Risk
of Ocular Events in Patients With Atopic Dermatitis
In
large-scale epidemiologic studies, the prevalence of ocular
comorbidities were noted to be higher in the AD population compared
to the general population, in a severity-dependent manner.1,2
Chronic rubbing and scratching around the eyes due to uncontrolled
AD and ocular inflammation even in the absence of visible skin
symptoms, may contribute to the risk of developing an ocular
comorbidity.3
The
etiology of specific ocular events in the context of AD is complex
and several factors are thought to contribute to the complexity
including
dysregulation
of the intrinsic immune system
physical
trauma from eye rubbing
side
effects from AD medications, and
genetics.2
Patients
with AD have an increased risk of conjunctivitis and atopic
keratoconjunctivitis. Other ocular diseases associated with AD
include eyelid dermatitis, keratoconjunctivitis, keratoconus,
cataract, and retinal detachment. Patients with AD are also at
higher risk for bacterial and viral ocular infections.3
Ocular
Events in the BREEZE-AD Clinical Development Program
Clinical
Trial Exclusion Criteria
In
the BARI AD clinical trial program, there were no specific exclusion
criteria regarding ocular events. Patients were excluded
from enrollment if they had a current or recent clinically
serious viral, bacterial, fungal, parasitic infection, or any other
infection within 4 weeks of randomization that, in the opinion of
the investigator, would pose an unacceptable risk to the patient if
participating in the study.4
Treatment-Emergent
Eye Disorders in the Atopic Dermatitis Clinical Trials
Table
3 describes integrated data
sets used to evaluate safety in the AD clinical trials.
Table
1 summarizes the incidence
of ocular events by PT within the eye disorders SOC in the BARI AD
clinical trial program.
Table
1. Treatment-Emergent Adverse Events Within the Eye Disorders System
Organ Class4
|
|
|
|
|
|
|
|
|
|
|
|
|
BARI
2 mg Placebo-Controlleda
n
(adj %)b
|
BARI
4 mg Placebo-Controlleda
n
(adj %)b
|
BARI
2 mg vs 4 mga
n
(adj %)b
|
BARI
2 mg vs 4 mg ext
n (adj %)b
[adj IR]
|
All
BARI AD
n (%) [IR]
|
|
|
Placebo
n=889
|
BARI
2 mg
n=721
|
Placebo
n=743
|
BARI
4 mg
n=489
|
BARI
2 mg
n=576
|
BARI
4 mg
n=489
|
BARI
2 mg
n=576
|
BARI
4 mg
n=489
|
All
Doses
N=2531
|
|
Eye
disorders SOC
|
21
(2.8)
|
13
(1.7)
|
18
(2.5)
|
15
(2.6)
|
12
(1.6)
|
15
(2.6)
|
23
(2.9) [5.1]
|
33
(5.9) [7.7]c
|
114
(4.5) [5.1]
|
|
Conjunctivitis
allergic
|
8
(1.0)
|
4
(0.6)
|
7
(0.9)
|
1
(0.2)
|
4
(0.6)
|
1
(0.2)
|
7
(1.0) [1.5]
|
7
(1.2) [1.4]
|
34
(1.3) [1.5]
|
|
Cataract
|
0
|
2
(0.3)
|
0
|
3
(0.4)
|
2
(0.3)
|
3
(0.4)
|
2
(0.3) [0.5]
|
4
(0.6) [0.9]
|
12
(0.5) [0.5]
|
|
Blepharitis
|
1
(0.2)
|
1
(0.1)
|
1
(0.2)
|
0
|
1
(0.1)
|
0
|
4
(0.4) [0.8]
|
3
(0.6) [0.6]
|
10
(0.4) [0.4]
|
|
Eye
pruritus
|
0
|
3
(0.3)
|
0
|
2
(0.3)
|
3
(0.3)
|
2
(0.3)
|
3
(0.3) [0.5]
|
3
(0.5) [0.9]
|
10
(0.4) [0.4]
|
|
Chalazion
|
0
|
1
(0.1)
|
NR
|
NR
|
NR
|
NR
|
0
|
2
(0.4) [0.4]
|
6
(0.2) [0.3]
|
|
Vision
blurred
|
1
(0.1)
|
0
|
1
(0.1)
|
2
(0.4)
|
0
|
2
(0.4)
|
0
|
2
(0.4) [0.5]
|
5
(0.2) [0.2]
|
|
Conjunctival hemorrhage
|
2
(0.3)
|
0
|
2
(0.3)
|
0
|
0
|
0
|
0
|
0
|
4
(0.2) [0.2]
|
|
Conjunctival hyperemia
|
0
|
1
(0.1)
|
0
|
0
|
1(0.1)
|
0
|
1
(0.1) [0.2]
|
1
(0.2) [0.3]
|
4
(0.2) [0.2]
|
|
Retinal
detachment
|
0
|
1
(0.2)
|
0
|
1
(0.1)
|
1(0.2)
|
1
(0.1)
|
1
(0.2) [0.3]
|
3
(0.5) [0.6]
|
4
(0.2) [0.2]
|
|
Eczema
eyelids
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
2
(0.2) [0.4]
|
0
|
3
(0.1) [0.1]
|
|
Eye
swelling
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
1
(0.2)
|
1
(0.2)
|
1
(0.2) [0.3]
|
1
(0.2) [0.2]
|
3
(0.1) [0.1]
|
|
Dry
eye
|
4
(0.7)
|
0d
|
3
(0.6)
|
0
|
0
|
0
|
0
|
0
|
2
(0.1) [0.1]
|
|
Eye
pain
|
0
|
0
|
0
|
1
(0.1)
|
0
|
1
(0.1)
|
1
(0.1) [0.2]
|
1
(0.1) [0.2]
|
2
(0.1) [0.1]
|
|
Eyelid
edema
|
0
|
1
(0.1)
|
0
|
1
(0.2)
|
1
(0.1)
|
1
(0.2)
|
1
(0.1) [0.2]
|
1
(0.2) [0.3]
|
2
(0.1) [0.1]
|
|
Glaucoma
|
1
(0.1)
|
0
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
2
(0.1) [0.1]
|
|
Hypermetropia
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
1
(0.2) [0.2]
|
2
(0.1) [0.1]
|
|
Keratitis
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2) [0.3]
|
2
(0.1) [0.1]
|
|
Ocular
hypertension
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
1
(0.2) [0.3]
|
1
(0.2) [0.2]
|
2
(0.1) [0.1]
|
|
Swelling
of eyelid
|
2
(0.2)
|
0
|
2
(0.2)
|
0
|
0
|
0
|
0
|
0
|
2
(0.1) [0.1]
|
|
Vitreous
floaters
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
2
(0.4) [0.4]
|
2
(0.1) [0.1]
|
|
Angle
closure glaucoma
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Blepharitis
allergic
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Conjunctival
irritation
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
1
(0.1) [0.2]
|
0
|
1
(0.0) [0.0]
|
|
Corneal
epithelial microcysts
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2) [0.3]
|
1
(0.0) [0.0]
|
|
Corneal
erosion
|
0
|
0
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Eye
allergy
|
0
|
0
|
0
|
1
(0.1)
|
0
|
1
(0.1)
|
0
|
1
(0.1) [0.2]
|
1
(0.0) [0.0]
|
|
Eye
inflammation
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Eye
irritation
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
1
(0.2) [0.2]
|
1
(0.0) [0.0]
|
|
Eyelid
disorder
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Keratoconus
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2) [0.3]
|
1
(0.0) [0.0]
|
|
Meibomian
gland dysfunction
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Meibomianitis
|
0
|
1
(0.1)
|
0
|
0
|
1
(0.1)
|
0
|
1
(0.1) [0.2]
|
0
|
1
(0.0) [0.0]
|
|
Noninfective
conjunctivitis
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2) [0.3]
|
1
(0.0) [0.0]
|
|
Periorbital
swelling
|
0
|
0
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Photopsia
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2) [0.2]
|
1
(0.0) [0.0]
|
|
Ulcerative
keratitis
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
1
(0.1) [0.2]
|
0
|
1
(0.0) [0.0]
|
|
Xerophthalmia
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Giant
papillary conjunctivitis
|
1
(0.1)
|
0
|
1
(0.1)
|
0
|
0
|
0
|
NR
|
NR
|
NR
|
|
Visual
acuity reduced
|
1
(0.1)
|
0
|
1
(0.1)
|
0
|
0
|
0
|
NR
|
NR
|
NR
|
Abbreviations:
AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; ext =
extended; IR = incidence rate; NR = not reported; SOC = system organ
class.
a
Data through 16-week placebo-controlled period.
b
For the integrated controlled analysis sets where the
randomized ratio of patients receiving BARI to placebo or BARI to
active control is not the same across all the integrated studies
(eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were
calculated for the adverse events to provide appropriate direct
comparisons between treatment groups.
c
p≤.05 vs BARI 2 mg.
d
p≤.01 vs placebo.
Placebo-Controlled
Data Set
During
the 16-week placebo-controlled period, there were
3
SAEs including
1
(0.1%) retinal detachment in the placebo group
1
(0.1%) cataract in the BARI 4 mg group, and
1
(0.2%) allergic conjunctivitis in the BARI 4 mg group
2
events, which led to temporary interruption of treatment including
1
(0.1%) conjunctival hemorrhage in the placebo group
1
(0.1%) cataract in the BARI 4 mg group, and
1
(0.2%) case of allergic conjunctivitis in the BARI 2 mg group,
which led to permanent discontinuation from the study.4
One
patient on BARI 2 mg who discontinued from the study due to allergic
conjunctivitis, resumed treatment with BARI 4 mg in the BARI
long-term extension study.4
The
study-size adjusted percentages reported here were calculated for
the adverse events to provide appropriate direct comparisons between
treatment groups.
All
BARI AD Data Set
In
the All BARI data set, evaluating 2531 patients treated across all
BARI doses studied in AD, there were 114 (4.5%) TEAEs related to eye
disorders including
5
(0.2%) SAEs including
2
(0.1%) cataracts
1
(0.0%) allergic conjunctivitis
1
(0.0%) corneal erosion
1
(0.0%) retinal detachment
3
(0.1%) temporary treatment interruptions including
1
(0.0%) case of cataract
1
(0.0%) case of chalazion
1
(0.0%) case of retinal detachment, and
2
(0.1%) permanent discontinuations from study including
1
(0.0%) case of eye pruritis, and
1
(0.0%) case of swelling of eyelid.4
Treatment-Emergent
Events Occurring Within the Conjunctivitis SMQ
In
addition to the SOC and PT analyses, a cluster analysis was
performed to assess groupings of nearly synonymous preferred and
related terms associated with conjunctival disorders using
standardized MedDRA queries.
Table
2 summarizes the TEAEs
reported within the conjunctival disorders SMQ in the BARI AD
clinical trial program .
Table
2. Treatment-Emergent Adverse Events Within the Conjunctival
Disorders SMQ4
|
|
|
|
|
|
|
|
|
|
|
|
|
BARI
2 mg Placebo-Controlleda
n
(adj %)b
|
BARI
4 mg Placebo-Controlleda
n
(adj %)b
|
BARI
2 mg vs 4 mg
n (adj %)b
|
BARI
2 mg vs 4 mg ext
n (adj %)b [adj
IR]
|
All
BARI AD
n (%) [IR]
|
|
|
Placebo
n=889
|
BARI
2 mg
n=721
|
Placebo
n=743
|
BARI
4 mg
n=489
|
BARI
2 mg
n=576
|
BARI
4 mg
n=489
|
BARI
2 mg
n=576
|
BARI
4 mg
n=489
|
All
Doses
N=2531
|
|
Conjunctival
Disorders (SMQ)
|
18
(2.4)
|
15
(2.0)
|
15
(2.1)
|
6
(1.2)
|
12
(1.6)
|
6
(1.2)
|
21
(3.0) [4.9]
|
18
(3.3) [4.6]
|
96
(3.8) [4.3]
|
|
Conjunctivitis
|
2
(0.3)
|
7
(0.9)
|
2
(0.3)
|
3
(0.6)
|
6
(0.8)
|
3
(0.6)
|
10
(1.5) [2.4]
|
8
(1.5) [2.2]
|
39
(1.5) [1.7]
|
|
Conjunctivitis
allergic
|
8
(1.0)
|
4
(0.6)
|
7
(0.9)
|
1
(0.2)
|
4
(0.6)
|
1
(0.2)
|
7
(1.0) [1.5]
|
7
(1.2) [1.4]
|
34
(1.3) [1.5]
|
|
Seasonal
allergy
|
2
(0.2)
|
3
(0.3)
|
1
(0.1)
|
0
|
1
(0.1)
|
0
|
2
(0.3) [0.5]
|
0
|
9
(0.4) [0.4]
|
|
Conjunctival
hemorrhage
|
2
(0.3)
|
0
|
2
(0.3)
|
0
|
0
|
0
|
0
|
0
|
4
(0.2) [0.2]
|
|
Conjunctival
hyperemia
|
0
|
1
(0.1)
|
0
|
0
|
1
(0.1)
|
0
|
1
(0.1) [0.2]
|
1
(0.2) [0.3]
|
4
(0.2) [0.2]
|
|
Dry
eye
|
4
(0.7)
|
0c
|
3
(0.6)
|
0
|
0
|
0
|
0
|
0
|
2
(0.1) [0.1]
|
|
Keratitis
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2) [0.3]
|
2
(0.1) [0.1]
|
|
Conjunctival
irritation
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
1
(0.1) [0.2]
|
0
|
1
(0.0) [0.0]
|
|
Noninfective
conjunctivitis
|
0
|
0
|
0
|
1
(0.2)
|
0
|
1
(0.2)
|
0
|
1
(0.2) [0.3]
|
1
(0.0) [0.0]
|
|
Xerophthalmia
|
NR
|
NR
|
NR
|
NR
|
NR
|
NR
|
0
|
0
|
1
(0.0) [0.0]
|
|
Giant
papillary conjunctivitis
|
1
(0.1)
|
0
|
1
(0.1)
|
0
|
0
|
0
|
NR
|
NR
|
NR
|
Abbreviations:
AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; ext =
extended; IR = incidence rate; MedDRA = Medical Dictionary for
Regulatory Activities; NR = not reported; SMQ = Standardized MedDRA
Query.
a
Data through 16-week placebo-controlled period.
b
For the integrated controlled analysis sets where the
randomized ratio of patients receiving BARI to placebo or BARI to
active control is not the same across all the integrated studies
(eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were
calculated for the adverse events to provide appropriate direct
comparisons between treatment groups.
c
p≤.01 vs placebo.
Treatment-Emergent
Adverse Events by Cluster in the Placebo-Controlled Data Set
In
the 16-week placebo-controlled data set
more
placebo-treated patients reported events in the cluster compared to
the BARI-treated groups
the
specific PT of conjunctivitis was more frequently reported in the
BARI 2 mg group compared to the placebo and BARI 4 mg groups, and
none
of the conjunctival disorders in the cluster were significantly
higher in the BARI-treated groups compared to placebo.4
Treatment-Emergent
Adverse Events by Cluster in the All BARI AD Data Set
In
the All BARI AD data set, evaluating 2531 patients treated across all
BARI doses studied in AD, there were
1
(0.0%) SAE reported due to allergic conjunctivitis, and
1
(0.0%) temporary interruption of BARI due to conjunctivitis.4
There
were no treatment discontinuations reported due to conjunctivitis.4
Integrated
Safety Data Set
Table
3. Integrated Analysis Datasets Used to Evaluate Safety in Atopic
Dermatitis Clinical Trials4
|
Analysis
Set
|
Description
|
|
BARI
2 mg Placebo-Controlled
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and
BREEZE-AD7
|
Compares
BARI 2 mg vs placebo
Includes
patients with AD from 1 phase 2 and 5 phase 3 studies who were
randomized to
BARI
2 mg (n=721, PYE=210.6), or
placebo
(n=889, PYE=252.7).
Treatment
period was 0 to 16 weeks.
|
|
BARI
4 mg Placebo-Controlled
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7
|
Compares
BARI 4 mg vs placebo
Includes
patients with AD from 1 phase 2 and 4 phase 3 studies who were
randomized to
BARI
4 mg (n=489, PYE=147.1), or
placebo
(n=743, PYE=211.8).
Treatment
period was 0 to 16 weeks.
|
|
BARI
2 mg vs 4 mg
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7
|
Compares
BARI 2 mg vs BARI 4 mg through 16 weeks
Includes
patients with AD from 1 phase 2 and 4 phase 3 studies who were
randomized to
BARI
2 mg (n=576, PYE=169.1), or
BARI
4 mg (n=489, PYE=147.1).
Treated
for 0 to 16 weeks during the placebo-controlled period.
|
|
BARI
2 mg vs 4 mg Extended
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and
extension study BREEZE-AD3
|
Compares
BARI 2 mg vs BARI 4 mg including extended evaluations
Includes
patients with AD from 1 phase 2 and 4 phase 3 studies and any
further exposure for those patients in the phase 3 extension
study, BREEZE-AD3, who were randomized to
BARI
2 mg (n=576, PYE=425.5), or
BARI
4 mg (n=489, PYE=459.3).
Data
censored at dose or treatment change (rescue, dose switch, or
re-randomization to a different BARI dose or placebo) for
BREEZE-AD4 and BREEZE-AD3.
|
|
All
BARI AD
Studies:
JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7,
and extension studies BREEZE-AD3, BREEZE-AD6
|
No
between-group comparisons
Includes
2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase
3, and 2 phase 3 extension studies who received BARI at a variety
of doses, including
BARI
1 mg (n=538, PYE=245.9)
BARI
2 mg (n=1580, PYE=1129.5), and
BARI
4 mg (n=914, PYE=872.8).
Includes
all patients who were exposed to any BARI dose at any time during
the studies, either from randomization or from switch or rescue
from placebo.
No
censoring of data at dose change.
|
Abbreviations:
AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of
exposure.
Note:
BARI 1 mg was studied in pivotal trials, however it is not approved.
Please refer to section 4.2 of the Olumiant Summary of Product
Characteristics for approved dosage.
References
1.
Thyssen JP, Toft PB, Halling-Overgaard AS, Gislason GH, Skov L,
Egeberg A. Incidence, prevalence, and risk of selected ocular disease
in adults with atopic dermatitis. J Am Acad Dermatol.
2017;77(2):280-286.e1. doi:10.1016/j.jaad.2017.03.003
2.
Hsu JI, Pflugfelder SC, Kim SJ. Ocular complications of atopic
dermatitis. Cutis. 2019;104(3):189-193.
https://pubmed.ncbi.nlm.nih.gov/31675394/
3.
Beck, K.M., Seitzman, G.D., Yang, E.J. et al. Ocular
co-morbidities of atopic dermatitis. part I: associated ocular
diseases. Am J Clin Dermatol. 2019;20:797–805.
https://doi.org/10.1007/s40257-019-00455-5
4.
Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Glossary
AD =
atopic dermatitis
BARI
= baricitinib
MedDRA
= Medical Dictionary for Regulatory Activities
PT =
preferred term
SAE
= serious adverse event
SMQ
= standardized MedDRA query
SOC
= system organ class
TEAE
= treatment-emergent adverse event
▼ This
medicinal product is subject to additional monitoring. This will
allow quick identification of new safety information. Healthcare
professionals are asked to report any suspected adverse reactions.