The Effects of a Single Intravenous Administration of Secukinumab (AIN457) or Canakinumab (ACZ885) in Dry Eye Patients

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01250171
• Collaborator: (none)
• Enrollment: 72
• Location: 1
• Arms: 3
• Duration (Months): 10
• Patients Per Site Per Month: 7.2

Study Details

Study Description

Brief Summary

This study assessed the effects of a single intravenous dose of secukinumab (AIN457) 10 mg/kg or canakinumab (ACZ885) 10 mg/kg on the signs and symptoms of dry eye. In addition, the pharmacokinetic, pharmacodynamic, and safety profiles of secukinumab and canakinumab were assessed. Blood samples were collected for the analysis of the effect of secukinumab and canakinumab on select biomarkers.

Condition or Disease	Intervention/Treatment	Phase
Dry Eye	Biological: Secukinumab 10 mg/kg; Biological: Canakinumab 10 mg/kg; Biological: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Placebo-controlled, Double-blind, Proof-of-concept Study of Intravenous Secukinumab (AIN457) or Canakinumab (ACZ885) in Dry Eye Syndrome
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Sep 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Secukinumab 10 mg/kg Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Biological: Secukinumab 10 mg/kg; Secukinumab was prepared in a sterile water solution.; Other Names: AIN457
Experimental: Canakinumab 10 mg/kg Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Biological: Canakinumab 10 mg/kg; Canakinumab was prepared in a sterile water solution.; Other Names: ACZ885
Placebo Comparator: Placebo Patients received a single placebo infusion intravenously over a 2 hour period.	Biological: Placebo; The placebo solution for infusion contained 5% glucose.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline on the National Eye Institute Corneal Staining Scale (NEI-CSS) at Week 4 [Baseline to Week 4]

   Corneal staining was done with 2% sodium fluorescein instilled into the lower palpebral conjunctiva of each eye. Staining was assessed in 5 zones of the cornea (central plus 4 quadrants) and rated on a scale of 0 (no staining) to 3 (severe, confluent staining). A mean of the 5 zones for the study eye was calculated. A higher score indicates a drier eye. A negative change score indicates improvement in dryness.

Secondary Outcome Measures

1. Change From Baseline on the Ora Corneal Staining Scale at Weeks 1, 4, and 8 [Baseline to Weeks 1, 4, and 8]

   Corneal staining was done with 2% sodium fluorescein instilled into the lower palpebral conjunctiva of the study eye. Staining was assessed in 3 regions (inferior, superior, and central) of the cornea and rated on a scale of 0 (no staining) to 4 (confluent staining). A mean of the 3 zones was calculated. A higher score indicates a drier eye. A negative change score indicates improvement in dryness.

2. Change From Baseline on the Schirmer Test at Weeks 1, 4, and 8 [Baseline to Weeks 1, 4, and 8]

   The Schirmer test measures the production of tears. A small strip of filter paper is placed inside the lower eyelid (conjunctival sac) of each eye and the eyes are kept closed for 5 minutes. The paper is removed and the length of paper that is wet is measured as an index of tear production. The amount of tear production in the study eye was ranked on a 4 point scale: 0=Normal (≥ 15 mm wetting of the paper), 1=Mild (14-9 mm wetting of the paper), 2=Moderate (8-4 mm wetting of the paper), and 3=Severe (< 4 mm wetting of the paper). A higher score indicates a drier eye. A negative change score indicates improvement in dryness.

3. Change From Baseline in Tear Film Breakup Time at Weeks 1, 4, and 8 [Baseline to Weeks 1, 4, and 8]

   Tear film breakup time was defined as the time of last blink to the appearance of the first growing micelle after instilling 5 μl of non-preserved 2% sodium fluorescein into the lower palpebral conjunctiva of the study eye. Measurement was repeated 3 times and a mean tear film breakup time calculated. A lower score indicates a drier eye. A positive change score indicates improvement in dryness.

4. Change From Baseline on the Conjunctival Redness Scale (Ora) at Weeks 1, 4, and 8 [Baseline to Weeks 1, 4, and 8]

   Conjunctival redness was measured in the study eye at each visit by a masked evaluator. The evaluator compared the patient's study eye with a set of 5 reference photos showing a normal eye and eyes with various degrees of redness. Redness was scored on a scale of 0-5 with a white normal eye = 0 and an eye with the most redness = 5. A higher score indicates more redness. A negative change score indicates improvement in redness.

5. Change From Baseline in the Ocular Surface Disease Index (OSDI) at Weeks 1, 4, and 8 [Baseline to Weeks 1, 4, and 8]

   The OSDI is an instrument for measuring dry eye disease severity and effect on vision-related functions. Patients were asked a series of 12 questions; patients responded to the questions in regard to both eyes. Responses ranged from 0=None of the time to 4=All of the time. OSDI was calculated as the sum of the 12 question scores x 25/number of questions answered. The total score ranged from 0-100. A higher score indicates drier eyes. A negative change score indicates improvement in dryness.

6. Desire for Artificial Tear Use at Day 1 and Weeks 1, 4, and 8 [Day 1 and Weeks 1, 4, and 8]

   Patients were instructed to record each occurrence of a desire for topical lubricant use in a patient diary. The percentage of patients in each of 6 categories (0-5, 6-10, 11-15, 16-20, 21-25, > 25 times) indicating the number of times a patient records a desire for artificial tear use per day was calculated at each time point. The percentage was calculated using the number of patients with any reported data on that day in the respective treatment group as the denominator.

7. Change From Baseline in Best Corrected Visual Acuity at Weeks 1, 4, and 8 [Baseline to Weeks 1, 4, and 8]

   Best corrected visual acuity (BCVA) was assessed in the study eye. BCVA measurements were taken in a standing position using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance specific to the test charts. The BCVA score is the number of letters read correctly by the patient. A decrease in the BCVA score indicates a worsening of vision. A positive change score indicates improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female patients age 18-85 with a diagnosis of moderate to severe dry eye.

• Schirmer test without anesthesia ≥ 1 and < 10 mm wetting over 5 minutes in at least 1 eye.

• Tear break up time < 7 seconds in at least 1 eye.

• Corneal staining score ≥ 3 (National Eye Institute [NEI] grading scale).

• Conjunctival redness of ≥ 1.

• Ocular surface disease index of modest to severe.

• Ability to provide informed consent.

Exclusion Criteria:

• Pregnant or breastfeeding women.

• Hemoglobin < 10 g/dl.

• Total white blood count (WBC) outside the range of 3000-14,000/µl.

• Platelets < 100,000/µl.

• Use of ocular, periocular, or systemic steroids within 60 days prior to screening.

• Use of contact lenses or prior corneal refractive surgery in either eye.

• Requirement of eye drop use during the study.

• Anesthetic or neurotrophic corneas.

• Temporary punctal plugs.

• Recent or planned exposure to live vaccinations.

• Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ora Inc, 300 Brickstone Square,	Andover	Massachusetts	United States	01810

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01250171
• Other Study ID Numbers: CPJMR0092202
• First Posted: Nov 30, 2010
• Last Update Posted: Jan 7, 2013
• Last Verified: Dec 1, 2012

• Keywords provided by Novartis Pharmaceuticals: Dry eye; IL17/ IL-1β; Biologic
• Additional relevant MeSH terms: Dry Eye Syndromes; Keratoconjunctivitis Sicca

Study Results

Participant Flow

Pre-assignment Detail	One patient randomized to the secukinumab group did not receive study drug and was not included in any of the analysis sets.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Period Title: Overall Study
STARTED	26	22	24
COMPLETED	25	22	24
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo	Total
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.	Total of all reporting groups
Overall Participants	25	22	24	71
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55 (13)	54 (11)	59 (13)	56 (13)
Sex: Female, Male (Count of Participants)
Female	18 72%	17 77.3%	18 75%	53 74.6%
Male	7 28%	5 22.7%	6 25%	18 25.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline on the National Eye Institute Corneal Staining Scale (NEI-CSS) at Week 4
Description	Corneal staining was done with 2% sodium fluorescein instilled into the lower palpebral conjunctiva of each eye. Staining was assessed in 5 zones of the cornea (central plus 4 quadrants) and rated on a scale of 0 (no staining) to 3 (severe, confluent staining). A mean of the 5 zones for the study eye was calculated. A higher score indicates a drier eye. A negative change score indicates improvement in dryness.
Time Frame	Baseline to Week 4

Outcome Measure Data

Analysis Population Description

All patient population: All randomized patients that received 1 full dose of a study drug per protocol. Two patients were not included in the all patient population (1 in each drug group) as they were not dosed per protocol or they did not receive the full dose of the assigned treatment.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Measure Participants	24	21	24
Mean (Standard Deviation) [Units on a scale]	0.23 (0.4)	0.12 (0.5)	0.26 (0.5)

2. Secondary Outcome

Title	Change From Baseline on the Ora Corneal Staining Scale at Weeks 1, 4, and 8
Description	Corneal staining was done with 2% sodium fluorescein instilled into the lower palpebral conjunctiva of the study eye. Staining was assessed in 3 regions (inferior, superior, and central) of the cornea and rated on a scale of 0 (no staining) to 4 (confluent staining). A mean of the 3 zones was calculated. A higher score indicates a drier eye. A negative change score indicates improvement in dryness.
Time Frame	Baseline to Weeks 1, 4, and 8

Outcome Measure Data

Analysis Population Description

All patient population: All randomized patients that received 1 full dose of a study drug per protocol. Two patients were not included in the all patient population (1 in each drug group) as they were not dosed per protocol or they did not receive the full dose of the assigned treatment.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Measure Participants	24	21	24
Week 1	0.3 (0.6)	0.2 (0.6)	0.4 (0.5)
Week 4	0.4 (0.6)	0.2 (0.5)	0.4 (0.5)
Week 8	0.3 (0.5)	0.3 (0.7)	0.2 (0.5)

3. Secondary Outcome

Title	Change From Baseline on the Schirmer Test at Weeks 1, 4, and 8
Description	The Schirmer test measures the production of tears. A small strip of filter paper is placed inside the lower eyelid (conjunctival sac) of each eye and the eyes are kept closed for 5 minutes. The paper is removed and the length of paper that is wet is measured as an index of tear production. The amount of tear production in the study eye was ranked on a 4 point scale: 0=Normal (≥ 15 mm wetting of the paper), 1=Mild (14-9 mm wetting of the paper), 2=Moderate (8-4 mm wetting of the paper), and 3=Severe (< 4 mm wetting of the paper). A higher score indicates a drier eye. A negative change score indicates improvement in dryness.
Time Frame	Baseline to Weeks 1, 4, and 8

Outcome Measure Data

Analysis Population Description

All patient population: All randomized patients that received 1 full dose of a study drug per protocol. Two patients were not included in the all patient population (1 in each drug group) as they were not dosed per protocol or they did not receive the full dose of the assigned treatment.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Measure Participants	24	21	24
Week 1	-0.5	0.1	0.3
Week 4	-0.1	0.0	0.1
Week 8	-0.1	0.0	0.3

4. Secondary Outcome

Title	Change From Baseline in Tear Film Breakup Time at Weeks 1, 4, and 8
Description	Tear film breakup time was defined as the time of last blink to the appearance of the first growing micelle after instilling 5 μl of non-preserved 2% sodium fluorescein into the lower palpebral conjunctiva of the study eye. Measurement was repeated 3 times and a mean tear film breakup time calculated. A lower score indicates a drier eye. A positive change score indicates improvement in dryness.
Time Frame	Baseline to Weeks 1, 4, and 8

Outcome Measure Data

Analysis Population Description

All patient population: All randomized patients that received 1 full dose of a study drug per protocol. Two patients were not included in the all patient population (1 in each drug group) as they were not dosed per protocol or they did not receive the full dose of the assigned treatment.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Measure Participants	24	21	24
Week1	0.29	0.21	0.26
Week 4	0.74	-0.16	0.52
Week 8	0.62	0.37	1.15

5. Secondary Outcome

Title	Change From Baseline on the Conjunctival Redness Scale (Ora) at Weeks 1, 4, and 8
Description	Conjunctival redness was measured in the study eye at each visit by a masked evaluator. The evaluator compared the patient's study eye with a set of 5 reference photos showing a normal eye and eyes with various degrees of redness. Redness was scored on a scale of 0-5 with a white normal eye = 0 and an eye with the most redness = 5. A higher score indicates more redness. A negative change score indicates improvement in redness.
Time Frame	Baseline to Weeks 1, 4, and 8

Outcome Measure Data

Analysis Population Description

All patient population: All randomized patients that received 1 full dose of a study drug per protocol. Two patients were not included in the all patient population (1 in each drug group) as they were not dosed per protocol or they did not receive the full dose of the assigned treatment.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Measure Participants	24	21	24
Week 1	0.19	0.10	0.31
Week 4	0.15	-0.07	0.31
Week 8	0.02	-0.19	0.21

6. Secondary Outcome

Title	Change From Baseline in the Ocular Surface Disease Index (OSDI) at Weeks 1, 4, and 8
Description	The OSDI is an instrument for measuring dry eye disease severity and effect on vision-related functions. Patients were asked a series of 12 questions; patients responded to the questions in regard to both eyes. Responses ranged from 0=None of the time to 4=All of the time. OSDI was calculated as the sum of the 12 question scores x 25/number of questions answered. The total score ranged from 0-100. A higher score indicates drier eyes. A negative change score indicates improvement in dryness.
Time Frame	Baseline to Weeks 1, 4, and 8

Outcome Measure Data

Analysis Population Description

All patient population: All randomized patients that received 1 full dose of a study drug per protocol. Two patients were not included in the all patient population (1 in each drug group) as they were not dosed per protocol or they did not receive the full dose of the assigned treatment.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Measure Participants	24	21	24
Week 1	5.6	8.7	5.5
Week 4	4.8	9.9	4.6
Week 8	2.4	8.2	3.8

7. Secondary Outcome

Title	Desire for Artificial Tear Use at Day 1 and Weeks 1, 4, and 8
Description	Patients were instructed to record each occurrence of a desire for topical lubricant use in a patient diary. The percentage of patients in each of 6 categories (0-5, 6-10, 11-15, 16-20, 21-25, > 25 times) indicating the number of times a patient records a desire for artificial tear use per day was calculated at each time point. The percentage was calculated using the number of patients with any reported data on that day in the respective treatment group as the denominator.
Time Frame	Day 1 and Weeks 1, 4, and 8

Outcome Measure Data

Analysis Population Description

All patient population: All randomized patients that received 1 full dose of a study drug per protocol. Two patients were not included in the all patient population (1 in each drug group) as they were not dosed per protocol or they did not receive the full dose of the assigned treatment.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Measure Participants	24	21	24
Day 1, 0-5 times (n=24, 21, 24)	46	50	57
Day 1, 6-10 times	18	15	9
Day 1, 11-15 times	0	0	0
Day 1, 16-20 times	0	0	0
Day 1, 21-25 times	0	0	0
Day 1, > 25 times	0	0	0
Week 1, 0-5 times (n=24, 21, 24)	50	57	38
Week 1, 6-10 times	21	5	21
Week 1, 11-15 times	8	5	8
Week 1, 16-20 times	0	5	0
Week 1, 21-25 times	0	0	0
Week 1, > 25 times	0	0	0
Week 4, 0-5 times (n=24, 21, 24)	38	43	50
Week 4, 6-10 times	8	10	8
Week 4, 11-15 times	21	4	4
Week 4, 16-20 times	5	0	8
Week 4, 21-25 times	0	0	0
Week 4, > 25 times	0	0	0
Week 8, 0-5 times (n=16, 15, 13)	56	53	62
Week 8, 6-10 times	19	7	0
Week 8, 11-15 times	6	7	0
Week 8, 16-20 times	6	0	0
Week 8, 21-25 times	0	0	0
Week 8, > 25 times	0	0	0

8. Secondary Outcome

Title	Change From Baseline in Best Corrected Visual Acuity at Weeks 1, 4, and 8
Description	Best corrected visual acuity (BCVA) was assessed in the study eye. BCVA measurements were taken in a standing position using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance specific to the test charts. The BCVA score is the number of letters read correctly by the patient. A decrease in the BCVA score indicates a worsening of vision. A positive change score indicates improvement.
Time Frame	Baseline to Weeks 1, 4, and 8

Outcome Measure Data

Analysis Population Description

All patient population: All randomized patients that received 1 full dose of a study drug per protocol. Two patients were not included in the all patient population (1 in each drug group) as they were not dosed per protocol or they did not receive the full dose of the assigned treatment.

Arm/Group Title	Secukinumab 10 mg/kg	Canakinumab 10 mg/kg	Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.	Patients received a single placebo infusion intravenously over a 2 hour period.
Measure Participants	24	21	24
Week 1	0.5 (4)	0.3 (8)	0.9 (3)
Week 4	0.1 (4)	1.2 (4)	-0.1 (4)
Week 8	-0.4 (4)	1.6 (5)	-0.7 (5)

Adverse Events

Arm/Group Title	Secukinumab 10 mg/kg		Canakinumab 10 mg/kg		Placebo
Arm/Group Description	Patients received a single dose of secukinumab 10 mg/kg infused intravenously over a 2 hour period.		Patients received a single dose of canakinumab 10 mg/kg infused intravenously over a 2 hour period.		Patients received a single placebo infusion intravenously over a 2 hour period.
All Cause Mortality
	Secukinumab 10 mg/kg		Canakinumab 10 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Secukinumab 10 mg/kg		Canakinumab 10 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)		0/22 (0%)		0/24 (0%)
Infections and infestations
Acute diverticulitis	1/26 (3.8%)		0/22 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Secukinumab 10 mg/kg		Canakinumab 10 mg/kg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/26 (11.5%)		8/22 (36.4%)		4/24 (16.7%)
Gastrointestinal disorders
Diarrhoea	0/26 (0%)		0/22 (0%)		2/24 (8.3%)
Infections and infestations
Nasopharyngitis	2/26 (7.7%)		4/22 (18.2%)		3/24 (12.5%)
Investigations
White blood cell count decreased	0/26 (0%)		3/22 (13.6%)		0/24 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/26 (3.8%)		2/22 (9.1%)		0/24 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.