U.S. patent application number 14/939294 was filed with the patent office on 2016-09-29 for topical treatment for chemotherapy induced eyelash loss or hypotrichosis using prostamide f2 alpha agonists.
The applicant listed for this patent is Allergan, Inc.. Invention is credited to Gurpreet Ahluwalia, Frederick C. Beddingfield, Sydney G. Edwards, Scott M. Whitcup.
Application Number | 20160279143 14/939294 |
Document ID | / |
Family ID | 51259745 |
Filed Date | 2016-09-29 |
United States Patent
Application |
20160279143 |
Kind Code |
A1 |
Ahluwalia; Gurpreet ; et
al. |
September 29, 2016 |
TOPICAL TREATMENT FOR CHEMOTHERAPY INDUCED EYELASH LOSS OR
HYPOTRICHOSIS USING PROSTAMIDE F2 ALPHA AGONISTS
Abstract
The present invention is directed to compositions and methods
for the treatment of post-chemotherapeutic hypotrichosis. More
specifically, the present invention is directed to the use of
compositions comprising bimatoprost for the treatment of
post-chemotherapeutic hypotrichosis which may be applied before,
during and after receiving chemotherapeutic treatment.
Inventors: |
Ahluwalia; Gurpreet;
(Orange, CA) ; Beddingfield; Frederick C.;
(Pacific Palisades, CA) ; Edwards; Sydney G.;
(Aliso Viejo, CA) ; Whitcup; Scott M.; (Laguna
Hills, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Allergan, Inc. |
Irvine |
CA |
US |
|
|
Family ID: |
51259745 |
Appl. No.: |
14/939294 |
Filed: |
November 12, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14251394 |
Apr 11, 2014 |
9216183 |
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14939294 |
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14199402 |
Mar 6, 2014 |
9226931 |
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14251394 |
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13738732 |
Jan 10, 2013 |
8758733 |
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14199402 |
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61611920 |
Mar 16, 2012 |
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61584877 |
Jan 10, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61Q 1/10 20130101; A61K
2800/10 20130101; A61K 8/4953 20130101; A61K 31/5575 20130101; A61K
9/0048 20130101; A61K 9/0014 20130101; A61Q 7/00 20130101; A61K
9/08 20130101; A61K 8/42 20130101; A61K 8/63 20130101; A61K 31/165
20130101 |
International
Class: |
A61K 31/5575 20060101
A61K031/5575; A61K 9/00 20060101 A61K009/00 |
Claims
1) A method of growing eyelashes in chemotherapy patients, the
method comprising applying 0.03% w/v bimatoprost at least once a
day to the eyelids of a chemotherapy patient from at least one
selected from the group consisting of before, during, and after
chemotherapeutic treatment wherein patients receiving 0.03% w/v
bimatoprost resulted in greater eyelash growth as compared to
patients not receiving 0.03% w/v bimatoprost.
2) The method of claim 1, wherein 0.03% w/v bimatoprost is applied
after chemotherapeutic treatment and results in greater eyelash
growth in patients as compared to patients not receiving 0.03% w/v
bimatoprost.
3) The method of claim 2, wherein the method results in eyelashes
which are longer or thicker as compared to patients not receiving
0.03% w/v bimatoprost.
4) The method of claim 1, wherein the patients receiving 0.03% w/v
bimatoprost before starting chemotherapeutic treatment resulted in
greater eyelash growth as compared to patients receiving 0.03% w/v
bimatoprost during or after chemotherapeutic treatment.
5) The method of claim 1, wherein 0.03% w/v bimatoprost is applied
to the upper eyelid.
6) The method of claim 1, wherein 0.03% w/v bimatoprost is applied
to the lower eyelid.
7) The method of claim 1, wherein the bimatoprost is added before,
during and after chemotherapeutic treatment.
8) A method of treating eyelashes loss in chemotherapy patients,
the method comprising applying 0.03% w/v bimatoprost at least once
a day to the eyelids of a chemotherapy patient from at least one
selected from the group consisting of before, during, and after
chemotherapeutic treatment wherein patients receiving 0.03% w/v
bimatoprost resulted in greater eyelash growth as compared to
patients not receiving 0.03% w/v bimatoprost.
9) The method of claim 8, wherein 0.03% w/v bimatoprost is applied
after chemotherapeutic treatment and results in greater eyelash
growth in patients as compared to patients not receiving 0.03% w/v
bimatoprost.
10) The method of claim 9, wherein the method results in eyelashes
which are longer or thicker as compared to patients not receiving
0.03% w/v bimatoprost.
11) The method of claim 8, wherein the patients receiving 0.03% w/v
bimatoprost before starting chemotherapeutic treatment resulted in
greater eyelash growth as compared to patients receiving 0.03% w/v
bimatoprost during or after chemotherapeutic treatment.
12) The method of claim 8, wherein 0.03% w/v bimatoprost is applied
to the upper eyelid.
13) The method of claim 8, wherein 0.03% w/v bimatoprost is applied
to the lower eyelid.
14) The method of claim 8, wherein the bimatoprost is applied after
completing chemotherapeutic treatment.
15) The method of claim 14, wherein the method is applied for at
least 12 months after completing chemotherapeutic treatment.
16) The method of claim 12 wherein the method is applied prior to
receiving chemotherapeutic treatment.
17) The method of claim 16, wherein the method is applied for six
months after receiving chemotherapeutic treatment.
18) The method of claim 8 wherein the bimatoprost is in the form of
a solution or an emulsion.
19) The method of claim 8 wherein the bimatoprost is applied to the
upper eyelid or both the upper and lower eyelid.
20) The method of claim 8 wherein the method is applied after the
patient completes chemotherapeutic treatment.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/251,394, filed Apr. 11, 2014, which in turn
is a continuation-in-part of U.S. patent application Ser. No.
14/199,402, filed Mar. 6, 2014, which is a continuation of U.S.
patent application Ser. No. 13/738,732, filed Jan. 10, 2013, now
U.S. Pat. No. 8,758,733 issued Jun. 24, 2014, which claims priority
to U.S. Provisional Application No. 61/611,920, filed Mar. 16,
2012, and U.S. Provisional Application No. 61/584,877, filed Jan.
10, 2012. This application is also a continuation-in-part of U.S.
patent application Ser. No. 13/937,512, filed Jul. 9, 2013, now
U.S. Pat. No. 8,926,953 issued Jan. 6, 2015, which is a
continuation of U.S. patent application Ser. No. 13/441,783, filed
Apr. 6, 2012, now U.S. Pat. No. 8,632,760, issued Jan. 21, 2014,
which is a continuation of U.S. Pptent application Ser. No.
13/356,284, filed Jan. 23, 2012, now U.S. Pat. No. 8,263,054,
issued Sep. 11, 2012, which is a continuation of U.S. patent
application Ser. No. 12/425,933, filed Apr. 17, 2009, now U.S. Pat.
No. 8,298,518, issued Oct. 30, 2012, which is a continuation of
U.S. patent application Ser. No. 11/943,714, filed Nov. 21, 2007,
now U.S. Pat. No. 8,038,988, issued Oct. 18, 2011, which is a
continuation of U.S. patent application Ser. No. 11/805,122, filed
May 22, 2007, now U.S. Pat. No. 8,101,161, issued Jan. 24, 2012,
which is a continuation of U.S. patent application Ser. No.
10/345,788, filed on Jan. 15, 2003, now U.S. Pat. No. 7,351,404,
issued Apr. 1, 2008, which claims the benefit of U.S. Provisional
Application No. 60/354,425, filed on Feb. 4, 2002, all of which are
hereby incorporated by reference in their entireties.
FIELD OF THE INVENTION
[0002] The present invention is directed to methods and treatments
of post-chemotherapeutic hypotrichosis. More specifically, the
present invention is directed to the use of compositions comprising
bimatoprost for the treatment of post-chemotherapeutic
hypotrichosis.
BACKGROUND OF THE INVENTION:
[0003] Eyelashes, in addition to their contribution to appearance,
serve a functional role by protecting sensitive eye structures
against foreign particles entering the eye. The nerve plexus that
surrounds hair follicles has a very low threshold for excitation
(Moses, 1970); as a result, dust or other particles that may come
into contact with the eyelash hair fiber are sufficient stimuli to
produce a blink reflex, thereby protecting the eye. In terms of the
aesthetic function of eyelashes, eyelash prominence has been
observed to be related to the attractiveness of individuals, with
long, thick eyelashes considered to be a desirable physical
attribute with a positive psychological effect (Shaikh and Bodla,
2006).
[0004] Inadequate or not having enough eyelashes is known as
hypotrichosis of the eyelashes. Etiologies of hypotrichosis of the
eyelashes in an adult population include idiopathic hypotrichosis,
alopecia-inducing medication (e.g., chemotherapeutic agents) and
underlying cutaneous or systemic diseases/conditions (eg, alopecia
areata or hypothyroidism).
[0005] In healthy adults, eyelash hypotrichosis is often idiopathic
and may be related to age. There is an inverse relationship between
age and length of eyelashes; younger populations naturally tend to
have longer eyelashes, while older populations tend to have shorter
eyelashes (Pucci, 2005). For this reason, many otherwise healthy
adults experience hypotrichosis as a consequence of aging.
[0006] A treatment is available for the natural hypotrichosis
condition which may be result of person's genetic makeup or could
be age related. Bimatoprost solution 0.03% (LATISSE.RTM.) is
marketed for the treatment of hypotrichosis of the eyelashes.
Bimatoprost is a synthetic prostamide. Topical application of
bimatoprost solution can be used in normal healthy adults with
inadequate amount of eyelashes or subject who want to further
enhance the prominence of their eyelashes (Yoelin, 2010). Treatment
with bimatoprost has been demonstrated to increase the percentage
of eyelash follicles in anagen, which accounts for its ability to
lengthen eyelashes. Bimatoprost-induced stimulation of
melanogenesis in melanocytes present in dermal papilla which are
responsible for hair shaft pigmentation results in darker eyelashes
and, at the same time, appears to increase the size of the dermal
papilla and hair bulb, affecting lash thickness and fullness
(Cohen, 2010; Fagien, 2010; Law, 2010).
[0007] In contrast to the natural eyelash hypotrichosis condition
where the hair follicle is normal except it produces shorter and
inadequate amount of eyelashes, chemotherapy treatment results in
damage to the hair follicle components that make the hair fiber
such that after the chemotherapy drug treatment, the natural
eyelashes either fall off completely or result in patchy hair loss.
Chemotherapeutic agents are well known for their ability to cause
hair loss. Other drugs that can cause hair loss to varied degrees
include anticoagulants, antithyroid drugs, oral contraceptives,
lithium, interferons, antihyperlipidemic drugs, and retinoids
(Tosti et al, 1994). Chemotherapy-induced hair loss is known to
result from the direct toxic insult to rapidly dividing cells of
the hair follicle (Trueb, 2009). During the anagen phase of the
hair cycle, the epithelial compartment of the follicle undergoes
proliferation, with the greatest proliferative activity occurring
in the bulb matrix cells as they build up the hair shaft. When cell
mitosis abruptly ceases as a result of cytotoxic therapy, the
partially keratinized hair shaft weakens and falls out, resulting
in anagen dystrophic effluvium (Ulrich et al, 2008). In addition,
some chemotherapeutic agents can cause apoptosis (ie, programmed
cell death) in the follicular epithelium resulting in premature
transitioning from anagen to catagen phases of the hair cycle; this
process is known as telogen effluvium (Ulrich et al, 2008). The
consequence of these processes is hair shedding, which can begin
within 1 to 3 weeks and is often complete within 1 to 2 months
after beginning chemotherapy (Trueb, 2009). Hair loss occurs with
an estimated incidence of 65% in adult patients receiving
chemotherapy (Trueb, 2009). While eyelash loss can be part of the
experience of chemotherapy-induced hair loss (Trueb, 2009), there
are no reliable data in the published literature that specifically
address the incidence of eyelash loss due to chemotherapy. However,
the known mechanism by which chemotherapy induces alopecia
indicates that any active hair follicle in anagen would be
susceptible, including scalp, body, eyebrow, and eyelash hair.
[0008] For most cancer treatments, after the chemotherapy regimen
is completed, the patient recovers from the treatment side effects
relatively quickly, ie, most side effects of chemotherapy resolve
within a few weeks of the last treatment; however, hair growth can
continue to be depressed for a period of time. It can take several
months to a year, or even longer in some subjects, for hair growth
to restore to pre-chemotherapy levels. Moreover, when the hair does
recover early, it is generally much finer and thinner than the
original hair and can take several hair cycles to restore to the
pre-chemotherapy levels.
[0009] Hair loss is known to be one of the most psychologically
upsetting side effects of cancer therapy (Botchkarev, 2003, Lemieux
et al, 2008; Hunt, 2005); it has been described by patients as a
constant reminder of their illness and is associated with a loss of
control, an altered sense of self, and reduced social functioning
(Beisecker et al, 1997; Cowley, 2000; Freedman, 1994; Luoma and
Hakamies-Blomqvist, 2004; Richer and Ezer, 2002; Williams et al,
1999). The loss not just of scalp hair but body hair can lead to
psychosocial problems such as diminished quality of life expressed
as anxiety, depression, and low self-esteem (Ulrich et al,
2008).
[0010] In the focus group studies, patients stated that the loss of
eyelashes and eyebrows was worse than the loss of scalp hair
because the latter could be easily concealed by a wig, whereas
there was no way to make their eyelashes look "normal". False
eyelashes were not a reasonable treatment in the opinion of the
respondents because they did not have enough natural eyelashes to
help the glue adhere to their eyelid margins. Moreover, such
measures can result in severe irritation and skin damage and are
therefore not ideal, especially in the post-chemotherapy
population. In focus-group studies, many postchemotherapy patients
commented that their eyelashes never fully recovered to their
pre-chemotherapy levels. Even though they noticed some re-growth,
most complained that their eyelashes were sparse (ie, gaps between
lashes), short, and lighter in color.
[0011] Currently there are no treatments available for chemotherapy
induced eyelash loss. We discovered that treatment with LATISSE
(bimatoprost 0.03% solution) restores eyelash growth and prominence
quickly compared with the natural course of slower recovery. Thus
the protective function of eyelashes is resumed earlier in treated
patients as compared to non-treated patients. The postchemotherapy
patients treated with bimatoprost 0.03% solution express a higher
overall satisfaction with their eyelashes as compared to patients
treated with vehicle. Bimatoprost treatment in postchemotherapy
patients also restored length, thickness/fullness and darkness of
eyelashes.
BRIEF SUMMARY OF THE INVENTION
[0012] The present invention is directed to the use of bimatoprost
for the use in growing eyelashes in post-chemotherapeutic patients.
The present invention is also directed to the use of bimatoprost
during chemotherapy to prevent the loss of eyelashes during
chemotherapeutic treatment. The present invention is also directed
to the use of bimatoprost to prevent the loss of eyelashes prior to
the start of chemotherapy. The present invention is also directed
to the use of bimatoprost before, during and after chemotherapeutic
treatment.
[0013] The present invention may be applied as 0.03% w/v
bimatoprost available in the commercial product called LATISSE
.RTM. and may be applied in concentrations 0.3% w/v to 0.001% w/v
and including concentrations such as 1.0% w/v, 0.9% w/v, 0.8% w/v,
0.7% w/v, 0.6% w/v, 0.5% w/v, 0.4% w/v, 0.3% w/v, 0.2% w/v, 0.1%
w/v, 0.09% 0.08% w/v, 0.07% w/v, 0.06% w/v, 0.05% w/v, 0.04% w/v,
0.03% w/v, 0.02% w/v, 0.01% w/v, 0.009% w/v, 0.008% w/v, 0.007%
w/v, 0.006% w/v, 0.005% w/v, 0.004% w/v, 0.003% w/v, 0.002% w/v,
0.001% w/v, 0.009% w/v, 0.008% w/v, 0.007% w/v, 0.006% w/v, 0.005%
w/v, 0.004% w/v, 0.003% w/v, 0.002% w/v, and 0.001% w/v
bimatoprost.
[0014] Bimatoprost may be applied as a solution, emulsion, gel,
foam, spray, ointment, cream, or other form suitable for
administration to the eyelid margin. Bimatoprost may be in the form
of a salt, pro-drug, analogs including esters of bimatoprost. The
bimatoprost composition, including LATISSE .RTM., may also be
applied in conjunction with other therapeutics known to grow hair
such as Minoxidil.RTM. and Propecia.RTM..
[0015] "Treatment", "treat" or "treating" can refer to curing any
disease or condition or reducing or alleviating the symptoms of the
disease or condition.
[0016] "Prevent", "preventing" or "prevention" can refer to
stopping any disease, condition or symptoms or reducing symptoms in
a clinically significant manner, particularly as compared to
patients receiving no treatment at all.
[0017] Some embodiments of the present invention include the
following paragraphs: [0018] 1) A method of growing eyelashes in
chemotherapy patients, the method comprising applying 0.03% w/v
bimatoprost at least once a day to the eyelids of a chemotherapy
patient from at least one selected from the group consisting of
before, during, and after chemotherapeutic treatment wherein
patients receiving 0.03% w/v bimatoprost resulted in greater
eyelash growth as compared to patients not receiving 0.03% w/v
bimatoprost. [0019] 2) The method of paragraph 1, wherein 0.03% w/v
bimatoprost is applied before starting chemotherapeutic treatment
and results in greater eyelash growth in patients as compared to
patients not receiving 0.03% w/v bimatoprost. [0020] 3) The method
of paragraph 2, wherein the method results in eyelashes which are
longer or thicker as compared to patients not receiving 0.03% w/v
bimatoprost. [0021] 4) The method of paragraph 1, wherein the
patients receiving 0.03% w/v bimatoprost before starting
chemotherapeutic treatment resulted in greater eyelash growth as
compared to patients receiving 0.03% w/v bimatoprost during or
after chemotherapeutic treatment. [0022] 5) The method of paragraph
1, wherein 0.03% w/v bimatoprost is applied to the upper eyelid.
[0023] 6) The method of paragraph 1, wherein 0.03% w/v bimatoprost
is applied to the lower eyelid. [0024] 7) The method of paragraph
1, wherein the bimatoprost is added before, during and after
chemotherapeutic treatment. [0025] 8) A method of preventing or
treating eyelashes loss in chemotherapy patients, the method
comprising applying 0.03% w/v bimatoprost at least once a day to
the eyelids of a chemotherapy patient from at least one selected
from the group consisting of before, during, and after
chemotherapeutic treatment wherein patients receiving 0.03% w/v
bimatoprost resulted in greater eyelash growth as compared to
patients not receiving 0.03% w/v bimatoprost. [0026] 9) The method
of paragraph 8, wherein 0.03% w/v bimatoprost is applied before
starting chemotherapeutic treatment and results in greater eyelash
growth in patients as compared to patients not receiving 0.03% w/v
bimatoprost. [0027] 10) The method of paragraph 9, wherein the
method results in eyelashes which are longer or thicker as compared
to patients not receiving 0.03% w/v bimatoprost. [0028] 11) The
method of paragraph 8, wherein the patients receiving 0.03% w/v
bimatoprost before starting chemotherapeutic treatment resulted in
greater eyelash growth as compared to patients receiving 0.03% w/v
bimatoprost during or after chemotherapeutic treatment. [0029] 12)
The method of paragraph 8, wherein 0.03% w/v bimatoprost is applied
to the upper eyelid. [0030] 13) The method of paragraph 8, wherein
0.03% w/v bimatoprost is applied to the lower eyelid. [0031] 14)
The method of paragraph 8, wherein the bimatoprost is added before,
during and after chemotherapeutic treatment. [0032] 15) The method
of paragraph 14, wherein the method is applied for at least 12
months after completing chemotherapeutic treatment. [0033] 16) The
method of paragraph 12 wherein the method is applied prior to
receiving chemotherapeutic treatment. [0034] 17) The method of
paragraph 16, wherein the method is applied for three months prior
to receiving chemotherapeutic treatment. [0035] 18) The method of
paragraph 8 wherein the bimatoprost is in the form of a solution or
an emulsion. [0036] 19) The method of paragraph 8 wherein the
bimatoprost is applied to the upper eyelid, the lower eyelid or
both the upper and lower eyelid. [0037] 20) The method of paragraph
8 wherein the method is applied after the patient completes
chemotherapeutic treatment.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1 shows an Example of the Effect of Bim 0.03% on
Eyelash Growth Compared to Vehicle--postchemotherapy
population;
[0039] FIG. 2 Percentage of Subjects With at Least a 1-Grade
Improvement in GEA Score--Postchemotherapy;
[0040] FIG. 3 Shows treatment Responders (%) Based on Primary
Composite Variable by Month: Postchemotherapy (Intent-to-treat
Population);
[0041] FIG. 4 Shows Mean Change From Baseline in Eyelash Length
(mm) by Month: Postchemotherapy;
[0042] FIG. 5 is a plot of primary composite efficacy for the
duration of the trial for subjects with idiopathic
hypotrichosis;
[0043] FIG. 6 is a plot of responder rates in bimatoprost-treated
subjects by individual components of the primary composite efficacy
measure for the duration of the for subjects with idiopathic
hypotrichosis;
[0044] FIG. 7 is a plot of improvement in eyelash length for the
duration of the trial for subjects with idiopathic
hypotrichosis;
[0045] FIG. 8 is a plot of primary composite efficacy for the
duration of the trial for subjects with chemotherapy-induced
hypotrichosis;
[0046] FIG. 9 is a plot of responder rates in bimatoprost-treated
subjects by individual components of the primary composite efficacy
measure for the duration of the trial for subjects with
chemotherapy-induced hypotrichosis;
[0047] FIG. 10 is a plot of improvement in eyelash length for the
duration of the trial for subjects with chemotherapy-induced
hypotrichosis;
[0048] FIG. 11 shows study design, treatments, and subject
disposition;
[0049] FIG. 12 shows representative photographs of subjects with
hypotrichosis undergoing 6 months of treatment with bimatoprost
0.03% or vehicle, wherein
[0050] panel (a) shows subjects with idiopathic hypotrichosis;
[0051] subject 1037 (bimatoprost 0.03%, idiopathic) on the left
side with a GEA score of .gtoreq.1-grade change from the baseline
at months 4 and 6 and ESQ domain 2 score of .gtoreq.3-point change
from baseline at months 4 and 6;
[0052] subject 1265 (vehicle, idiopathic) on the right side of the
panel with a GEA score of no change from baseline at months 4 and
6, and ESQ domain 2 score of no change from baseline at months 4
and 6;
[0053] panel (b) shows subjects with chemotherapy-induced
hypotrichosis;
[0054] subject 1262 (bimatoprost 0.03%, post-chemotherapy) on the
left side of the panel with a GEA score of .gtoreq.1-grade change
from the baseline at months 4 and 6 and ESQ domain 2 score of
.gtoreq.3-point change from baseline at months 4 and 6;
[0055] subject 1389 (vehicle, post-chemotherapy) on the right side
of the panel with a GEA score of no change from baseline at months
4 and 6, and ESQ domain 2 score of no change from baseline at
months 4 and 6, and,
[0056] FIG. 13 shows Responder rates for idiopathic hypotrichosis
and chemotherapy-induced hypotrichosis subpopulations according to
study treatments and time points.
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLE 1
TABLE-US-00001 [0057] TABLE I List of Components and Quantitative
Composition Concen- Concen- tration tration Ingredients (% w/v)
(mg/mL) Function Active ingredient Bimatoprost.sup.a 0.03 0.3
Active ingredient Other ingredients Benzalkonium chloride.sup.b
0.005 0.05 Preservative Sodium phosphate 0.268 2.68 Buffering
dibasicheptahydrate agent Citric acid monohydrate 0.014 0.14
Buffering agent Sodium chloride 0.83 8.3 Tonicity agent
Hydrochloric acid.sup.c and/or sodium Adjust to pH 7.2-7.4 pH
adjuster hydroxide.sup.c Purified water q.s. ad q.s. ad Vehicle
100% 1 mL
Clinical Data:
[0058] A clinical study was conducted that demonstrated the
clinical benefits of bimatoprost 0.03% solution in treating eyelash
loss resulting from chemotherapy treatment.
Study Design and Structure:
[0059] This was a 1-year, multicenter, double-masked, randomized,
parallel-group study to evaluate the safety and efficacy of
bimatoprost solution 0.03% in increasing overall eyelash prominence
following dermal application to the upper eyelid margins in normal
adults and postchemotherapy adults exhibiting hypotrichosis of the
eyelashes. Subjects enrolled in the study were adult subjects at
least 18 years of age, with idiopathic or chemotherapy-induced
hypotrichosis (Global Eyelash Assessment [GEA] score of 1 or 2) and
had a score of 1 or 2 on each of the 3 items (16, 18, and 19) on
the Eyelash Satisfaction Questionnaire (ESQ) Domain 2, which
represented psychological impact of eyelash loss.
[0060] The full 12-month study consisted of 2 distinct 6-month
treatment periods, treatment period 1 (TP1) and treatment period 2
(TP2). Eligible post-chemotherapy subjects were randomly assigned
in a 3:1 ratio to receive bimatoprost or vehicle for TP1. In TP2,
the subjects were either maintained on or switched to bimatoprost
treatment.
[0061] A total of 130 subjects with chemotherapy-induced
hypotrichosis were randomized. Of these, 96 subjects were
randomized to the Bim 0.03% group and 34 subjects to the vehicle
group. The overall mean age of the postchemotherapy subjects was
50.7 years (range 26 to 76 years), and the majority of the
population was Caucasian (79.2%). All except 1 of the subjects
enrolled were female (99.2%; 129/130). Per inclusion criteria, all
enrolled subjects had a baseline GEA score of 1 (71.3%) or 2
(28.7%), with a similar distribution of GEA scores in both
treatment groups at baseline. The mean total score.+-.SD of ESQ
Domain 2 for was 3.9.+-.1.23. All enrolled subjects had a baseline
ESQ score of 1 or 2 for items 16, 18 and 19 that relates to
psychological impact of eyelash loss or hypotrichosis
condition.
Primary Composite Efficacy Endpoint:
[0062] The primary efficacy endpoint was the proportion of
treatment responders at month 4 based on a composite endpoint,
defined by: a) at least a 1-grade improvement from baseline in the
GEA score, and b) at least a 3-point improvement from baseline in
the total score for Domain 2 of the ESQ. The GEA is an investigator
assessment of eyelash prominence and the ESQ score is patients own
perception of their eyelashes.
6-Month Data:
[0063] After 4 months of daily treatment, in the post-chemotherapy
subpopulation, the treatment responder rates based on the primary
efficacy end point were 37.5% (36/96) in the bimatoprost 0.03%
group and 18.2% (6/33) in the vehicle group. Data in the table
below shows response rate by visit at month 1, 2, 4, and 6. A
continuous improvement in efficacy is observed over the six month
time period.
TABLE-US-00002 TABLE II Primary Composite Efficacy Variable:
Treatment Responders by Visit Postchemotherapy population Bim 0.03%
Vehicle Visit (N = 96) (N = 34) P-value.sup.b Month 1 6/96 2/33
>0.999.sup.c (6.3%) (6.1%) Month 2 22/96 5/33 0.344 (22.9%)
(15.2%) Month 4 36/96 6/33 0.041 (37.5%) (18.2%) Month 6 45/96 6/33
0.004 (46.9%) (18.2%)
[0064] The response rate was also determined solely based on the
investigator GEA scoring. As shown in FIG. 1, the Bim 0.03% group
had a higher responder rate at the month 2, 4, and 6 visits
compared with the vehicle group. The difference in responder rate,
based on GEA of eyelash prominence, approached statistical
significance at month 4 (p=0.051) and was statistically significant
at the month 6 visit (p=0.001). The relatively high responder rate
in the vehicle group of the post-chemotherapy population compared
to the vehicle group of the normal adult population is attributable
to the natural re-growth that occurs to some degree upon completion
of chemotherapy treatment. FIG. 2 shows the percentage of subjects
with at least a 1-grade improvement in GEA
Score--Post-chemotherapy.
[0065] Efficacy was also assessed using more conservative criteria
of 2-grade improvement in GEA. At month 4, the responder rates for
the 2-grade increase in the Bim 0.03% group was 36.5% (35/96)
compared to vehicle response of 6.1% (2/33) for this 2 grade
increase. In addition to the investigator global assessment (GEA)
and subjects own assessment (ESQ), the eyelash length,
thickness/fullness and darkness were measures using digital image
analysis.
[0066] The mean change in eyelash length from baseline at month 4
was 1.48 mm in the Bim 0.03% group and 0.72 mm in the vehicle
group. By month 6, the mean change in eyelash length from baseline
was 1.99 mm for the Bim 0.03% group and 1.01 mm for the vehicle
group.
[0067] The mean changes in eyelash thickness from baseline at month
4 were 0.67 mm.sup.2 in the Bim 0.03% group and -0.05 mm.sup.2 in
the vehicle group. By month 6, the mean changes in eyelash
thickness from baseline were 0.83 mm.sup.2 for the Bim 0.03% group
and 0.04 mm.sup.2 for the vehicle group.
[0068] The mean change from baseline in eyelash darkness was
greater in the Bim 0.03% than in the vehicle group. At the month 4
and 6 visits, it was -22.48 and -26.46, respectively, in the Bim
0.03% group and -11.25 and -10.19, respectively, in the vehicle
group. The greater negative number on this measure reflects the
greater intensity or darkness of eyelashes.
Summary of Efficacy Data on Effect of Bimatoprost on Increasing
Eyelash Growth in Post-Chemotherapy Population:
[0069] For the primary composite efficacy endpoint, the Bim 0.03%
group had a statistically significantly higher responder rate than
the vehicle group at month 4 (p=0.041). At month 4, the responder
rate was 37.5% (36/96) in the Bim 0.03% group and 18.2% (6/33) in
the vehicle group. By month 6, the responder rate in the Bim 0.03%
group increased to 46.9% (45/96), whereas there was no change in
the vehicle group (18.2%, 6/33).
[0070] The Bim 0.03% group had a higher percentage of subjects with
at least a 1-grade increase from baseline in GEA score compared to
the vehicle group at all follow-up visits. The difference between
the 2 groups approached statistical significance at month 4
(p=0.051) and was statistically significantly different at the
month 6 visit (p=0.001). At the month 4 visit, 72.9% in the Bim
0.03% group and 54.5% in the vehicle group had at least a 1-grade
increase from baseline in GEA score. By month 6, the percentage of
responders increased to 80.2% in the Bim 0.03% group, whereas in
the vehicle group it decreased to 51.5%.
[0071] The percentage of subjects with at least a 1-grade increase
from baseline in GEA in the Bim 0.03% group of the postchemotherapy
subpopulation (72.9%) was comparable to that of the normal adult
subpopulation (74.3%) at month 4. Relative to the vehicle group in
the normal adult subpopulation, the vehicle group in the
postchemotherapy subpopulation showed higher GEA response at all
visits which is likely related to some degree of natural regrowth
in the postchemotherapy subpopulation
[0072] Statistically significant improvements from baseline in
upper eyelash length, thickness, and darkness were seen in the Bim
0.03% group compared to the vehicle group at month 4 and month
6.
[0073] At month 4, 36.5% of subjects in the Bim 0.03% group of the
postchemotherapy subpopulation had at least a 2-grade increase from
baseline in GEA scores.
[0074] Statistically significant improvements in favor of Bim 0.03%
group were observed for ESQ Domains 1 and 3 scores at months 4 and
6. For Domain 2, although the improvements were not statistically
significantly different between the two treatment groups, the Bim
0.03% group had a higher mean change in total score from baseline
than the vehicle group (2.8 versus 1.7).
Postchemotherapy Population (Safety Summary):
[0075] In the postchemotherapy subpopulation, 57.3% (55/96) of
subjects in the Bim 0.03% group and 45.5% (15/33) of subjects in
the vehicle group reported at least 1 adverse event over the first
6-month study period. Adverse events that were more common in the
Bim 0.03% group (more than 5% of subjects) than in the vehicle
group were conjunctival hyperaemia, punctate keratitis and eye
pruritus. The majority of adverse events were reported as mild or
moderate in severity. The treatment-related adverse events were
reported by 27.1% (26/96) and 6.1% (2/33) of subjects in the Bim
0.03% and vehicle groups, respectively. Treatment-related adverse
events reported by more than 1 subject in the Bim 0.03% group were
conjunctival hyperaemia (12 subjects), punctate keratitis (7
subjects), eyelids pruritus (3 subjects), eye pruritus (3
subjects), skin hyperpigmentation (3 subjects) and eyelid
irritation (2 subjects). The 2 treatment-related adverse events
reported in the vehicle group were punctate keratitis (1 subject)
and eyelids pruritus (1 subject).
[0076] None of the treatment-related adverse events were reported
as severe, and none of them led to study or treatment
discontinuation.
12-Month Data:
[0077] For subjects receiving bimatoprost for up to 12 months
(Bim/Bim group), the efficacy demonstrated for the composite end
point, ie, the proportion of responders increased from month 6 to
the month 12 period as shown in the figure below. The responder
rate, based on the primary efficacy composite measure, increased
from 46.9% at month 6 to 61.5% at month 12. These data indicate
continuous improvement seen in the postchemotherapy population
through month 12 of treatment. These data also demonstrate that
efficacy is maintained over 12 months of daily exposure, with no
indication for development of any resistance to the treatment.
[0078] Subjects that received vehicle in the first 6 months of
treatment and then switched to bimatoprost in TP2 (Veh/Bim groups),
the drug effect was rapidly realized, the responder rate increased
from 17.6% (6/34) at month 6 to 67.6% (23/34) at month 12 as shown
in FIG. 3.
Eyelash Length:
[0079] For the idiopathic hypotrichosis subpopulation treated for
up to 12 months with bimatoprost, the mean eyelash length at
baseline was 5.69 mm and increased by 1.44 mm at month 6 of
treatment, and then remained fairly constant throughout the
treatment period. This corresponds to a mean percent increase from
baseline of 26.17% at month 6 and 25.86% at month 12, and a median
percent increase from baseline of 22.4% at month 6 and 22.63% at
month 12 This indicates that eyelash length increase is maintained,
with no evidence of development of resistance, from month 6 through
12 of daily treatment.
TABLE-US-00003 Mean Change .+-. Standard Deviation (SD) from
Baseline in Eyelash Length (mm) Postchemotherapy Bim/Bim Veh/Bim
TP1/TP2/Visit.sup.a (N = 96) (N = 34) Baseline 4.86 .+-. 1.189 4.65
.+-. 1.413 Month 4 1.48 .+-. 1.391 0.72 .+-. 1.396 Month 6 1.99
.+-. 1.557 1.01 .+-. 1.275 Month 10 2.14 .+-. 1.455 2.27 .+-. 1.439
Month 12 2.01 .+-. 1.504 2.07 .+-. 1.442 Bim = bimatoprost 0.03%;
TP1 = treatment period 1 (day 1 to month 6); TP2 = treatment period
2 (month 6 to 12); Veh = vehicle
[0080] For the post-chemotherapy subjects treated for up to 12
months with bimatoprost, the mean eyelash length at baseline was
4.86 mm and increased by 1.99 mm at month 6 of treatment, and then
remained fairly constant throughout the treatment period. This
corresponds to a mean percent increase from baseline of 48.08% at
month 6 and 49.88% at month 12, and a median percent increase from
baseline of 37.84% at month 6 and 39.08% at month 12), again
indicating that eyelash length increase is maintained, with no
evidence of loss of effect upon continuous daily treatment from
months 6 through 12 as shown in FIG. 4.
[0081] For the postchemotherapy subjects treated for up to 12
months with bimatoprost, the mean thickness at baseline was 0.39
mm.sup.2, which increased by 0.83 mm.sup.2 at month 6 of treatment,
and then remained fairly constant throughout the treatment period.
This corresponds to a mean percent increase from baseline of 428%
at month 6 and 478% at month 12, and a median percent increase from
baseline of 245% at month 6 and 212% at month 12, again the eyelash
thickness increase was maintained, with no evidence of loss of
effect upon continuous daily treatment from month 6 through 12.
TABLE-US-00004 Mean Change .+-. Standard Deviation (SD) from
Baseline in Average Progressive Eyelash Thickness (mm.sup.2) At
Least a 2-grade Increase in Global Eyelash Assessment Score
Postchemotherapy Bim/Bim Veh/Bim TP1/TP2/Visit.sup.a (N = 96) (N =
34) Baseline 0.39 .+-. 0.302 0.67 .+-. 0.995 Month 4 0.67 .+-.
0.514 -0.05 .+-. 0.955 Month 6 0.83 .+-. 0.576 0.04 .+-. 1.009
Month 10 0.88 .+-. 0.516 0.63 .+-. 1.042 Month 12 0.85 .+-. 0.575
0.58 .+-. 1.085 Bim = bimatoprost 0.03%; TP1 = treatment period 1
(day 1 to month 6); TP2 = treatment period 2 (month 6 to 12); Veh =
vehicle
[0082] A secondary analysis of the GEA component of the primary
efficacy variable using a more stringent criterion was the
percentage of subjects who experienced at least a 2-grade increase
and a 3-grade increase from baseline on the GEA scale. For
postchemotherapy hypotrichosis subjects treated for up to 12 months
with bimatoprost, 45.8% of the subjects had at least a 2-grade
increase in GEA at month 6, which increased to 57.3% at month 12.
This indicates a progressive increase in eyelash prominence from
month 6 to 12.
[0083] The postchemotherapy subjects treated with vehicle for the
first 6 months and then switched to bimatoprost treatment (Veh/Bim)
had only 8.8% (3/34) of the subjects with a 2-grade GEA increase at
month 6; this increased to 50% by month 10 (4 months after starting
bimatoprost treatment) and to 52.9% by month 12.
[0084] Efficacy in the post-chemotherapy hypotrichosis population
showed a gradual increase in the number of responders through 12
months of treatment. Though an early peak in the percent responders
was observed at month-6 (46.9%) and a minimal change between
months-6 and -8, there was a gradual further increase to 54.2% at
month-10 and an increase to 61.5% at month-12, indicating a
continuous improvement in this population. A similar gradual
increase in the percent responders was noted based on at least
1-grade increase in GEA or at least 3-point increase in ESQ
Domain-2 from month-6 to the month-12 treatment. The GEA responders
increased from 80.2 to 90.6% and the ESQ Domain-2 responders
increased from 47.9 to 63.5% between month-6 and -12.
[0085] Majority of the common adverse events observed for the
entire 12-month period were from the first 6 months of treatment,
indicating that continuous treatment does not lead to increased
incidence of adverse events. For example, the incidence rate for
three of the most common AEs in the postchemotherapy population,
conjunctival hyperaemia, punctate keratitis and eyelids pruritus
was 15.6%, 8.3% and 3.1%, respectively, in the first 6 months of
treatment vs. only 1.1% (new AE) for each of these three events for
months 6 -12.
EXAMPLE 2
[0086] This is a long-term safety and efficacy study of bimatoprost
ophthalmic solution 0.03% (LATISSE.RTM.) bimtoprost carried out in
idiopathic and post-chemotherapy hypotrichosis populations. In this
study, eyelash loss from chemotherapy was studied.
Study Design:
[0087] A one-year, multicenter, randomized, double-masked,
vehicle-controlled study. Adult post-chemotherapy and idiopathic
eyelash hypotrichosis subjects were enrolled based on their score
of 1 or 2 on a four point ordinal Global Eyelash Assessment (GEA)
scale, and in addition having a low score on a PRO measure
associated with `psychological impact` of the condition, a domain-2
of the Eyelash Satisfaction Questionnaire (ESQ). The study involved
two treatment periods of six months each. In the first treatment
period, subjects for both populations were randomized 3:1 for QD
bimatoprost: vehicle treatment. In the second 6-month treatment
period, all subjects were moved to bimatoprost treatment, except
for a group of bimatoprost treated idiopathic hypotrichosis
subjects (n=55) who were switched to vehicle to investigate the
effect of drug discontinuation. The study included 9 visits over
the 12-month treatment period. The primary end point was the
proportion of responders within each treatment group based on a
composite measure of GEA and ESQ Domain-2 (investigator assessed
eyelash prominence and subject's assessment of `psychological
impact` related to eyelashes) at month-4.
Results:
[0088] A total of 368 subjects were randomized, 238 idiopathic and
130 post-chemotherapy. The primary efficacy end point was met for
both idiopathic and post-chemotherapy populations. A baseline,
majority of the post-chemotherapy subjects showed sparse, patchy
eyelashes to near complete loss. In both populations, majority of
the subjects (>70%) demonstrated increased eyelash prominence
(.gtoreq.1 grade GEA improvement) at month-4 following daily
bimatoprost treatment. There were no drug related serious adverse
events in the study.
[0089] In subjects with idiopathic hypotrichosis, 40.2% efficacy (a
greater than 1-grade increase in GEA score and at least 3 point
improvement in ESA domain score) was achieved at month 4, while
only 6.8% of the vehicle treated subjects had a similar increase in
GEA after 4 months. Efficacy was maintained over the 12-month trial
period. After drug discontinuation, efficacy was maintained for
about 2 months, and return to near pre-treatment levels occurred 4
to 6 months after discontinuation. In subjects with
chemotherapy-induced hypotrichosis, 37.5% increase in efficacy was
achieved at month 4 whereas only 18.2% of the vehicle treated
subjects had a similar increase in GEA after 4 months. Efficacy was
enhanced over the 12-month trial period.
[0090] In subjects with idiopathic hypotrichosis, 74.3% of the
bimatoprost treated subjects had an increase in GEA of greater than
1 after 4 months, while only 13.6% of the vehicle treated subjects
had a similar increase in GEA after 4 months. In subjects with
chemotherapy-induced hypotrichosis, 72.9% of those receiving
bimatoprost treatment had an increase of GEA of greater than 1
after 4 months, while 54.5% of the vehicle-treated subjects had a
similar increase in GEA after 4 months (due to the natural
untreated regrowth of eyelashes after cessation of chemotherapy).
Both populations had statistically significant improvements in
eyelash length, thickness/fullness, and darkness by bimatoprost
compared with vehicle at months 4 and 6 (not shown).
[0091] The changes in eyelash length, thickness and darkness are
shown in the table below:
TABLE-US-00005 Eyelash length, thickness, and darkness Percent
change from baseline at Month 4 Idiopathic Chemotherapy-Induced
Hypotrichosis Hypotrichosis (mean % change) (median % change) a Bim
Bim Endpoint 0.03% Vehicle P-value 0.03% Vehicle P-value Length
22.90% -4.90% <.001 28.50% 11.30% 0.022 Thickness 95.90% -7.20%
<.001 180.10% 25.00% 0.002 Darknessb -15.70% 1.40% <.001
-14.40% -5.70% 0.012 a Median values are provided because data from
the post-chemotherapy subpopulation did not follow a normal
distribution. bNegative change from baseline indicates darker
lashes.
Results for Subjects with Idiopathic Hypotrichosis:
[0092] FIG. 5 is a plot of primary composite efficacy for the
duration of the trial. Bim/Bim indicates subjects receiving
bimatoprost for 12 months. Bim/Veh indicates subjects receiving
bimatoprost for 6 months followed by vehicle for 6 months. Veh/Bim
indicates subjects receiving vehicle for 6 months followed by
bimatoprost for 6 months.
[0093] FIG. 6 is a plot of responder rates in bimatoprost-treated
subjects by individual components of the primary composite efficacy
measure for the duration of the trial. FIG. 6 shows a GEA response
rate of about 75% to about 80% and a maintenance of the effect
and/or continuous improvement up to month 12.
[0094] FIG. 7 is a plot of improvement in eyelash length for the
duration of the trial. Bim/Bim indicates subjects receiving
bimatoprost for 12 months. Bim/Veh indicates subjects receiving
bimatoprost for 6 months followed by vehicle for 6 months. Veh/Bim
indicates subjects receiving vehicle for 6 months followed by
bimatoprost for 6 months.
Results for Subjects with Chemotherapy-Induced Hypotrichosis:
[0095] FIG. 8 is a plot of primary composite efficacy for the
duration of the trial. Bim/Bim indicates subjects receiving
bimatoprost for 12 months. Bim/Veh indicates subjects receiving
bimatoprost for 6 months followed by vehicle for 6 months.
[0096] FIG. 9 is a plot of responder rates in bimatoprost-treated
subjects by individual components of the primary composite efficacy
measure for the duration of the trial. FIG. 9 shows a GEA response
rate of about 80% that is similar to the idiopathic population, and
continuous improvement up to month 12.
[0097] FIG. 10 is a plot of improvement in eyelash length for the
duration of the trial. Bim/Bim indicates subjects receiving
bimatoprost for 12 months. Bim/Veh indicates subjects receiving
bimatoprost for 6 months followed by vehicle for 6 months.
[0098] Over 12 months of bimatoprost treatment, the most common
adverse events (>5%) in either idiopathic or post-chemotherapy
population were conjunctival hyperaemia, punctate keratitis, eyelid
pruritus, erythema of eyelids, and eye pruritus. Common adverse
events (conjunctival hyperaemia, punctate keratitis, and eye
pruritus) were reported at a higher rate in the post-chemotherapy
population. This may have been related to the enduring effect of
chemotherapy drugs on eyes. Common ocular and dermal adverse events
occurred at a lower rate in the second 6-month trial period (months
6-12) compared with the first 6-month trial period. No drug-related
serious adverse occurred in either subpopulation.
TABLE-US-00006 0 to 12 Months 0 to 6 Months 6 to 12 Months
Idiopathic Post- Idiopathic Post- Idiopathic Post- Hypotrichosis
Chemotherapy Hypotrichosis Chemotherapy Hypotrichosis Chemotherapy
(N = 118) (N = 96) (N = 118) (N = 96) (N = 106) (N = 89) Eye
disorders, n (%) Conjunctival 10 (8.5) 16 (16.7) 7 (5.9) 15 (15.6)
4 (3.8) 1 (1.1) hyperaemia Punctate keratitis 3 (2.5) 9 (9.4) 3
(2.5) 8 (8.3) 0 (0.0) 1 (1.1) Eyelids pruritus 7 (5.9) 3 (3.1) 6
(5.1) 3 (3.1) 1 (0.9) 1 (1.1) Erythema of eyelid 6 (5.1) 3 (3.1) 2
(1.7) 1 (1.0) 5 (4.7) 2 (2.2) Eye pruritus 1 (0.8) 6 (6.3) 1 (0.8)
5 (5.2) 0 (0.0) 1 (1.1) Skin and subcutaneous disorders, n (%) Skin
2 (1.7) 5 (5.2) 0 (0.0) 3 (3.1) 2 (1.9) 2 (2.2)
hyperpigmentation
Conclusions:
[0099] Bimatoprost ophthalmic solution 0.03% significantly
increased eyelash growth in subjects with idiopathic as well as
chemotherapy-induced hypotrichosis as measured by the primary
composite endpoint (.gtoreq.1-grade increase in the GEA score AND
at least 3-point improvement in ESQ domain-2 score at week 16) and
all secondary endpoints (eyelash length, thickness/fullness, and
darkness). Bimatoprost treatment effects were maintained through
the 12-month trial period. Bimatoprost treatment was safe and
well-tolerated in the 2 populations. No new safety signals were
detected in the 6- to 12-month trial period. Fewer common ocular
and dermal AEs occurred in the second 6-month period than in the
first 6 months of bimatoprost treatment. Efficacy was maintained
for about 2 months after bimatoprost discontinuation; return to
near pre-treatment levels occurred at about 4 to 6 months after
discontinuation. Thus, daily application of bimatoprost ophthalmic
solution to the eyelid margin over a one-year period was found to
be safe, well tolerated and effective in both idiopathic and
post-chemotherapy populations as assessed by several safety and
efficacy measures.
EXAMPLE III
Objective:
[0100] To evaluate long-term safety and efficacy of bimatoprost
among subjects with idiopathic or chemotherapy-induced
hypotrichosis.
Methods:
[0101] This multicenter, double-masked, randomized, parallel-group
study included two 6-month treatment periods. Subjects with
idiopathic hypotrichosis were randomized to 3 treatment groups: 1)
treatment period 1 (TP1) and TP2: bimatoprost; 2) TP1: bimatoprost;
TP2: vehicle; and 3) TP1: vehicle; TP2: bimatoprost. Subjects with
chemotherapy-induced hypotrichosis were randomized to 2 treatment
groups: 1) TP1: bimatoprost or vehicle; and 2) TP2: bimatoprost.
The primary endpoint was a composite of at least a 1-grade
improvement in investigator-assessed Global Eyelash Assessment
(GEA), and at least a 3-point improvement in subject-reported
Eyelash Satisfaction Questionnaire (ESQ) Domain 2 (self-perceived
confidence, attractiveness, and professionalism) at month 4.
Secondary measures included digitally assessed eyelash
characteristics (i.e., eyelash length, fullness, and darkness).
Results:
[0102] The study randomized 368 subjects. The primary efficacy
endpoint was met in both populations (responder rates: idiopathic:
40.2% bimatoprost vs. 6.8% vehicle; post-chemotherapy: 37.5%
bimatoprost vs. 18.2% vehicle). Efficacy by month 6 was maintained
(idiopathic) or enhanced (post-chemotherapy) at 12 months.
Treatment effects were maintained for approximately 2 months but
markedly diminished 4 to 6 months following treatment cessation in
subjects with idiopathic hypotrichosis. No drug-related serious
adverse events were reported.
[0103] Conclusions: Daily treatment with bimatoprost ophthalmic
solution 0.03% for 1 year was effective and well tolerated in
subjects with idiopathic and chemotherapy-induced
hypotrichosis.
Materials and Methods:
[0104] This was a 1-year, multicenter, double-masked, randomized,
parallel-group study of 1-year treatment duration with two 6-month
treatment periods. Two subpopulations evaluated in the study
included subjects with idiopathic hypotrichosis and those with
hypotrichosis caused by recent chemotherapy. Additionally, the
effect of drug discontinuation was studied in subjects with
idiopathic hypotrichosis.
[0105] The study consisted of 9 visits and 2 telephone visits over
12 months. Treatment period 1 (TP1) extended from screening to
month 6, including 6 visits: screening/baseline (day -14 to 1),
telephone visit (week 1), and months 1, 2, 4, and 6. Treatment
period 2 (TP2) began at the 6-month visit and included visits at
months 7, 8, 10, and 12/early termination) and 1 telephone visit (1
week post-month 6).
[0106] Idiopathic hypotrichosis subjects were randomized to 3
treatment arms in a 2:1:1 ratio: bimatoprost during both treatment
periods; vehicle in TP1 and bimatoprost in TP2; and bimatoprost in
TP1 and vehicle in TP2. Chemotherapy-induced hypotrichosis subjects
were randomized in a 3:1 ratio to receive bimatoprost during both
treatment periods or vehicle in TP1 followed by bimatoprost in
TP2.
[0107] Male or female subjects at least 18 years of age who met
these criteria were eligible for inclusion in the study: a score of
1 or 2 on the clinician-graded global eyelash assessment ("GEA"); a
score of 1 (very much disagree) or 2 (disagree) on each of 3 items
(16 [confidence], 19 [attractiveness], and 18 [professionalism]) on
the subject-assessed eyelash satisfaction questionnaire ("esq");
best-corrected visual acuity ("bcva") score equivalent to a snellen
acuity of 20/100 or better in each eye; and intraocular pressure
("iop") 20 mm hg or less in each eye. Subjects in the
chemotherapy-induced hypotrichosis population also met the
following inclusion criteria: inadequate eyelashes after completing
chemotherapy; treatment for solid tumor type stage 1, 2, or 3a
cancer; last chemotherapy treatment at least 4 to less than 16
weeks prior to baseline; and considered free of cancer. Key
exclusion criteria included subjects with any eye disease or
abnormality or a history of eye surgery.
[0108] This study was conducted in accordance with the
International Conference on Harmonization Guideline for Good
Clinical Practice and the Declaration of Helsinki. Local ethical
committee approval was obtained prior to study initiation. Informed
consent was obtained from all subjects prior to any study-related
procedure.
[0109] Subjects placed 1 drop of study treatment (i.e., bimatoprost
0.03% or vehicle) onto a sterile single-use-per eye applicator and
applied it to the upper eyelid margin of 1 eye; a second applicator
was used for the contralateral eye. Treatment was applied once
daily in the evening throughout the study. The primary efficacy
measure was the proportion of treatment responders based on a
composite endpoint at month 4, defined a priori as: at least a
1-grade improvement from baseline in the GEA score (4-point
photonumeric scale of eyelash prominence based on these
descriptors: minimal, moderate, marked, and very marked), and at
least a 3-point improvement from baseline in the total score for
Domain 2 of the ESQ. Domain 2 consists of questions that evaluate
subjects' feelings of confidence, attractiveness, and
professionalism rated on a 5-point Likert-type scale (1, very much
disagree; 2, disagree; 3, neutral; 4, agree; 5, very much agree)
with higher scores indicating a higher degree of subject-reported
satisfaction with the subjective attributes of the eyelashes.
[0110] Secondary efficacy measures were based on digital image
analysis (DIA) of eyelash characteristics: upper eyelash length
(millimeters [mm]), thickness (mm.sup.2), and darkness (intensity
units). For darkness, a negative value in terms of change from
baseline indicated darker eyelashes.
[0111] Safety measures included adverse events (AEs), ophthalmic
examination (ophthalmoscopy [dilated], biomicroscopy, IOP, iris
color assessment, and BCVA). AEs were monitored throughout the
study by the investigator.
Statistical Analysis
[0112] The 6-month primary analysis was based on data from the
first 6 months of the study, i.e., TP1, which followed a
parallel-group design, allowing for hypothesis testing and
between-group comparisons (bimatoprost 0.03% vs. vehicle).
Statistical testing was not performed beyond the 6-month analysis
because all subjects treated with vehicle during TP2 had been
treated with bimatoprost in TP1; hence, there was no vehicle-only
control group for TP2. The intent-to-treat (ITT) population
consisted of all randomised subjects. The ITT population was used
for all efficacy analyses. The safety population consisted of all
subjects who received 1 or more doses of study medication. The
study was sized to have adequate power to evaluate the primary
efficacy variable at month 4 for the overall study population
(idiopathic and chemotherapy-induced hypotrichosis subpopulations
combined).
[0113] GEA and ESQ data were collected at each scheduled visit. The
primary efficacy endpoint was defined as the proportion of
treatment responders at month 4. The analysis of responders was
performed using frequency distributions (counts and percentages).
For the 12-month study analysis, the baseline value was the value
collected on day 1 or the most recent evaluation prior to day 1.
For the TP2 analysis, the baseline value was the value collected at
month 6; if month-6 data were missing, data from the most recent
previous evaluation were used. For the ITT population analysis, the
last observation carried forward method was used to impute missing
values in each of the 2 components of the primary composite
efficacy variable. Between-group comparisons for TP1 were performed
using the Cochran-Mantel-Haenszel test stratified by hypotrichosis
etiology. Individual components of the composite efficacy measure
as well as at least a 2-grade improvement from baseline GEA score
were also assessed at these time points.
[0114] Upper eyelash characteristics of length, thickness, and
darkness were determined by a validated DIA method. The reliability
and reproducibility of DIA have been verified within the acceptance
criteria of 0.05% or less of mean coefficient of variance. The
principal variables for the secondary efficacy assessments are:
change from baseline in upper eyelash length (mm), average
progressive eyelash thickness (mm.sup.2), and eyelash darkness
(intensity units) at months 4, 6, 10, and 12 or early termination.
Descriptive statistics of the raw value at baseline and percent
change from baseline at follow-up visits were summarized by
treatment group for each principal measure of the 3 secondary
variables of eyelash characteristics. Between-group comparisons
were performed using a van Elteren test stratified by hypotrichosis
etiology.
Safety Analysis
[0115] The 12-month data were the primary focus of the safety
evaluation. Safety data were summarized with descriptive statistics
(n, or frequency distributions [counts or percentages]).
Biomicroscopic examinations and assessments of iris color, IOP, and
BCVA were performed for each subject at screening/baseline and
months 1, 2, 4, 6, 8, and 12 (or early termination prior to month
12); ophthalmoscopic examinations (dilated) were performed at
screening/baseline and months 6 and 12 (or early termination prior
to month 12). Two IOP measurements were taken for each eye at each
visit; a third measurement was taken if the difference between the
first 2 measurements was more than 2 mm Hg. The average or median
IOP was determined in the event that 2 or 3 measurements were made,
respectively. The IOP value analyzed at each visit was the average
IOP of the subject's 2 eyes. Change and percent change from
baseline in IOP were summarized by descriptive statistics.
Between-group comparison will be performed using the 1-way analysis
of variance.
[0116] Iris color assessments were performed using a 10-category
subjective classification: blue, blue-gray, blue/gray-brown, gray,
green, green-brown, hazel, brown, dark brown, and other.
Results:
[0117] A total of 368 subjects were randomized at 39 sites (32 US
centers and 7 European Union centers), of which 238 had idiopathic
hypotrichosis and 130 had chemotherapy-induced hypotrichosis.
Subject disposition (FIG. 11) and baseline characteristics (Table
1) are provided. Per inclusion criteria, all enrolled subjects had
baseline GEA scores of 1 (minimal; 39.8%) or 2 (moderate; 60.2%),
with a similar distribution of GEA scores in both treatment groups
at baseline, although a greater proportion of subjects in the
chemotherapy-induced hypotrichosis subpopulation had baseline GEA
scores of 1 compared with subjects in the idiopathic hypotrichosis
subpopulation (71.3% vs. 22.7%). The majority of subjects completed
the clinical trial with only 14.9% of subjects discontinuing from
the study. The most common reason for discontinuation was AEs for
idiopathic hypotrichosis and loss to follow-up for
chemotherapy-induced hypotrichosis subpopulation.
TABLE-US-00007 TABLE III Overall baseline demographic
characteristics (intent-to-treat population) Idiopathic
Post-Chemotherapy- Overall Hypotrichosis Induced Hypotrichosis
Characteristic (n = 368) (n = 238) (n = 130) Age, y, mean (SD) 49.8
(10.47) 49.3 (11.09) 50.7 (9.22) Sex, n (%) Male 4 (1.1) 3 (1.3) 1
(0.8) Female 364 (98.9) 235 (98.7) 129 (99.2) Race, n (%) White 305
(82.9) 202 (84.9) 103 (79.2) Black 34 (9.2) 19 (8.0) 15 (11.5)
Asian 13 (3.5) 9 (3.8) 4 (3.1) Hispanic 15 (4.1) 7 (2.9) 8 (6.2)
Other.sup.a 1 (0.3) 1 (0.4) 0 (0.0) GEA score, n (%) Minimal 147
(39.3) 54 (22.7) 93 (71.5) Moderate 221 (60.1) 184 (77.3) 37 (28.5)
Marked 0 0 0 Very marked 0 0 0 Total ESQ Domain 2, mean (SD) 4.1
(1.35) 4.2 (1.40) 3.9 (1.23) ESQ, Eyelash Satisfaction
Questionnaire; GEA, Global Eyelash Assessment; SD, standard
deviation. .sup.aOther race: black and white. Note: Missing data on
total ESQ Domain 2 for 1 post-chemotherapy subject.
Composite and Individual Component Efficacy Measures of Bimatoprost
Treatment
[0118] During TP1, the primary composite efficacy endpoint at month
4 was met for the overall study population and both subpopulations.
The composite efficacy endpoint responder rates at months 4 and 6
were statistically significantly greater for active drug compared
with vehicle for both subpopulations (Table 2). The responder rates
for subjects with idiopathic hypotrichosis treated with bimatoprost
compared with vehicle were 40.2% vs. 6.8% (P<0.001) and 47.5%
vs. 3.4% (P<0.001) at months 4 and 6, respectively.
Corresponding responder rates for subjects with
chemotherapy-induced hypotrichosis were 37.5% vs. 18.2% (P=0.041)
at month 4 and 46.9% vs. 18.2% (P=0.004) at month 6. Although a
greater vehicle treatment effect was observed in post-chemotherapy
subjects who experienced natural eyelash regrowth compared with
those with idiopathic hypotrichosis, the results for
vehicle-treated groups were consistently lower than the
corresponding results from bimatoprost-treated groups across all
endpoints. More than 4 of 5 post-chemotherapy subjects were still
nonresponders in the placebo group at month 6 after study
start.
[0119] Statistically significant differences were observed in the
responder rates for subjects with idiopathic hypotrichosis
achieving at least a 1-grade improvement in GEA score when the
bimatoprost-treated and vehicle-treated groups were compared: 74.3%
vs. 13.6% (P<0.001) at month 4 and 77.7% vs. 13.6% (P<0.001)
at month 6, respectively (Table 2). The differences in the
corresponding responder rates for subjects with
chemotherapy-induced hypotrichosis were not as pronounced due to
natural eyelash regrowth in this subpopulation. However, this
difference was statistically significant at month 6: 80.2%
(bimatoprost 0.03%) vs. 51.5% (vehicle; P<0.001).
[0120] A marked increase was observed in the percentage of subjects
in the idiopathic hypotrichosis subpopulation with at least a
3-point increase in ESQ Domain 2 at the 4- and 6-month time points
when the groups receiving bimatoprost and vehicle were compared
(Table IV). Although the corresponding responder rates for the
chemotherapy-induced hypotrichosis subpopulation were higher in the
bimatoprost-treated compared with vehicle-treated groups, the
differences between these groups were not statistically significant
at either month 4 or 6.
TABLE-US-00008 TABLE IV Summary of improvements from baseline to
months 4 and 6 for idiopathic hypotrichosis and
chemotherapy-induced hypotrichosis subpopulations: efficacy
endpoints based on GEA and/or ESQ scores (intent-to-treat
population): Idiopathic Hypotrichosis Idiopathic Hypotrichosis
Bimatoprost (n = 179) Vehicle (n = 59) Time Treatment Responders, n
Treatment Responders, n Efficacy Endpoint.sup.a Point (%) (%)
P-value.sup.b Composite endpoint: .gtoreq.1-grade Month 4.sup.a 72
(40.2) 4 (6.8) <0.001 increase in GEA score and .gtoreq.3- Month
6 85 (47.5) 2 (3.4) <0.001 point improvement in ESQ Domain 2
.gtoreq.1-grade increase in GEA Month 4 133 (74.3) 8 (13.6)
<0.001 Month 6 139 (77.7) 8 (13.6) <0.001 .gtoreq.3-point
increase in ESQ Month 4 85 (47.5) 9 (15.3) <0.001 Domain 2 Month
6 100 (55.9) 9 (15.3) <0.001 .gtoreq.2-grade increase in GEA
Month 4 46 (25.7) 0 (0.0) <0.001 Score Month 6 55 (30.7) 0 (0.0)
<0.001 Chemotherapy-Induced Hypotrichosis Subjects
Chemotherapy-Induced Receiving Bimatoprost Hypotrichosis Subjects
(n = 96) Receiving Vehicle (n = 34) Treatment Responders, n
Treatment Responders, n (%) (%) P-value.sup.b Composite endpoint:
.gtoreq.1-grade Month 4.sup.a 36 (37.5) 6.sup.c (18.2) 0.041
increase in GEA score and .gtoreq.3- Month 6 45 (46.9) 6.sup.c
(18.2) 0.004 point improvement in ESQ Domain 2 .gtoreq.1-grade
increase in GEA Month 4 70 (72.9) 18.sup.c (54.5) 0.051 Month 6 77
(80.2) 17.sup.c (51.5) 0.001 .gtoreq.3-point increase in ESQ Month
4 39 (40.6) 8.sup.c (24.2) 0.092 Domain 2 Month 6 46 (47.9)
12.sup.c (36.4) 0.250 .gtoreq.2-grade increase in GEA Month 4 35
(36.5) 2.sup.c (6.1) <0.001 score Month 6 44 (45.8) 3.sup.c
(9.1) <0.001 .sup.aMonth 4 is the primary analysis time point;
.sup.bA Pearson's chi-square test is performed. If 25% or more of
the cells have expected counts less than 5, then Fisher's exact
test is used instead; .sup.cOverall population of subjects with
chemotherapy-induced hypotrichosis receiving vehicle is 33
subjects. Bimatoprost: bimatoprost ophthalmic solution 0.03%. ESQ,
Eyelash Satisfaction Questionnaire; GEA, Global Eyelash
Assessment.
[0121] No subjects with idiopathic hypotrichosis receiving vehicle
met the more stringent criteria of at least a 2-grade improvement
in GEA score, although this rate was 25.7% (month 4) and 30.7%
(month 6) in the bimatoprost-treated subjects (Table IV). Although
the corresponding responder rates for subjects with
chemotherapy-induced hypotrichosis receiving vehicle were higher
(6.1% at month 4 and 9.1% at month 6), the higher eyelash regrowth
rates in the bimatoprost-treated group were evident compared with
the vehicle-treated group: 36.5% and 6.1% (P<0.001),
respectively, at month 4.
Analysis of Eyelash Characteristics by Digital Imaging Analysis
(DIA)
[0122] Representative subject photographs of eyelash growth in
subjects with idiopathic hypotrichosis and chemotherapy-induced
hypotrichosis after up to 6 months of treatment are shown in FIG.
12 (panels a and b, respectively). Statistically significant
changes in the percentage improvement from baseline of eyelash
length, thickness, and darkness were observed between
bimatoprost-treated and vehicle-treated groups in both
subpopulations at months 4 and 6 (Table V). However, month-6
measurements of eyelash characteristics of vehicle-treated
post-chemotherapy subjects were similar to eyelash characteristics
of subjects with idiopathic hypotrichosis at baseline indicating
that natural eyelash regrowth in this subpopulation was
insufficient at month 6.
TABLE-US-00009 TABLE V Summary of improvements from baseline at
months 4 and 6 for idiopathic hypotrichosis and
chemotherapy-induced hypotrichosis subpopulations: efficacy
endpoints based on eyelash characteristics (intent-to-treat
population) Idiopathic Hypotrichosis.sup.b Chemotherapy-Induced
Hypotrichosis.sup.b Bimatoprost Vehicle Vehicle Efficacy Time (n =
179), (n = 59), Bimatoprost (n = 34), Endpoint.sup.a Point n (%) n
(%) P-value.sup.c (n = 96), n (%) n (%) P-value.sup.c Upper eyelash
Month 4 22.9 (177) -4.9 (58) <0.001 28.5 (94) 11.3 (31) 0.022
length (mm) Month 6 26.0 (177) -1.0 (58) <0.001 37.8 (94) 16.3
(31) 0.008 Upper eyelash Month 4 95.9 (150) -7.2 (52) <0.001
180.1 (64) 25.0 (19) 0.002 thickness (mm.sup.2) Month 6 91.4 (150)
-7.7 (52) <0.001 245.9 (64) 33.3 (19) 0.002 Upper eyelash Month
4 -15.7 (150) 1.4 (52) <0.001 -14.4 (65) -5.7 (18) 0.012
darkness.sup.d Month 6 -14.1 (150) 1.6 (52) <0.001 -16.3 (65)
-6.5 (18) <0.001 (intensity units) .sup.aMonth 4 is the primary
analysis time point. .sup.bMean values are presented for the
idiopathic hypotrichosis subpopulation. The median is reported for
the chemotherapy-induced hypotrichosis subpopulation where the
distribution of the values is skewed with a small number of very
high values in percent change from baseline from those subjects who
had very few or no eyelashes at baseline. .sup.cP-value for
between-group comparison is based on Wilcoxon rank-sum test.
.sup.dA negative change from baseline indicates darker eyelashes
compared with baseline. Bimatoprost: bimatoprost ophthalmic
solution 0.03%.
[0123] The improvement in eyelash prominence observed by month 4 or
6 of treatment were either maintained (idiopathic) or further
enhanced (post-chemotherapy) through the 12-month period with
once-daily treatment regimen (FIG. 13). FIG. 13 shows Responder
rates for idiopathic hypotrichosis and chemotherapy-induced
hypotrichosis subpopulations according to study treatments and time
points. Panel a: Responder rates in subjects with idiopathic
hypotrichosis treated with bimatoprost 0.03% or vehicle-primary
composite efficacy measure; Panel b: responder rates in subjects
with chemotherapy-induced hypotrichosis treated with bimatoprost
0.03% or vehicle-primary composite efficacy measure; Panel c:
responder rates in subjects with idiopathic hypotrichosis treated
with bimatoprost 0.03%-individual components of the primary
composite efficacy measure; Panel d: responder rates in subjects
with chemotherapy-induced hypotrichosis treated with bimatoprost
0.03%-individual components of the primary composite efficacy
measure; Panel e: changes in eyelash length for subjects with
idiopathic hypotrichosis; Panel f: changes in eyelash length for
subjects with chemotherapy-induced hypotrichosis.
[0124] The effect of treatment discontinuation was studied in the
idiopathic hypotrichosis subpopulation only. For subjects treated
with bimatoprost during TP1 and switched to vehicle during TP2, the
efficacy demonstrated at the end of TP1 was maintained through
month 8, before diminishing at months 10 and 12 as demonstrated by
the proportion of responders on the composite endpoint, and the
efficacy endpoints based on components of the composite endpoint
(Table VI).
TABLE-US-00010 TABLE VI Summary of efficacy results for idiopathic
hypotrichosis subjects treated with bimatoprost in treatment period
1 and switched to vehicle in treatment period 2 (intent-to-treat
population) .gtoreq.1-Grade .gtoreq.3-Point .gtoreq.2-Grade Primary
Improvement From Improvement From Improvement From Efficacy
Composite Baseline GEA Baseline ESQ Baseline GEA
Variable)/Visit.sup.a, n Endpoint Score Domain 2 Score Score (%
Treatment (n = 60) (n = 60) (n = 60) (n = 60) Month 1 Bimatoprost 0
(0.0) 6 (10.0) 8 (13.3) 0 (0.0) Month 2 8 (13.3) 24 (40.0) 15
(25.0) 2 (3.3) Month 4 25 (41.7) 43 (71.7) 29 (48.3) 15 (25.0)
Month 6 29 (48.3) 46 (76.7) 34 (56.7) 18 (30.0) Month 7 Vehicle 31
(51.7) 47 (78.3) 34 (56.7) 18 (30.0) Month 8 30 (50.0) 47 (78.3) 33
(55.0) 17 (28.3) Month 10 12 (20.0) 28 (46.7) 26 (43.3) 5 (8.3)
Month 12 7 (11.7) 21 (35.0) 23 (38.3) 3 (5.0) Note: Bim/Veh
indicates the treatment group that received bimatoprost 0.03%
during treatment period 1 and vehicle during treatment period 2.
.sup.aVisit was based on visit window. Baseline was defined as the
most recent evaluation prior to day 1. Last observation carried
forward was performed. Bim/Veh: bimatoprost ophthalmic solution
0.03% during treatment period 1 followed by vehicle in treatment
period 2. ESQ, Eyelash Satisfaction Questionnaire; GEA, Global
Eyelash Assessment.
[0125] FIG. 13, panel a, illustrates the impact of treatment
discontinuation at 6 months with the composite endpoint responder
rate. Similar trends were observed with eyelash characteristics
following treatment discontinuation with bimatoprost at 6 months
(Table VII; FIG. 13, panel e).
TABLE-US-00011 TABLE VII Summary of upper eyelash characteristics
in idiopathic hypotrichosis subjects treated with bimatoprost in
treatment period 1 and switched to vehicle in treatment period 2
(intent-to-treat population). Mean (Standard Deviation) at Baseline
and Mean Value (Mean % Change From Baseline) Darkness (intensity
Upper Eyelash Length (mm) Thickness (mm.sup.2) units).sup.b
Characteristics/Visit.sup.a Treatment (n = 60) (n = 60) (n = 60)
Baseline, mean (SD) Bimatoprost 5.7 (0.90) 0.8 (0.32) 152.5 (20.05)
Month 4, n (%) 6.8 (21.01) 1.2 (73.7) 126.3 (-16.01) Month 6, n (%)
7.1 (25.70) 1.2 (79.9) 128.0 (-14.89) Month 10, n (%) Vehicle 6.0
(6.46) 0.8 (13.0) 143.7 (-3.97) Month 12, n (%) 5.9 (4.62) 0.9
(15.9) 143.6 (-4.29) Note: Bim/Veh indicates the treatment group
that received bimatoprost 0.03% during treatment penod 1 and
vehicle during treatment period 2. .sup.aVisit was based on visit
window. Baseline was defined as the most recent evaluation prior to
day 1. Last observation carried forward was performed. .sup.bThe
scale of intensity units is 0 to 255, where 0 is black and 255 is
white. Therefore, lower values indicate darker eyelash color and
higher values indicate lighter eyelash color, and negative changes
from baseline indicate darker eyelashes compared with baseline.
Bim/Veh: bimatoprost ophthalmic solution 0.03% during treatment
period 1 followed by vehicle in treatment period 2.
[0126] For subjects with idiopathic hypotrichosis treated with
vehicle during TP1 and switched to bimatoprost for TP2, the
bimatoprost treatment effect was observed during the same time in
TP2 that had been observed for bimatoprost-treated subjects in TP1
(FIG. 13, panel a). Subjects with chemotherapy-induced
hypotrichosis assigned to vehicle for TP1 followed by treatment
with bimatoprost for TP2 demonstrated eyelash characteristics
equal, or similar, to those subjects who received 12 months of
treatment with bimatoprost (FIG. 13, panel f). These results
indicate that bimatoprost solution 0.03% is an effective treatment
for hypotrichosis of the eyelashes across both subpopulations,
regardless whether it was started on day 1 or month 6 as well as
the severity of the condition prior to treatment. It also indicates
that early treatment (TP1) with bimatoprost 0.03% can achieve
patient-desired results for eyelash growth sooner than would be
achieved through natural regrowth or by starting later. Thus, the
inclusion data of being at least 4 weeks
post-chemotherapy-initiating therapy may be a reasonable time for
physicians to start bimatoprost if such therapy is desired and
warranted.
Safety Observations
[0127] A summary of the AEs occurring among at least 2% of subjects
from either treatment group by treatment period and etiology
subpopulation is shown in Table VIII.
TABLE-US-00012 TABLE VIII Number of subjects treated with
bimatoprost 0.03% for up to 12 months reporting adverse events
(incidence of .gtoreq.2%) in the eye or skin system organ classes
(safety population) Bimatoprost ophthalmic solution 0.03% in each
treatment period. 0 to 12 Months 0 to 6 Months 6 to 12 Months
Chemotherapy- Chemotherapy- Chemotherapy- Idiopathic Induced
Idiopathic Induced Idiopathic Induced System Organ Class
Hypotrichosis Hypotrichosis Hypotrichosis Hypotrichosis
Hypotrichosis Hypotrichosis Preferred Term.sup.a (n = 118) (n = 96)
(n = 118) (n = 96) (n = 106) (n = 89) Eye disorders, n (%)
Conjunctival 10 (8.5) 16 (16.7) 7 (5.9) 15 (15.6) 4 (3.8) 1 (1.1)
hyperaemia Punctate keratitis 3 (2.5) 9 (9.4) 3 (2.5) 8 (8.3) 0
(0.0) 1 (1.1) Eyelid pruritus 7 (5.9) 3 (3.1) 6 (5.1) 3 (3.1) 1
(0.9) 1 (1.1) Erythema of eyelid 6 (5.1) 3 (3.1) 2 (1.7) 1 (1.0) 5
(4.7) 2 (2.2) Eye pruritus 1 (0.8) 6 (6.3) 1 (0.8) 5 (5.2) 0 (0.0)
1 (1.1) Skin and subcutaneous disorders, n (%) Skin 2 (1.7) 5 (5.2)
0 (0.0) 3 (3.1) 2 (1.9) 2 (2.2) hyperpigmentation .sup.aWithin each
preferred term a subject was counted once for either treatment
period or once for the entire treatment period.
[0128] The majority of AEs reported in the study were described as
mild. There were no serious AEs attributed to study treatment. Ten
subjects (2.8%) discontinued due to a treatment-related AE. All of
these subjects were in the idiopathic hypotrichosis subpopulation.
AEs leading to discontinuation in this subpopulation were
conjunctival hyperaemia and erythema of eyelid (3 each), eye
irritation (2), allergic conjunctivitis, enophthalmos (i.e.,
deepened eyelid sulcus), eye pruritus, dry eye, eyelid margin
crusting, eyelid oedema, eyelid pruritus, and eyelid exfoliation (1
each). One subject discontinued due to decreased TOP, and another
for contact dermatitis. The most frequently reported (>2%) AEs
for the overall population during bimatoprost treatment periods
were conjunctival hyperaemia (12.1%), punctuate keratitis (5.6%),
eyelid pruritus (4.7%), and erythema (4.2%). Most treatment-related
AEs resolved without sequelae at the end of the study. One case of
mild punctuate keratitis resolved with sequelae for which treatment
and follow-up were deemed unnecessary; 1 case of madarosis was
ongoing. A higher rate of conjunctival hyperaemia was noted in the
chemotherapy-induced subpopulation (16.7%) compared with the
idiopathic population (8.5%).
[0129] The percentage of subjects with biomicroscopy and
ophthalmoscopy findings of at least a 2-severity grade increase
from baseline for 1 or more visits during the bimatoprost treatment
periods were 4.2% (9/214) for the group receiving bimatoprost
during both treatment periods (12-month treatment period), 5.0%
(3/60) for the group receiving bimatoprost 0.03% followed by
vehicle (6-month treatment period), and 2.4% (2/84) for the group
receiving vehicle followed by bimatoprost (6-month treatment
period). No new safety signals arose in the second 6 months of
treatment, indicating that longer-term treatment was not associated
with an increased incidence of AEs. AEs of particular interest with
prostamide F2.alpha. analogues include enophthalmos, TOP reduction,
and iris hyperpigmentation.
[0130] Enophthalmos leading to treatment discontinuation occurred
in only 1 bimatoprost-treated subject, and this was the only
enophthalmos-related AE reported in the study. Reported as
mild/moderate in severity, the onset of this AE was approximately 2
months after bimatoprost initiation. The AE was reported to be
ongoing 6 months after the subject discontinued from the study.
[0131] The greatest magnitude of mean change from baseline TOP at
any time point, for any group, was less than 2 mm Hg. The mean
change from baseline in TOP was greater for bimatoprost-treated
compared with vehicle-treated subjects with idiopathic
hypotrichosis at all follow-up visits. These differences though
statistically significant were considered not to be clinically
relevant. At month 4, the mean change from baseline was -1.17 in
the bimatoprost-treated subjects and 0.17 in the subjects receiving
vehicle. In the chemotherapy-induced subpopulation, changes in TOP
from baseline for the bimatoprost-treated subjects compared with
vehicle-treated subjects were statistically significant at month 2
only; at the 2-month visit, the mean change from baseline was -1.22
and -0.14 in the bimatoprost-treated and vehicle-treated groups,
respectively (P=0.022).
[0132] A 1-category change in iris hyperpigmentation was reported
as an AE for only 1 subject in the study, occurring approximately 2
months after discontinuation of bimatoprost and initiation of
vehicle. The AE was reported as mild in severity, with a color of
blue-gray to blue/gray-brown, which was a 1-grade change on the
10-grade subjective classification. The subject did not discontinue
from the study and the AE was reported to have resolved in a
post-study communication. Resolution of iris hyperpigmentation is
not typical of true prostaglandin-induced hyperpigmentation. For
subjects treated with bimatoprost, there were reports of 5 subjects
with a 1-category iris color change from light to dark; 6 subjects
had iris color changes corresponding to a 1- to 2-category change
in the direction of dark to light. In addition, iris color changes
were reported in 2 subjects who had not received treatment with
bimatoprost 0.03%. None of these color changes were considered to
be clinically relevant. Some changes of 1 or 2 points on a 10-point
scale are not unexpected from chance alone and may be, in part,
consistent with less-than-perfect intra-rater reliability of the
scale.
[0133] The AE profile demonstrated by this study was consistent
with the known safety profile of bimatoprost solution 0.03%.
Discussion:
[0134] The composite efficacy endpoint used in this study,
supported by the individual efficacy component measurements,
provided for clinician and patient assessments of treatment
results. In addition, DIA of eyelash characteristics allowed for an
objective independent measure of treatment efficacy. Every group
receiving bimatoprost in both subpopulations demonstrated
statistically significant improvements from baseline compared with
vehicle-treated control subjects for all efficacy endpoints after 4
months of treatment. These results were independent of whether
treatment with bimatoprost was administered at baseline or delayed
6 months from baseline. This latter finding in the
chemotherapy-induced hypotrichosis subpopulation indicated that
bimatoprost can accelerate eyelash regrowth even when initiated
months after chemotherapy cessation. In addition, for subjects in
the groups receiving bimatoprost during both treatment periods, a
more pronounced treatment effect from bimatoprost was observed in
the chemotherapy-induced subpopulation compared with the idiopathic
subpopulation at month 12. These results may be attributed to
natural eyelash regrowth in subjects with chemotherapy-induced
hypotrichosis in addition to the treatment effect of bimatoprost.
However, month-6 measurements of mean eyelash characteristics of
vehicle-treated subjects with chemotherapy-induced hypotrichosis
were below mean eyelash characteristics of those with idiopathic
hypotrichosis at baseline. Furthermore, about 80% of
post-chemotherapy subjects were still nonresponders by the
composite endpoint definition at month 6 suggesting that natural
regrowth at 6 months is, in the vast majority of subjects, well
below their desired and objective measures of growth. Thus, the
natural eyelash regrowth following completion of chemotherapy
appears to be a slow recovery process without intervention with
bimatoprost.
[0135] The impact of bimatoprost discontinuation, evaluated in the
idiopathic hypotrichosis subpopulation only, demonstrated that the
treatment effect diminished after 2 months. These study findings
are expected to be applicable to the chemotherapy-induced
hypotrichosis subpopulation based on the similarities between the
subpopulations, the known mechanism by which cytotoxic agents cause
hair loss (i.e., no permanent damage to the hair follicle), and the
putative mechanism of action of bimatoprost in stimulating hair
growth following hair loss due to chemotherapy. However, whereas
subjects with idiopathic hypotrichosis revert back to their
baseline levels of eyelash prominence upon treatment
discontinuation, the eyelash characteristics of subjects with
chemotherapy-induced hypotrichosis would be expected to revert back
to a level of prominence their eyelashes would naturally have
achieved after chemotherapy cessation, and this result may be quite
variable between individuals.
[0136] The majority of common AEs observed throughout the 12-month
period occurred during the first 6 months of treatment, indicating
that continuous long-term treatment does not lead to an increased
incidence of AEs. In general, the AEs reported during this study
were similar to those reported in previous studies of bimatoprost
0.03% for the treatment of hypotrichosis of the eyelashes; the AEs
deemed by the investigator to be treatment related were largely
localized to the treatment area, nonserious, mild in severity,
reversible with treatment cessation, and predictable based on the
known pharmacology of bimatoprost The incidences of
treatment-related conjunctival hyperaemia, punctate keratitis, and
eye pruritus were higher in the chemotherapy-induced hypotrichosis
subpopulation than in the idiopathic hypotrichosis subpopulation.
This difference may be due to the higher likelihood of eye
conditions in a population with recent exposure to chemotherapeutic
agents due to an effect of the chemotherapy. With respect to
changes in TOP, it has been observed that TOP measurements in
healthy subjects can vary by 3 to 6 mm Hg even throughout a single
day. Thus, the mean changes in TOP were not considered clinically
relevant in any treatment group. Similarly, the limited number of
changes in iris color observed during the study was not considered
clinically relevant, as most recorded changes were 1- or 2-category
changes on a 10-category scale, and were transient. The reported
changes are most likely attributable to assessment variability.
Conclusions:
[0137] Bimatoprost 0.03% application once daily over a 1-year
period to the upper eyelids was found to be effective, safe, and
well tolerated in subjects with idiopathic and chemotherapy-induced
hypotrichosis. The primary treatment goals of these subpopulations
are not identical since the subjects with chemotherapy-induced
hypotrichosis seek to rapidly restore diminished eyelash
prominence, a constant reminder of the disease, to their
pre-chemotherapy state. Nevertheless, treatment with bimatoprost
provided statistically significant and clinically meaningful
benefits to both populations regardless of the severity of the
condition prior to treatment. The AE profile demonstrated during
this study was consistent with the previously reported safety
profile of bimatoprost 0.03%. No new safety concerns were observed
during the second 6-month treatment period compared with the safety
profile observed in the first 6 months of treatment.
* * * * *