Efficacy and safety of clemastine-pseudoephedrine-acetaminophen versus pseudoephedrine-acetaminophen in the treatment of seasonal allergic rhinitis in a 1-day, placebo-controlled park study.

BACKGROUND: Allergic rhinitis afflicts more than 40 million people in the United States and is a leading cause of reduced productivity at work and in school. Patients with allergic rhinitis have a wide range of symptoms that are often treated with oral combination products that contain antihistamines, decongestants, and analgesics. OBJECTIVE: To evaluate the onset of action and the extent of efficacy and safety of a combination (CPA) of clemastine (0.68 mg), pseudoephedrine (60 mg), and acetaminophen (1,000 mg) versus a combination (PA) of pseudoephedrine and acetaminophen versus placebo in the treatment of seasonal allergic rhinitis (SAR). The primary goal was to evaluate the benefit of adding clemastine to the PA combination product to treat the symptoms of SAR. METHOD: A 1-day, multicenter, double-blind, double-dummy, randomized, parallel-group park study was organized, and medication was given at 9:00 AM and 3:00 PM. RESULTS: A total of 298 subjects participated at two outdoor facilities. The primary efficacy outcome was the major symptom complex score averaged over the period of 2 to 5 hours after each dose. Mean absolute and percentage reduction in major symptom complex averaged over the period of 2 to 5 hours in the CPA group was significantly superior to those of either the PA (P < 0.01) or placebo (P < 0.03) groups. Somnolence, fatigue, and nausea were the most common volunteered adverse events; only somnolence was significantly greater after CPA than after either PA or placebo. CONCLUSIONS: Treatment with CPA was safe and highly effective in reducing symptoms associated with SAR. It was more effective than either PA or placebo over most of the postdose observation period.

Single-patient drug trial methodology for allergic rhinitis.

BACKGROUND: Historically, single-patient trials (SPTs) have been specifically designed for each patient, requiring significant time and effort for execution. There has been no previous attempt to standardize an SPT for routine commercial availability. OBJECTIVE: To validate the use of an SPT method to discriminate effectiveness and adverse events while comparing drugs/doses in patients with allergic rhinitis. DESIGN: Double-blind, randomized, 4 paired-period, multiple-crossover SPT. SETTING: Academic and commercial investigative sites. PATIENTS: Thirty-six patients with allergic rhinitis were evaluated for the most appropriate treatment; 6 of these participated in 2 different SPTs. INTERVENTIONS: Treatment of symptoms of allergic rhinitis by comparing either loratadine with chlorpheniramine maleate or loratadine with placebo in a series of SPTs. MEASUREMENTS: Effectiveness endpoints were selected from a modern, Food and Drug Administration (FDA)-approved new drug application. Expected adverse events were directly solicited; unsolicited events were also recorded. Total signs and symptoms cumulatively included sneezing, runny nose, itchy nose, teary eyes, and itchy eyes. Quality of life was measured by the most bothersome symptom and the patient's global evaluation. RESULTS: Of 42 initiated SPTs, 40 (95%) provided complete data and 1 (2%) provided partial data, resulting in 41 (98%) evaluable tests. Thirty-one evaluable SPTs compared loratadine 10 mg/d with chlorpheniramine maleate 12 mg twice daily, and 10 SPTs compared loratadine 10 mg/d with placebo. Four of 31 SPTs (13%) showed significant superiority for loratadine over chlorpheniramine maleate and 5 of 31 (16%) for chlorpheniramine maleate over loratadine. Twenty-two of 31 (71%) showed parity performance between loratadine and chlorpheniramine maleate. Loratadine was significantly superior to placebo in 3 of 10 trials (30%), consistent with rates found in 3 pivotal group trials used for FDA approval (24%, 17%, and 0%). Sleepiness could be discriminated for loratadine versus placebo and for chlorpheniramine maleate versus loratadine. CONCLUSIONS: The allergic rhinitis SPT proved to be acceptable to patients, feasible to administer, and reproducible. It can statistically discriminate effectiveness and adverse events, serving as a useful, prognostic tool in community practice.

Validation of a single-patient drug trial methodology for personalized management of gastroesophageal reflux disease.

BACKGROUND: Single-patient trials (SPTs) are randomized, often multiple-crossover trials where patients serve as their own control to determine their appropriate treatment. Historically, SPTs have been individually customized, requiring significant time and cost for execution. The patient.s progress is tracked and evaluated in a blinded, multiple-crossover design comparing different therapies. Standardized, cost-efficient SPTs could help avoid (a) inappropriate extrapolation of the average-group outcomes from parallel, clinical trials to community-practice patients and (b) wasteful prescribing of high-cost drugs. Aggregate SPT results can also provide new data on appropriate drug prescribing in subpopulations. OBJECTIVE: To validate a standardized, commercially useful SPT method for comparing drugs/doses in patients with gastroesophageal reflux disease (GERD) requiring maintenance therapy. METHODS: A double-blind, single-dummy, randomized, 3 paired-period (28 days per period, 14 days per leg), multiple-crossover, SPT comparing omeprazole 20 mg daily and ranitidine hydrochloride (ranitidine) 150 mg twice daily was employed for 32 patients with GERD taking acid-suppressing medications chronically. Endpoints to determine effectiveness were selected from a recently approved new-drug application. Heartburn, regurgitation, difficulty swallowing, epigastric pain, and nausea were evaluated daily. Use of rescue medications was also measured. Quality of life was measured weekly by the patient.s global evaluation. Observations for days 1 to 4 were excluded by using aggregate database sensitivity analyses to define appropriate surrogate washout periods. Frequently reported adverse events found in labeling for acid-suppressing drugs were directly solicited and compared between treatments. Unsolicited events were recorded. Patients completed a test-kit-acceptability questionnaire. RESULTS: Fourteen of 27 evaluable SPTs (52%) showed significant superiority for omeprazole over ranitidine and 7 of 27 (26%) for ranitidine over omeprazole. Four of 27 (15%) showed parity performance. Neither agent could be recommended in 2 of 27 (7%) of SPTs due to significant adverse events experienced with both drugs. For those patients taking proton pump inhibitors (PPIs) prior to enrollment, the estimated step-down substitution rate from omeprazole to ranitidine, combined with the drug therapy discontinuation rate, was 40% (90% confidence interval: 22% to 68%). The majority of patients rated the test kits as appropriate and desirable. CONCLUSION: Omeprazole was the appropriate treatment in only 52% of these chronic users of acid-suppressing drugs. Eleven of 27 trials (41%) indicated that ranitidine was the preferred treatment. The SPT method proved acceptable to patients, feasible to administer, and reproducible. It can statistically discriminate effectiveness and adverse events and serve as a useful, prognostic tool in community practice by determining the least costly, evidence-based, appropriate treatment.