National Cooperative Crohn's Disease Study: study design and conduct of the study.

The design and execution of the National Cooperative Crohn's Disease Study are described in this paper. The Study incorporated several noteworthy features developed to meet specific demands of the disease and its therapy. A standard clinical grading system, the Crohn's Disease Activity Index (CDAI) was developed to allow uniform decentralized clinical evaluation and decision-making throughout the 5 yr of the study. All three drugs in widespread clinical use in Crohn's disease were studied both for suppressive and prophylactic efficacy and for toxicity. The study employed a scheme for double-blind evaluation of patient progress which allowed adjustment of prednisone dose according to the degree of illness and ensured continuous monitoring for serious toxicity of any study drug. Results were analyzed primarily by ranking the clinical outcome of every patient according to a uniform and detailed scheme and applying Wilcoxon nonparametric statistics. Outcome was also analyzed by life-table methods. Eleven hundred nineteen patients were entered and 604 patients were randomized at 14 study centers during the 5-yr duration of the study. Twenty patients were eliminated from analysis as not meeting diagnostic criteria for Crohn's disease, and another 15 patients were eliminated as not meeting other preestablished criteria for analysis. Nine percent of randomized patients, equally distributed in the four treatment groups, withdrew as noncompliant. Ninety percent of patients completed all or all but one protocol-specified visits, and 95% completed the final radiologic and sigmoidoscopic evaluation.

National Cooperative Crohn's Disease Study: results of drug treatment.

The response of active and quiescent Crohn's disease to prednisone, sulfasalazine, or azathioprine has been studied in 569 patients in a placebo-controlled, randomized, multicenter cooperative trial. The response of active symptomatic disease to prednisone or sulfasalazine was significantly better than to placebo. Response to azathioprine was better than to placebo, but the difference did not reach conventional levels of statistical significance. Patients with colonic involvement were especially responsive to sulfasalazine, and those with small bowel involvement were especially responsive to prednisone. Patients' drug therapy immediately before entry to the study significantly affected subsequent response. For patients with quiescent disease, none of the drugs was superior to placebo in prophylaxis against flare-up or recurrence. There is less than a 5% risk that a clinically significant prophylactic effect of any of the drug regimens was missed.

A trial of sulfasalazine as adjunctive therapy in Crohn's disease.

The effect of the combination of sulfasalazine and prednisone has been compared with that of prednisone and placebo in 89 actively symptomatic patients with Crohn's disease in a double-blind, randomized, multicenter controlled trial. The combination was less effective than prednisone alone in treatment of active symptomatic disease. The probability of obtaining this result, if sulfasalazine truly has a clinically useful effect equal to or greater than that specified in the calculation, is less than 1%. Patients who were in remission at the end of 8 wk were rerandomized to receive either the two drugs together or prednisone plus placebo while repeated systematic attempts to withdraw prednisone were made over the next 6 mo. Sulfasalazine showed no prednisone-sparing effect as judged either by outcome ranking or total dose of prednisone consmed by the two treatment groups. However, in this comparison the probability is greater than 5% that, given the results observed, a clinically useful effect of sulfasalazine of specified minimum degree truly exists. It was possible to withdraw prednisone from 25% of patients at the first attempt and ultimately in 37%.

Rederived values of the eight coefficients of the Crohn's Disease Activity Index (CDAI).

A previous paper reported derivation of the Crohn's Disease Activity Index (CDAI) from data on 112 patients. We have now rederived the values of the eight coefficients of the CDAI using data from 1058 visits of patients enrolled in the National Cooperative Crohn's Disease Study and the Trial of Adjunctive Sulfasalazine in Crohn's Disease. The rederived coefficients are similar to the original ones. New and original index values calculated on the same data from patient visits correlated very highly. Because there is so little difference between the original and the rederived versions, continued use of the original version is suggested in order to maintain comparability of new studies employing this tool with those previously accomplished.

Clinical implications of sickle-cell trait and glucose-6-phosphate dehydrogenase deficiency in hospitalized black male patients.

To determine whether sickle-cell trait and glucose-6-phosphate dehydrogenase deficiency influence the course and fatality rates of certain diseases requiring hospitalization, especially those associated with thrombotic phenomena, we conducted a co-operative study of 65,154 consecutively admitted, black male patients in 13 Veterans Administration hospitals. The overall frequency of sickle-cell trait was 7.8 per cent and of glucose-6-phosphate dehydrogenase dificiency 11.2 per cent. Both conditions were present in 0.9 per cent of those examined. There were regional, but no age-dependent, differences in the frequency of sickle-cell trait. Sickle-cell trait had no effect on average age at hospitalization or death, overall mortality, length of hospitalization on medical and surgical wards and frequency of any diagnosis, except essential hematuria and pulmonary embolism. Although statistically significant (P less than 0.001), the differences for the latter were small (1.5 per cent of all patients with normal hemoglobin and 2.2 per cent of patients with sickle-cell trait). Glucose-6-phosphate dehydrogenase deficiency had no adverse effect.

Evaluation of clinical chemistry laboratory performance in twenty Veterans Administration hospitals.

Twenty highly automated Veterans Administration (VA) Hospital laboratories participated in a study to evaluate their performances of routine chemistry tests. Ten of the laboratories had been identified as "superior" on the basis of previous College of American Pathologists Surveys. Several aspects of proficiency surveys were simultaneously examined: use of masked vs. unmasked survey specimens, methods of ranking, and comparison of medically useful performance criteria. The laboratories were found in general to be performing at the level of the state of the art and, more importantly, realistically meeting the criteria for medical needs for most routine tests. There was no difference between results obtained with masked and unmasked specimens. The ten "superior" laboratories showed slightly greater precision than the others, but were not more accurate, and two of them performed very poorly in the present study. The sum of squared SDI's was found to be a helpful technic for ranking and identifying outstanding and poor performances.

Pooled normal values, a useful technic.

Few laboratories determine their normal values, because of the work involved. This study attempted to see whether a group of laboratories, each contributing a portion of the samples, could pool their information to yield data applicable to the whole group. Each of 20 VA Hospital laboratories obtained approximately 20 fasting early morning specimens from healthy men, aged 20-29 years, during a four-week period. Routine chemistry examinations (16) were performed on Technicon AutoAnalyzers (12/60, 6/60, and AAII), and model S Coulter Counters were used for five hematology tests (381 values for each constituent). Within-day, day-to-day, and interlaboratory variance were determined in parallel-method variability studies. The data showed: (1) it is valid to pool normal values from different laboratories when non-random variables have been eliminated; (2) non-random variables can be identified by increased interlaboratory variance, whether differences such as methods and equipment are obvious or not; (3) normal values so derived agree well with those from large series performed in single laboratories.

Effect of temperature on binding of warfarin by human serum albumin.

The in vitro binding of warfarin by human serum albumin was studied at various temperatures and at pH 7.4 by a frontal gel filtration technique. The results can be best described in terms of a two class-of-binding site model, in which the numbers of primary and secondary sites are constrained to the average values for all experiments (n1 = 1.38 and n2 = 3.73). Analysis of the temperature dependence of the binding yielded the following thermodynamic parameters: deltaH1 =-2.55 kcal/mole, deltaS1=16.1 eu, and deltaF1=-7.34 kcal/mole for the primary binding and deltaH2=-5.08 kcal/mole, deltaS2=-1.10 eu, and deltaF2=4.72 kcal/mole for the secondary binding. Calculations based on these results showed that, for the therapeutic concentration range, warfarin was over 99% bound to albumin present in physiological concentration. These findings are compared and contrasted to binding data in the literature for warfarin and salicylate.

Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study.

Needing a single index of degree of illness in Crohn's disease, the National Cooperative Crohn's Disease Study group collected data prospectively from 187 visits of 112 patients with Crohn's disease of the small bowel, colon, or both. Information on 18 predictor variables was gathered at each visit. In addition, the attending physician rated his over-all evaluation of how well the patient was doing and compared the patient's status with that at the previous visit. A multiple regression computer program was utilized to derive an equation for prediction of the physician's over-all ratings from a subset of the predictor variables fulfilling a combination of constraints. This equation, numerically simplified and utilizing eight selected variables, is the Crohn's Disease Activity Index. Index values of 150 and below are associated with quiescent disease; values above that indicate active disease, and values above 450 are seen with extremely severe disease.