mycin was negative in the mouse lymphoma forward mutation assay, did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.
Subcutaneous administration of up to 100 mg/kg of tobramycin did not affect mating behavior or cause impairment of fertility in male or female rats.
14 CLINICAL STUDIES
The Phase 3 clinical development program included two placebo-controlled studies (Studies 2 and 3) and one open-label study (Study 1), which randomized and dosed 157 and 517 patients, respectively, with a clinical diagnosis of cystic fibrosis, confirmed by quantitative pilocarpine iontophoresis sweat chloride test, well-characterized disease causing mutations in each CFTR gene, or abnormal nasal transepithelial potential difference characteristic of cystic fibrosis.
In the placebo-controlled studies, all patients were aged between 6 and 21 years old and had an FEV1 at screening within the range of 25% to 80% (inclusive) of predicted normal values for their age, sex, and height based upon Knudson criteria. In addition, all patients were infected with P. aeruginosa as demonstrated by a positive sputum or throat culture (or bronchoalveolar lavage) within 6 months prior to screening, and also in a sputum culture taken at the screening visit. Among the 76 patients treated with TOBI Podhaler, 37% were males and 63% were females. Thirty-six patients were between 6 and 12 years of age, and 40 patients were between 13 and 21 years of age. Patients had a mean baseline FEV1 of 56% of predicted normal value.
In both studies, >90% of patients received concomitant therapies for cystic fibrosis related indications. The most frequently used other antibacterial drugs (any route of administration) were azithromycin, ciprofloxacin, and ceftazidime. Consistent with the population of cystic fibrosis patients, the most frequently used concomitant medications included oral pancreatic enzyme preparations, mucolytics (especially dornase alfa), and selective β2-adrenoreceptor agonists.
Study 2
Study 2 was a randomized, three-cycle, two-arm trial. Each cycle comprised of 28 days on treatment followed by 28 days off treatment. The first cycle was double-blind, placebo-controlled with eligible patients randomized 1:1 to TOBI Podhaler (4 x 28 mg capsules twice daily) or placebo. Upon completion of the first cycle, patients who were randomized to the placebo treatment group received TOBI Podhaler for Cycles 2 and 3. The total treatment period was 24 weeks.
A total of 95 patients were randomized into Study 2 and received TOBI Podhaler (n=46) or placebo (n=49) in Cycle 1. All patients were less than 22 years of age (mean age 13.3 years) and had not received inhaled antipseudomonal antibiotics within four months prior to screening; 56% were female and 84% were Caucasian. This study was stopped early for demonstrated benefit and the primary analysis used the set of patients included in the interim analysis (n=79); 16 patients did not have data on the primary endpoint at that time. Of the 79 patients included in the interim analysis, 18 patients were excluded due to a failure to meet spirometry quality review criteria as determined by an external review panel. This resulted in a total of 61 patients, 29 in the TOBI Podhaler arm and 32 in the placebo arm, who were included in the primary analysis.
In the primary analysis, TOBI Podhaler significantly improved lung function compared with placebo as measured by the relative change in F |
