A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease

Study Overview
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Brief Summary
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This will be a 2 stage study in which Stage 1 will evaluate the safety of AGN-242428 and AGN-231868, how well they are tolerated and how they move through the body when administered. After the sponsor's determination of adequate safety and tolerability of the interventions in Stage 1, Stage 2 will begin. Stage 2 will also evaluate the safety and tolerability of AGN-242428 and AGN-231868, how effective they are in treating dry eye disease and assess the plasma and tear exposure of both ophthalmic solutions.

Official Title
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A Multicenter, Vehicle-controlled, Double-Masked, Randomized Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Exploratory Efficacy of AGN-242428 and AGN-231868 in Participants With Dry Eye Disease

Conditions
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Dry Eye Disease, Dry Eye Syndrome

Intervention / Treatment
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* Drug: AGN-242428
* Drug: AGN-231868
* Other: AGN-242428 Vehicle
* Other: AGN-231868 Vehicle
* Drug: Lifitegrast


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage 1 & Stage 2 Male participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study; Female participants willing to minimize the risk of inducing pregnancy for the duration of the clinical study; Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol; Stage 1 Both of the following signs of DED in at least 1 eye at Screening and Baseline visits (the same eye does not need to qualify at both visits); Total corneal fluorescein staining score ≥ 2 and ≤ 9 based on the NEI grading scale, with no score > 2 in any 1 region; Schirmer test with topical anesthesia score ≥ 1 and ≤ 10 mm/5 min; Stage 2 ALL of the following in at least 1 eye at both the Screening and Baseline visits and the same eye must qualify at both Screening and Baseline visits; Corneal fluorescein staining score ≥ 2 in at least 1 eye region and a total corneal fluorescein staining score of ≥ 4 and ≤ 12 based on NEI grading scale Schirmer test with topical anesthesia score ≥ 2 and ≤ 10 mm/5 min; Mean TBUT of ≥ 2 and ≤ 10 seconds Stage 1 Symptoms of DED at both the Screening and Baseline visits as defined by an OSDI total score of ≥ 13 with ≤ 3 responses of not applicable (NA); Stage 2; Symptoms of DED at both the Screening and Baseline visits as defined by both: OSDI score of ≥ 23 with ≤ 3 responses of not applicable (NA) in at least 1 eye; Eye Dryness Score (assessed using the Visual Analog Scale (VAS) Symptom Items score ≥ 30 Exclusion Criteria: Current diagnosis of glaucoma or ocular hypertension; evidence of glaucoma or mean intraocular pressure > 21 mm Hg determined by Goldmann applanation tonometry, in either eye; Diagnosis of recurrent, ongoing, or active ocular infection including, but not limited to herpes simplex or zoster, vaccinia, varicella, tuberculosis of the eye, acanthamoeba, or fungal disease; Participation in a blood or plasma donation program within 60 or 30 days, respectively, prior to study intervention administration; Positive test results for anti-HIV type 1 and 2, hepatitis B surface antigen, or anti-hepatitis C virus at the Screening visit; Positive test results for benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, or phencyclidine at the Screening or Baseline visits; Positive pregnancy test at Screening or Baseline visits; Currently breastfeeding or plans to breastfeed during the study; History or presence of any ocular disorder or condition (other than DED) in either eye that would, in the opinion of the investigator, likely interfere with the interpretation of the study results or participant safety.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: AGN-242428 Cohort 1A<br>Administration of AGN-242428 ophthalmic solution | Drug: AGN-242428<br>* Ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 1: AGN-242428 Cohort 1B<br>Administration of AGN-242428 ophthalmic solution | Drug: AGN-242428<br>* Ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 1: AGN-242428 Cohort 1C<br>Administration of AGN-242428 ophthalmic solution | Drug: AGN-242428<br>* Ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 1: AGN-231868 Cohort 1A<br>Administration of AGN-231868 ophthalmic solution | Drug: AGN-231868<br>* Ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 1: AGN-231868 Cohort 1B<br>Administration of AGN-231868 ophthalmic solution | Drug: AGN-231868<br>* Ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 1: AGN-231868 Cohort 1C<br>Administration of AGN-231868 ophthalmic solution | Drug: AGN-231868<br>* Ophthalmic solution administered as a topical eye drop<br>|
| Placebo Comparator: Stage 1: AGN-242428 Vehicle<br>Administration of matching placebo (vehicle) ophthalmic solution | Other: AGN-242428 Vehicle<br>* Matching placebo (vehicle) ophthalmic solution administered as a topical eye drop<br>|
| Placebo Comparator: Stage 1: AGN-231868 Vehicle<br>Administration of matching placebo (vehicle) ophthalmic solution | Other: AGN-231868 Vehicle<br>* Matching placebo (vehicle) ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 2: AGN-242428 Group 1<br>Administration of AGN-242428 ophthalmic solution | Drug: AGN-242428<br>* Ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 2: AGN-242428 Vehicle Group 2<br>Administration of matching placebo (vehicle) ophthalmic solution | Other: AGN-242428 Vehicle<br>* Matching placebo (vehicle) ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 2: AGN-231868 Group 3<br>Administration of AGN-231868 ophthalmic solution | Drug: AGN-231868<br>* Ophthalmic solution administered as a topical eye drop<br>|
| Experimental: Stage 2: AGN-231868 Vehicle Group 4<br>Administration of matching placebo (vehicle) ophthalmic solution | Other: AGN-231868 Vehicle<br>* Matching placebo (vehicle) ophthalmic solution administered as a topical eye drop<br>|
| Active Comparator: Lifitegrast<br>Administration of Lifitegrast ophthalmic solution | Drug: Lifitegrast<br>* Ophthalmic solution administered as a topical eye drop<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 1: The incidence of adverse events (safety and tolerability) | The number of participants who experience one or more treatment emergent adverse events (TEAE) | 15 Day Treatment Period | 
| Stage 1: Area under the plasma concentration versus time curve from time 0 to time of the last measurable concentration (AUC0-tlast) after a single dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Area under the tear concentration versus time curve from time 0 to time of the last measurable concentration (AUC0-tlast) after a single dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Maximum plasma drug concentration (Cmax) after a single dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Maximum tear drug concentration (Cmax) after a single dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Time of maximum plasma drug concentration (Tmax) after a single dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Time of maximum tear drug concentration(Tmax) after a single dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Terminal elimination half-life (t1/2) after a single dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Area under the plasma concentration versus time curve from time 0 to the end of the dosing interval (AUC0-τ) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Area under the tear concentration versus time curve from time 0 to the end of the dosing interval (AUC0-τ) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Maximum plasma drug concentration (Cmax) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Maximum tear drug concentration (Cmax) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Time of maximum plasma drug concentration (Tmax) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Time of maximum tear drug concentration (Tmax) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Minimum plasma drug concentration at steady state (Cmin,ss) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Minimum tear drug concentration at steady state (Cmin,ss) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Terminal elimination half-life of the study drugs (t1/2) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Accumulation index of drug concentration (AI) following repeat dose administration |  | Predose and up to 12 hours postdose | 
| Stage 1: Drop Tolerability Questionnaire Score | Rate of the acute overall tolerability attributes of study interventions on an 8-question visual analog scale (VAS) Drop Tolerability Questionnaire. Visual scale ranges from 0=not at all comfortable to 100=very comfortable. | 15 Day Treatment Period | 
| Stage 1: Number of patients experiencing one or more adverse events (AEs) during the 15 day treatment period |  | 15 Day Treatment Period | 
| Stage 1: Potentially clinically significant (PCS) clinical laboratory values | The percentage of participants who have PCS postbaseline clinical laboratory values | 15 Day Treatment Period | 
| Stage 1: Vital sign values (blood pressure, pulse rate, weight, respiration rate, and temperature) | The percentage of participants who have PCS postbaseline vital sign values | 15 Day Treatment Period | 
| Stage 1: Electrocardiogram (ECG) heart rate | The percentage of participants who have PCS postbaseline ECG | 15 Day Treatment Period | 
| Stage 1: ECG PR interval | The percentage of participants who have PCS postbaseline ECG | 15 Day Treatment Period | 
| Stage 1: ECG QRS duration | The percentage of participants who have PCS postbaseline ECG | 15 Day Treatment Period | 
| Stage 1: ECG QT interval | The percentage of participants who have PCS postbaseline ECG | 15 Day Treatment Period | 
| Stage 1: ECG QTc | The percentage of participants who have PCS postbaseline ECG | 15 Day Treatment Period | 
| Stage 1: Change from baseline in intraocular pressure (IOP) |  | 15 Day Treatment Period | 
| Stage 1: Change from baseline in best-corrected visual acuity (BCVA) |  | 15 Day Treatment Period | 
| Stage 1: Change from baseline in slit-lamp biomicroscopy |  | 15 Day Treatment Period | 
| Stage 1: Change from baseline in dilated fundus examination |  | 15 Day Treatment Period | 
| Stage 2: The incidence of adverse events (safety and tolerability) | The number of participants who experience one or more treatment emergent adverse events (TEAE) | 42 Day Treatment Period | 
| Stage 2: Potentially clinically significant (PCS) clinical laboratory values | The percentage of participants who have PCS postbaseline clinical laboratory values | 42 Day Treatment Period | 
| Stage 2: Vital sign values (blood pressure, pulse rate, weight, respiration rate, and temperature) | The percentage of participants who have PCS postbaseline vital sign values | 42 Day Treatment Period | 
| Stage 2: Number of patients experiencing one or more adverse events (AEs) during the 42 day treatment period |  | 42 Day Treatment Period | 
| Stage 2: Electrocardiogram (ECG) heart rate | The percentage of participants who have PCS postbaseline ECG | 42 Day Treatment Period | 
| Stage 2: ECG PR interval | The percentage of participants who have PCS postbaseline ECG | 42 Day Treatment Period | 
| Stage 2: ECG QRS duration | The percentage of participants who have PCS postbaseline ECG | 42 Day Treatment Period | 
| Stage 2: ECG QT interval | The percentage of participants who have PCS postbaseline ECG | 42 Day Treatment Period | 
| Stage 2: ECG QTc | The percentage of participants who have PCS postbaseline ECG | 42 Day Treatment Period | 
| Stage 2: Change from baseline in intraocular pressure (IOP) |  | 42 Day Treatment Period | 
| Stage 2: Change from baseline in best-corrected visual acuity (BCVA) |  | 42 Day Treatment Period | 
| Stage 2: Change from baseline in slit-lamp biomicroscopy |  | 42 Day Treatment Period | 
| Stage 2: Change from baseline in dilated fundus examination |  | 42 Day Treatment Period | 
| Stage 2: Drop Tolerability Questionnaire Score | Rate of the acute overall tolerability attributes of study interventions on an 8-question visual analog scale (VAS) Drop Tolerability Questionnaire. Visual scale ranges from 0=not at all comfortable to 100=very comfortable. | 42 Day Treatment Period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stage 2: Plasma exposure of AGN-242428 and AGN-231868 in participants with dry eye disease (DED) following twice daily dosing for up to 6 weeks | Plasma samples to determine concentrations will be collected at the nominal times | 42 Day Treatment Period | 
| Stage 2: Tear exposure of AGN-242428 and AGN-231868 in participants with dry eye disease (DED) following twice daily dosing for up to 6 weeks | Tear samples to determine concentrations will be collected at the nominal times | 42 Day Treatment Period | 
| Stage 2: Tear exposure of active comparator in participants with dry eye disease (DED) following twice daily dosing for up to 6 weeks | Tear samples to determine concentrations will be collected at the nominal times | 42 Day Treatment Period |