The impact of medical therapy on bother due to symptoms, quality of life and global outcome, and factors predicting response. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group.

PURPOSE: We determine the effect of placebo, finasteride, terazosin and a combination of drugs on bother due to symptoms, quality of life and patient perception of improvement, and identify baseline clinical factors that predict clinical response to medical therapy. MATERIALS AND METHODS: A total of 1,229 subjects with clinical benign prostatic hyperplasia (BPH) were randomized to 1 year of placebo, finasteride, terazosin or drug combination. The primary outcome measures were American Urological Association (AUA) symptom score and peak flow rate. Relevant secondary outcome measures were symptom problem score, BPH impact score and global rating of improvement. RESULTS: Group mean differences in symptom problem and BPH impact scores between the finasteride versus placebo, and terazosin versus combination groups were not statistically or clinically significant. Group mean differences in all outcome measures were highly statistically significant between the terazosin and finasteride, and combination and finasteride groups. The percentage of subjects who rated improvement as marked or moderate with placebo, finasteride, terazosin and combination was 39, 44, 61 and 65%, respectively. In the subsets of men in the placebo, finasteride, terazosin and combination groups with prostates greater than 50 cm.3 group mean decrease from baseline in AUA symptom score was -2.5, -3.6, -6 and -7, group mean increase in peak flow rate was 0.6, 2.7, 3.6 and 3.7 ml. per second, group mean decrease in symptom problem score was -2.2, - 1.9, -3.1 and -4.5, and group mean decrease in BPH impact score was -0.6, -0.3, -1.1 and -1.5, respectively. A correlational analysis failed to show a significant relationship between baseline prostate volume and treatment response to finasteride. There was a significant but weak relationship between change in AUA symptom score and peak flow rate in the finasteride and combination groups. The symptom responses with terazosin were independent of baseline peak flow rate. CONCLUSIONS: In men with clinical BPH finasteride and placebo are equally effective, while terazosin and combination are significantly more effective. In men with clinical BPH and large prostates the advantage of finasteride over placebo in terms of symptom reduction, impact on bother due to symptoms and quality of life is small at best, while the advantage of terazosin and combination over finasteride and placebo is highly significant. Baseline prostate volume was not a predictor of response to finasteride in the overall study population. On the basis of our results alpha1 blockers, such as terazosin, should be first line medical treatment for BPH.

Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active ankylosing spondylitis (AS) that is not controlled with nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred sixty-four patients with AS were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on morning stiffness, back pain, and physician and patient global assessments. RESULTS: While longitudinal analysis revealed a trend favoring SSZ in the middle of treatment, no difference was seen at the end of treatment. Response rates were 38.2% for SSZ and 36.1% for placebo (P = 0.73). The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). AS patients with associated peripheral arthritis showed improvement that favored SSZ (P = 0.02). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints. CONCLUSION: SSZ at a dosage of 2,000 mg/day does not seem to be more effective than placebo in the treatment of AS patients with chronic, longstanding disease. SSZ is well tolerated and may be more effective than placebo in the treatment of AS patients with peripheral joint involvement. This effect is more pronounced in treatment of the peripheral arthritis in this subgroup of AS patients.

Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active psoriatic arthritis (PsA) resistant to nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred twenty-one patients with PsA were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on joint pain/ tenderness and swelling scores and physician and patient global assessments. RESULTS: Longitudinal analysis revealed a trend favoring SSZ treatment (P = 0.13). At the end of treatment, response rates were 57.8% for SSZ compared with 44.6% for placebo (P = 0.05). The Westergren erythrocyte sedimentation rate declined more in the PsA patients taking SSZ than in those taking placebo (P < 0.0001). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints, including dyspepsia, nausea, vomiting, and diarrhea. CONCLUSION: SSZ at a dosage of 2,000 mg/day is well tolerated and may be more effective than placebo in the treatment of patients with PsA.

Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter's syndrome). A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective in the treatment of reactive arthritis (ReA) that has been unresponsive to nonsteroidal antiinflammatory drug (NSAID) therapy. METHODS: One hundred thirty-four patients with ReA who had failed to respond to NSAIDs were recruited from 19 clinics, randomized (double-blind) to receive either SSZ or placebo, and followed up for 36 weeks. The definition of treatment response was based on joint pain/tenderness and swelling scores and physician and patient global assessments. RESULTS: Longitudinal analysis revealed improvement in the patients taking SSZ compared with those taking placebo, which appeared at 4 weeks and continued through the trial (P = 0.02). At the end of treatment, response rates were 62.3% for SSZ treatment compared with 47.7% for placebo treatment. The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints. CONCLUSION: SSZ at a dosage of 2,000 mg/day is well tolerated and effective in patients with chronically active ReA.

Immunoprophylaxis against klebsiella and pseudomonas aeruginosa infections. The Federal Hyperimmune Immunoglobulin Trial Study Group.

To determine if passive immunization could decrease the incidence or severity of Klebsiella and Pseudomonas aeruginosa infections, patients admitted to intensive care units of 16 Department of Veterans Affairs and Department of Defense hospitals were randomized to receive either 100 mg/kg intravenous hyperimmune globulin (IVIG), derived from donors immunized with a 24-valent Klebsiella capsular polysaccharide plus an 8-valent P. aeruginosa O-polysaccharide-toxin A conjugate vaccine, or an albumin placebo. The overall incidence and severity of vaccine-specific Klebsiella plus Pseudomonas infections were not significantly different between the groups receiving albumin and IVIG. There was some evidence that IVIG may decrease the incidence (2.7% albumin vs. 1.2% IVIG) and severity (1.0% vs. 0.3%) of vaccine-specific Klebsiella infections, but these reductions were not statistically significant. The trial was stopped because it was statistically unlikely that IVIG would be protective against Pseudomonas infections at the dosage being used. Patients receiving IVIG had more adverse reactions (14.4% vs. 9.2%).

Masking drug treatments in the Cardiac Arrhythmia Pilot Study (CAPS). FASHP for the CAPS Investigators.

The effectiveness of masking in the Cardiac Arrhythmia Suppression Study (CAPS) was assessed by surveying investigators and study coordinators. CAPS patients were assigned one of five treatments: encainide, flecainide, imipramine, moricizine, or placebo. Had all treatments appeared identical and equal numbers of patients been assigned to each, 20% of guesses of treatment assignment would be correct by chance alone. Since neither was possible in CAPS, higher rates of correct guessing were expected. Overall, respondents correctly identified treatment 39% of the time. Investigators identified the drug 30% of the time with rates of 20%, 24%, 37%, 20%, and 55% for the five treatment groups, respectively, whereas coordinators identified the treatments 47% of the time with scores of 42%, 45%, 50%, 40%, and 60%. Side effects and a suboptimal masking design detracted from masking; electrocardiographic changes did not imipramine, which caused characteristic side effects, was the most frequently identified active treatment. Scores were higher for investigators who had prior experience with the drugs, but scores did not improve over the course of the trial. Findings suggest that to improve masking all drugs should have been matched in appearance or persons evaluating treatments should not have been allowed to see the drugs.

The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign Prostatic Hyperplasia Study Group.

BACKGROUND: Men with benign prostatic hyperplasia can be treated with alpha 1-adrenergic-antagonist drugs that relax prostatic smooth muscle or with drugs that inhibit 5 alpha-reductase and therefore reduce tissue androgen concentrations. However, the effects of the two types of drugs have not been compared. METHODS: We compared the safety and efficacy of placebo, terazosin (10 mg daily), finasteride (5 mg daily), and the combination of both drugs in 1229 men with benign prostatic hyperplasia. American Urological Association symptom scores and peak urinary-flow rates were determined at base line and periodically for one year. RESULTS: The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.1, and 6.2 points, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of 1.4, 1.6, 2.7, and 3.2 ml per second, respectively (P<0.001 for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, 1.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups. CONCLUSIONS: In men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone.

Adherence and arrhythmic mortality in the cardiac arrhythmia suppression trial (CAST).

Patient adherence to therapy is essential to assess treatment efficacy, particularly in clinical trials. Active treatment usually is expected to benefit patients. The healthy adherer effect, the association or greater adherence to all health-promoting behaviors, including medication and overall concern for health, explains the improved survival of more adherent patients in both active and placebo medication groups of several clinical trials. The Cardiac Arrhythmia Suppression Trial (CAST), a placebo-controlled double-blind clinical trial of post-myocardial infarction (MI) patients with asymptomatic ventricular arrhythmias, in which active medication (encainide or flecainide) led to increased mortality, provided an opportunity to examine the relationship of adherence to survival from a different perspective. We consider whether adherence to active treatment was related to arrhythmic mortality and whether a healthy adherer effect might counteract the effect of treatment on mortality among patients taking active medication. Adherence (average pill count) at the first follow-up visit did not differ in the active treatment (92.2%, standard deviation (SD) = 11.97, n = 574) and placebo (90.8%, SD = 13.66, n = 579) groups. In a Cox proportional hazard regression model, medication adherence predicted arrhythmic mortality among the active (P < 0.0062) but not the placebo medication group. The effect of adherence on arrhythmic mortality was significant beyond the effects of ejection fraction, race, spouse, smoking status, diuretic medication, and history of MI. A 10% increase in adherence led to more than a threefold increase of risk of arrhythmic death. The design of the CAST, which included a titration phase, may have tended to select relatively adherent patients since only those whose arrhythmias were suppressed with active medication were randomized into the trial. The data do not support a strong healthy adherer effect in the CAST. There was no evidence in this study that a healthy adherer effect counterbalanced the effect of the active medication.

Intrapleural tetracycline for the prevention of recurrent spontaneous pneumothorax. Results of a Department of Veterans Affairs cooperative study.

This prospective, multicenter, randomized, "unblinded," controlled clinical trial was designed to determine if the intrapleural instillation of 1500 mg of tetracycline hydrochloride would be effective in diminishing the ipsilateral rate of recurrence for spontaneous pneumothorax. During the 4-year enrollment period, 113 patients were assigned to the tetracycline group; 116 patients were assigned to the control group. During the 5-year study period, the recurrence rate in the tetracycline group (25%) was significantly less than that in the control group (41%). Use of tetracycline seemed to reduce the recurrence rates for patients with either primary or secondary spontaneous pneumothorax and for patients with either an initial or a recurrent pneumothorax. We conclude that the intrapleural administration of tetracycline in patients with spontaneous pneumothorax significantly reduces the rate of ipsilateral recurrence but is associated with intense chest pain. Intrapleural tetracycline therapy is indicated for patients with a spontaneous pneumothorax who are hospitalized and are treated with tube thoracostomy.

Chronic calcium antagonist use in carcinoma of the lung and colon: a retrospective cohort observational study.

Detailed records were maintained prospectively of all medications taken by 719 patients with advanced carcinoma of the lung or colon. Of this total, a cohort of 19 patients was identified who had ingested incidentally either nifedipine, diltiazem, verapamil, or trifluoperazine in standard therapeutic doses for a minimum of one month and a mean of 5.8 months and median of three months. Treatment with these calcium antagonists was well tolerated and, upon comparison with otherwise comparable patients who did not ingest a calcium antagonist, appeared to be associated with certain favorable outcomes, including delayed tumor progression and prolonged survival. These preliminary findings suggest that beneficial effects of such drugs observed with chronic treatment in experimental animal tumor models may occur in human disease and that definitive prospective, randomized, clinical trials of calcium antagonists administered continuously in ordinary therapeutic doses are both feasible and justified.

Effect of mopidamol on survival in carcinoma of the lung and colon: final report of Veterans Administration Cooperative Study No. 188.

Mopidamol (RA-233), a derivative of dipyridamole, is a phosphodiesterase inhibitor that has been shown previously to limit progression of malignancy in certain experimental animal models and in a pilot study in humans. RA-233 plus chemotherapy was compared with chemotherapy alone in a 5-year double-blind trial involving 719 patients with advanced carcinomas of the lung and of the colon. RA-233 treatment was associated with a statistically significant prolongation of survival in patients with non-small cell lung cancer (N-SCLC) limited to one hemithorax and with reduction in mean plasma fibrogen concentration. RA-233 was not toxic. The favorable effects on survival could not be explained by any factor other than the RA-233 treatment. In other tumor categories tested, no differences in survival were observed. These results suggest that RA-233 is useful in the treatment of N-SCLC of limited extent. They also suggest that therapeutic intervention aimed at modified intracellular pathways might constitute a novel investigative approach to the treatment of cancer.

Study protocol: a randomized clinical trial of total parenteral nutrition in malnourished surgical patients.

CSP #221 is a randomized multiinstitutional clinical trial to assess the efficacy of 10 d of perioperative total parenteral nutrition (TPN) in reducing morbidity and mortality in malnourished patients undergoing intraperitoneal and/or intrathoracic operations. In this paper a detailed protocol for the clinical efficacy trial is presented primarily as a reference document for use in interpretation of the results of the clinical trial. It is also anticipated, however, that review of this protocol may be useful to other investigators planning future clinical nutrition intervention trials.

The investigator-sponsored IND in clinical trials.

The Food, Drug, and Cosmetic Act requires that clinical investigations conducted in the United States involving unapproved drugs be done under an Investigational New Drug Application (IND). INDs are often sponsored by pharmaceutical firms or noncommercial research institutions. Most INDs, however, are sponsored by individual researchers. Since the procedures for filing an IND may not be well understood, this article seeks to clarify these procedures. Specifically, this article describes a "Sponsor-Investigator IND," the conditions under which one is required, and the possible advantages of filing one. The information presented aids the investigator in determining whether an IND need be submitted. The authors have developed an IND workbook that can be used to organize and present the IND application in a form likely to facilitate expeditious review and approval by the FDA. The authors have also developed IND guidelines to assist investigators in preparing, submitting, and maintaining an IND. Obligations and responsibilities of both sponsors and investigators are discussed.

Riboflavin use as a drug marker in Veterans Administration cooperative studies.

Most Veterans Administration (VA) cooperative studies have used only the pill count method to measure and describe patient adherence to a drug regimen. The use of a drug marker is considered when adherence is expected to be a problem in a study, especially if the therapeutic drug or metabolite cannot be measured in the blood or urine of all patients or if reliability of pill counts is open to serious question. In a VA-NHLBI hypertension study using riboflavin as a marker for assessing patient adherence, group data suggest that similar adherence scores can be expected when comparing pill counts and urine tests. However, when an individual patient's adherence was examined by each method at a particular visit, discrepancies were noted. In a VA cooperative study on disulfiram for the treatment of alcoholism, riboflavin used as a marker provided additional information that was needed to assess the adherence of the study population. By employing this second measure of adherence in this study, we were able to obtain at least one measure of adherence at 84% of all clinic visits. If the pill count method had been the sole adherence measure, only 60% of visits would have produced an adherence score. At 65% of clinic visits, the pill count and urine test were in agreement. Results of urine tests taken in the interval between visits were similar to those taken at the clinic visit. Patient cooperation in providing urine specimens or in returning pills to the clinic was slightly associated with positive adherence scores.(ABSTRACT TRUNCATED AT 250 WORDS)

National survey of pharmacy-coordinated investigational drug services.

A national survey of 703 pharmacy departments was conducted to obtain information on the status and scope of investigational drug services (IDS). Questionnaires were mailed to the directors of pharmacy departments of general medical and surgical hospitals with 300 or more beds and a university affiliation. The survey consisted of 27 questions that were primarily based on the ASHP guidelines for the use of investigational drugs in institutions. A total of 403 questionnaires were returned, 386 of which could be evaluated, 386 of which could be evaluated. Only 33% of the pharmacy departments adopted a minimal subset (7 of 11) of the recommended procedures based on the ASHP guidelines. All pharmacy departments with more than 40 protocols reported having a research pharmacist or a need for one. Of all of the protocols, 43% were sponsored by the National Institutes of Health, 34% by pharmaceutical companies, 16% by investigators and physicians, and 7% by various other sponsors. Drug information, monetary reimbursement for services,a dn coordination and communication were the most frequently cited areas in need of improvement by the drug sponsors. The most common types of protocols involved cancer research (56%) and infectious disease and cardiovascular studies (12% and 13%, respectively). Directors of pharmacy departments should review their investigational drug policies and procedures for compliance with ASHP guidelines as the first step in developing the IDS concept.