U.S. patent application number 10/243341 was filed with the patent office on 2003-07-24 for method of treating middle ear infections.
This patent application is currently assigned to Alcon, Inc.. Invention is credited to Conroy, Peter J., Wall, G. Michael.
Application Number | 20030139382 10/243341 |
Document ID | / |
Family ID | 23261416 |
Filed Date | 2003-07-24 |
United States Patent
Application |
20030139382 |
Kind Code |
A1 |
Wall, G. Michael ; et
al. |
July 24, 2003 |
Method of treating middle ear infections
Abstract
Aqueous suspension formulations containing dexamethasone and
ciprofloxacin are disclosed for the treatment of middle ear
infections in human patients having an open tympanic membrane.
Inventors: |
Wall, G. Michael; (Fort
Worth, TX) ; Conroy, Peter J.; (Fort Worth,
TX) |
Correspondence
Address: |
Alcon Research, Ltd.
Patrick M. Ryan(Q-148)
R&D Counsel
6201 South Freeway
Fort Worth
TX
76134-2099
US
|
Assignee: |
Alcon, Inc.
|
Family ID: |
23261416 |
Appl. No.: |
10/243341 |
Filed: |
September 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60323951 |
Sep 21, 2001 |
|
|
|
Current U.S.
Class: |
514/171 ;
514/200 |
Current CPC
Class: |
A61K 9/10 20130101; A61K
47/02 20130101; A61K 31/495 20130101; A61P 31/04 20180101; A61P
27/16 20180101; A61K 47/32 20130101; A61K 31/56 20130101; A61K
31/496 20130101; A61P 31/00 20180101; A61K 47/38 20130101; A61K
31/57 20130101; A61K 31/573 20130101; A61K 47/12 20130101; A61K
9/0046 20130101; A61P 43/00 20180101; A61K 31/545 20130101; A61K
31/495 20130101; A61K 2300/00 20130101; A61K 31/545 20130101; A61K
2300/00 20130101; A61K 31/56 20130101; A61K 2300/00 20130101; A61K
31/57 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/171 ;
514/200 |
International
Class: |
A61K 031/56; A61K
031/545 |
Claims
What is claimed is:
1. A method of treating a middle ear infection in a human patient
comprising the steps of: (a) diagnosing the patient as having
otitis media and an open tympanic membrane in at least one ear; and
(b) topically applying into the ear canal of the patient's ear an
aqueous suspension composition containing a combination of
ciprofloxacin and dexamethasone.
2. The method of claim 1 wherein the aqueous suspension composition
comprises a) 0.01-0.5% (wt.) dexamethasone; b) 0.1-0.4% (wt.)
ciprofloxacin; c) a tonicity agent consisting essentially of NaCl
in an amount sufficient to cause the composition to have an
osmolality of about 250-350 mOsm; d) 0.1-0.5% (wt.) of a nonionic
polymer; e) 0.01-0.2% (wt.) of a nonionic surfactant; and f) a
buffer, wherein the composition has a pH from about 3-5.
3. The method of claim 1 wherein the dexamethasone is dexamethasone
alcohol and the ciprofloxacin is ciprofloxacin hydrochloride,
monohydrate.
4. The method of claim 1 wherein the aqueous suspension composition
contains 0.1% (wt.) dexamethasone and 0.3% (wt.) ciprofloxacin.
5. The method of claim 4 wherein three or four drops of the aqueous
suspension composition are administered to the patient's ear twice
a day, wherein each drop is 30-35 .mu.L.
6. The method of claim 1 wherein the aqueous suspension composition
consists essentially of a) 0.1% (wt.) dexamethasone alcohol; b)
0.35% (wt.) ciprofloxacin hydrochloride, monohydrate; c) NaCl in an
amount sufficient to cause the composition to have an osmolality of
about 250-350 mOsm; d) 0.2% (wt.) hydroxyethyl cellulose; e) 0.05%
(wt.) tyloxapol; f) a buffer comprising sodium acetate and acetic
acid; g) 0.01% (wt.) benzalkonium chloride; h) 0.01% (wt.) edetate
disodium; i) 0.6% (wt.) boric acid; and wherein the composition has
a pH of about 4.5.
7. The method of claim 1 wherein the method further comprises the
step of pumping the tragus to force the aqueous suspension
composition through the open tympanic membrane and into the middle
ear.
8. The method of claim 1 wherein the dexamethasone has an average
particle size on a mean volume basis of less than 3 .mu.m.
9. The method of claim 1 wherein the otitis media is acute otitis
media.
10. The method of claim 1 wherein the otitis media is chronic
supprative otitis media.
11. The method of claim 1 wherein the aqueous suspension
composition containing a combination of ciprofloxacin and
dexamethasone is packaged with directions for use that indicate the
composition may be used to treat otitis media in patients with an
open tympanic membrane.
Description
[0001] This application claims priority to U.S. Provisional
Application, Serial No. 60/323,951, filed Sep. 21, 2001.
BACKGROUND OF THE INVENTION
[0002] This invention relates to the use of formulations of
ciprofloxacin and dexamethasone to treat otic infections.
Specifically, the invention relates to the topical use of such a
fixed combination to treat middle ear infections in humans.
[0003] External ear infections, known as acute otitis externa
("AOE"), are currently treated with oral antibiotics, topical
single-entity antibiotics, or topical antibiotic/steroid
combination products. An example of an oral antibiotic product used
to treat AOE is AUGMENTIN.RTM. (amoxicillin and clavulanic acid).
An example of a single-entity antibiotic product approved for
topical use in treating AOE is FLOXIN.RTM. (ofloxacin). Examples of
combination products approved for this use include CORTISPORIN.RTM.
(hydrocortisone, neomyciri sulfate, and polymyxin b sulfate) and
CIPRO.RTM.HC (ciprofloxacin and hydrocortisone). A product called
SOFRADEX (gramicidin, framycetin and hydrocortisone) is available
in some European countries and in Australia. External ear
infections typically involve bacteria of the following types:
Pseudomonas aeruginosa, Staphylococcus aureus. Staphylococcus sp.
and Coryneforms.
[0004] In contrast, middle ear infections known as otitis media
("OM") typically involve bacteria of the following types: S.
pneumonia, H. influenzae and M. catarrhalis. Patients with chronic
or severe middle ear infections may have their ear drums (tympanic
membranes) intentionally punctured and drainage tubes, often
referred to as a tympanostomy tubes, implanted. In other cases,
particularly in patients with severe OM, the tympanic membrane may
rupture. Whether surgically punctured or accidentally ruptured,
open tympanic membranes allow the bacteria characteristic of AOE
and OM to mix.
[0005] Patients with OM are currently treated with oral antibiotics
such as AUGMENTIN.RTM. When drainage through an open tympanic
membrane into the outer ear persists, either an oral antibiotic
(e.g., AUGMENTIN.RTM.) or a topical antibiotic (e.g., FLOXIN.RTM.)
is often prescribed. Additionally, topical antibiotic/steroid
combination products approved for AOE have been used "off-label" in
some cases to treat OM in patients with an open tympanic membrane,
including CORTISPORIN.RTM., CIPRO.RTM.HC, and TOBRADEX.RTM.
(tobramycin and dexamethasone). To date, however, no topical
antibiotic/steroid combination product has been approved by the
Food and Drug Administration in the U.S. for the treatment of OM in
patients with an open tympanic membrane.
[0006] Fixed combination products containing ciprofloxacin and
dexamethasone are known. Although no such product is currently
approved in the U.S., this combination is commercially available
for ophthalmic use in certain countries in South America as
Biomotil-D (Allergan Frumtost) and Cilodex (Alcon Laboratories).
Although the use of ciprofloxacin/dexamethasone combinations for
the treatment of ocular and/or otic infections has been disclosed
in the scientific and patent literature (see, for example, Spanish
Patent Application No. 2,065,846 Al (Feb. 16, 1995), WO 90/01933
and U.S. Pat. No. 6,284,804), there has been no disclosure of the
use of such a combination specifically for treating OM in patients
with open tympanic membranes.
SUMMARY OF THE INVENTION
[0007] The present invention provides a method of topically
treating OM in human patients who have open tympanic membranes. The
method involves the topical application of a fixed combination of
ciprofloxacin and dexamethasone as an aqueous suspension product.
Although the dosing regimen may vary depending on the age and
weight of the patient, as well as the severity of the infection, in
most cases, the combination product would be applied twice a day.
Each application would involve topically administering three or
four drops into the ear canal, preferably pumping the tragus to
force product through the opening in the tympanic membrane and to
the site of the infection/inflammation in the middle ear.
[0008] Among other factors, the present invention is based on the
finding that an aqueous combination of ciprofloxacin and
dexamethasone was not statistically more effective than
ciprofloxacin alone in the treatment of AOE, but was surprisingly
statistically more effective that ciprofloxacin alone in the
treatment of OM in patients with an open tympanic membrane. The
fact that a contribution of elements for ciprofloxacin and
dexamethasone could be demonstrated for only OM and not AOE was not
predictable, nor was the fact that such a contribution of elements
would be shown in OM.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows the average number of days to time of cessation
of ear pain in a human clinical study comparing a
ciprofloxacin/dexamethasone combination product to a ciprofloxacin
single-entity product.
[0010] FIG. 2 shows the average number of days to cessation of
otorrhea in a human clinical study comparing a
ciprofloxacin/dexamethasone combination product to a ciprofloxacin
single-entity product.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Unless indicated otherwise, all ingredient amounts presented
as a percentage are in units of weight %.
[0012] The methods of the present invention involve diagnosing a
human patient as having OM and an open tympanic membrane. "Open
tympanic membrane" means that the membrane has been intentionally
punctured, with or without tympanostomy tube implantation, or has
accidentally ruptured. Once diagnosed with OM and an open tympanic
membrane, the method of the present invention involves topically
administering to the ear canal of the patient's affected ear an
aqueous suspension formulation of a fixed combination of
ciprofloxacin and dexamethasone. OM includes, but is not limited
to, acute otitis media and chronic supprative otitis media.
[0013] Dexamethasone can be present in any ophthalmically or
otically acceptable form having poor water solubility such that the
resulting formulation is a suspension formulation. Suitable forms
of dexamethasone include dexamethasone alcohol (alcohol form of
dexamethasone), dexamethasone acetate and dexamethasone phosphate.
Dexamethasone alcohol is the preferred form of dexamethasone. The
average particle size (mean volume basis) of the dexamethasone
ingredient should be less than 10 .mu.m to avoid irritation or
discomfort The average particle size is preferably less than 6
.mu.m and most preferably less than 3 .mu.m. Dexamethasone
particles can be sized using known techniques, such as
ball-milling, microfluidization and sonication. The ciprofloxacin
ingredient can be any otically acceptable form such that the
ciprofloxacin ingredient is in solution in the final formulation. A
preferred form of ciprofloxacin is ciprofloxacin hydrochloride,
monohydrate.
[0014] The dexamethasone ingredient will comprise about 0.01-0.5%
and the ciprofloxacin ingredient will comprise about 0.1-0.4% of
the aqueous suspension formulations administered according to the
present invention. The preferred amounts of dexamethasone and
ciprofloxacin in the formulations used in the present invention are
0.1% and 0.3%, respectively.
[0015] In addition to the active agents, the suspension
formulations used in the present invention contain a tonicity
agent. The tonicity agent may be ionic (e.g., NaCl) or nonionic
(e.g., mannitol). The tonicity agent is preferably NaCl. The amount
of NaCl will depend on the desired tonicity for the final
formulation, but will generally range from 0.1-0.9%. The suspension
formulations of the present invention preferably contain an amount
of tonicity agent sufficient to cause the formulations to have an
osmolality of about 250-350 mOsm.
[0016] The suspension formulations also contain a nonionic polymer
as a suspending agent. Many otically acceptable nonionic polymers
are known. These polymers include hydroxyethyl cellulose;
hydroxypropylmethyl cellulose; methyl cellulose; carboxymethyl
cellulose; polyvinyl pyrrolidone and polyvinyl alcohol. The
preferred nonionic polymer is hydroxyethyl cellulose. The nonionic
polymer will be present in the formulations of the present
invention in an amount of about 0.1-0.5%. In the case of
hydroxyethyl cellulose, the preferred concentration of nonionic
polymer is 0.2%.
[0017] The formulations of the present invention also contain a
nonionic surfactant in an amount from about 0.01-0.2%. Many
otically acceptable nonionic surfactants are known. Suitable
nonionic surfactants include tyloxapol; polyoxyethylene sorbitan
esters, such as polysorbate 20, polysorbate 60, and polysorbate 80;
polyethoxylated castor oils, such as Cremaphor EL; polyethoxylated
hydrogenated castor oils, such as HCO-40; and poloxamers. The
preferred surfactant is tyloxapol.
[0018] If desired, the formulations may contain a quaternary
ammonium halide as a preservative. Suitable quaternary ammonium
halides include polyquaternium-1 and benzalkonium halides.
Preferred benzalkonium halides are benzalkonium chloride ("BAC")
and benzalkonium bromide. In general, the amount of the
preservative ingredient will range from about 0.005-0.3%. In the
preferred case where the preservative is BAC, it is preferably
present at a concentration of 0.01%.
[0019] If desired, a chelating agent may also be present in the
suspension formulations used in the methods of the present
invention. Suitable chelating agents include edetate disodium
("EDTA"); edetate trisodium; edetate tetrasodium; and
diethyleneamine pentaacetate. Most preferred is EDTA. The chelating
agent, if any, will typically be present in an amount from about
0.001-0.1%. In the case of EDTA, the chelating agent is preferably
present at a concentration of 0.01%.
[0020] In the case of preserved or multi-dose formulations, the
suspension formulations of the present invention may contain boric
acid in an amount from 0.1-1.5%.
[0021] The formulations administered according to the present
invention have a pH from 3-6, preferably 4.5. pH can be adjusted
with NaOH/HCl. The preferred buffering system for these
formulations is a combination of sodium acetate and acetic acid.
The concentration of sodium acetate will generally range from
0.015-0.06%, and will preferably be about 0.03%. The concentration
of acetic acid will generally range from 0.02-0.08, and will
preferably be about 0.04%.
[0022] Though physicians may prescribe other dosing regimens
depending on a number of factors including the severity of the OM,
the age and weight of the patient, etc., the
ciprofloxacin/dexamethasone combination products administered
according to the present invention will generally be administered
twice a day. Each administration will typically involve placing 3-4
drops (with a typical drop volume of 30-35 .mu.L) of the suspension
product in the affected ear. Preferably, the patient will pump the
tragus of the affected ear to force the administered product
through the opening in the tympanic membrane and to the site of the
infection/inflammation in the middle ear.
[0023] In one embodiment, the present invention relates to a
ciprofloxacin/dexamethasone aqueous suspension composition that is
packaged with directions for use that indicate the composition may
be used to treat otitis media in patients with an open tympanic
membrane. As used herein, "directions for use" includes information
contained in product labeling, package inserts and cartons or other
packaging materials that accompany the ciprofloxacin/dexamethasone
aqueous suspension composition of the present invention.
[0024] The following examples are intended to illustrate, but not
limit, the present invention.
EXAMPLE 1
Representative Formulations
[0025]
1 A B C D E Ingredients % (w/w) % (w/w) % (w/w) % (w/w) % (w/w)
Ciprofloxacin HCl, 0.35* 0.35 0.35 0.35 0.35 Monohydrate
Dexamethasone Alcohol 0.1 0.1 0.1 0.1 0.1 Hydroxyethyl Cellulose
0.2 0.2 0.2 0.2 0.2 Benzalkonium Chloride 0.01 0.01 0.01 0.01 0.01
Sodium Acetate (Trihydrate) 0.03 0.03 0.03 0.03 0.03 Acetic Acid
0.04 0.04 0.04 0.04 0.04 Sodium Chloride 0.25 0.25 0.80 0.53 --
Edetate Disodium 0.01 0.01 0.01 0.01 0.01 Tyloxapol 0.05 0.05 0.05
0.05 0.05 Glycerin 1.5 -- -- -- 2.35 Boric Acid -- -- -- 0.6 --
NaOH/HCl q.s. pH q.s. pH q.s. pH q.s. pH q.s. pH 4.5 .+-. 0.2 4.5
.+-. 0.2 4.5 .+-. 0.2 4.5 .+-. 0.2 4.5 .+-. 0.2 Purified Water q.s.
100 q.s. 100 q.s. 100 q.s. 100 q.s. 100 Osmolality (mOsm) 272 99
274 286 290 *equivalent to 0.3% ciprofloxacin base
[0026] Formulations A-E were made using the following method:
[0027] (1) For a formulation batch size of 500 ml, form a slurry by
combining 75 g of 3 mm zirconium beads, 12 g of tyloxapol 1.0%
stock solution and 0.5 g dexamethasone alcohol in a 30 ml
polypropylene milling bottle (approx. 48% of the final batch
requirement of tyloxapol is used);
[0028] (2) steam sterilize (autoclave) the slurry, including
beads;
[0029] (3) aseptically ball mill the sterilized slurry for 18 hrs
at 50 to 55 rpm;
[0030] (4) prepare an aqueous solution containing the remaining
requirement of tyloxapol and the required amounts of all remaining
ingredients (e.g., in the case of Formulation D, the remaining
ingredients are ciprofloxacin hydrochloride monohydrate,
benzalkonium chloride, sodium acetate, acetic acid, sodium
chloride, hydroxyethylcellulose, boric acid, edetate disodium, and
purified water;
[0031] (5) steam sterilize (autoclave) the aqueous solution
prepared in step (4);
[0032] (6) combine the sterile slurry obtained in step 3 to the
sterile solution obtained in step 5 by aseptically pouring the
slurry through a sterile sieve (to remove the beads) into the
solution obtained in step 5;
[0033] (7) adjust the formulation weight to 80-90% of batch weight
using sterile-filtered purified water;
[0034] (8) check the final pH and adjust to pH 4.5.+-.0.2 by
sterile-filtered sodium hydroxide or hydrochloric acid, if needed;
and
[0035] (9) bring the formulation to 100% of batch weight using
sterile-filtered purified water.
[0036] An alternative method of preparing Formulations A-E,
especially when the dexamethasone raw material is supplied or
available already meeting the desired particle size specifications,
is as follows:
[0037] (1) dry heat sterilize the dexamethasone raw material
(recommended specification: between 7-11 hrs. at 130-140.degree. C.
(internal powder temperature);
[0038] (2) prepare a tyloxapol solution containing the batch
requirement of tyloxapol in purified water;
[0039] (3) sterilize the tyloxapol solution by passing it through a
0.2 .mu.m filter;
[0040] (4) aseptically combine the sterilized dexamethasone with
the sterilized tyloxapol solution to form a sterile slurry and stir
until homogenous;
[0041] (5) prepare an aqueous solution containing the required
amounts of the remaining ingredients (e.g., in the case of
Formulation D, the remaining ingredients are ciprofloxacin
hydrochloride, monohydrate benzalkonium chloride, sodium acetate,
acetic acid, sodium chloride, hydroxyethylcellulose, boric acid,
edetate disodium and purified water;
[0042] (6) steam sterilize (autoclave) the aqueous solution
prepared in step (5);
[0043] (7) aseptically combine the sterile slurry prepared in step
(4) with the sterilized solution prepared in step (6);
[0044] (8) adjust the formulation weight to 80-90% of batch weight
using sterile-filtered, purified water.
[0045] (9) check the final pH and adjust to pH 4.5.+-.0.2 by
sterile-filtered sodium hydroxide or hydrochloric acid, if needed;
and
[0046] (10) bring the formulation to 100% of batch weight using
sterile-filtered purified water.
EXAMPLE 2
AOE Clinical Study in Human Patients
[0047] A clinical study with a primary objective of demonstrating
superiority of a ciprofloxacin/dexamethasone combination product
(ciprofloxacin 0.3%, dexamethasone 0.1%; Formulation D above)
("CIPRODEX") relative to the marketed CILOXAN.RTM. single-agent
(ciprofloxacin 0.3%; Alcon Laboratories, Inc.) product for time to
cessation of ear pain in patients with moderate to severe acute
otitis externa (AOE) was conducted. A summary of the study details
for this AOE study is provided below.
2 Summary of AOE Study CIPRODEX (Ciprofloxacin 0.3%) Suspension vs.
CILOXAN (Ciprofloxacin 0.3%) Solution vs. CORTISPORIN Suspension
(Neomycin 0.35%, Polymyxin B 10,000 IU/mL, Hydrocortisone 1.0%) for
Topical Treatment of patients with moderate to severe Acute Otitis
Externa (AOE). Study Design: Phase III multicenter, randomized,
single-blind, active controlled, parallel group study. Study
Primary objectives of the study were to demonstrate: Objectives:
Superiority of CIPRODEX combination relative to CILOXAN single
agent for time to cessation of ear pain. Therapeutic
non-inferiority of CIPRODEX combination relative to CILOXAN single
agent based on clinical response at the test of cure (TOC) visit
(Day 18). Therapeutic non-inferiority of CIPRODEX combination
relative to CORTISPORIN combination for clinical response at the
TOC visit. Therapeutic non-inferiority of CILOXAN single agent
relative to CORTISPORIN combination for clinical response at the
TOC visit. Patient A total of 909 patients enrolled into the study
at 48 investigative sites in Population: the United States between
April 1998 and May 2000. Inclusion Clinical diagnosis of moderate
or severe AOE, at least one year of age, Criteria: gave informed
consent, and agreed to follow study procedures. Posology: Eligible
patients were treated for 7 days with three drops BID CIPRODEX (n =
305), three drops BID CILOXAN (n = 305), or four drops TID
CORTISPORIN (n = 299). Study Visits: Day 1, Day 3, Day 8 (End of
Therapy, EOT), and Day 18 (TOC). Clinical Patient assessment of
pain and tenderness using a daily diary. Evaluation: Physician
evaluation of signs and symptoms of AOE, including inflammation,
tenderness, edema, and otic discharge by visit. Microbiology:
Microbiology outcomes were based on presumed or confirmed bacterial
eradication. Efficacy Cessation of ear pain was defined as the
first day where the patient dairy Criteria: pain score was zero,
with no analgesics used in the prior 24 hours, and the ear pain
score remained zero for all subsequent entries. Physician's
assessment of clinical response of the patient at TOC on a 4-point
scale (0 = cured, 1 = improved, 2 = no change, 3 = worse). Safety
Based on the frequency and incidence of adverse events reported.
Evaluation: Overall Time to cessation of pain is not different
between CIPRODEX and Conclusions: CILOXAN treatments (i.e., no
contribution of elements). CIPRODEX is non-inferior to CILOXAN for
clinical cures and microbiological eradication. CIPRODEX produces
more clinical cures than CORTISPORIN and is non-inferior for
microbiological eradication. CILOXAN is superior to CORTISPORIN for
clinical response in culture positive patients, and non-inferior
for microbial eradication. CIPRODEX and CILOXAN are safe and well
tolerated in pediatric and adult patients with AOE.
[0048] Time to no pain was evaluated for CIPRODEX and CILOXAN, with
the results shown in Table 1 and FIG. 1. These results show the
average number of days to cessation of ear pain for the "modified
intent-to-treat" ("MITT") population of the study. MITT is a term
of art in the clinical sciences. For this study, the MITT
population is defined as the population that received study drug,
met inclusion criteria and was culture positive for bacteria on Day
1. The MITT population for this study comprised 267 patients for
CIPRODEX and 261 patients for CILOXAN.
3TABLE 1 MITT: Time to No Pain (in days) Treatment Mean Median
CIPRODEX 6.8* 5.0 CILOXAN 6.3 5.0 *p-value = 0.29 (Log-Rank Test;
Kaplan-Meier Life Table Survival Estimates)
[0049] Data obtained in this AOE study demonstrate that time to
cessation of ear pain was not different between CIPRODEX and
CILOXAN, and therefore, no contribution of elements was shown for
CIPRODEX. These results show a slight advantage for CILOXAN (6.8
days) over CIPRODEX (6.3 days) in average time to no otorrhea, but
the differences were not statistically significant
(p-value=0.29).
EXAMPLE 3
OM with Open Tympanic Membrane Clinical Study in Human Patients
[0050] A clinical study with a primary objective of showing
therapeutic superiority of CIPRODEX (Formulation D above) relative
to CILOXAN for cessation of otorrhea (ear discharge) in
tympanostomy tube patients with Acute Otitis Media (AOM) was
conducted. A summary of the study details for this OM study is
provided below.
4 Summary of AOM Study Safety and Efficacy of Topical CIPRODEX
(Ciprofloxacin 0.3%, Dexamethasone 0.1%) Suspension Compared to
CILOXAN (Ciprofloxacin 0.3%) Solution in the Treatment of Acute
Otitis Media with Tympanostomy Tubes (AOMT) Study Design: Phase II
multicenter, randomized, evaluator-blind, active controlled,
parallel group study. Study The study objectives were to:
Objectives: Demonstrate therapeutic superiority of CIPRODEX
combination relative to CILOXAN single agent for cessation of
otorrhea, and to Evaluate the efficacy and safety of topical
CIPRODEX Suspension in AOMT patients Patient A total of 201
patients enrolled into the study at 21 investigative sites in
Population: the United States between March 2000 and January 2001.
Inclusion Pediatric patients (6 months to 12 years) with a patent
tympanostomy Criteria: tube and clinically diagnosed with acute
otitis media with otorrhea that is visible by the parent/guardian
of 3 weeks or less duration. Posology: Eligible patients were
treated for 7 days with BID CIPRODEX (n = 103) or 7 days with BID
CILOXAN (n = 98). Study Visits: Day 1, Day 3, Day 8 (End of
Therapy, EOT), and Day 14 (Test of Cure, TOC). Clinical Twice daily
patient assessment of cessation of otorrhea using a daily
Evaluation: diary. Physician evaluation of signs and symptoms of
AOMT, including presence of otorrhea, characteristics of otorrhea,
presence of granulation tissue, tube patency, and overall clinical
response by visit. Microbiology: Microbiology outcomes were based
on presumed or confirmed bacterial eradication. Efficacy Cessation
of otorrhea was defined as ending on the first day on which
Criteria: the otorrhea is absent and remains absent for all
subsequent diary entries. Physician's assessment of clinical
response of the patient at TOC on a 4-point scale (0 = resolved, 1
= improved, 2 = no change, 3 = worse). Safety Based on the
frequency and incidence of adverse events reported. Evaluation:
Overall CIPRODEX has a statistically significantly shorter Time to
Conclusions: Cessation of Otorrhea when compared to CILOXAN (using
Log-Rank test of equality over strata). CIPRODEX is statistically
significantly more effective than CILOXAN for Physician's Clinical
Impression at the Day 3 Visit, but not at the Day 8 or Day 14
Visits (using Cochran-Mantel-Haenszel Rank Scores Test). No
statistically significant differences were detected between
CIPRODEX and CILOXAN for Microbiological Eradication Rates at the
Test of Cure Visit (using Fisher's Exact Test). CIPRODEX and
CILOXAN are safe and well tolerated in pediatric with AOMT.
[0051] The results of this study for the MITT population are
presented in Table 2 and FIG. 2. For this study, the MITT
population is defined as the population that received study drug,
met inclusion criteria, participated in at least one on-therapy
visit, and was culture positive for bacteria on Day 1. The MITT
population for this study comprised 87 patients for CIPRODEX and 80
patients for CILOXAN.
5TABLE 2 MITT: Time to No Otorrhea (in days) Treatment Mean Median
Std. N Min. Max. CIPRODEX 4.22* 4 2.04 87 2 10 CILOXAN 5.31 5 1.94
80 2 10 *p-value = 0.0040 (Log-Rank test of equality over
strata)
[0052] The results of this OM demonstrate a clinically and
statistically significant difference in the time to cessation of
otorrhea for CIPRODEX-treated patients (4.03 days) compared to
CILOXAN-treated patients (5.06 days), approximately a 20% reduction
in time to no otorrhea. In this study, contribution of elements for
CIPRODEX was shown.
EXAMPLE 4
CIPRODEX vs. FLOXIN Study
[0053] A clinical study comparing CIPRODEX (Formulation D above) to
FLOXIN in the treatment of tympanostomy tube patients with Acute
Otitis Media (AOM) was conducted. A summary of the study details
for this OM study is provided below.
Summary of CIPRODEX vs. FLOXIN Study
[0054] Safety and Efficacy of Topical CIPRODEX Otic (Ciprofloxacin
0.3%/Dexamethason 0.1%) Suspension Compared to FLOXIN Otic
(Ofloxacin 0.3%) Solution in the Treatment of Acute Otitis Media
with Tympanostomy Tubes (AOMT)
[0055] Study Design: Phase III, randomized, evaluator-masked,
active-controlled, parallel-group study.
[0056] Objectives:
[0057] To demonstrate the non-inferiority of CIPRODEX Otic
Suspension relative to FLOXIN Otic Solution in clinical and
microbiological response at the test of cure (TOC) visit; and
[0058] To evaluate the efficacy and safety of CIPRODEX Otic
Suspension for the treatment of patients with acute otitis media
and otorrhea with tympanostomy tubes (AOMT).
[0059] Patient Population: Approximately 500 pediatric patients
with AOMT and post-tympanostomy tube otorrhea (250/arm) were
planned. A total of 599 patients were enrolled.
[0060] Diagnosis and Main Criteria for Inclusion: Pediatric
patients, from 6 months to 12 years of age, with a patent
tympanostomy tube, clinically diagnosed with acute otitis media and
otorrhea of 3 weeks or less duration, visible by the
parent/guardian, were enrolled.
[0061] Test Product, Dose and Mode of Administration, Batch
Number(s): CIPRODEX Otic (ciprofloxacin 0.3%/dexamethasone 0.1%)
Suspension; topical otic administration of 4 drops into the
infected ear(s) twice daily (BID) for 7 days.
[0062] Duration of Treatment: Patients were required to undergo
treatment for either seven (7) days if randomized to receive
CIPRODEX or ten (10) days if randomized to receive FLOXIN.
[0063] Reference Therapy, Dose and Mode of Administration, Batch
Number(s): FLOXIN Otic (ofloxacin 0.3%) Solution; topical otic
administration of 5 drops into the infected ear(s) twice daily
(BID) for 10 days.
[0064] Criteria for Evaluation: Subsequent to the demonstration of
non-inferiority, superiority analyses were conducted. Analyses for
the determination of superiority were based on the data set of
patients who received treatment, had a positive pre-therapy culture
and met the inclusion/exclusion criteria for enrollment (modified
intent-to-treat, MITT). Analyses were also conducted for the
intent-to-treat (ITT), per protocol (PP) and modified per protocol
(MPP) data sets.
[0065] Efficacy: The two primary variables were (1) the clinical
response at the TOC visit; those patients rated as resolved/cured
by the physicians based on a 4-point scale (0=resolved/cured,
1=improved, 2=not changed, 3=worsened); and (2) the microbiological
response, success or failure, at the TOC visit for patients with
positive pre-therapy cultures. Secondary efficacy variables were
(1) the time to cessation of otorrhea as recorded in the patient
diary; and as assessed by the physician's at each visit (2) the
clinical response based on a 4-point scale (0=resolved/cured,
1=improved, 2=not changed, 3=worsened); (3) the granulation tissue,
based on a 4-point scale (0=none, 1=mild, 2=moderate and 3=severe);
(4) the presence or absence of otorrhea; (5) the otorrhea volume
based on a 4-point scale (0=absent, 1=scant, 2=moderate and
3=severe); and the color/type of otorrhea based on a 5-point scale
(0=absent, 1=serous, 2=mucoid, 3=purulent, 4=sanguineous).
[0066] Safety: The safety evaluation was conducted on all patients
who were randomized into the study and received at least one dose
of study drug. The safety analysis was based on the following;
extent of exposure to study drug; adverse events; and audiometry
examination.
[0067] Statistical Methods: The statistical objective was to
demonstrate the non-inferiority of CIPRODEX relative to FLOXIN in
clinical and microbiological response at the TOC visit. Two-sided
95% confidence intervals for the difference between proportions
between the two treatment groups were constructed. However, due to
the lack of zero within the confidence limits, non-inferiority was
demonstrated, and analyses allowed for a claim of superiority.
Therefore, differences between the two treatments for clinical and
microbiological response were evaluated using the Chi-square test
of independence. For analyses of the secondary variables, the
number and proportion of patients per response in each treatment
group was presented and differences were assessed using LSMEANS
(Mixed Model Analysis of Variance) or the Chi-square test of
independence as appropriate. The log-rank test (Kaplan-Meier
survival analysis was conducted to compare median time to cessation
of otorrhea between the two treatments.
[0068] Summary--Conclusions
[0069] CIPRODEX Otic Suspension is superior to FLOXIN Otic Solution
in clinical and microbiological response at the test of cure (TOC)
visit; and
[0070] CIPRODEX Otic Suspension is effective and safe for the
treatment of pediatric patients with acute otitis media and
otorrhea with tympanosotomy tubes (AOMT).
[0071] These data demonstrate the superior effectiveness of
CIPRODEX, an antibiotic-steroid combination drug, for the treatment
of AOMT as shown in comparative analyses to a marketed product
approved for the same indication.
[0072] This study evaluated the efficacy and safety of CIPRODEX, an
antibiotic-steroid combination product (ciprofloxacin
0.3%/dexamethasone 0.1%) compared to FLOXIN, which contains
antibiotic alone (ofloxacin 0.3%). The study duration was
approximately three weeks long with four scheduled visits.
Conditions between the treatment groups were identical except for
the study drugs and the respective dosing regimens. Both drugs were
topically administered BID, however, the FLOXIN group received 5
drops per dose for 10 days (per the package insert) and the
CIPRODEX group, 4 drops per dose for 7 days. Outcome differences
between the two groups are therefore attributed to the differences
in treatment.
[0073] Efficacy Results:
[0074] A total of 599 patients were evaluable for the ITT analyses,
424 for the MITT, 460 for the PP and 357 for the MPP analyses. Of
the ITT data set, 62% were male, 81% were Caucasian, 41% enrolled
the right ear, 36% enrolled the left ear, and 23% enrolled both
ears. The mean age was 2.45 years and the mean duration of the
current episode of AOMT was 4.49 days in the right ear and 4.71
days in the left ear. In primary analyses, at the TOC visit,
CIPRODEX was superior to FLOXIN for clinical cures for all data
sets (p.ltoreq.0.0027) and for microbiological eradication for MITT
and MPP data sets (p.ltoreq.0.0061). Additionally, for all data
sets, CIPRODEX was superior to FLOXIN for treatment failure rate
(p.ltoreq.0.0189). In analyses of the secondary efficacy variables,
CIPRODEX was superior to FLOXIN for time to cessation of otorrhea
for all data sets (p.ltoreq.0.018). Clinically, this translates to
the cessation of otorrhea in 20 to 33% less time for the CIPRODEX
treated patients in comparison to the FLOXIN treated patients
(median time of 4 days for CIPRODEX versus 5-6 days for FLOXIN).
For the remaining secondary efficacy variables, improvement in
clinical response, absence of otorrhea, reduction in otorrhea
volume and absence of otorrhea color, CIPRODEX was superior to
FLOXIN at every study visit after baseline (p.ltoreq.0.0023,
p.ltoreq.0.0012, p.ltoreq.0.0003, and p.ltoreq.0.0003,
respectively). Moreover, at study visits Day 11 and Day 18,
CIPRODEX was superior to FLOXIN for reduction in granulation tissue
(p=0.0086 and p=0.0383, respectively). These outcomes demonstrate
that CIPRODEX is not only a more effective treatment for AOMT in
comparison to FLOXIN, but also results in a more rapid response to
treatment and resolution of the clinical signs and symptoms of AOMT
relative to FLOXIN. CIPRODEX is effective in treating acute otitis
media with otorrhea in tympanostomy (AOMT) patients and results in
90% patients with clinical cure, 92% patients with microbiological
success and a 4-day median time to cessation of otorrhea.
[0075] Efficacy Conclusions:
[0076] 1. CIPRODEX is superior to FLOXIN for clinical cures at the
TOC visit.
6 Clinical Cure Rates and 95% Confidence Intervals by Treatment
Group (All Data Sets) Treatment CIPRODEX FLOXIN Clinical Cure
Clinical Cure No Yes No Yes Data Set N % N % N % N % Delta Lower
Upper P-value.sup.a ITT 75 25.25 222 74.75 117 38.74 185 61.26
13.49 6.10 20.88 0.0004 MITT 43 20.67 165 79.33 78 36.11 138 63.89
15.44 6.99 23.88 0.0004 PP 28 12.07 204 87.93 50 22.73 170 77.27
10.66 3.71 17.60 0.0027 MPP 18 10.00 162 90.00 37 21.76 133 78.24
11.76 4.17 19.36 0.0025 .sup.aChi-square test of
independence(Fisher's exact test when N < 5).
[0077] 2. CIPRODEX is superior to FLOXIN for microbiological
eradication at the TOC visit.
7 Microbiological Eradication Rates and 95% Confidence Intervals by
Treatment Group (All Data Sets) Treatment CIPRODEX FLOXIN
Microbiological Microbiological Eradication Eradication Failure
Success Failure Success Data Set N % N % N % N % Delta Lower Upper
P-value.sup.a ITT 128 43.10 169 56.90 154 50.99 148 49.01 7.90
-0.07 15.87 0.0529 MITT 41 19.71 167 80.29 72 33.33 144 66.67 13.62
5.33 21.91 0.0015 PP 67 28.88 165 71.12 81 36.82 139 63.18 7.94
-0.70 16.58 0.0722 MPP 15 8.33 165 91.67 31 18.24 139 81.76 9.90
2.83 16.97 0.0061 .sup.aChi-square test of independence(Fisher's
exact testwhen N < 5).
[0078] 3. CIPRODEX is superior to FLOXIN for treatment failure
rate.
8 Discontinuations Due to Treatment Failure by Treatment Group
Treatment CIPRODEX FLOXIN Treatment Failure Treatment Failure No
Yes No Yes Data Set N % N % N % N % P-value ITT 281 94.61 16 5.39
270 89.40 32 10.60 0.0189 MITT 199 95.67 9 4.33 192 88.89 24 11.11
0.0091 PP 220 94.83 12 5.17 188 85.45 32 14.55 0.0008 MPP 172 95.56
8 4.44 146 85.88 24 14.12 0.0017 .sup.aChi-square test of
independence (Fisher's exact test when N < 5).
[0079] 4. CIPRODEX is superior to FLOXIN for improvement in
clinical response at Days 3, 11 and 18.
9 Clinical Response by Treatment Group (MITT) Treatment CIPRODEX
FLOXIN Visit Clinical Response N % N % P-value.sup.a Day 3 Missing
1 0 0 0 <.000 1 Cured 64 30.92 38 17.59 Improved 130 62.80 134
62.04 Unchanged 9 4.35 35 16.20 Worse 4 1.93 9 4.17 Day 11 Missing
1 0 0 0 <.0001 Cured 174 84.06 136 62.96 Improved 25 12.08 58
26.85 Unchanged 4 1.93 12 5.56 Worse 4 1.93 10 4.63 Day 18 Missing
1 0 0 0 0.0023 Cured 174 84.06 153 70.83 Improved 20 9.66 38 17.59
Unchanged 6 2.90 12 5.56 Worse 7 3.38 13 6.02 .sup.aTreatment
difference from LSMEANS (Mixed Model Analysis of Variance).
[0080] 5. CIPRODEX is superior to FLOXIN for time to cessation of
otorrhea.
10 Time to Cessation of Otorrhea by Treatment Group (MITT)
Treatment CIPRODEX FLOXIN P-value.sup.a Mean 6.02 7.10 0.0204
Median 4.00 5.00 Std 4.87 4.68 N 208 216 Min 2 2 Max 21 21
.sup.aLog-rank test (Kaplan-Meier survival analysis).
[0081] 6. CIPRODEX is superior to FLOXIN for absence of otorrhea at
Days 3, 11 and 18.
11 Presence/Absence of Otorrhea by Treatment Group (MITT) Treatment
CIPRODEX FLOXIN Visit Otorrhea N % N % P-value.sup.a Day 1 Present
208 100.00 216 100.00 Day 3 Absent 67 32.21 40 18.52 0.0012 Present
141 67.79 176 81.48 Day 11 Absent 176 84.62 137 63.43 <.0001
Present 32 15.38 79 36.57 Day 18 Missing 1 0 0 0 0.0004 Absent 176
85.02 153 70.83 Present 31 14.98 63 29.17 .sup.aChi-square test of
independence (Fisher's exact test when N < 5).
[0082] 7. CIPRODEX is superior to FLOXIN for reduction in
granulation tissue at Days 11 and 18.
12 Granulation Tissue by Treatment Group (MITT) Treatment CIPRODEX
FLOXIN Visit Granulation Tissue N % N % P-value.sup.a Day 1 Absent
159 76.44 175 81.02 0.3449 Mild 30 14.42 21 9.72 Moderate 15 7.21
16 7.41 Severe 4 1.92 4 1.85 Day 3 Missing 1 0 0 0 0.3285 Absent
177 85.51 182 84.26 Mild 24 11.59 22 10.19 Moderate 6 2.90 10 4.63
Severe 0 0.00 2 0.93 Day 11 Missing 1 0 0 0 0.0086 Absent 198 95.65
186 86.11 Mild 8 3.86 22 10.19 Moderate 1 0.48 8 3.70 Day 18
Missing 1 0 0 0 0.0383 Absent 203 98.07 192 88.89 Mild 3 1.45 21
9.72 Moderate 1 0.48 3 1.39 .sup.aTreatment difference from LSMEANS
(Mixed Model Analysis of Variance).
[0083] 8. CIPRODEX is superior to FLOXIN for reduction in otorrhea
volume at Days 3, 11 and 18.
13 Volume by Treatment Group (MITT) Treatment CIPRODEX FLOXIN Visit
Volume N % N % P-value.sup.a Day 1 Scant 17 8.17 14 6.48 0.3195
Moderate 104 50.00 99 45.83 Copious 87 41.83 103 47.69 Day 3
Missing 1 0 0 0 <.0001 Absent 66 31.88 39 18.06 Scant 98 47.34
84 38.89 Moderate 34 16.43 77 35.65 Copious 9 4.35 16 7.41 Day 11
Missing 1 0 0 0 <.0001 Absent 175 84.54 136 62.96 Scant 19 9.18
42 19.44 Moderate 7 3.38 26 12.04 Copious 6 2.90 12 5.56 Day 18
Missing 2 0 0 0 0.0003 Absent 175 84.95 153 70.83 Scant 14 6.80 21
9.72 Moderate 8 3.88 27 12.50 Copious 9 4.37 15 6.94
.sup.aTreatment difference from LSMEANS (Mixed Model Analysis of
Variance).
[0084] 9. CIPRODEX is superior to FLOXIN for absence of otorrhea
color and less purulent otorrhea at Day 3, and absence of otorrhea
color and less mucoid otorrhea at Days 11 and 18.
14 Color/Type by Treatment Group (MITT) Treatment CIPRODEX FLOXIN
Visit Color/Type N % N % P-value.sup.a Day 1 Absent 0 0 0 0 b
Serous 21 60.00 14 40.00 0.2301 Mucoid 100 54.64 83 45.36 0.1417
Purulent 149 46.71 170 53.29 0.0607 Sanguineous 14 48.28 15 51.72
0.8335 Day 3 Absent 67 63.21 39 36.79 0.0003 Serous 55 48.67 58
51.33 0.8593 Mucoid 63 43.75 81 56.25 0.2244 Purulent 36 38.71 57
61.29 0.0461 Sanguineous 1 14.29 6 85.71 0.1244 Day 11 Absent 176
56.23 137 43.77 0.0000 Serous 12 34.29 23 65.71 0.0770 Mucoid 7
15.91 37 84.09 0.0000 Purulent 14 40.00 21 60.00 0.2879 Sanguineous
0 0.00 3 100.00 0.2488 Day 18 Absent 176 53.50 153 46.50 0.0002
Serous 8 44.44 10 55.56 0.7183 Mucoid 7 18.42 31 81.58 0.0001
Purulent 18 41.86 25 58.14 0.3510 Sanguineous 0 0.00 2 100.00
0.4992 .sup.aChi-square test of independence (Fisher's exact test
when N < 5). b Could not be calculated.
[0085] Safety Results:
[0086] The safety of CIPRODEX and FLOXIN was evaluated in 599
pediatric patients with acute otitis media with tympanostomy tubes.
No serious adverse events related to therapy were reported during
this study. Seventy-eight patients (CIPRODEX: 32; FLOXIN: 46) were
discontinued from the study due to adverse events, of which 76 were
due to treatment-unrelated events. Adverse events in the overall
safety population were all nonserious with the exception of three
reports (abdominal pain, pneumonia, cellulitis), were generally
mild to moderate, usually resolved with or without treatment, and
generally did not interrupt patient continuation in the study.
Similar types of otic and nonotic adverse events were noted in the
infant and toddler population and the children population for
CIPRODEX and FLOXIN. There were no trends observed in the analysis
of adverse events according to age category either within or
between CIPRODEX and FLOXIN treatment groups. Only three patients
in the adolescent population were enrolled, and none of the
adolescents reported adverse events.
[0087] Audiometry testing was performed to further assess the
safety of CIPRODEX in the pediatric population. No clinically
relevant or statistically significant (p=0.3863) difference in mean
change of speech reception threshold (SRT) from baseline was
observed between CIPRODEX and FLOXIN, and no clinically relevant
decrease in hearing from baseline was observed with CIPRODEX or
FLOXIN, based upon an assessment of bone and air conduction
audiometry parameters.
[0088] CIPRODEX administered twice daily in the affected ear(s) is
safe and well tolerated in pediatric patients with acute otitis
media with tympanostomy tubes, based upon a review of adverse
events and an assessment of audiometry parameters.
[0089] Safety Conclusions:
[0090] 1. CIPRODEX administered twice daily in the affected ear(s)
is safe and well tolerated in pediatric patients with acute otitis
media with tympanostomy tubes, based upon a review of adverse
events and an assessment of audiometry parameters.
[0091] 2. Adverse events in the overall safety population were all
nonserious with the exception of three reports (abdominal pain,
pneumonia, cellulitis), were generally mild to moderate, usually
resolved with or without treatment, and generally did not interrupt
patient continuation in the study.
[0092] 3. No clinically relevant or statistically significant
difference in mean change of speech recognition threshold (SRT)
from baseline was observed between CIPRODEX and FLOXIN.
[0093] 4. No clinically relevant decrease in hearing from baseline
was observed with CIPRODEX or FLOXIN, based upon an assessment of
bone and air conduction audiometry parameters.
[0094] The invention has been described by reference to certain
preferred embodiments; however, it should be understood that it may
be embodied in other specific forms or variations thereof without
departing from its spirit or essential characteristics. The
embodiments described above are therefore considered to be
illustrative in all respects and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description.
* * * * *