New quinolone/steroid combination for topical treatment of acute otitis: early- and late-phase study results.

Over the past 5 years, work has progressed on the development of a topical quinolone/steroid combination for the treatment of patients with acute otitis media with tympanostomy tubes (AOMT) and patients with acute otitis externa (AOE). The components of this otic suspension are ciprofloxacin 0.3% and dexamethasone 0.1%.

At the time of publication of this supplement, the New Drug Application (NDA) for ciprofloxacin/dexamethasone sterile otic suspension was under review by the federal Food and Drug Administration (FDA). A decision on FDA approval for the indications of AOMT and AOE was expected on or before July 25, 2003. This article summarizes the results of several early- and late-phase studies that support the NDA.

NDA studies

The results of six studies totaling 2,783 patients were included in the NDA for ciprofloxacin/dexamethasone otic suspension, which was accepted by the FDA in November 2002:

Safety/pharmacokinetics. A safety study of 606 patients found no skin sensitization with either ciprofloxacin/ dexamethasone otic or single-agent ciprofloxacin ophthalmic solution. A pharmacokinetic study in 11 of these patients found that the administration of topical ciprofloxacin/dexamethasone resulted in a 7-fold lower serum dexamethasone level than did administration of 0.5 mg of oral dexamethasone and a 640-fold lower serum level of ciprofloxacin than did 250 mg of oral ciprofloxacin.

AOMT indication. Two studies with a combined population of 800 patients were performed to test the combination drug's efficacy in AOMT. In one, ciprofloxacin/ dexamethasone was compared with ciprofloxacin alone to assess the contribution of the dexamethasone component. The time to cessation of otorrhea was significantly shorter among patients who received the combination product. In the other study, which included almost 600 patients, ciprofloxacin/dexamethasone was superior to ofloxacin otic solution with respect to all measured endpoints, including clinical cure, time to cessation of otorrhea, and microbiologic eradication. The presence of the steroid was also found to have a significant effect on resolution of granulation tissue present at baseline.

AOE indication. Two trials of a combined 1,377 patients were conducted for the AOE indication. The first, a three-arm study in 909 patients, found that ciprofloxacin/ dexamethasone was not interior to either ciprofloxacin or neomycin/polymyxin B/hydrocortisone (NPH) with respect to clinical cure and microbiologic eradication. The second study, which included 468 patients, showed that ciprofloxacin/dexamethasone treatment resulted in higher clinical and microbiologic cure rates than did treatment with NPH.

Phase I and II studies

Pharmacokinetics, safety, and efficacy in AOMT were assessed in two early-phase studies:

Pharmacokinetics. In a randomized, controlled, double-blind, phase I/II study, ciprofloxacin/dexamethasone otic was compared with ciprofloxacin ophthalmic in 11 patients, aged 1 to 12 years, who were undergoing surgical incision for the placement of tympanostomy tubes. Patients in both groups received a single dose of 4 or 5 drops in each ear immediately following tube insertion. Serum levels of ciprofloxacin and dexamethasone were measured six times over a 6-hour period. Maximum concentrations of ciprofloxacin and dexamethasone were 1.55 and 0.86 ng/ml, respectively. The respective half life of each drug was 2.9 and 2.8 hours. To assess bioavailability, the otic solution was compared with a 0.5-mg oral formulation of dexamethasone. Serum dexamethasone levels were approximately 7-fold lower with the drops. This finding indicates that any suppression of the hypothalamic-pituitary-adrenal axis is likely to be low and very reversible following twice-daily treatment for 7 days with ciprofloxacin/dexamethasone otic suspension.

AOMT indication. A randomized, controlled, double-blind contribution-of-elements trial was conducted in approximately 200 patients with AOMT at 18 sites throughout the United States. (1) Patients received 3 drops of either ciprofloxacin/dexamethasone or ciprofloxacin alone twice daily for 7 days. The median time to cessation of otorrhea was 4 days with the combination product and 5 days with the single agent. This difference is both statistically significant and clinically meaningful. Although ciprofloxacin alone was effective, the addition of dexamethasone made treatment more effective because it led to the earlier resolution of inflammation. At the test-of-cure visit (approximately day 14), clinical cure rates were 94% with the combination and 98% with the single agent; the corresponding microbiologic success rates were 94 and 93%. Of particular note is the fact that clinical cure rates at days 3 and 8 were significantly higher in the combination group. Treatment failure rates were lower in patients treated with the steroid product.

Phase III studies

One phase III study for the AOMT indication and two for the AOE indication were conducted:

AOMT indication. Ciprofloxacin/dexamethasone was compared with ofloxacin otic solution in 599 patients at 40 sites in the United States and Canada. (Ofloxacin is already indicated for the treatment of AOMT, AOE, and chronic suppurative otitis media.) Ciprofloxacin/dexamethasone was administered at 4 drops twice a day for 7 days, and ofloxacin was given at its indicated dosage, which is 5 drops twice a day for 10 days.

Microbiologic data were based on swabs taken prior to treatment. A second swab was obtained only if there was either a treatment failure or some other reason to discontinue therapy. No second swabs were taken from patients who had already shown a clean, dry ear by the end of the trial. All ears were cleaned prior to treatment--most with suction but a few with dry swabs. Specimens were obtained from the lumen of the tympanostomy tube, and care was taken not to touch the walls of the external ear canal.

Patients were evaluated on day 1 (baseline), day 3, day 11 (end of therapy), and day 18 (test-of-cure). The median time to cessation of otorrhea was 4 days in the ciprofloxacin/dexamethasone group and 6 days in the ofloxacin group--a significant difference both statistically and clinically (table 1). Clinical cure rates on day 18 were 90 and 79%, respectively, and the corresponding microbiologic cure rates were 91 and 82%. (2) Failure rates were 5 and 15%, respectively. The differences in all of these rates are also clinically and statistically significant.

Granulation tissue was present in 90 patients, a sample that was large enough to allow for therapeutic comparisons. Again, the combination product was significantly more effective than ofloxacin in treating granulation tissue at days 11 and 18; the difference at day 3 was not statistically significant, but it was clearly in favor of ciprofloxacin/dexamethasone. (3) In terms of all other measured endpoints, ciprofloxacin/dexamethasone was superior to ofloxacin.

Both treatments were safe and well tolerated; adverse events were mild to moderate and usually resolved without intervention. No clinically or statistically significant differences were observed in the mean change in speech reception threshold in the two groups. Bone- and air-conduction audiometry detected no clinically relevant decrease in hearing from baseline in either group.

AOE indication. Of the two phase III studies for the AOE indication, one was a two-arm study and the other was a three-arm trial.

In the two-arm study, ciprofloxacin/dexamethasone was compared with NPH in 468 patients at 23 sites in the United States. (4) In the ciprofloxacin/dexamethasone group, children received 3 drops twice daily for 7 days and adults 4 drops; children and adults in the NPH group followed the same regimen except that they were dosed three times daily. Patients were assessed at day 1, day 3, day 8, and at the test-of cure visit on day 18. Clinical cure rates were 92% in the ciprofloxacin/dexamethasone group and 89% in the NPH group; microbiologic success rates were 92 and 85%, respectively; and the corresponding inflammation reduction rates were 90 and 81% (table 2). The quinolone/steroid combination also provided a higher rate of eradication of Pseudomonas aeruginosa.

The three-arm trial involved 909 patients (unpublished data). Patients received either ciprofloxacin/dexamethasone otic, ciprofloxacin ophthalmic, or NPH. Clinical cure rates and microbiologic success rates in the two ciprofloxacin groups were marginally higher than those in the NPH group. The median time to the end of pain was 5 days in all three groups. All agents were well tolerated and side effects were minimal.

Table 1. Phase III study results for the AOMT *
indication (N=599)

                             Ciprofloxacin/
Clinical variable            dexamethasone    Ofloxacin

Median time (days) to         4 ([dagger])        6
cessation of otorrhea

Clinical cure rate at        90% ([dagger])      79%
the test-of-cure visit

Microbiologic success rate   91% ([dagger])      82%
at the test-of-cure visit

Treatment failure rate        5% ([dagger])      15%

* AOMT = acute otitis media with otorrhea through tympanostomy tubes.

([dagger]) Statistically significant difference (p <0.05).

Table 2. Phase III study results for the AOE *
indication at the test-of-cure visit (N=468)

                                 Ciprofloxacin/
Clinical variable                dexamethasone           NPH ([dagger])

Clinical cure rate at                 92%                      89%

Microbiologic success rate            92%                      85%

Reduction in inflammation rate   90% ([double dagger])         81%

* AOE = acute otitis externa.

([dagger]) NPH = neomycin/polymyxin B/hydrocortisone.

([double dagger]) Statistically significant difference (p <0.05).

References

(1.) Roland PS, Anon JB, Conroy PJ, et al. Topical ciprofloxacin/ dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media with tympanostomy tubes. Laryngoscope 2003 [in press].

(2.) Roland PS, Kreisler LS, Reese B, et al. Topical ciprofloxacin/ dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of children with acute otitis media with otorrhea through tympanostomy tubes. Pediatrics 2003 [in press].

(3.) Roland PS, Dohar JE, Lanier BJ, et al. Topical ciprofloxacin/ dexamethasone otic suspension is superior to ofloxacin otic solution in the reduction of granulation tissue in children with acute otitis media with otorrhea through tympanostomy tubes [submitted for publication].

(4.) Roland PS, Pien FD, Schultz CC, et al. Topical ciprofloxacin/ dexamethasone is superior to neomycin/polymyxin B/hydrocortisone for acute otitis externa [submitted for publication].