Clinical trial NCT03479307
Conditions: Allergic Conjunctivitis
Sponsor: Faes Farma, S.A.
Start date: 2018-04-07; Completion date: 2018-08-10
Enrollment: 228 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy of Bilastine ophthalmic solution 0.6% compared to vehicle and Zaditen (Ketotifen ophthalmic solution 0.025%) for the treatment of the signs and symptoms of allergic conjunctivitis.

Detailed description:

Arms: arm 1: Bilastine Ophthalmic Solution 0.6%

1 drop in each eye at 2 separate times during an 8 day period. arm 2: Ketotifen Ophthalmic Solution 0.025% (Zaditen)

1 drop in each eye at 2 separate times during an 8 day period. arm 3: Vehicle of Bilastine Ophthalmic Solution

1 drop in each eye at 2 separate times during an 8 day period.
Interventions: intervention 1: Bilastine Ophthalmic Solution 0.6% intervention 2: Ketotifen Ophthalmic Solution 0.025% (Zaditen) intervention 3: Vehicle of Bilastine Ophthalmic Solution
Intervention descriptions: intervention 1: 1 drop in each eye at 2 separate times during an 8 day period. intervention 2: 1 drop in each eye at 2 separate times during an 8 day period. intervention 3: 1 drop in each eye at 2 separate times during an 8 day period.

Protocol documents:
Prot_SAP_001.pdf: 
Bilastine Ophthalmic Solution 0.6% 
FAES FARMA 
Clinical Trial Protocol: 17-100-0012/BOFT-0218/AC-CAC 
Version 1.0/29Jan2018 
 
Confidential 
 
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SYNOPSIS 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, 
Vehicle- and Active-Controlled, Phase 3 Study 
Evaluating the Efficacy and Safety of Bilastine 
Ophthalmic Solution 0.6% Compared to Vehicle and 
Zaditen (Ketotifen Ophthalmic Solution 0.025%) for 
the Treatment of Allergic Conjunctivitis in the 
Conjunctival Allergen Challenge (Ora-CAC®) 
Model  
Protocol Number: 
17-100-0012/BOFT-0218/AC-CAC 
Investigational Product: 
Bilastine Ophthalmic Solution 0.6% 
Study Phase: 
Phase 3 
Primary Objective: 
To evaluate the efficacy of Bilastine ophthalmic 
solution 0.6% compared to vehicle and Zaditen 
(Ketotifen ophthalmic solution 0.025%) for the 
treatment of the signs and symptoms of allergic 
conjunctivitis. 
Secondary Objectives: 
 To evaluate the safety and tolerability of Bilastine 
ophthalmic solution 0.6% compared to vehicle and 
Zaditen (Ketotifen ophthalmic solution 0.025%)  
Overall Study Design: 
Structure: 
Screening Period: At Visit 1, subjects will sign the 
informed consent and an allergic skin test will be 
performed, if required. At Visit 2, each qualifying 
subject will undergo a bilateral conjunctival allergen 
challenge (CAC) titration using an allergen they had 
a positive reaction to on their skin test. Subjects who 
elicit a positive reaction post-CAC will undergo the 
confirmation CAC at Visit 3 using the same allergen 
they qualified with at Visit 2.  
 
Treatment Period: Treatment will begin at Visit 4a 
after subjects are randomized. At this visit, subjects 
will receive an in-office dose of the treatment they 
were randomized to receive. Approximately 16 
hours post-instillation of study medication, subjects 
will undergo CAC at Visit 4b. Subjects will receive 
a final dose of study medication at Visit 5 


Bilastine Ophthalmic Solution 0.6% 
FAES FARMA 
Clinical Trial Protocol: 17-100-0012/BOFT-0218/AC-CAC 
Version 1.0/29Jan2018 
 
Confidential 
 
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approximately 15 minutes prior to CAC.  
 
Follow-Up Period:  A documented telephone call 
will be made by the investigator (or investigator’s 
designee) on Day 15 (±3) to all randomized subjects 
approximately one week after their last visit to query 
if there have been any changes in their medical 
history or medications or if they have had any 
emergency room visits or hospitalizations since their 
last study visit. Documentation will be made to 
record this telephone call follow-up. 
Duration: 
This study consists of six (6) office visits over a 
period of approximately five to nine (5-9) weeks. 
Controls: 
 Vehicle of Bilastine Ophthalmic Solution 
 Zaditen (Ketotifen ophthalmic solution 
0.025%)  
Dosage/Instillation: 
At Visit 4a, a trained study technician will instill one 
(1) drop of assigned investigational product into 
each eye approximately 16 hours (+1 hour) prior to 
the Visit 4b CAC using the designated bottle . 
 
At Visit 5, a trained study technician will instill one 
(1) drop of assigned investigational product into 
each eye approximately 15 minutes (+1 minute) 
prior to the Visit 5 CAC using the designated bottle 
l. 
The pre-specified technicians responsible for 
instilling the investigational product will not be 
involved with any other clinical study procedures at 
the site.  
Summary of Visit Schedule: 
Visit 1 (Day -50 to Day -22): Screening / Informed 
Consent / Skin Test 
 
Visit 2 (Day -21 ± 3): Titration CAC 
 
Visit 3 (Day -14 ± 3): Confirmation CAC  
 
Visit 4a (Day 1): Enrollment / Randomization / In-
Office Instillation 
 
Visit 4b (16 hours from Visit 4a): 16 Hour 


Bilastine Ophthalmic Solution 0.6% 
FAES FARMA 
Clinical Trial Protocol: 17-100-0012/BOFT-0218/AC-CAC 
Version 1.0/29Jan2018 
 
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Duration of Action CAC 
 
Visit 5 (Day 8 ± 3): In-Office Instillation / 15-
Minute Onset of Action CAC 
 
Day 15 (± 3): Follow-Up Telephone Call  
Measures Taken to Reduce 
Bias: 
Randomization will be used to avoid bias in the 
assignment of subjects to investigational product, to 
increase the likelihood that known and unknown 
subject attributes (e.g. demographics and baseline 
characteristics) are evenly balanced across treatment 
groups, and to enhance the validity of statistical 
comparisons across treatment groups. Finally, 
masked treatment will be used to reduce potential of 
bias during data collection and evaluation of clinical 
endpoints.   
Study Population Characteristics: 
Number of Subjects: 
Approximately 225 subjects will be enrolled at up to 
seven (7) sites. 
Condition/Disease: 
Allergic Conjunctivitis 
Inclusion Criteria: 
1) be at least 18 years of age at Visit 1 of either 
gender and any race (a government issued ID 
will be verified at the time ICF is signed); 
2) provide written informed consent and sign the 
HIPAA form; 
3) be willing and able to follow all instructions and 
attend all study visits; 
4) have a positive history of ocular allergies and a 
positive skin test reaction to a seasonal (grass, 
ragweed, and/or tree pollen) or perennial 
allergen (cat dander, dog dander, dust mites, 
cockroach) as confirmed by an allergic skin test 
conducted at Visit 1 or within the last 2 months; 
5) be able and willing to avoid all disallowed 
medications for the appropriate washout period 
and during the study (see exclusion 6); 
6) be able and willing to discontinue wearing 
contact lenses for at least 72 hours prior to Visit 
2 and during the study trial period; 
7)   (for females capable of becoming pregnant) 
agree to have urine pregnancy testing performed 
at screening on Visit 2 and Visit 4a (must be 


Bilastine Ophthalmic Solution 0.6% 
FAES FARMA 
Clinical Trial Protocol: 17-100-0012/BOFT-0218/AC-CAC 
Version 1.0/29Jan2018 
 
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negative) and exit visit; must not be lactating; 
and must agree to use a medically acceptable 
form of birth control1 throughout the study 
duration. Women considered capable of 
becoming pregnant include all females who have 
experienced menarche and have not experienced 
menopause (as defined by amenorrhea for greater 
than 12 consecutive months) or have not 
undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy); 
8)   have a calculated visual acuity of 
 
or better in each eye as measured using an 
ETDRS chart;   
9)   have a positive bilateral post-CAC reaction 
 
 
 within 10 (±2) 
minutes of instillation of the last titration of 
allergen at Visit 2;  
10) have a positive bilateral post-CAC reaction 
 
 for at least two out 
of the first three time points2 following the 
challenge at Visit 3. 
Exclusion Criteria: 
1) have known contraindications or sensitivities 
to the use of the investigational product or any 
of its components;  
2) have any ocular condition that, in the opinion 
of the investigator, could affect the subject’s 
safety or trial parameters (including but not 
limited to narrow angle glaucoma, clinically 
significant blepharitis, follicular conjunctivitis, 
iritis, pterygium or a diagnosis of dry eye);   
3) have had ocular surgical intervention within 
three (3) months prior to Visit 1 or during the 
study and/or a history of refractive surgery 
within the past six (6) months; 
4) have a known history of retinal detachment, 
diabetic retinopathy, or active retinal disease; 
                                                 
1Acceptable forms of birth control are spermicide with barrier, oral contraceptive, injectable or implantable method of 
contraception, transdermal contraceptive, intrauterine device, or surgical sterilization of partner.  For non-sexually 
active females, abstinence will be considered an acceptable form of birth control. 
2 not necessarily at the same time point 


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FAES FARMA 
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5) have the presence of an active ocular infection 
(bacterial, viral or fungal) or positive history 
of an ocular herpetic infection at any visit; 
6) use any of the following disallowed 
medications during the period indicated prior 
to Visit 2 and during the study:     
7 Days 
 systemic or ocular H1 antihistamine, H1 
antihistamine/mast cell stabilizers, H1 
antihistamine- vasoconstrictor drug 
combinations; 
 decongestants; 
 monoamine oxidase inhibitors; 
 all other topical ophthalmic preparations 
(including artificial tears); 
 lid scrubs; 
 topical prostaglandins or prostaglandin 
derivatives; 
 ocular, topical, or systemic nonsteroidal anti-
inflammatory drugs (NSAIDs); 
*Baby aspirin (81 mg) is allowed as long as 
a stable dose has been maintained for at 
least 30 days prior to Visit 1 and will 
continue to be maintained for the duration of 
the study. 
14 Days 
 inhaled, ocular, topical, or systemic 
corticosteroids or mast cell stabilizers; 
45 Days 
 depo-corticosteroids; 
Note: Currently marketed over-the-counter anti-
allergy eye drops (i.e. anti-histamine/ 
vasoconstrictor combination products such as 
Visine®-A®) may be administered to subjects by 
trained study personnel at the end of Visits 2, 3, 
4b, and 5, after all evaluations are completed. 
7) have any significant illness (e.g. any autoimmune 
disease requiring therapy, severe cardiovascular 
disease [including arrhythmias] the investigator 
feels could be expected to interfere with the 
subject’s health or with the study parameters 


Bilastine Ophthalmic Solution 0.6% 
FAES FARMA 
Clinical Trial Protocol: 17-100-0012/BOFT-0218/AC-CAC 
Version 1.0/29Jan2018 
 
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and/or put the subject at any unnecessary risk 
(includes but is not limited to: poorly controlled 
hypertension or poorly controlled diabetes, a 
history of status asthmaticus, organ transplants, a 
known history of persistent moderate or severe 
asthma, or a known history of moderate to severe 
allergic asthmatic reactions to any of the study 
allergens; 
8) have received allergy immunotherapy within the 
last 2 years; 
9) manifest signs or symptoms of clinically active 
allergic conjunctivitis in either eye at the start of 
Visits 2, 3 or 4
 
 
; 
10) have a history of glaucoma or ocular 
hypertension;  
11) have planned surgery (ocular or systemic) during 
the trial period or within 30 days after;  
12) have used an investigational drug or medical 
device within 30 days of the study or be 
concurrently enrolled in another investigational 
product trial; 
13) be a female who is currently pregnant, planning a 
pregnancy, or lactating. 
Study Formulations and 
Formulation Numbers: 
 Bilastine Ophthalmic Solution 0.6% 
 Zaditen (Ketotifen ophthalmic solution 
0.025% ) 
 Vehicle of Bilastine Ophthalmic Solution 
Evaluation Criteria: 
 
Efficacy Measures and 
Endpoints: 
Primary: 
 Ocular itching evaluated by the subject at 
3(±1), 5(±1), and 7(±1) minutes post-CAC 
 at 
Visits 4b and 5.  
 
Secondary:  
The following assessments will occur at 7(±1), 
15(±1), and 20(±1) minutes post-CAC 
 










Bilastine Ophthalmic Solution 0.6% 
FAES FARMA 
Clinical Trial Protocol: 17-100-0012/BOFT-0218/AC-CAC 
Version 1.0/29Jan2018 
 
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reported in the vehicle group. Eight of the 19 TEAEs were ocular TEAEs, and 11 were 
non-ocular TEAEs. Most (13) subjects who reported TEAEs identified them as mild in 
severity, while 5 subjects reported TEAEs of moderate severity. The Bilastine 0.6% 
group had one non-ocular TEAE (hypoasethesia) that was mild in severity and 
considered not related to treatment; the investigator decided to withdraw treatment for 
this subject. One subject in the Bilastine 0.4% group had a TEAE (mild headache) that 
was considered to be related (definite/certain) to treatment. Visual acuity reduced was 
reported by two subjects in the Bilastine 0.2% group and were not reported in any of the 
other treatment groups; these TEAEs were mild in severity and were considered not 
related to treatment. 
 
The most frequently reported ocular TEAE in the Phase 2 study was visual acuity 
reduced. Other ocular TEAEs reported (one TEAE each) included blepharitis, macular 
fibrosis, hordeolum, and keratitis in the bilastine groups, and corneal deposits and eye 
discharge in the vehicle group. The most frequently reported non-ocular TEAE was 
viral upper respiratory tract infection. Other non-ocular TEAEs reported (one each) 
included pyrexia, nephrolithiasis, headache, and hypoasethesia in the bilastine groups 
and gastroenteritis viral and arthralgia in the vehicle group. Subjects assessed 
tolerability (drop comfort) as comfortable in all treatment groups. Bilastine 0.6% 
showed strong efficacy for onset of action at 15 minutes and at 16 hours, indicating that 
it could be used for once daily treatment of allergic conjunctivitis.   
Several bilastine clinical studies via oral administration have shown efficacy and safety 
for the treatment of nasal as well as non-nasal (i.e., ocular) symptoms of 
rhinoconjuncitivitis. The incidence of somnolence and fatigue as adverse events in 10 
Phase II and III studies in patients treated with oral bilastine was comparable to placebo 
and significantly lower than in patients receiving active comparators, including 
cetirizine. Preclinical studies in several species with oral bilastine and subsequent 
toxicokinetic (TK) modeling for ocular administration demonstrated that bilastine 
showed systemic toxicity only at concentrations significantly higher than the proposed 
topical ocular dosing. Bilastine 20 mg tablets are authorized in the European Economic 
Area (29 countries) and in over 86 other countries worldwide for the symptomatic 
treatment of allergic rhinoconjunctivitis and urticaria in adults and adolescents older 
than 12 years. Post-marketing experience in the EEA and other countries has included 
cumulative human exposure of approximately 71,769,892 therapeutic cycles or 
4,129,226 patient-years to oral bilastine 20 mg tablets, with no new safety findings. The 
most frequently reported treatment-related TEAEs across 10 Phase II and Phase III 
bilastine oral administration clinical studies were headache, somnolence, fatigue, 
dizziness, and upper abdominal pain, with similar percentages of patients 
reporting related TEAEs in the bilastine and placebo groups. Other possible, uncommon 
adverse reactions include abnormal ECG and liver changes indicated by blood tests. The 
safety profile of oral bilastine in adolescent patients, in children from 2 to 11 years, and 
in elderly patients has been similar to that in adults.  
Zaditen has been associated with the following side effects: 


Bilastine Ophthalmic Solution 0.6% 
FAES FARMA 
Clinical Trial Protocol: 17-100-0012/BOFT-0218/AC-CAC 
Version 1.0/29Jan2018 
 
Confidential 
 
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After drug instillation, transient blurred vision or somnolence may occur, which can 
affect driving or the capacity to operate machines. 
 
Immune system disorders 
Uncommon: Hypersensitivity 
 
Nervous system disorders 
Uncommon: Headache 
 
Eye disorders 
Common: Eye irritation, eye pain, punctate keratitis, punctate corneal epithelial erosion. 
Uncommon: Vision blurred (during instillation), dry eye, eyelid disorder, conjunctivitis, 
photophobia, conjunctival haemorrhage. 
 
Gastrointestinal disorders 
Uncommon: Dry mouth 
 
Skin and subcutaneous tissue disorders 
Uncommon: Rash, eczema, urticaria 
 
General disorders and administration site conditions 
Uncommon: Somnolence 
 
Adverse drug reactions from post-marketing experience (Frequency not known): 
Hypersensitivity reactions including local allergic reaction (mostly contact dermatitis, 
eye swelling, eyelid pruritis and oedema), systemic allergic reactions including facial 
swelling/oedema (in some cases associated with contact dermatitis) and exacerbation of 
pre-existing allergic conditions such as asthma and eczema. 
 
The use of oral dosage forms of ketotifen may potentiate the effect of CNS depressants, 
antihistamines and alcohol. Although this has not been observed with Zaditen eye drops, 
the possibility of such effects cannot be excluded.