Note: Descriptions are shown in the official language in which they were submitted.
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TREATING ALLERGIC AND INFLAMMATORY CONDITIONS
BACKGROUND OF THE INVENTION
This invention relates to the use of desloratadine for the preparation of a
medicament for substantially returning work-related performance and/or
workplace productivity of a patient suffering from an allergic and/or
inflammatory
condition to the person's baseline work-related performance and baseline
workplace productivity.
The symptoms and side effects of an allergic and/or inflammatory condition
of the skin or upper and lower airway passages such as seasonal allergic
rhinitis
("SAR") include itchy, watery eyes, sneezing, runny nose, nasal congestion,
urticaria, somnolence and general malaise. The pharmacologic effects of
treating
allergic and/or inflammatory condition such as SAR with sedating
antihistamines
include somnolence, blurred vision, dry mouth and individual performance
impairment at home, in school and at work as well as impairment of workplace
productivity. SAR affects up to 45 million people in the United States and
many
more millions worldwide.
Cockurn, lain M, et al., in Business & Health, March 1999, pages 49-
50 and in J Occup Eniviron Med., November 1999, Vol. 41 (11 ), pages 948-953
disclose treating allergic reactions with sedating antihistamines, alone or in
combination with decongestants, leads to impaired individual performance and
decreased workplace productivity of workers compared to treatment with non-
sedating antihistamines.
In view of the high prevalence of SAR, even relatively small effects on
individual performance will have a significant impact on work-related
performance
and workplace productivity in the worldwide population, Thus, there is a need
for
a clinically more effective therapy for treating/preventing an allergic and or
inflammatory condition of the skin and upper or lower airway passages in
workers
while simultaneously enhancing their work-related performance as well as their
workplace productivity.
SUMMARY OF THE INVENTION
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The present invention provides a method of substantially returning the
work-related performance of a person suffering from an allergic and/or
inflammatory condition of the skin or airway passages to the person's baseline
work-related performance which comprises administering an amount of
desloratadine to said person effective for such returning.
The present invention provides a method of returning workplace
productivity of a person suffering from an allergic and/or inflammatory
condition of
the skin or airway passages to the person's baseline workplace productivity
which
comprises administering an effective amount of desloratadine to said person
effective for such returning.
In a preferred embodiment, the present invention provides a method of
substantially returning work-related performance of a person suffering from
seasonal allergic rhinitis to the person's baseline work-related performance
which
comprises administering an amount of desloratadine to such person effective
for
such returning.
In a preferred embodiment, the present invention provides a method of
substantially returning workplace productivity of a person suffering from
seasonal
allergic rhinitis to the person's baseline workplace productivity which
comprises
administering an amount of desloratadine to said person effective for such
returning.
In another preferred embodiment, the present invention provides a method
of enhancing work-related performance of a patient suffering from atopic
dermatitis or urticaria which comprises administering an amount of
desloratadine
effective for such enhancing.
In another preferred embodiment, the present invention provides a method
of substantially returning workplace productivity of a person suffering from
atopic
dermatitis or urticaria to the person's baseline work-related performance to
the
person's baseline work-related performance which comprises administering an
amount of desloratadine effective for such returning.
In another preferred embodiment, the present invention provides a method
of returning performance of a person suffering from atopic dermatitis or
urticaria to
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the person's baseline workplace productivity which comprises administering an
amount of desloratadine to said person effective for such returning.
In another preferred embodiment, the present invention provides a method
of substantially returning workplace productivity of a person suffering from
an
allergic and/ or inflammatory condition of the skin or passages to the
person's
baseline workplace productivity by administering an initial amount of
desloratadine
to said person effective for such returning.
In another preferred embodiment, the present invention provides a method
of substantially returning performance of a person suffering from an allergic
and/
or inflammatory condition of the skin or airway passages to the person's
baseline
workplace productivity by administering an initial amount of desloratadine to
said
person effective for such returning.
The invention also contemplates pharmaceutical compositions for
substantially returning work-related performance and/or workplace productivity
of
a person suffering from an allergic and/or inflammatory condition of the skin
or
airway passage to the person's baseline work-related performance and/or
workplace performance comprising an amount of desloratadine effective for such
returning.
DETAILED DESCRIPTION OF THE INVENTION
Persons afflicted with the symptoms and side effects of an allergic and/or
inflammatory condition of the skin and upper or lower airway passages -such as
seasonal allergic rhinitis- who are treated with an initial effective amount
of
desloratadine exhibit a significantly higher work-related performance and a
significantly higher workplace productivity in a controlled clinical setting
compared
to untreated persons as well as with persons treated with an initial standard
dose
of the sedating antihistamine, diphenhydramine.
The phrase "the person's baseline work-related performance" as used
herein means the person's work-related performance at a time prior to the
person's exhibiting signs and/or symptoms of allergic and/or inflammatory
conditions of the skin or airway passages as measured by art-recognized
methods
hereinafter described.
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The phrase "the person's baseline workplace productivity" as used herein
means the person's baseline workplace productivity as used herein means the
person's performance at a time prior to the person's exhibiting the signs
and/or
symptoms of allergic and/or inflammatory conditions of the skin or airway
passages as measured by art-recognized methods hereinafter described.
The phrase "substantially returning" as used herein in reference to a
person's baseline work-related performance or baseline workplace productivity
means returning to within about 5-10%, preferably within about 5% and more
preferably within about 1-2% of the baseline values.
The phrase "allergic and/ or inflammatory conditions of the skin or airway
passages" as used herein means those allergic and/or inflammatory conditions
and symptoms found on the skin and in the airway passages from the nose to the
lungs. Typical allergic and/or inflammatory conditions of the skin and upper
and
lower airway passages include seasonal and perennial allergic rhinitis, non-
allergic rhinitis, asthma including allergic and non-allergic asthma,
sinusitis, colds
(in combination with a NSAID, e.g., aspirin ibuprofen or APAP) and/or a
decongestant e.g. pseudoephedrine), dermatitis, especially allergic and atopic
dermatitis, and urticaria and symptomatic dermographism as well as
retinophathy,
and small vessel diseases, associated with diabetes mellitus.
The amount of desloratadine effective for treating or preventing allergic
and/or inflammatory conditions of the skin and upper and lower airway passages
will vary with the age, sex, body weight and severity of the allergic and
inflammatory condition of the patient. Typically, the amount of desloratadine
effective for treating or preventing such allergic and inflammatory conditions
is in
the range of about 2.5 mg/day to about 45 mg/day, preferably about 2.5 mg/day
to
about 20 mg/day, or about 4.0 mg/day to about 15 mg/day, or about 5.0 mg/day
to
about 10 mg/day, more preferably about 5.0 mg/day to about 7.5 mg/day, and
most preferably about 5.0 mg/day in single or divided doses, e.g. two 2.5 mg
doses, or about 5.0 mg/day in a single dose.
Desloratadine is a non-sedating long acting histamine antagonist with
potent selective peripheral H1-receptor antagonist activity. Following oral
administration, loratadine is rapidly metabolized to descarboethoxyloratadine
or
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desloratadine, a pharmacologically active metabolite. In vitro and in vivo
animal
pharmacology studies have been conducted to assess various pharmacodynamic
effects of desloratadine and loratadine. In assessing antihistamine activity
in mice
(comparison of EDSO value), desloratadine was relatively free of producing
5 alterations in behavior alterations in behavior, neurologic or autonomic
function.
The potential for desloratadine or loratadine to occupy brain H1-receptors was
assessed in guinea pigs following i.p. administration and results suggest poor
access to central histamine receptors for desloratadine or loratadine.
In vivo studies also suggest that an inhibitory effect of desloratadine on
allergic bronchospasm and cough can also be expected.
The clinical efficacy and safety of desloratadine has been documented in
over 3,200 seasonal allergic rhinitis patients in 4 double-blind, randomized
clinical
trials. The results of these chemical studies demonstrated the efficacy of
desloratadine in the treatment of adult and adolescent patients with seasonal
rhinitis.
Desloratadine is particularly useful for the treatment and prevention of the
nasal (stuffiness/congestion, rhinorrhea, nasal itching, sneezing) and non-
nasal
(itchy/burning eyes, tearing/watery eyes, redness of the eyes, itching of the
ears/palate) symptoms of seasonal allergic rhinitis, including nasal
congestion, in
patients in need of such treating and/ or preventing. Desloratadine may be
used
alone, or in combination with a decongestant, e.g., pseudeoephridine and/or an
analgesic, e.g., a NSAID such as acetominophen or ibuprofen.
STUDY DESIGNS AND CONCEPTS
A series of randomized, double-blinded(treatment), placebo-controlled
studies have been designed to quantify the impact of seasonal allergic
rhinitis
("SAR") and SAR treatments on work-related performance and workplace
productivity of subjects as measured by art-recognized selected areas of
performance and workplace productivity. In one series of studies, the effects
of
SAR (burden of disease) in subjects will be quantified by comparing the work-
related performance levels in asymptomatic SAR subjects to the work-related
subjects performance levels in symptomatic SAR subjects. In another series of
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studies, the differential impact following two different treatments for SAR on
work-
related performance of subjects will be quantified: the effects of
desloratadine 5
mg tablets will be compared to diphenhydramine 50 mg (and placebo of each
drug) among subjects with symptomatic SAR during exposure of the subjects to
ragweed pollen. A consistent level of ragweed pollen exposure will be assured
by
conducting these studies in an environmental exposure unit (EEU). The baseline
work-related performance and baseline workplace productivity of each subject
will
be measured at day 0 prior to exposure to ragweed pollen in the EEU.
WORK-RELATED PERFORMANCE TESTS
The work-related performance abilities of the subjects to be examined in
one study series were selected based on the consensus of an expert panel
consisting of neuropsychologists, industrial psychologists, and allergists.
These
work-related performance abilities cover the domains thought to be most
affected
by the symptoms of SAR and/or by sedation caused by SAR treatments. In
addition, the expert panel prioritized those performance domains that are most
closely related to abilities associated with safety and productivity. The work-
related performance abilities were then mapped by the expert panel to
neuropyschological performance tests.
PRIMARY ENDPOINT:
The effects of SAR(also called the burden of disease) will be measured by
measuring the selective attention in asymptomatic versus symtomatic subjects
and in symptomatic subjects treated with desloratadine 5 mg tablets versus
symptomatic subjects treated diphenhydramine 50 mg.
Performance Domain Definition Performance Measure
Selective Attention The ability to concentrateKay Continuous
and not be distracted Performance Test (Omission
while
performing a task overErrors Score)
a
period of time.
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SECONDARY ENDPOINTS:
1. Impact of Treatment (Desloratadine vs. Diphenhydramine) will be
determined by measuring the perceptual speed in asymptomatic versus
symtomatic subjects and in symptomatic subjects treated with desloratadine 5
mg
tablets versus symptomatic subjects treated diphenhydramine 50 mg.
Performance Domain Definition Performance Measure
Perceptual Speed The ability to quicklyAutomated
and
accurately compare Neuropsychological Matrices
letters,
numbers, objects, pictures(ANAM) Running Memory
or patterns. The thingsCPT (Accuracy Score)
to
be compared may be
presented at the same
time
or one after the other.
This
ability also includes
comparing a presented
object with a remembered
object
Near Vision The ability to see CogScreen Visual Sequence
details of
objects at a close Comparison (Accuracy
range
(within a few feet Score)
of the
observer).
2. Burden of Disease will be measured in asymptomatic vs. symptomatic
subjects; and in symptomatic subjects vs. those treated with Desloratadine by
measuring the information ordering as follows:
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Performance Domain Definition Performance Measure
Information Ordering The ability to followCogScreen Digit Symbol
a
given set of rules Coding (with Delay)
or
instructions in order(Response Time Score)
to
arrange things or
actions
in a certain order.
The
things or actions
can
include numbers,
letters,
words, pictures,
procedures, sentences,
and mathematical
or
logical operations.
3. OTHER ENDPOINTS:
Additional measures of some of the performance domains will also be
included as secondary endpoints. These include, but are not limited to,
problem
sensitivity, memorization, number facility, time sharing, and response
orientation,
and rate control.
INCLUSION AND EXCLUSION CRITERIA
Finally, standard inclusion and exclusion criteria will be used to assure that
other factors, such as nicotine and/or alcohol use or sleep disturbances, are
not
contributing to any observed effect.
ENVIRONMENTAL EXPOSURE UNIT ~(EEUJ~
The EEU is a scientifically recognized pollen exposure system that has
been used to evaluate the efficacy of anti-allergic medications, including
determinations of the "onset of action" of these medications to relieve the
signs
and symptoms of pollen-induced allergic rhinitis. The controlled exposure to
an
aeroallergen, usually short ragweed pollen, has eliminated variables
associated
with other methods of clinical evaluation of these medications. The clinical
relevance of the results of this test system have been validated by comparison
of
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the results of clinical trails in this unit with those of other modes of
allergen
challenge, in particular exposure of allergic subjects to natural
environmental
increases in pollen levels.
Prior to those study days when the subjects are to be symptomatic and will
undergo work-related performance and work-place productivity testing, they
will
be exposed during two to six priming sessions of 3 hours each to controlled
pollen
levels (3500 ~ 500 grains/m3) in the EEU. Subjects will record symptom
severity
every 30 minutes until the symptom severity criteria for enrollment in the
study are
met or the 3 hours have lapsed following which they will be transferred to a
pollen-
free room for up to one hour of observation. Subjects whose symptoms are so
severe that they cannot remain in the EEU for at least 3 hours are moved to a
pollen-free room and discharged from the study. To qualify for enrollment the
subjects are required to achieve a total SAR symptom severity score of >_10
made
up of a nasal symptom score of >_6 and of >_4 for the non-nasal symptoms. On
leaving the EEU those subjects who meet the severity scores inclusion criteria
will
be assigned to computer-generated randomization.
On the Baseline (symptomatic) and treatment-study days the enrolled
subjects will report to the EEU at 7:30 AM. They will complete the daily
baseline
pre-exposure evaluation of their SAR symptom severity at 8:00 AM, following
which they will begin exposure to ragweed pollen (3500~500 grain/m3) for 8
hours,
i.e., from 8:00 AM to 4:00 PM. Promptly following symptom severity ratings at
9:30 AM, the subjects will be evaluated for qualification for dosing and
continuation in the study. Immediately after completing the 10:00 AM dairy
card,
all subjects will take their medications with a glass (180 mL) of water.
The work-related performance and work-place productivity testing will begin
approximately 1 '/2 hours after the initial dosing and will continue until
approximately 2 hours after the initial dosing. This timing will allow for
testing to
be completed during the time that the two drugs are expected to show efficacy.
WORK-PLACE PRODUCTIVITY TESTS
The work-place productivity tests selected will be based on their
sensitivity to the effects of sedation and seasonal allergic rhinitis
symptoms, and
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their relevance to the skills required for word processing. The same subject
inclusion/exclusion criteria used for the work-related performance studies
will be
used. A consistent level of ragweed pollen exposure will be assured by
conducting
these studies in the above-described environmental exposure unit (EEU).
5
PRIMARY STUDY OBJECTIVE:
To show that work-place productivity is higher when subjects with
symptomatic SAR are treated with desloratadine, 5 mg tablets antihistamine,
than
when subjects are treated with diphenhydramine 50 mg, a sedating antihistamine
10 after exposure of both sets of subjects to ragweed pollen in an above-
described
EEU.
SECONDARY STUDY OBJECTIVES:
1. To show that work-related performance and workplace productivity are higher
when subjects with symptomatic SAR are treated with desloratadine than
when they are not treated; and
2. To show that SAR negatively impacts workplace productivity.
RESEARCH BACKGROUND FOR THE STUDIES
The hypotheses that relate to the objectives for these studies are based on
the documented findings that dosing with diphenhydramine causes somnolence
and impairment of cognitive and psychomotor functions and vigilance and
intuitive
projections, and that the signs and symptoms of SAR adversely affect those
same
functions. SAR may exert its impairing effects not only by affecting visual
and
auditory responses and upper airway breathing capacity but also by a sense of
general malaise and discomfort. These impairments of work-related performance
should result in diminished workplace productivity.
The study subjects, who will have a history of ragweed pollen associated
SAR and a documented positive skin test to short ragweed pollen, will be
evaluated while asymptomatic and symptomatic to establish baseline work-
related
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performance and workplace productivity data to meet the study objectives.
Because these subjects will be evaluated for the effects of their SAR signs
and
symptoms and of the two study medications on individual performance and
workplace productivity, they will need to meet at least minimal requirements
for
typing/word processing skills.
Both medications (desloratadine and diphenhydramine) are expected to
relieve the signs and symptoms of SAR during the course of the treatment study
day, beginning as soon as one-and-one half-hours after dosing and continuing
during the testing periods.
GENERAL EXPERIMENTAL
U.S.Patent No. 4,659,716 discloses desloratadine as a non-sedating
antihistamine as well as methods of making desloratadine, pharmaceutical
compositions containing it and methods of using desloratadine and
pharmaceutical compositions containing it to treat allergic reaction in
mammals.
U.S.Patent No. 5,595,997 discloses pharmaceutical compositions
containing desloratadine and methods of using desloratadine for treating
allergic
rhinitis.
Desloratadine is available from Schering Corporation, Kenilworth, N.J.
Diphenhydramine is available under the BENADRYL trademark on a non-
prescription basis.
The pharmaceutical compositions of desloratadine be adapted for any
mode of administration e.g., for oral, parenteral, e.g., subcutaneous ('SC"),
intramuscular ("IM"), intravenous ("IV") and intraperitoneal ("IP"), topical
or vaginal
administration or by inhalation (orally or intranasally). Preferably
desloratadine is
administered orally.
Such compositions may be formulated by combining desloratadine or an
equivalent amount of a pharmaceutically acceptable salt thereof with a
suitable,
inert, pharmaceutically acceptable carrier or diluent which may be either
solid or
liquid. Desloratadine may be converted into the pharmaceutically acceptable
acid
addition salts by admixing it with an equivalent amount of a pharmaceutically
acceptable acid. Typically suitable pharmaceutically acceptable acids include
the
mineral acids, e.g., HN03, H2S04, H3P04, HCI, HBr, organic acids, including,
but
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not limited to, acetic, trifluoroacetic, propionic, lactic, malefic, succinic,
tartaric,
glucuronic and citric acids as well as alkyl or arylsulfonic acids, such as p-
toluenesulfonic acid, 2-naphthalenesulfonic acid, or methanesulfonic acid. The
preferred pharmaceutically acceptable salts are trifluoroacetate, tosylate,
mesylate, and chloride. Desloratadine is more stable as the free base than as
an
acid addition salt and the use of the desloratadine free base in
pharmaceutical
compositions of the present invention is more preferred.
Solid form compositions include powders, tablets, dispersible granules,
capsules, cachets and suppositories. The powders and tablets may be comprised
of from about 5 to about 95 percent active ingredient. Suitable solid carriers
are
known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or
lactose. Tablets, powders, cachets and capsules can be used as solid dosage
forms suitable for oral administration. Examples of pharmaceutically
acceptable
carriers and methods of manufacture for various compositions may be found in
A.
Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack
Publishing Co., Easton, Pennsylvania.
Liquid form preparations include solutions, suspensions and emulsions. As
an example may be mentioned water or water-propylene glycol solutions for
parenteral injection. Solid form preparations may be converted into liquid
preparations shortly before use for either oral or administration. Parenteral
forms
to be injected intravenously, intramuscularly or subcutaneously are usually in
the
form of sterile solutions and may contain tonicity agents (salts or glucose),
and
buffers. Opacifiers may be included in oral solutions, suspensions and
emulsions.
Liquid form preparations may also include solutions for intranasal
administration.
Aerosol preparations suitable for inhalation may include solutions and
solids in powder form, which may be in combination with a pharmaceutically
acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
Also included are solid form preparations that are intended to be converted,
shortly before use, to liquid form preparations for either oral or parenteral
administration. Such liquid forms include solutions, suspensions and
emulsions.
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Desloratadine may also be deliverable transdermally. The transdermal
compositions can take the form of creams, lotions, aerosols and/or emulsions
and
can be included in a transdermal patch of the matrix or reservoir type as are
conventional in the art for this purpose.
Preferably, the pharmaceutical composition is in a unit dosage form. In
such form, the preparation is subdivided into suitably sized unit doses
containing
appropriate quantities of desloratadine and other, if any active component,
e.g.,
effective amounts to achieve the desired purpose.
