To treat pneumocystis infections in patients, is used in combination with sulfamethoxazole

This study was a randomized, double-blind, controlled trial comparing the efficacy and safety of atovaquone with those of trimethoprim-sulfamethoxazole to treat mild (alveolar-arterial oxygen gradient, <35 mm Hg) and moderately severe (alveolar-arterial oxygen gradient, 35 to 45 mm Hg) P. carinii pneumonia in adults with AIDS. The patients were stratified before enrollment on the basis of the severity of their disease. The end point chosen to determine the sample size was the proportion of subjects with mild disease in whom therapy was considered successful. The sample was calculated with the objective of establishing that atovaquone was no less successful therapeutically than trimethoprim-sulfamethoxazole9. A clinically important difference was defined as an arithmetic difference of 0.15 in success rates.

Patients received either trimethoprim-sulfamethoxazole or atovaquone for 21 days, unless there was no response or drug toxicity was encountered. Surviving patients were evaluated by chest radiography at four weeks and by clinical history at eight weeks after the completion of therapy. Patients were categorized according to end points defined as follows.

Definitions of End Points

Therapeutic Failure Due to Lack of Efficacy

Four definitions of therapeutic failure due to lack of efficacy were used: (1) deterioration after the first 3 days of therapy and a requirement for mechanical ventilation; (2) deterioration after 7 days of therapy, defined by the presence of any two of three conditions: worsening gas exchange (i.e., an increase in the alveolar-arterial oxygen gradient by 20 mm Hg or more over the base-line value, with an absolute value greater than 30 mm Hg), worsening findings on chest radiography, and worsening clinical symptoms; (3) lack of improvement in alveolar-arterial oxygen gradient, chest radiograph, or clinical symptoms after 10 days of therapy; and (4) a requirement for alternative therapy within 4 weeks of the discontinuation of the study medication, although no patient was considered to have had a therapeutic failure according to this criterion.

Treatment-Limiting Adverse Effects

The discontinuation of treatment resulting from suspected toxicity of the study drug and necessitating alternative therapy was considered a treatment-limiting adverse effect. Adverse reactions requiring the discontinuation of therapy included neutropenia ( ≤ 500 cells per cubic millimeter); thrombocytopenia ( ≤ 25,000 cells per cubic millimeter); hepatotoxicity, as defined by aspartate aminotransferase or alanine aminotransferase levels increased to more than 5 times the base-line value or more than 10 times the upper limit of normal, or a bilirubin level increased to more than 5 times the upper limit of normal; nephrotoxicity (a creatinine level more than 2.5 times the upper limit of normal, or a calculated reduction in creatinine clearance of more than 40 percent from base line); a hemoglobin level less than 6.5 g per deciliter despite transfusion; a prothrombin time twice the upper limit of normal, or 1.5 times the upper limit of normal with a platelet count of less than 40,000 per cubic millimeter; pancreatic toxicity (amylase level more than 5 times the upper limit of normal); vomiting for more than two consecutive days despite antiemetic therapy; the Stevens-Johnson syndrome; urticaria with systemic symptoms; and serious exfoliative dermatitis.

Successful Therapy

A successful course free of adverse effects was defined as therapy with sustained improvement in clinical and respiratory measures at least four weeks after the cessation of the study medication and without discontinuation of the initial study drug due to treatment failure or adverse effects.

Survival

Patients who remained alive without ventilatory support for at least four weeks after the termination of therapy were considered survivors.

Patients Who Could Not Be Evaluated

Any patient whose therapy was discontinued for any reason other than lack of response or a treatment-limiting adverse effect (e.g., noncompliance or loss to follow-up) was considered unable to be evaluated.

Patients

To be eligible for the study, patients were required to have AIDS and untreated P. carinii pneumonia as documented by the histologic demonstration of pulmonary P. carinii infection, plus fever, symptoms of respiratory disease, or radiographic evidence of pneumonitis. Enrollment was limited to patients with alveolar-arterial oxygen gradients ≤ 45 mm Hg measured with the patient breathing room air and with partial pressures of oxygen ≥ 60 mm Hg.

Clinical and Laboratory Assessment

Table 1.

Table 1. Characteristics of All Patients with Histologically Documented P. carinii Pneumonia (PCP) at Entry into the Study.

Patients were monitored for therapeutic efficacy and signs of drug toxicity by chest radiography, arterial-blood gas measurements, complete blood counts with differential count and platelet count, urinalysis, and measurements of the prothrombin time, creatinine, creatinine clearance, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, amylase, albumin, total protein, bilirubin, and electrolytes. A scoring system was used to measure the extent of dyspnea, cough, and chest pain or tightness (Table 1). The patients were evaluated initially and on days 2, 4, 7, 10, 14, 17, and 21 of therapy and at 4 and 8 weeks after therapy.

Blood samples were collected at enrollment and on days 4, 7, 14, and 21 of therapy to determine the concentrations of atovaquone (each such sample was obtained within 24 hours of the previous dose) or trimethoprim-sulfamethoxazole (each sample was obtained within 8 hours of the previous dose). The plasma concentrations of atovaquone determined on or after day 7 and within 24 hours of the previous dose were averaged to determine the mean steady-state concentration. Concentrations of trimethoprim and sulfamethoxazole in plasma samples obtained on or after day 4 and within eight hours of the previous dose were included to determine the mean concentration of these agents. Radiographs of the chest were evaluated at study entry and determined to be normal or abnormal. Before the study code was broken, the radiographs obtained on days 7 and 21 were interpreted by the radiologist at the site with respect to the type and extent of pneumonia. Each radiograph was classified according to whether the patient's condition appeared resolved, improved, stable, or deteriorated in comparison to the radiograph obtained before treatment.

Medication, Dosage, and Duration

The patients were randomly assigned to one of two treatment groups: 750 mg of atovaquone (three 250-mg tablets) three times daily or 320 mg of trimethoprim plus 1600 mg of sulfamethoxazole (two Septra DS [Burroughs Wellcome] or Septrin forte [Wellcome Research Laboratories] tablets) three times daily for 21 days. The study involved two placebos, with one group randomly assigned to receive oral atovaquone and tablets of placebo resembling trimethoprim-sulfamethoxazole and the other group assigned to receive trimethoprim-sulfamethoxazole and tablets of placebo resembling atovaquone.

After an amendment to the protocol in February 1991, while the study was ongoing, all the patients in the United States and Canada who were in the moderate-disease stratum (alveolar-arterial oxygen gradient, 35 to 45 mm Hg) were required to receive oral prednisone as recommended in a consensus report10.

Prophylaxis against P. carinii pneumonia was recommended for all patients who completed treatment successfully. The choice of the drug used for prophylaxis was left to the discretion of the patient's physician.

Statistical Analysis

The primary analyses of therapeutic-response end points and other measures were performed with the intention-to-treat rule -- i.e., excluding only patients who did not have confirmed P. carinii pneumonia. Patients who could not be evaluated for therapeutic efficacy were excluded from the intention-to-treat analysis if the supply of data corresponding to them had ended before the first therapeutic failure in this assessment. Subgroup analyses were also made of all patients who could be evaluated and were confirmed to have P. carinii pneumonia.

The combined-stratum analyses of the proportions of patients reporting adverse effects were based on the odds ratio, with adjustment for differences between strata11,12. For cells containing five patients or more, the Mantel-Haenszel estimate and the related test-based confidence interval are given (for this analysis we used SAS PROC FREQ software). Otherwise, Fisher's exact test and the 95 percent confidence interval for the estimated common odds ratio are used (STAT Xact. Cytel software).

Fisher's exact test was used to compare end points of therapeutic efficacy within each stratum, and confidence intervals for the differences between treatments were estimated with the large-sample normal approximation. The Cochran-Mantel-Haenszel test was used in the analyses of the combined strata, and the test-related 95 percent confidence interval for the relative risk was also calculated.

Medians were used to summarize the measured values and changes from base line. Differences between medians were examined by the Wilcoxon rank-sum test and the associated 95 percent confidence intervals. Logistic-regression analysis was used to predict the probability of a therapeutic response as a function of the steady-state plasma concentration of atovaquone. After the adequacy of the model was confirmed, an approximate 95 percent confidence interval around the plasma concentration needed to achieve a 90 percent rate of therapeutic success was calculated with SAS PROC PROBIT and PROC LOGISTIC software13.

An explanatory analysis of factors that might have affected survival was done. The patients were classified according to whether they remained alive at the end of follow-up, and comparisons within treatment groups were made by Fisher's exact test for categorical variables and by the Wilcoxon rank-sum test for continuous variables. The analysis of time-to-event data was done by Kaplan-Meier survival analysis and the log-rank test.