, severity of measles, and vitamin A and general nutritional states. In 91% of the children serum vitamin A concentrations were less than 0.56 mumol/l. Of the 88 subjects given vitamin A supplements, six (7%) died; of the 92 controls, 12 (13%) died (p = 0.13). This difference in mortality was most obvious for children aged under 2 years (one death out of 46 children receiving supplements versus seven deaths out of 42 controls; p less than 0.05) and for cases complicated by croup or laryngotracheobronchitis. Mortality was several times higher in marasmic than in better nourished children, regardless of study allocation (p less than 0.01).
Orthostatic intolerance is a syndrome characterized by chronic orthostatic symptoms of light-headedness, fatigue, nausea, orthostatic tachycardia, and aggravated norepinephrine levels while standing. The aim of this study was to assess the protective effect of exercise endurance training on orthostatic symptoms and to examine its usefulness in the treatment of orthostatic intolerance. 2768 military recruits were screened for orthostatic intolerance by questionnaire. Tilt-table testing identified 36 cases of orthostatic intolerance out of the 2768 soldiers. Subsequently, 31 of these subjects with orthostatic intolerance entered a randomized, controlled trial. The patients were allocated randomly to either a "training" (3 months jogging) or a "control" group. The influence of exercise training on orthostatic intolerance was assessed by determination of questionnaire scores and tilt-table testing before and after intervention. After training, only 6 individuals of 16 still had orthostatic intolerance compared with 10 of 11 in the control group. The Fisher exact test showed a highly significant difference in diagnosis between the 2 groups (P=0.008) at the end of the study. Analysis of the questionnaire-score showed significant interaction between time and group (P=0.001). The trained subjects showed an improvement in the average symptom score from 1.79+/-0.4 to 1.04+/-0.4, whereas the control subjects showed no significant change in average symptom score (2.09+/-0.6 and 2.14+/-0.5, respectively). Our data demonstrate that endurance exercise training leads to an improvement of symptoms in the majority of patients with orthostatic intolerance. Therefore, we suggest that endurance training should be considered in the treatment of orthostatic intolerance patients.
Survey researchers believe that self reports, in general, are more accurate than reports obtained by proxy. This paper focuses on the reassessment of previous self/proxy comparisons and presents findings from a telephone adaptation of the National Health Interview Survey (NHIS) designed to investigate response error associated with self and proxy reports. Unlike previous studies in which the type of report is confounded with characteristics of the population home at the time of the interview, the design of this study (random allocation to self or proxy report) allows comparison of reports from similar populations. The results show that when self response is limited to a randomly selected respondent, the self respondents report fewer health events for themselves versus for others in their household.