U.S. patent application number 15/909090 was filed with the patent office on 2018-07-26 for treatment of papulopustular rosacea with ivermectin.
The applicant listed for this patent is Galderma S.A.. Invention is credited to Philippe BRIANTAIS, Jean-Paul CHAPPUIS, Michael GRAEBER, Jean JACOVELLA, Alexandre KAOUKHOV, Michel PONCET, Laurence SALIN.
Application Number | 20180207188 15/909090 |
Document ID | / |
Family ID | 52133217 |
Filed Date | 2018-07-26 |
United States Patent
Application |
20180207188 |
Kind Code |
A1 |
JACOVELLA; Jean ; et
al. |
July 26, 2018 |
TREATMENT OF PAPULOPUSTULAR ROSACEA WITH IVERMECTIN
Abstract
Methods and compositions for safe and effective treatment of
papulopustular rosacea in a subject are described. The methods
involve topically applying to an affected skin area a topical
composition containing ivermectin and a pharmaceutically acceptable
carrier. Treatment with ivermectin represents an innovative therapy
that is more robust and effective than the conventional
treatments.
Inventors: |
JACOVELLA; Jean; (Antibes,
FR) ; CHAPPUIS; Jean-Paul; (Valbonne, FR) ;
KAOUKHOV; Alexandre; (Newport Beach, CA) ; GRAEBER;
Michael; (Lawrenceville, NJ) ; PONCET; Michel;
(Mougins, FR) ; BRIANTAIS; Philippe; (Antibes,
FR) ; SALIN; Laurence; (La Roquette Sur Siagne,
FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Galderma S.A. |
Cham |
|
CH |
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|
Family ID: |
52133217 |
Appl. No.: |
15/909090 |
Filed: |
March 1, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14973037 |
Dec 17, 2015 |
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15909090 |
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14209958 |
Mar 13, 2014 |
9233118 |
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14973037 |
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61927717 |
Jan 15, 2014 |
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61919208 |
Dec 20, 2013 |
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61843540 |
Jul 8, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/26 20130101;
A61K 9/0014 20130101; A61K 47/32 20130101; A61K 31/7048 20130101;
A61K 47/14 20130101; A61P 17/00 20180101; A61K 31/4174 20130101;
A61K 47/10 20130101; A61K 31/4164 20130101; A61K 47/02 20130101;
A61P 33/14 20180101; A61K 9/06 20130101; A61K 47/12 20130101; A61K
47/24 20130101; A61K 31/7048 20130101; A61K 2300/00 20130101; A61K
31/4164 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/7048 20060101
A61K031/7048; A61K 31/4174 20060101 A61K031/4174; A61K 47/02
20060101 A61K047/02; A61K 47/32 20060101 A61K047/32; A61K 47/12
20060101 A61K047/12; A61K 47/18 20060101 A61K047/18; A61K 47/24
20060101 A61K047/24; A61K 47/14 20060101 A61K047/14; A61K 47/10
20060101 A61K047/10; A61K 31/4164 20060101 A61K031/4164; A61K 9/00
20060101 A61K009/00; A61K 47/26 20060101 A61K047/26; A61K 9/06
20060101 A61K009/06 |
Claims
1. A method of treating papulopustular rosacea or inflammatory
lesions of rosacea in a subject in need thereof, comprising
topically administering, once daily, to a skin area affected by the
papulopustular rosacea or inflammatory lesions of rosacea a
therapeutically effective amount of a pharmaceutical composition
comprising 1% by weight ivermectin and a pharmaceutically
acceptable carrier.
2. The method of claim 1, wherein the method results in less
adverse events than a vehicle control.
3. The method of claim 1, wherein no more than 1% of the subjects
treated with the method for at least 3 months have an adverse
reaction of skin irritation.
4. The method of claim 1, wherein the therapeutically effective
amount of the pharmaceutical composition is administered at
bedtime.
5. The method of claim 1, wherein starting from 2 weeks of
treatment, the method results in a significant reduction in
inflammatory lesion count.
6. The method of claim 1, wherein starting from 4 weeks of
treatment, the method results in more effective treatment than the
vehicle control, as measured by a reduction in inflammatory lesion
count and a reduction in investigator's global assessment (IGA)
score.
7. The method of claim 1, wherein the subject has moderate to
severe papulopustular rosacea before the treatment.
8. The method of claim 1, wherein the subject has 15 or more
inflammatory lesions of the papulopustular rosacea before the
treatment.
9. The method of claim 1, wherein the pharmaceutical composition
further comprises one or more ingredients selected from the group
consisting of: an oily phase comprising dimethicone,
cyclomethicone, isopropyl palmitate and/or isopropyl myristate, the
oily phase further comprising fatty substances selected from the
group consisting of cetyl alcohol, cetostearyl alcohol, stearyl
alcohol, palmitostearic acid, stearic acid and self-emulsifiable
wax; at least one surfactant-emulsifier selected from the group
consisting of glyceryl/PEG100 stearate, sorbitan monostearate,
sorbitan palmitate, Steareth-20, Steareth-2, Steareth-21 and
Ceteareth-20; a mixture of solvents and/or propenetrating agents
selected from the group consisting of propylene glycol, oleyl
alcohol, phenoxyethanol and glyceryl triacetate; one or more
gelling agents selected from the group consisting of carbomers,
cellulose gelling agents, xanthan gums, aluminum magnesium
silicates but excluding aluminum magnesium silicate/titanium
dioxide/silica, guar gums, polyacrylamides and modified starches;
and water.
10. The method of claim 9, wherein the pharmaceutical composition
further comprises carbomer copolymer type B; cetyl alcohol; citric
acid monohydrate; dimethicone 20 Cst; edetate disodium; glycerin;
isopropyl palmitate; methyl paraben; oleyl alcohol; phenoxyethanol;
polyoxyl 20 cetostearyl ether; propylene glycol; propyl paraben;
purified water; sodium hydroxide; sorbitan monostearate and stearyl
alcohol.
11. A method of treating papulopustular rosacea or inflammatory
lesions of rosacea in a subject in need thereof, comprising
topically administering, once daily, to a skin area affected by the
papulopustular rosacea or inflammatory lesions of rosacea a
therapeutically effective amount of a pharmaceutical composition
comprising 1% by weight ivermectin and a pharmaceutically
acceptable carrier, wherein the method results in more reduction in
inflammatory lesion count in the subject in comparison to that
achieved by topically administering to the subject, twice daily, a
second pharmaceutical composition comprising 0.75% by weight
metronidazole.
12. The method of claim 11, wherein the subject has moderate to
severe papulopustular rosacea before the treatment.
13. The method of claim 11, wherein the subject has 15 or more
inflammatory lesions of the papulopustular rosacea before the
treatment.
14. The method of claim 11, wherein the pharmaceutical composition
further comprises carbomer copolymer type B; cetyl alcohol; citric
acid monohydrate; dimethicone 20 Cst; edetate disodium; glycerin;
isopropyl palmitate; methyl paraben; oleyl alcohol; phenoxyethanol;
polyoxyl 20 cetostearyl ether; propylene glycol; propyl paraben;
purified water; sodium hydroxide; sorbitan monostearate and stearyl
alcohol.
15. A method of treating papulopustular rosacea or inflammatory
lesions of rosacea in a subject in need thereof, comprising
topically administering, once daily, to a skin area affected by the
papulopustular rosacea or inflammatory lesions a therapeutically
effective amount of a pharmaceutical composition comprising 1% by
weight ivermectin and a pharmaceutically acceptable carrierr,
wherein the method results in longer relapse-free time of the
papulopustular rosacea or inflammatory lesions of rosacea in the
subject in comparison to that achieved by topically administering
to the subject, twice daily, a second pharmaceutical composition
comprising 0.75% by weight metronidazole.
16. The method of claim 15, wherein the subject has moderate to
severe papulopustular rosacea before the treatment.
17. The method of claim 15, wherein the subject has 15 or more
inflammatory lesions of the papulopustular rosacea before the
treatment.
18. The method of claim 15, wherein the pharmaceutical composition
further comprises carbomer copolymer type B; cetyl alcohol; citric
acid monohydrate; dimethicone 20 Cst; edetate disodium; glycerin;
isopropyl palmitate; methyl paraben; oleyl alcohol; phenoxyethanol;
polyoxyl 20 cetostearyl ether; propylene glycol; propyl paraben;
purified water; sodium hydroxide; sorbitan monostearate and stearyl
alcohol.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application a continuation of U.S. patent application
Ser. No. 14/973,037, filed Dec. 17, 2015, which is a continuation
of U.S. patent application Ser. No. 14/209,958, filed Mar. 13,
2014, which is entitled to priority pursuant to 35 U.S.C. .sctn.
119(e) to U.S. Provisional Patent Application No. 61/843,540, filed
Jul. 8, 2013, U.S. Provisional Patent Application No. 61/919,208
filed Dec. 20, 2013, and U.S. Provisional Patent Application No.
61/927,717, filed Jan. 15, 2014, the disclosure of each of which is
hereby incorporated by reference herein in its entirety.
BACKGROUND OF THE INVENTION
[0002] Papulopustular rosacea (PPR) is a chronic inflammatory
disorder characterized by facial papules, pustules, and persistent
erythema..sup.1 It is highly prevalent and associated with adverse
impact on quality of life and depression..sup.2 The etiology of
rosacea is multifactorial. In addition to neurovascular
dysregulation, the facial skin of patients with rosacea is affected
by augmented proinflammatory immune responses..sup.3 The principal
active cathelicidin peptide (LL-37) is highly concentrated in skin
affected by rosacea and can contribute to acute inflammation..sup.4
Moreover, PPR is characterized by the presence of inflammatory
infiltrates that accompany flares, along with a heightened immune
response involving neutrophilic infiltration and increased gene
expression of IL-8..sup.5 In addition to exogenous factors
(including UV light, heat and alcohol), it may be triggered by
Demodex folliculorum mites..sup.3 Some studies of PPR observed
higher mite densities compared to controls..sup.6-7 Therefore, a
multitude of factors can activate neurovascular and/or immune
responses, and consequential inflammation leading to flares of
rosacea..sup.3
[0003] Inflammatory lesions of rosacea, particularly moderate to
severe PPR, are difficult to treat. Only a few therapeutic
alternatives currently exist in the treatment of inflammatory
lesions of rosacea. In the United States, only three FDA-approved
treatments are indicated for the reduction of inflammatory lesions
of rosacea, including two topical treatments. A recent Cochrane
review noted some evidence supporting the effectiveness of topical
metronidazole and azelaic acid in the treatment of moderate to
severe rosacea,.sup.8 yet it is clear that not all patients respond
to these medications. In a national survey of current rosacea
medication users, 46% of patients had previously changed
medications, usually due to a lack of improvement..sup.9
[0004] Ivermectin is an anti-parasitic drug derivative from the
macrocyclic lactones family approved for human use for treatment
and chemoprophylaxis of onchocerciasis and strongyloidiasis since
1996 in the USA and since 1988 in France. In addition, it has been
approved in France for the treatment of human scabies. Oral
ivermectin in human and animal demodicidosis was effective in
reducing Demodex folliculorum and improving demodicidosis.
Moreover, when administered orally, ivermectin combined with a
subsequent weekly application of topical permethrin showed
treatment efficacy in a patient presenting chronic rosacea-like
demodicidosis (14).
[0005] U.S. Pat. No. 5,952,372 discloses a method of treating
rosacea in humans involving orally or topically administering
ivermectin. However, according to U.S. Pat. No. 5,952,372, because
of the skin barrier effect, topical treatment with ivermectin would
be anticipated to require once- or twice-daily applications for as
long as four weeks to achieve sufficient follicle penetration and
effective miticidal activity. It further describes that after
ivermectin carries out its miticidal activity on skin Demodex
folliculorum organisms, inflammatory responses to them begin to
diminish but remnants of the dead mites still elicit some flushing
and lesion formation until the cleanup processes of the body remove
them, a process that requires six to eight weeks. It suggests to
employ conventional anti-rosacea medications, such as oral
tetracycline and topical metronidazole, to suppress early flareups
and to give early clinical response during the initial phase of
ivermectin administration. U.S. Pat. No. 5,952,372 contains no
specific disclosure on topical treatment of PPR.
[0006] U.S. Pat. No. 6,133,310 and U.S. Pat. No. 8,415,311 also
disclose a method of treating acne rosacea by topical application
of ivermectin. However, they contain no specific disclosure on
treating inflammatory lesions of rosacea or PPR.
[0007] Accordingly, treatments demonstrated to have a greater
efficacy in treating PPR, particularly moderate to severe PPR, than
the currently available compositions, such as metronidazole
compositions, are still needed to provide greater, longer lasting,
or more rapid relief to those in need of the treatment. There is a
need for improved effective treatment of PPR, particularly moderate
to severe PPR. Such need is met by the present invention.
BRIEF SUMMARY OF THE INVENTION
[0008] It is now demonstrated that topical administration of
ivermectin provided more rapid relief of papulopustular rosacea as
well as longer period of time that is free of relapse as compared
to the currently available treatments, such as the topical
treatment with 0.75% by weight of metronidazole.
[0009] In one general aspect, embodiments of the present invention
relate to a method of treating papulopustular rosacea in a subject
in need thereof, comprising topically administering to a skin area
affected by the papulopustular rosacea a therapeutically effective
amount of a pharmaceutical composition comprising ivermectin and a
pharmaceutically acceptable carrier.
[0010] Another general aspect of the present invention relates to a
method of treating inflammatory lesions of papulopustular rosacea
in a subject in need thereof, comprising topically administering to
a skin area affected by the inflammatory lesions of papulopustular
rosacea a pharmaceutical composition comprising ivermectin and a
pharmaceutically acceptable carrier. In a preferred embodiment of
the present invention, the pharmaceutical composition comprises
about 0.5% to 1.5% by weight ivermectin.
[0011] In another preferred embodiment of the present invention,
the subject has moderate to severe papulopustular rosacea before
the treatment.
[0012] In yet another preferred embodiment of the present
invention, the subject has at least 10, preferably at least 12 and
more preferably at least 15, inflammatory lesions of papulopustular
rosacea, before the treatment.
[0013] According to embodiments of the present invention, once
daily topical treatment with ivermectin is significantly superior
than twice-daily topical treatment with metronidazole in treating
papulopustular rosacea.
[0014] Other aspects, features and advantages of the invention will
be apparent from the following disclosure, including the detailed
description of the invention and its preferred embodiments and the
appended claims.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0015] The foregoing summary, as well as the following detailed
description of the invention, will be better understood when read
in conjunction with the appended drawings. For the purpose of
illustrating the invention, there are shown in the drawings
embodiments which are presently preferred. It should be understood,
however, that the invention is not limited to the precise
embodiments shown in the drawings.
[0016] FIG. 1 shows the median percentage change from baseline in
lesion counts (ITT-LOCF population) in a dose range study, after
various topical treatments;
[0017] FIG. 2 illustrates subjects' response to the statement "the
product improves my rosacea" after various topical treatments (ITT
Observed);
[0018] FIG. 3 shows subject disposition in 2 clinical studies on
the safety and efficacy of ivermectin topical treatment;
[0019] FIGS. 4A-4C illustrate proportions of subjects achieving IGA
success ("clear" or "almost clear"), FIG. 4A: at week 12 in studies
1 and 2; FIG. 4B: at weeks 2, 4, 8 and 12 in study 1; and FIG. 4C:
at weeks 2, 4, 8 and 12 in study 2, wherein SOOLANTRA is a 1%
ivermectin cream;
[0020] FIGS. 5A-5D show the change from baseline in inflammatory
lesion counts (ITT-LOCF), FIG. 5A: mean absolute change
(.+-.standard error) in study 1; FIG. 5B: mean absolute change
(.+-.standard error) in study 2; FIG. 5C: median percent change in
study 1; and FIG. 5D: median percent change in study 2, wherein
SOOLANTRA is a 1% ivermectin cream;
[0021] FIGS. 6A-6B show subjects' rating of rosacea improvement at
week 12 from two studies, FIG. 6A: Study 1 and FIG. 6B: Study
2;
[0022] FIG. 7 are photographs of a patient at Baseline and Week 12
(standard light);
[0023] FIG. 8 shows subject disposition in a clinical study
comparing the topical treatments with ivermectin and
metronidazole;
[0024] FIG. 9 illustrates the mean percent change from baseline in
inflammatory lesion counts (ITT-LOCF) after the topical treatments
with ivermectin and metronidazole, *p<0.05, **p<0.001;
[0025] FIG. 10 shows the success rate based on IGA of "clear" or
"almost clear" after the topical treatments with ivermectin and
metronidazole, *p<0.05, **p<0.001;
[0026] FIG. 11 shows subjects' rating of rosacea improvement after
the topical treatments with ivermectin and metronidazole; and
[0027] FIG. 12 shows time to first relapse defined as first
re-occurrence of IGA.gtoreq.2 after the successful treatments with
ivermectin and metronidazole.
DETAILED DESCRIPTION OF THE INVENTION
[0028] Various publications, articles and patents are cited or
described in the background and throughout the specification; each
of these references is herein incorporated by reference in its
entirety. Discussion of documents, acts, materials, devices,
articles, or the like which have been included in the present
specification is for the purpose of providing context for the
present invention. Such discussion is not an admission that any or
all of these matters form part of the prior art with respect to any
inventions disclosed or claimed.
[0029] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention pertains.
Otherwise, certain terms used herein have the meanings as set forth
in the specification. All patents, published patent applications
and publications cited herein are incorporated by reference as if
set forth fully herein. It must be noted that as used herein and in
the appended claims, the singular forms "a," "an," and "the"
include plural references unless the context clearly dictates
otherwise.
[0030] Ivermectin is a member of the avermectin class, which has
been shown in immunopharmacological studies to exert
anti-inflammatory effects by inhibiting lipopolysaccharide-induced
production of inflammatory cytokines, such as tumor necrosis factor
alpha and interleukin (IL)-1b, while upregulating the
anti-inflammatory cytokine IL-10.sup.10. It is a semi-synthetic
derivative isolated from the fermentation of Streptomyces
avermitilis, that belongs to the avermectin family of macrocyclic
lactones. Ivermectin is a mixture containing
5-O-demethyl-22,23-dihydroavermectin A1a plus
5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydroaverme-
ctin A1a, generally referred to as 22,23-dihydroavermectin B1a and
B1b or H2B1a and H2B1b, respectively. The respective empirical
formulas of H2B1a and H2B1b are C.sub.48H.sub.74O.sub.14 and
C.sub.47H.sub.72O.sub.14 with molecular weights of 875.10 and
861.07 respectively.
[0031] Ivermectin is a macrocyclic lactone derivative, its
therapeutic effect is thought to be prominently due to its
anti-inflammatory properties, similar to that of other
macrolides..sup.11-12 Avermectin has been reported to exert
anti-inflammatory effects by inhibiting lipopolysaccharide-induced
production of inflammatory cytokines. In addition to its
anti-inflammatory mode of action, ivermectin possesses
antiparasitic properties. Its predecessor, avermectin, is an
antiparasitic agent of agricultural importance first isolated in
1974..sup.13 Several studies support ivermectin's role in the
effective oral treatment of cutaneous demodicidosis (in combination
with topical permethrin cream) and scabies, as well as topical
treatment of head lice..sup.14-16 Ivermectin causes death of
parasites, primarily through binding selectively and with high
affinity to glutamate-gated chloride channels, which occur in
invertebrate nerve and muscle cells. This leads to the interruption
of nerve impulses, causing paralysis and death of parasitic
organisms. Ivermectin is known to act on Demodex mites in localized
and generalized demodicidosis in animals and in humans.
[0032] In the present invention, studies were conducted to evaluate
the efficacy and safety of ivermectin in treating papulopustular
rosacea (PPR). It was discovered that, as early as 2 weeks after
the initial topical administration of a pharmaceutical composition
comprising 0.5 to 1.5% (w/w) ivermectin to the subject, a
significant reduction in inflammatory lesion count was
observed.
[0033] As used herein, a "significant reduction" refers to a
reduction that is statistically significant, not due to chance
alone, which has a p-value of 0.05 or less. A "significant
reduction" can have a p-value of less than 0.05, 0.04, 0.03, 0.01,
0.005, 0.001, etc. As used herein, "inflammatory lesion count"
refers to the number of inflammatory lesions associated with
rosacea or PPR. Inflammatory lesions can be papules and/or
pustules. A papule is a small, solid elevation less than one
centimeter in diameter, and a pustule is a small, circumscribed
elevation of the skin, which contains yellow-white exudates.
[0034] The lesions can be, e.g., papules and/or pustules of any
sizes (small or large). For example, at two weeks after the initial
treatment, about 30% (p<0.001) and 27.3% (p<0.01) median
reduction of the inflammatory lesion counts were observed from
patients treated with ivermectin in two separate clinical studies
using methods of the present invention. These reductions are
statistically significant because they had p values less than 0.01
or even less than 0.001.
[0035] This early onset of significant effectiveness is unexpected
and surprising in comparison with the conventional treatments. For
example, significant treatment differences were only observed from
week 4 or week 8 forward in two phase III studies for the topical
treatment of moderate PPR using twice-daily 15% azelaic acid
(Thiboutot et al., 2003, J. Am Acad Dermatol, 48 (6): 836-845),
while no statistically significant difference with respect to the
median inflammatory lesion counts or the median percentage change
in inflammatory lesion counts was observed at any evaluation time
during the study (P.gtoreq.0.29) of topical treatment of moderate
to severe PPR using once-daily 0.75% or 1.0% metronidazole (Dahl et
al., 2001, J. Am Acad Dermatol, 45 (5): 723-730).
[0036] This early onset of significant effectiveness is also
unexpected and surprising in view of the prior teaching, that
topical treatment with ivermectin would be anticipated to require
once- or twice-daily applications for as long as four weeks to
achieve sufficient follicle penetration and effective miticidal
activity; and that after ivermectin carries out its miticidal
activity on skin Demodex folliculorum organisms, remnants of the
dead mites still elicit some flushing and lesion formation until
the cleanup processes of the body remove them, a process that
requires six to eight weeks; and that conventional anti-rosacea
medications, such as oral tetracycline and topical metronidazole,
are suggested to be employed to suppress early flareups and to give
early clinical response during the initial phase of ivermectin
administration (see, e.g., U.S. Pat. No. 5,952,372).
[0037] Side-by-side clinical studies in the present invention also
showed that methods according to embodiments of the present
invention result in more effective treatment of PPR as well as
longer time for the relapse of PPR to occur than the conventional
topical treatment, such as that with metronidazole. In addition,
methods according to embodiments of the present invention also
result in less frequent adverse skin reactions than the
conventional topical treatments.
[0038] While not wishing to be bound by the theory, it is believed
that the mechanism of action of ivermectin in treating
papulopustular rosacea may be linked to anti-inflammatory effects
of ivermectin as well as the death of Demodex mites that have been
reported to be a factor in inflammation of the skin. Because
ivermectin has both anti-inflammatory and anti-parasitic
activities, treatment of PPR with ivermectin represents an
innovative therapy addressing these relevant pathogenic factors in
PPR, thus a novel addition to the current treatment
armamentarium.
[0039] According to an embodiment of the present invention, a
method of treating papulopustular rosacea in a subject in need
thereof, comprises topically administering to a skin area affected
by the papulopustular rosacea a pharmaceutical composition
comprising ivermectin and a pharmaceutically acceptable
carrier.
[0040] As used herein, "pharmaceutically acceptable carrier" refers
to a pharmaceutically acceptable vehicle or diluent comprising
excipients and auxiliaries that facilitate processing of the active
compounds into preparations which can be used pharmaceutically.
[0041] The pharmaceutical compositions according to the invention
are suited for treating the skin. They can be in liquid, pasty or
solid form, and more particularly in the form of ointments, creams,
milks, pomades, powders, impregnated pads, syndets, towelettes,
solutions, gels, sprays, foams, suspensions, lotions, sticks,
shampoos or washing bases. They can also be in the form of
suspensions of microspheres or nanospheres or of lipid or polymeric
vesicles or of polymeric patches and of hydrogels for controlled
release. These compositions for topical application can be in
anhydrous form, in aqueous form, or in the form of an emulsion.
[0042] In one embodiment of the present invention, the
pharmaceutical composition being formulated as an emulsion, the
topical pharmaceutical emulsion comprises ivermectin, and one or
more other ingredients selected from the group consisting of: an
oily phase comprising dimethicone, cyclomethicone, isopropyl
palmitate and/or isopropyl myristate, the oily phase further
comprising fatty substances selected from the group consisting of
cetyl alcohol, cetostearyl alcohol, stearyl alcohol, palmitostearic
acid, stearic acid and self-emulsifiable wax; at least one
surfactant-emulsifier selected from the group consisting of
glyceryl/PEG100 stearate, sorbitan monostearate, sorbitan
palmitate, Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; a
mixture of solvents and/or propenetrating agents selected from the
group consisting of propylene glycol, oleyl alcohol, phenoxyethanol
and glyceryl triacetate; one or more gelling agents selected from
the group consisting of carbomers, cellulose gelling agents,
xanthan gums, aluminum magnesium silicates but excluding aluminum
magnesium silicate/titanium dioxide/silica, guar gums,
polyacrylamides and modified starches; and water.
[0043] In a preferred embodiment of the present invention, the
pharmaceutical composition comprises 0.5-1.5% (w/w) ivermectin,
more preferably, about 1% (w/w) ivermectin, and a pharmaceutically
acceptable carrier.
[0044] In another preferred embodiment of the present invention,
the pharmaceutical composition comprises about 1% (w/w) ivermectin,
and one or more inactive ingredients selected from the group
consisting of carbomer, such as carbomer copolymer type B; cetyl
alcohol; citric acid monohydrate; dimethicone 20 Cst; edetate
disodium; glycerin; isopropyl palmitate; methyl paraben; oleyl
alcohol; phenoxyethanol; polyoxyl 20 cetostearyl ether; propylene
glycol; propyl paraben; purified water; sodium hydroxide; sorbitan
monostearate and stearyl alcohol.
[0045] As used herein, the term "subject" means any animal,
preferably a mammal, most preferably a human, to whom will be or
has been administered compounds or topical formulations according
to embodiments of the invention. Preferably, a subject is in need
of, or has been the object of observation or experiment of,
treatment or prevention of papulopustular rosacea.
[0046] As known to those skilled in the art, an "intent-to-treat
population" or "ITT population" refers to all subjects who are
randomized in a clinical study and to whom the study drug is
administered. "ITT-LOCF" refers to the ITT population using the
Last Observation Carried Forward (LOCF) method, a standard method
of handling missing data, which imputes or fills in values based on
existing data. "ITT-MI" refers to the ITT population using the
multiple imputations (MI) method based on all the data available in
the model, another method for processing data known to those
skilled in the art. A "per protocol population" or "PP population"
refers to subjects of the ITT population in a clinical study who
have no major deviations from the protocol of study.
[0047] In one embodiment, "treatment" or "treating" refers to an
amelioration, prophylaxis, or reversal of a disease or disorder, or
of at least one discernible symptom thereof. In another embodiment,
"treatment" or "treating" refers to an amelioration, prophylaxis,
or reversal of at least one measurable physical parameter related
to the disease or disorder being treated, not necessarily
discernible in or by the mammal. In yet another embodiment,
"treatment" or "treating" refers to inhibiting or slowing the
progression of a disease or disorder, either physically, e.g.,
stabilization of a discernible symptom, physiologically, e.g.,
stabilization of a physical parameter, or both. In yet another
embodiment, "treatment" or "treating" refers to delaying the onset
of a disease or disorder.
[0048] Success of treating PPR can be measured using methods known
in the art, such as by the reduction of inflammatory lesion count
from the baseline before treatment, by an improvement from the
baseline in an investigator's global assessment (IGA) score, or by
both the reduction of inflammatory lesion count and the IGA
score.
[0049] The IGA score is determined by a trained medical
professional evaluating the skin condition of a patient utilizing
an investigative global assessment of the skin condition.
Typically, such global assessments assign a value to the degree of
rosacea exhibited by the skin. In addition to the assessment made
by the medical professional, the patient's input and observations
of their skin condition and responses to various inquiries (e.g.,
stinging or burning sensations) also play a role in determining the
IGA score that is assigned. For example, the IGA score for rosacea
(Table 1) can range, for example, from 0 (clear) to 1 (almost
clear) to 2 (mild) to 3 (moderate) to 4 (Severe), including values
between these numeric gradings, such as 1.5, 2.6, 3.4 etc. (e.g.,
intervals of 0.1).
TABLE-US-00001 TABLE 1 Investigator's Global Assessment of Rosacea
Severity Grade Score Clinical Description Clear 0 No inflammatory
lesions present, no erythema Almost 1 Very few small
papules/pustules, very mild Clear erythema present Mild 2 Few small
papules/pustules, mild erythema Moderate 3 Several small or large
papules/pustules, moderate erythema Severe 4 Numerous small and/or
large papules/pustules, severe erythema
[0050] In view of the present disclosure, a skin area that is
affected by papulopustular rosacea can be identified using any
diagnostic signs or means known in the art, and can be treated by
methods according to embodiments of the present invention. Patients
can have papulopustular rosacea at different stages, from mild to
severe.
[0051] In a preferred embodiment, the patient has moderate to
severe papulopustular rosacea. As used herein, a patient having
"moderate to severe papulopustular rosacea" has at least moderate
facial erythema and at least 10 papulopustular lesions before
treatment. For example, the patient can have an IGA of rosacea of 3
or 4, and at least 10, 15, 20, 25 or more papulopustular lesions
before treatment.
[0052] According to embodiments of the present invention, the
papulopustular rosacea is treated by topically applying to a skin
area affected by the papulopustular rosacea a pharmaceutical
composition comprising ivermectin and a pharmaceutically acceptable
carrier, and the treatment results in a reduction in the
inflammatory lesion count from the baseline number of PPR lesions
(before treatment) by at least 1 to 100 lesions or more, such as at
least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 50, 60,
70, 80, 90 or 100 lesions or more. According to embodiments of the
present invention, at least about 10%, 20%, 30%, 40%, 50%, 60%,
70%, 80%, 90% or 100% reduction in inflammatory lesion count is
observed after the treatment. Depending on the number of
inflammatory lesions, and other factors, such as the conditions of
the patient, the treatment can last as long as it is needed, such
as 4 to 12 weeks.
[0053] According to other embodiments of the present invention, the
treatment reduces the IGA score in the treated subject. As used
herein, the "success rate" in a clinical study refers to the
percentage of subjects in the study having an IGA of 0 ("clear") or
1 ("almost clear") after the treatment.
[0054] According to embodiments of the present invention, the
pharmaceutical composition can be topically administered once or
twice daily, preferably once daily.
[0055] According to embodiments of the present invention, after the
initial successful treatment with ivermectin, i.e., to an IGA of 0
or 1, it takes a longer time to relapse, i.e., to an IGA of 2 or
above, as compared to the conventional treatments, such as topical
treatment with 0.75% by weight metronidazole. For example,
treatment with ivermectin (1%) once daily (QD) resulted in a
statistically significant extended remission (e.g., delayed time to
first relapse, and increase in the number of treatment free days)
of rosacea when compared to metronidazole 0.75% BID in subjects who
were successfully treated (IGA 0 or 1) for 16 weeks. There was also
a numerical trend in favor of ivermectin 1% QD for the relapse
rates.
[0056] As used herein, "time to first relapse" is defined as the
time elapsed between initial successful treatment to an IGA of
rosacea of 0 or 1 to the first reoccurrence of the IGA to 2 or more
in a subject. According to embodiments of the present invention,
the median time to first relapse is about 110, 115, 120, 125, 130,
135, 140, 145 or 150 days or more in subjects treated with
ivermectin, with a p value of 0.05 or less.
[0057] Another aspect of the present invention relates to a method
of treating inflammatory lesions of papulopustular rosacea in a
subject in need thereof, comprising topically administering to a
skin area affected by the inflammatory lesions of papulopustular
rosacea a pharmaceutical composition comprising ivermectin and a
pharmaceutically acceptable carrier.
[0058] Preferably the subject has moderate to severe PPR before the
treatment. More preferably, the subject has at least 15
inflammatory lesions of PPR before the treatment.
[0059] In another preferred embodiment, at two weeks after the
initial treatment, about 27% or more median reduction of the
inflammatory lesion counts is observed from subjects treated with
ivermectin, with a p value of 0.01 or less.
[0060] Preferably, the pharmaceutical composition comprises 0.5% to
1.5% by weight ivermectin, more preferably about 1% by weight
ivermectin.
[0061] In an embodiment of the present invention, as early as 2
weeks after the initial administration of the pharmaceutical
composition to the subject, significant reduction in the
inflammatory lesion count in the subject is observed. In other
embodiments of the present invention, the method results in more
reduction of the inflammatory lesion count and longer relapse-free
time of the inflammatory lesions of rosacea in the subject in
comparison to that achieved by topically administering to the
subject a second pharmaceutical composition comprising 0.75% by
weight metronidazole.
[0062] This invention will be better understood by reference to the
non-limiting examples that follow, but those skilled in the art
will readily appreciate that the examples are only illustrative of
the invention and the claims which follow thereafter.
[0063] Unless otherwise indicated, all percentages of the
ingredients in the present application are percentages by weight
(w/w).
EXAMPLE 1
Topical Ivermectin Compositions
[0064] Examples of pharmaceutical compositions that can be used in
the present invention are described in U.S. Pat. No. 8,415,311 and
US Pat. No. 8,470,788, which are incorporated herein by reference.
Compositions useful in the present invention include, but are not
limited to, the following:
TABLE-US-00002 Composition 1 % by weight relative to the total
Ingredients weight of the Composition Ivermectin 1.00 Glycerol 4.0
Aluminum magnesium silicate 1.0 Methyl para-hydroxybenzoate 0.2
Disodium EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl palmitate
4.0 Glyceryl/PEG 100 stearate 3.0 Self-emulsifiable wax 2.0
Palmitostearic acid 2.5 Steareth-20 3.0 Sorbitan stearate 2.0
Dimethicone 20 0.5 Propyl para-hydroxybenzoate 0.1 Propylene glycol
4.0 Glyceryl triacetate 1.0 Phenoxyethanol 0.5 10% sodium hydroxide
qs pH Water qs 100
TABLE-US-00003 Composition 2 % by weight relative to the total
Ingredients weight of the Composition Ivermectin 1.00 Glycerol 4.0
Acrylate C10-30 alkyl acrylate 0.15 Crosspolymer Methyl
para-hydroxybenzoate 0.2 Disodium EDTA 0.05 Citric acid monohydrate
0.05 Isopropyl myristate 4.0 Cetyl alcohol 3.0 Stearyl alcohol 2.0
Self-emulsifiable wax 0.8 Palmitostearic acid 0.5 Steareth-20 2.0
Sorbitan palmitate 1.0 Dimethicone 20 0.5 Propyl
para-hydroxybenzoate 0.1 Propylene glycol 4.0 Glyceryl triacetate
1.0 Phenoxyethanol 0.5 10% sodium hydroxide qs pH Water qs 100
TABLE-US-00004 Composition 3 % by weight relative to the total
Ingredients weight of the Composition Ivermectin 1.00 Glycerol 4.0
Aluminum magnesium silicate 1.0 Methyl para-hydroxybenzoate 0.2
Disodium EDTA 0.05 Citric acid monohydrate 0.05 Isopropyl palmitate
4.0 Glyceryl/PEG 100 stearate 3.0 Self-emulsifiable wax 2.0
Palmitostearic acid 3.0 Steareth-20 3.0 Sorbitan palmitate 2.0
Dimethicone 20 0.5 Propyl para-hydroxybenzoate 0.1 Propylene glycol
4.0 Glyceryl triacetate 1.0 Phenoxyethanol 0.5 10% sodium hydroxide
qs pH Water qs 100
TABLE-US-00005 Composition 4 % by weight relative to the total
Ingredients weight of the Composition Ivermectin 1.00 Glycerol 4.0
Acrylate C10-30 alkyl acrylate 0.2 Crosspolymer Methyl
para-hydroxybenzoate 0.2 Disodium EDTA 0.05 Citric acid monohydrate
0.05 Isopropyl palmitate 4.0 Cetyl alcohol 3.5 Stearyl alcohol 2.5
Oleyl alcohol 2.0 Ceteareth-20 3.0 Sorbitan monostearate 2.0
Dimethicone 200 20 cs 0.5 Propyl para-hydroxybenzoate 0.1 Propylene
glycol 2.0 Phenoxyethanol 1.0 10% sodium hydroxide qs pH Water qs
100
TABLE-US-00006 Composition 5 % by weight relative to the total
Ingredients weight of the Composition Ivermectin 1.4 Glycerol 4.0
Acrylate C10-30 alkyl acrylate 0.2 Crosspolymer Methyl
para-hydroxybenzoate 0.2 Disodium EDTA 0.05 Citric acid monohydrate
0.05 Isopropyl palmitate 4.0 Cetyl alcohol 3.5 Stearyl alcohol 2.5
Oleyl alcohol 2.0 Ceteareth-20 3.0 Sorbitan monostearate 2.0
Dimethicone 200 20 cs 0.5 Propyl para-hydroxybenzoate 0.1 Propylene
glycol 2.0 Phenoxyethanol 1.0 10% sodium hydroxide qs pH Water qs
100
EXAMPLE 2
Dosage Study on Topical Treatment of PPR with Ivermectin
[0065] A phase II, randomized, investigator-blinded,
parallel-group, active-and vehicle-controlled study was conducted
to determine the optimal concentration and dose regimen of topical
ivermectin cream for the treatment of inflammatory lesions of
rosacea, and evaluate efficacy and safety.
[0066] Eligible subjects were adults with PPR. The majority of the
subjects had at least 15 facial inflammatory lesions and at least
mild facial erythema based on IGA of rosacea severity. Table 2
shows the demographic and baseline clinical characteristics (ITT
population) of the subjects:
TABLE-US-00007 TABLE 2 Ivermectin Ivermectin Ivermectin Ivermectin
Metronidazole Vehicle 1% BID 1% QD 0.3% 0.1% 0.75% BID QD (N = 48)
(N = 52) (N = 47) (N = 51) (N = 48) (N = 50) Gender, n (%) Female
39 (81.3) 33 (63.5) 29 (61.7) 31 (60.8) 34 (70.8) 35 (70.0) Male 9
(18.8) 19 (36.5) 18 (38.3) 20 (39.2) 14 (29.2) 15 (30.0) Age, year
Mean .+-. SD 50.9 .+-. 12.3 50.4 .+-. 14.5 53.4 .+-. 14.5 52.7 .+-.
13.8 52.2 .+-. 15.9 52.2 .+-. 14.4 Phototype, n (%) I 7 (14.6) 4
(7.7) 6 (12.8) 4 (7.8) 3 (6.3) 7 (14.0) II 28 (58.3) 27 (51.9) 20
(42.5) 26 (51.0) 29 (60.4) 28 (56.0) III 12 (25.0) 14 (26.9) 17
(36.2) 18 (35.3) 14 (29.2) 15 (30.0) IV 1 (2.1) 7 (13.5) 4 (8.5) 3
(5.9) 2 (4.1) 0 Inflammatory lesion, n (%) Mean .+-. SD 37.3 .+-.
39.0 35.8 .+-. 18.2 35.1 .+-. 20.5 31.1 .+-. 15.0 37.4 .+-. 23.9
35.8 .+-. 19.9 Min, max 16, 270 16, 93 14, 108 15, 79 15, 153 15,
120 IGA, n (%) 1 = Almost Clear 2 (4.2) 0 1 (2.1) 1 (2.0) 1 (2.1) 1
(2.0) 2 = Mild 15 (31.3) 20 (38.5) 15 (31.9) 18 (35.3) 18 (37.5) 12
(24.0) 3 = Moderate 28 (58.3) 24 (46.2) 21 (44.7) 29 (56.9) 21
(43.8) 28 (56.0) 4 = Severe 3 (6.3) 8 (15.4) 10 (21.3) 3 (5.9) 8
(16.7) 9 (18.0)
[0067] The subjects were randomized to receive one of the following
six (6) regimens for 12 weeks: ivermectin 0.1% (w/w) once-daily
(QD), ivermectin 0.3% (w/w) QD, ivermectin 1% (w/w) QD, ivermectin
1% (w/w) twice-daily (BID), metronidazole gel 0.75% (w/w) BID, or
vehicle QD. The 6 groups were comparable in terms of demographic
and baseline disease characteristics (Table 1): majority were
female, Caucasian, with a skin phototype II and a mean age of
51.9.+-.14.2 years. On average, the subjects had 35.4.+-.23.8
inflammatory lesions, and the majority (51.0%) had an IGA of 3
(moderate).
[0068] Inflammatory lesion (sum of papules and pustules) counts,
rate of success [% subjects "clear" or "almost clear" based on
Investigator's Global Assessment (IGA), a scale from 0 (clear) to 4
(severe)], erythema [from 0 (none) to 3 (severe)], telangiectasia
[from 0 (none) to 3 (severe)], adverse events, and satisfaction
questionnaire (at the end of the study) were determined during the
study.
[0069] FIG. 1 shows the median percentage change from baseline in
lesion counts (ITT- LOCF population).
[0070] At week 12, both ivermectin 1% (w/w) QD and BID were
significantly more effective than vehicle QD in the ITT-LOCF
analysis based on the percentage change from baseline in
inflammatory lesion counts (median: -78.3% and -78.9% vs. -60.6%;
both p<0.05) (FIG. 1); this was also confirmed in the PP
analysis. Although ivermectin 1% (w/w) BID was significantly more
efficacious than vehicle, its magnitude of effect was not greater
than ivermectin 1% (w/w) QD. A numeric trend favoring ivermectin 1%
QD compared with metronidazole 0.75% BID was also observed in terms
of median % change from baseline in inflammatory lesion counts
[-78.3% vs. -69.2% at Week 12 (ITT-LOCF)]; the sample size was not
large enough to detect differences between these groups.
[0071] All ivermectin dose regimens led to a significantly greater
success rate than vehicle (70.8%, 65.4%, 63.8% and 62.7% for
ivermectin 1% BID, 1% QD, 0.3% QD and 0.1% QD, respectively, vs.
42.0% for vehicle at Week 12; all p<0.05). Furthermore, the
success rate for Metronidazole was 62.5%. No difference was
observed in the change in erythema or telangiectasia between the
active and control groups.
[0072] All regimens were safe and well-tolerated, with similarly
low incidence of adverse events. There were no serious related AEs.
The majority of related AEs were mild, transient and dermatologic
in nature, the most frequent for the ivermectin groups being skin
discomfort (4 subjects), skin burning sensation (4 subjects), and
worsening of rosacea (3 subjects).
[0073] FIG. 2 illustrates subjects' response to the statement "the
product improves my rosacea" (ITT Observed). With increasing dosage
of ivermectin, more subjects agreed with the statement "the product
improves my rosacea" (FIG. 2) and were satisfied with the product
(data not shown). The result was superior in ivermectin 1% QD and
BID groups compared to the metronidazole 0.75% BID group. The
majority of subjects in all Ivermectin groups considered that the
product was easy to use (at least 95.5%), pleasant to use (at least
77.3%), and did not irritate the skin (at least 70.2%).
[0074] Topical administration of all tested ivermectin dose
regimens (1% BID, 1% QD, 0.3% QD and 0.1% QD) led to a
significantly greater success rate in treating PPR than vehicle;
the result was superior in ivermectin 1% QD and BID groups compared
to the metronidazole 0.75% BID group; and once daily topical
administration of 1% (w/w) ivermectin was considered the optimal
dose regimen, because it was safe, well tolerated, and provided
significantly greater efficacy than vehicle for the treatment of
PPR. Once daily topical administration is further preferred because
it promotes better patient compliance.
EXAMPLE 3
Efficacy and Safety Study of Ivermectin 1% Cream
[0075] To demonstrate the efficacy and safety of once-daily
ivermectin 1% (w/w) cream in subjects with PPR, two identically
designed randomized, double-blind, controlled studies were
conducted (hereafter designated Study 1 and Study 2). Both studies
were conducted in accordance with the ethical principles of the
Declaration of Helsinki and Good Clinical Practices, and in
compliance with local regulatory requirements.
[0076] Each study had three parts. In the first part of the study,
subjects with PPR were treated with ivermectin 1% cream (IVM 1%) or
vehicle once daily at bedtime for 12 weeks. In the second part of
the study, subjects initially treated with IVM 1% once daily at
bedtime continued the same treatment, while subjects treated with
the vehicle once daily switched to topical treatment with azelaic
acid 15% gel twice daily, in the morning and evening. The third
part of the study consisted of 4 weeks safety follow-up, without
treatment.
[0077] Eligible subjects were 18 years or older, with moderate or
severe papulopustular rosacea as noted by an IGA of 3 ("several
small or large papules/pustules, moderate erythema") or 4
("numerous small and/or large papules/pustules, severe erythema"),
and presenting with 15-70 facial inflammatory lesions (papules and
pustules). A total of 683 subjects with moderate to severe PPR were
randomized in Study 1 (IVM 1%: 451, vehicle: 232), and 688 subjects
in Study 2 (IVM 1%: 459, vehicle: 229) (FIG. 3).
[0078] Eligible subjects received either ivermectin cream 1% cream
(once daily every day at bedtime) or vehicle cream (once daily
every day at bedtime) on the entire face for 12 weeks. They were
instructed to apply a thin film of cream on the entire face (right
and left cheeks, forehead, chin and nose), e.g., in a pea-size
amount of the cream, avoiding the upper and lower eyelids, lips,
eyes and mouth. Subjects were also instructed to avoid rosacea
triggers, such as sudden exposure to heat, certain foods, and
excessive sun exposure. Study visits during the first study were as
follows: screening visits, baseline, weeks 2, 4, 8, and 12 after
the initial administration.
[0079] Efficacy assessments at each visit were the IGA of disease
severity, and inflammatory lesion counts (papules and pustules) on
each of the five facial regions (forehead, chin, nose, right cheek,
left cheek). Safety assessments included adverse events (AEs)
throughout the study, local tolerance parameters (stinging/burning,
dryness, itching) at each study visit evaluated on a 4-point scale
[from 0 (none) to 3 (severe)], and laboratory parameters
(hematology and biochemistry) measured before and after treatment.
Other assessments included the subject's evaluation of their
rosacea improvement at the end of the study (week 12) compared to
their condition at baseline, and two quality of life (QoL)
questionnaires [a dermatology-specific instrument, the Dermatology
Life Quality Index (DLQI)],17 and a rosacea-specific instrument,
the RosaQoL.TM.18 completed at baseline and week 12.
[0080] The co-primary efficacy endpoints in both studies were the
success rate based on the IGA outcome and absolute change from
baseline in inflammatory lesion counts at the end of week 12 of the
studies. The success rate based on IGA score [% of subjects who
achieved "clear" or "almost clear" ratings on the IGA scale at week
12 (ITT-LOCF)] was analyzed by the Cochran-Mantel-Haenszel (CMH)
test stratified by analysis site, using the general association
statistic. The absolute change in inflammatory lesion counts from
baseline to week 12 (ITT-LOCF) was analyzed by analysis of
covariance (ANCOVA). Missing data at week 12 in the ITT population
were imputed by the LOCF approach. Also, sensitivity analyses were
conducted to impute missing data in order to assess the robustness
of the primary efficacy results. The secondary efficacy endpoint
was percent change in inflammatory lesion counts from baseline at
week 12 (ITT-LOCF). The QoL questionnaires were analyzed using the
Wilcoxon rank sum test, and other variables were descriptively
analyzed. High mean scores from the QoL questionnaires indicated a
low quality of life.
[0081] In Studies 1 and 2, the vast majority of subjects completed
the study (91.4% and 92.6%, respectively). The treatment groups
were similar at baseline in terms of demographics and baseline
disease characteristics, with about 31-33 inflammatory lesions on
average and the majority having moderate rosacea (Table 3). Most
subjects were female (68.2% and 66.7% in Studies 1 and 2,
respectively) and Caucasian/white (96.2% and 95.3%), with a mean
age of 50.4 and 50.2 years, respectively. Additionally, treatment
groups were comparable regarding rates/reasons for early study
discontinuation (FIG. 3).
TABLE-US-00008 TABLE 3 Demographic and baseline clinical
characteristics (ITT population) Study 1 Study 2 Total Total (n =
683) (n = 688) Age, years Mean .+-. SD 50.4 .+-. 12.09 50.2 .+-.
12.29 Min, Max 19, 88 18, 89 Gender, n (%) Female 466 (68.2%) 459
(66.7%) Male 217 (31.8%) 229 (33.3%) Race White 657 (96.2%) 656
(95.3%) Black or African 9 (1.3%) 10 (1.5%) American Asian 6 (0.9%)
15 (2.2%) Other 11 (1.6%) 7 (1.0%) Inflammatory Mean .+-. SD 30.9
.+-. 14.33 32.9 .+-. 13.70 lesion counts IGA 3 = Moderate 560
(82.0%) 403 (83.3%) 4 = Severe 123 (18.0%) 81 (16.7%)
[0082] The proportion of subjects achieving IGA success ("clear" or
"almost clear") at week 12 for Studies 1 and 2 were 38.4% and
40.1%, respectively for IVM 1% compared to 11.6% and 18.8% for
vehicle (both p<0.001; FIGS. 4A). A significant difference
between treatment arms in both studies was observed based on IGA
since week 4 (10.9% and 11.8% versus 5.6% and 5.7%, respectively;
both p<0.05), and was sustained until Week 12 (FIGS. 4B and
4C).
[0083] For inflammatory lesion counts, the mean difference between
IVM 1% and vehicle from baseline to week 12 was -8.13 lesions for
Study 1 and -8.22 for Study 2 (both p<0.001 versus vehicle),
with a 95% CI of [-10.12, -6.13] and [-10.18, -6.25], respectively
(FIGS. 5A and 5B). A mean reduction of 9 lesion counts was observed
at week 2 in both studies when treated with IVM 1% (FIGS. 5A and
5B). Median reduction from baseline in inflammatory lesion counts
for both studies was 76.0% and 75.0%, respectively, versus 50.0%
for both vehicle groups at week 12 (p<0.001), with significant
difference observed by week 2 at a median reduction of 30% and
27.3% (FIGS. 5C and 5D). This significant reduction in inflammatory
lesion counts as early as week 2 was exceptional when compared with
similar data from treatment with metronidazole or azelaic acid.
[0084] Table 4 summarizes efficacy outcomes of both studies at the
end of the first part 12 week studies
TABLE-US-00009 IVM 1% Vehicle IVM 1% Vehicle (N = 451) (N = 232) (N
= 459) (N = 229) IGA Number (%) of Subjects 173 27 184 43 Clear or
Almost Clear (38.4) (11.6) (40.1) (18.8) in the IGA at Week 12
Inflammatory Lesions Mean inflammatory 31.0 30.5 33.3 32.2 lesion
count at baseline Mean inflammatory 10.6 18.5 11.0 18.8 lesion
count at Week 12 Mean Absolute Change -20.5 -12.0 -22.2 -13.4 (%)
in Inflammatory (-64.9) (-41.6) (-65.7) (-43.4) Lesion Count from
Baseline at Week 12
[0085] The incidence of AEs was comparable between Studies 1 and 2
(40.5% and 36.5% for IVM 1% versus 39.4% and 36.5% for vehicle,
respectively). Fewer subjects in IVM 1% groups tended to report
related AEs than in vehicle groups (4.2% and 2.6% versus 7.8% and
6.5%, respectively), as well as for related dermatologic AEs (3.5%
and 1.5% versus 6.9% and 5.7%) and related AEs leading to
discontinuation (1.3% and 0.2%, versus 1.7% for both vehicle
groups). A similarly low proportion of subjects reported serious
AEs for IVM 1% and vehicle groups (0.7% and 1.5% versus 0.4% and
1.7%). There were no related serious AEs. The most common related
AE in Study 1 was sensation of skin burning: 8 (1.8%) in IVM 1%
subjects versus 6 (2.6%) for vehicle. For Study 2, the most common
related AEs for IVM 1% were pruritis and dry skin (3 subjects each
(0.7%)) compared to 0 and 2 subjects (0.9%) for vehicle,
respectively. In addition, laboratory tests did not demonstrate
clinically significant abnormalities.
[0086] At baseline before treatment application, a large proportion
of subjects presented with local cutaneous symptoms consistent with
rosacea, especially mild or moderate dry skin (for Studies 1 and 2,
63.0% and 57.0% for IVM 1%, and 59.3% and 60.0% for vehicle,
respectively) and mild or moderate itching (57.3% and 49.4% for IVM
1%, and 45.4% and 49.1% for vehicle). At week 12 (last available
data observed), the majority of subjects had none of the 2
cutaneous symptoms. A trend was observed in terms of absence of
dryness in 83-86% of IVM 1% subjects versus 72-76% for vehicle, as
well as for absence of itching in 82-85% for IVM 1% versus 70-78%
for vehicle.
[0087] Improvement after treatment was rated by subjects as
"excellent" or "good" by 69% and 66.2% for IVM 1% compared to 38.6%
and 34.4% for vehicle (p<0.001), respectively (FIG. 6).
"Excellent" improvement was reported by 34.3% and 32.0% for IVM 1%
versus 9.5% and 7.3% for vehicle.
[0088] After 12 weeks of treatment, improved QoL scores were
observed for subjects in the IVM 1% compared to vehicle groups. For
the DLQI, it is of note that no difference between treatment groups
was observed at baseline. At the end of each study, more subjects
in the IVM 1% group (about 53%) than vehicle (about 35%) considered
that their disease had no effect on their overall QoL (p<0.001).
For RosaQoL.TM., improvement in QoL from baseline was higher in
both studies for IVM 1% (-0.64.+-.0.7 and -0.60.+-.0.6 versus
-0.35.+-.0.5 for both vehicle groups (p<0.001 and p=0.001 for
Studies 1 and 2, respectively). This result indicates that a higher
proportion of subjects felt that their quality of life was not
negatively impacted by rosacea in the group treated with IVM,
compared to the control group treated with vehicle.
[0089] IGA was assessed during the second part of the studies (40
weeks). The percentages of subjects treated with IVM 1% achieving
an IGA score of 0 or 1 continued to increase up to week 52, the end
of the second part of the studies. The success rate (IGA=0 or 1) at
week 52 was 71.1% and 76% in studies 1 and 2 respectively. In both
studies, the incidences were comparable in the 2 groups of subjects
treated by IVM 1% cream QD and azelaic acid 15% gel BID across the
categories of related AEs, dermatologic AEs, serious AEs, related
AEs leading to discontinuation, and AEs of special interests. There
was no serious related AEs.
[0090] In the follow up third part of the studies, subjects treated
with IVM 1% cream QD and azelaic acid 15% gel BID during the second
part of the studies were comparable in reporting AEs. No subjects
reported related serious AEs, related AEs leading to
discontinuation.
[0091] The most frequent (>0.5% in any arm) AEs were skin
disorders, and were less frequent with IVM 1% cream QD than azelaic
acid 15% gel BID in both studies.
[0092] These two pivotal studies demonstrated the efficacy and
safety of topical ivermectin 1% cream in the treatment of
inflammatory lesions of rosacea with reproducibility. The effect
was robust and highly significant (p,0.001) in all primary and
secondary endpoints at week 12 (ITT-LOCF). Onset of treatment
effect was observed at week 4 in each study based on both IGA and
lesion counts. Onset of treatment effect was observed at week 2 in
each study based on lesion counts. The ivermectin 1% cream was well
tolerated and safe in both studies. No notable difference was
observed between the ivermectin 1% cream QD and corresponding
vehicle and azelaic acid 15% gel BID. The most frequent (>0.5%
in any arm) AEs were skin disorders, and were less frequent with
IVM 1% cream QD than with the respective comparator. In addition,
the continued daily application of the Ivermectin 1% Cream QD up to
1 year is well tolerated, with no unexpected safety findings
associated with chronic use.
[0093] In conclusion, ivermectin, such as 1% ivermectin cream, was
effective and safe in treating papulopustular rosacea.
EXAMPLE 4
Comparison of the Efficacy and Safety of Ivermectin 1% Cream vs.
Metronidazole 0.75% Cream
[0094] This was an investigator-blinded, randomized, parallel group
study comparing the efficacy and safety of ivermectin (hereafter
designated IVM) 1% (w/w) cream vs. metronidazole 0.75% (w/w) cream
with a 16-week period A and a 36-week period B to study recurrence.
Study visits during Period A were as follows: a screening visit,
and at baseline, weeks 3, 6, 9, 12 and 16.
[0095] Eligible subjects were 18 years or older, with moderate or
severe papulopustular rosacea as noted by an IGA of 3 ("several
small or large papules/pustules, moderate erythema") or 4
("numerous small and/or large papules/pustules, severe erythema"),
and presenting with 15-70 facial inflammatory lesions (papules and
pustules).
[0096] Subjects were randomized in a 1:1 ratio to receive either
IVM 1% cream (once daily, QD, at bedtime) or metronidazole 0.75%
cream (twice daily, BID, as per labelling at morning and bedtime)
for 16 weeks. Study drugs were applied in a thin film on the entire
face (right and left cheeks, forehead, chin and nose), avoiding the
upper and lower eyelids, lips, eyes and mouth. The subjects were
instructed to maintain a consistent lifestyle throughout the study
regarding rosacea triggers (i.e. avoiding environmental factors,
certain foods, and excessive sun exposure).
[0097] Efficacy assessments at each visit were inflammatory lesion
counts (papules and pustules) counted on five facial regions
(forehead, chin, nose, right cheek, left cheek), and the
Investigator's Global Assessment (IGA) of disease severity. Safety
assessments included adverse events (AEs) throughout the study,
local tolerance parameters (stinging/burning, dryness, itching) at
each visit evaluated on a 4-point scale (from 0 (none) to 3
(severe)), and laboratory parameters measured at baseline, weeks 9
and 16. Other assessments included the subject's evaluation of
rosacea improvement compared to their condition at baseline, and
subject's appreciation questionnaire at the end of the study
(regarding satisfaction with the study drug). Lastly, a quality of
life questionnaire (Dermatology Life Quality Index (DLQI)) was
completed at baseline and at the end of the study (week 16).
[0098] The ITT population included all subjects who were randomized
and to whom the study drug was administered. The safety population
included all subjects who received the study medication. The
primary efficacy endpoint, percent change in inflammatory lesion
counts from baseline to week 16, was analyzed using the CMH test
stratified on center, with ridit transformation and row mean score
difference statistic. Secondary efficacy endpoints included success
rate (percent of subjects with IGA rated 0 ("clear") or 1 ("almost
clear") (analyzed by CMH test stratified on center using general
association statistic), IGA and absolute change in lesion counts
(analyzed using ANCOVA, including treatments and analysis center as
factors, and baseline as covariate). LOCF was the primary method
for imputation of missing data, and multiple imputations (MI)
method was used for sensitivity. Other variables were descriptively
analyzed.
[0099] A total of 1,034 subjects were screened and 962 randomized
to receive IVM 1% cream (n=478) or metronidazole 0.75% cream
(n=484); 902 (93.8%) completed the study (FIG. 8). Treatment groups
were comparable at baseline in terms of demographics and baseline
disease characteristics, with about 32 inflammatory lesions on
average and the majority having moderate rosacea (83.3% with an IGA
of 3) (Table 5). As expected, the quantity of product applied in
the metronidazole group (BID applications) was nearly twice as much
as the product applied in the IVM 1% group (QD), with a mean of
1.31 g vs. 0.72 g, respectively.
TABLE-US-00010 TABLE 5 Demographic and baseline clinical
characteristics (ITT population) Ivermectin 1% Metronidazole 0.75%
Total (n = 478) (n = 484) (n = 962) Age, years Mean .+-. SD 51.22
.+-. 13.40 51.87 .+-. 13.24 51.54 .+-. 13.32 Min, Max 18, 85 18, 90
18, 90 Gender, n (%) Female 311 (65.1%) 316 (65.3%) 627 (65.2%)
Male 167 (34.9%) 168 (34.7%) 335 (34.8%) Race Asian 3 (0.6%) -- 3
(0.3%) White 475 (99.4%) 484 (100.0%) 959 (99.7%) Skin I 18 (3.8%)
17 (3.5%) 35 (3.6%) Phototype II 245 (51.3%) 234 (48.3%) 479
(49.8%) III 178 (37.2%) 213 (44.0%) 391 (40.6%) IV 36 (7.5%) 19
(3.9%) 55 (5.7%) V 1 (0.2%) 1 (0.2%) 2 (0.2%) Inflammatory Mean
.+-. SD 32.87 .+-. 13.95 32.07 .+-. 12.75 32.46 .+-. 13.36 lesion
Counts Investigator 3 = Moderate 398 (83.3%) 403 (83.3%) 801
(83.3%) Global 4 = Severe 80 (16.7%) 81 (16.7%) 161 (16.7%)
Assessment
[0100] Regarding the primary endpoint, at week 16 (ITT-LOCF), IVM
1% cream was significantly superior to metronidazole 0.75% cream in
terms of percent reduction from baseline in inflammatory lesion
counts (83.0% vs. 73.7%; p<.001; FIG. 9). This difference was
observed as early as week 3 (ITT-LOCF) (as soon as week 6 with
ITT-MI), and this continued through week 16 (all
p-values.ltoreq.0.04). It should be noted that in this study, there
was no study visit or assessment prior to Week 3, thus the
differences in treatment could have been observed earlier than week
3 if the first study visit was conducted earlier. Similar results
were found for the IGA success rate (subjects rated "clear" or
"almost clear"): 84.9% for IVM 1% cream vs. 75.4% for metronidazole
0.75% cream at week 16 (ITT-LOCF) (V.001). As illustrated in FIG.
10, the difference in IGA was the highest at week 12 (14.9%
superior for ivermectin).
[0101] About 13% more subjects were rated as "clear" in terms of
IGA for IVM 1% than metronidazole 0.75% (34.9% vs. 21.7%,
respectively). Furthermore, in a subgroup analysis of success rate
according to IGA severity, about 20% more subjects with severe
rosacea at baseline in the IVM 1% group achieved success (82.5% vs.
63.0%).
[0102] The incidence of adverse events (AEs) was similar between
groups (32.4% vs. 33.1% of subjects in the IVM 1% and metronidazole
0.75% groups, respectively), as well as for related AEs (2.3% vs.
3.7%). Furthermore, a comparably low number of subjects experienced
a related dermatologic AE (9 subjects (1.9%) in the IVM 1% group
and 12 (2.5%) in the metronidazole 0.75% group). The most common
related AE was skin irritation (3 subjects (0.6%) vs. 4 subjects
(0.8%) for IVM 1% and metronidazole 0.75%, respectively). Thirteen
subjects reported serious but unrelated AEs. A total of 3 subjects
(0.6%) in the IVM 1% group experienced related adverse events
leading to discontinuation (due to skin irritation and
hypersensitivity), compared to 10 (2.1%) subjects in the
metronidazole 0.75% group (due to skin irritation, allergic
dermatitis, aggravation of rosacea, erythema, pruritis, and general
disorders (hot feeling)).
[0103] In terms of local tolerance, the incidence of worsening from
baseline was higher in the metronidazole 0.75% group for
stinging/burning (15.5% vs. 11.1%), dryness (12.8% vs. 10.0%), and
itching (11.4% vs. 8.8%). Laboratory tests did not demonstrate
clinically significant abnormalities.
[0104] At the end of period A of this study, the majority (85.5%)
of subjects in the IVM 1% group rated their global improvement as
"excellent" or "good" compared to 74.8% in the metronidazole 0.75%
group. Furthermore, more subjects receiving IVM 1% reported an
"excellent" improvement of their rosacea (52.3% vs. 37.0%,
respectively; FIG. 11). Regarding the subject's appreciation
questionnaire, more subjects in the IVM 1% group were satisfied
with the study drug (76.0% vs. 61.3% in the metronidazole 0.75%
group). In addition, more subjects treated by IVM 1% tended to
consider the product easy to use and that the time needed for
application was satisfactory, whereas more subjects found
metronidazole 0.75% to be irritating (data not shown).
[0105] At baseline, the mean DLQI scores were similar between
groups (6.95 for IVM 1% and 6.05 for metronidazole 0.75%,
respectively). Patients treated with IVM 1% showed a higher
numerical decrease in their DLQI score than patients treated with
metronidazole 0.75% (-5.18 vs. -3.92; p<0.01), indicating a
higher improvement in quality of life. At the end of the study, 71%
of patients treated with IVM 1% reported no effect at all on their
quality of life (vs. 64% for metronidazole 0.75%), which means that
a higher proportion of subjects felt that their quality of life was
not negatively impacted by rosacea in the group treated with IVM,
compared to the group treated with metronidazole. The study drugs
diverged in favor of IVM 1% in the symptoms and feelings sub-scale
(level of itching, soreness, pain or stinging: "not at all" for
78.7% vs. 63.0% in the metronidazole 0.75% group; level of
embarrassment or self-consciousness: "not at all" for 70.3% vs.
60.1%, respectively).
[0106] Topical metronidazole 0.75% (w/w) has been one of the most
frequently used therapies in the treatment of papulopustular
rosacea. In this study, IVM 1% cream was significantly superior to
metronidazole 0.75% cream in terms of percent reduction from
baseline in inflammatory lesion counts, with an onset of efficacy
(first difference vs. metronidazole 0.75%) as early as 3 weeks (or
even earlier) that continued through 16 weeks. The findings show
that ivermectin is more efficacious than metronidazole, with a
tendency even in patients with higher lesion counts.
[0107] An overall good safety profile was observed for IVM, and it
was well-tolerated in comparison with metronidazole. It is not
surprising that for both products, patients experienced a similarly
low number of related adverse events, particularly since the
tolerability of metronidazole is known to be satisfactory.
Metronidazole's higher incidence of worsening from baseline
concerning stinging/burning, dryness, and itching may be attributed
to the usual signs and symptoms of rosacea. Nevertheless, this
affected the level of quality of life as measured by the DLQI, as
more patients in the metronidazole group reported itching,
soreness, pain or stinging.
[0108] Patient-reported outcomes for IVM 1% cream were consistent
with its superior efficacy results. More patients using IVM
indicated that the product was easy to use and that the time needed
for application was satisfactory, implying that the daily
application is more convenient than metronidazole's twice-daily
regimen. Related to quality of life measures, fewer patients using
IVM considered themselves to be embarrassed or self-conscious.
Thus, ivermectin appears to be adapted to the complex etiology of
rosacea, and in the study IVM 1% cream demonstrated superiority to
metronidazole 0.75% cream in terms of inflammatory lesion
reduction. As noted in the afore-mentioned Cochrane review, few
robust studies have compared topical metronidazole with another
rosacea treatment and in three identified studies, topical
metronidazole was either non-significantly different or less
effective than azelaic acid..sup.8 While metronidazole has been
used in the past as a reasonable treatment for the papulo-pustular
lesions of rosacea, its efficacy is surpassed by that of ivermectin
along with the advantage of once-daily dosing.
[0109] The relapse among subjects successfully treated at the end
of the Period A was studied during the treatment free Period B (36
weeks). At the end of Period A, only subjects with an IGA of "0" or
"1" (clear or almost clear) were eligible for entering Period B.
Then, their study treatment was discontinued and the subjects were
followed for up to 8 months (36 weeks). In case of reoccurrence of
an IGA of at least "2" (mild) at any time during Period B, the
subjects were retreated with the same treatment received during the
Period A. The re-treatment was stopped as soon as the IGA was back
to "0" or "1" (clear or almost clear). The maximum duration of
re-treatment was 16 consecutive weeks to mimic the Period A
treatment duration. In order to characterize the relapses, the
following parameters were assessed: (1) time of first relapse (time
elapsed between Week 16 and first reoccurrence of IGA at "2", "3"
or "4" inducing a retreatment course), (2) relapse rate (percentage
of subjects with reoccurrence of IGA at "2", "3" or "4" after a
period free of study treatment) and (3) number of days free of
treatment.
[0110] At the start of Period B, treatment groups were comparable
with respect to the demographic. Of the total 757 subjects included
in Period B (399 in Ivermectin 1% and 358 in Metronidazole 0.75%
groups, respectively), 504 (66.6%) were female, 754 (99.6%) were
Caucasian and the mean age was 51.9 years. In terms of disease
characteristics, the means inflammatory lesion counts were similar
in both groups (median 2.0). But, the proportion of subjects with
an IGA of 0 was higher in Ivermectin group than in Metronidazole
group (41.6% versus 29.1%) due to the higher efficacy of Ivermectin
treatment from Period A.
TABLE-US-00011 TABLE 6 End of Period A disease characteristics of
subjects entering Period B Ivermectin Metronidazole TOTAL
Inflammatory N 399 358 757 lesion counts Mean 2.58 2.96 2.76 SD
3.20 3.42 3.31 Median 2.00 2.00 2.00 Min~Max 0~19 0~24 0~24 P25~P75
0~4 0~4 0~4 Investigator N 399 358 757 Global 0 = Clear 166 (41.6%)
104 (29.1%) 270 (35.7%) Assessment 1 = 233 (58.4%) 254 (70.9%) 487
(64.3%) Almost Clear Nodules N 399 358 757 0 397 (99.5%) 357
(99.7%) 754 (99.6%) 1 2 (0.5%) 1 (0.3%) 3 (0.4%) Papules N 399 358
757 Mean 2.27 2.56 2.40 SD 2.77 2.83 2.80 Median 2.00 2.00 2.00
Min~Max 0~16 0~17 0~17 P25~P75 0~4 0~4 0~4 Pustules N 399 358 757
Mean 0.32 0.40 0.36 SD 0.91 1.20 1.06 Median 0.00 0.00 0.00 Min~Max
0~9 0~12 0~12 P25~P75 0~0 0~0 0~0
[0111] The time to first relapse, defined as time elapsed between
Week 16 and first reoccurrence of IGA at "2", "3" or"4" was
analyzed following 2 definitions: (1) the first one was based on
IGA only; and (2) the second one took also into account any major
deviations by imputing relapse the day of first major deviation.
For each definition, a sensitivity analysis was performed by
imputing relapse 4 weeks after discontinuation for all subjects who
discontinued early from Period B without relapse. Relapse rates
followed the same convention analyses as the time to relapse.
[0112] The median times to first relapse were 115 days for
ivermectin 1% QD and 85 days for Metronidazole 0.75% BID
(p=0.0365), the relapse rates were 62.7% and 68.4% respectively
(Table 7). See also FIG. 12. When conducting the sensitivity
analysis by imputing relapse 4 weeks later to subjects who
discontinued early without relapse, the medians were 114 days and
85 days (p=0.0594) and the relapse rates were 66.2% and 70.4%,
respectively. Similar results were obtained when taking also into
account the day of first major deviation.
TABLE-US-00012 TABLE 7 IVM 1% Metronidazole p-value (1) N 399 358
0.0365 Median and 95% 115.0[113; 165] 85.0[85; 113] -- Confidence
Interval Mean .+-. Standard 147.0 .+-. 4.66 133.6 .+-. 5.13 --
Error Relapse is based on IGA only (1) Logrank test
[0113] Number of days free of treatment was defined for each
subject enrolled in period B as the time interval between a visit
where IGA is assessed as 0 or 1 and the next visit. The number of
treatment-free days is the summation over all visits of period B
meeting this criterion. An additional analysis was also performed
by subtracting from the days free of treatment any time interval
between visits when the subject while being IGA 0 or 1 had a major
protocol deviation.
[0114] Based on IGA score showed a mean days free of treatment of
183 days for ivermectin 1% QD versus 170 days for metronidazole
(p=0.026). When taking into account the protocol deviations the
mean days free of treatment remained nearly the same 181 days
versus 168 days (p=0.021) in favor of ivermectin 1% QD.
[0115] Ivermectin 1% cream QD treatment resulted in a statistically
significant extended remission (i.e. delayed time to first relapse,
and increase in the number of treatment free days) of rosacea when
compared to Metronidazole 0.75% BID in subjects who were
successfully treated (IGA 0 (clear) or 1 (almost clear)) for 16
weeks. There was also a numerical trend in favor of Ivermectin 1%
cream QD for the relapse rates (62.7% and 68.4% in the Ivermectin
1% group and Metronidazole 0.75% group, respectively). It should be
noted that the differences observed in favor of Ivermectin 1% in
Period B are presumably the consequence of the higher efficacy of
Ivermectin compared to Metronidazole observed at the end of Period
A, with a higher proportion of subjects with an IGA=0 in the
Ivermectin group (41.6% and 29.1% in Ivermectin and Metronidazole,
respectively).
[0116] The overall pharmacoeconomic benefit of Ivermectin 1% cream
QD versus Metronidazole 0.75% cream BID over the one year duration
of the study (Period A & B), is considerable when viewed as the
sum of the following elements: benefit of Ivermectin over
Metronidazole observed at the end of Period A (84.9% of success in
Ivermectin group Vs. 75.4% in Metronidazole group), time to first
relapse (115 Vs. 85 days), relapse rate (62.7% Vs. 68.4%) and
number of days free of treatment (183.4 Vs. 170.4) .
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[0146] It will be appreciated by those skilled in the art that
changes could be made to the embodiments described above without
departing from the broad inventive concept thereof. It is
understood, therefore, that this invention is not limited to the
particular embodiments disclosed, but it is intended to cover
modifications within the spirit and scope of the present invention
as defined by the appended claims.
* * * * *