A Study of the Drugs AGN-242428 and AGN-231868 in Participants With Dry Eye Disease
- Conditions
- Dry Eye SyndromeDry Eye Disease
- Interventions
- Other: AGN-242428 VehicleOther: AGN-231868 Vehicle
- Registration Number
- NCT04030962
- Lead Sponsor
- AbbVie
- Brief Summary
This was a 2-stage study in which Stage 1 evaluated 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 began. Stage 2 also evaluated the safety and tolerability of AGN-242428 and AGN-231868, how effective they are in treating dry eye disease (DED), and assessed the plasma and tear exposure of both ophthalmic solutions.
- Detailed Description
Participants with DED in Cohort 1A were randomized 3:3:1:1 to receive AGN-242428 (Low Dose), AGN-231868 (Low Dose), or their respective vehicles (4 treatment groups total) to the left eye on Day 1 (Visit 2). If there were no significant study drug-related safety findings, starting on Day 2, participants administered the same randomized study drug twice daily to both eyes through Day 14, followed by a single dose administration to both eyes on Day 15 (Visit 5).
Upon completion of Cohort 1A, an independent data monitoring committee reviewed the data before proceeding to the next cohort. Cohort 1B participants were randomized 3:3:1:1 to receive AGN-242428 (High Dose), AGN-231868 (High Dose), or their respective vehicles (4 treatment groups total) and followed the same dosing regimen used in Cohort 1A.
All subjects enrolled in Stage 2 had DED. In addition, subjects were selected based on their response to a controlled adverse environment (CAE). Only subjects with DED who responded to the CAE exposure with an increase in the signs and symptoms of DED were enrolled in Stage 2.
During Stage 2, participants were randomized in a 1:1:1:1:1 ratio (within each site), to receive AGN-242428 (High Dose), AGN-242428 vehicle, AGN-231868 (High Dose), AGN-231868 vehicle, or Lifitegrast Ophthalmic Solution (Xiidra). Participants administered the assigned study drug in each eye twice daily for 41 days, followed by a single administration during the morning on Day 42.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 292
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).
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Stage 1 Cohort 1A: AGN-242428 Low Dose AGN-242428 Administration of AGN-242428 ophthalmic solution Stage 1 Cohort 1A: AGN-242428 Vehicle AGN-242428 Vehicle Administration of matching placebo (vehicle) ophthalmic solution Stage 1 Cohort 1A: AGN-231868 Lose Dose AGN-231868 Administration of AGN-231868 ophthalmic solution Stage 1 Cohort 1A: AGN-231868 Vehicle AGN-231868 Vehicle Administration of matching placebo (vehicle) ophthalmic solution Stage 1 Cohort 1B: AGN-242428 High Dose AGN-242428 Administration of AGN-242428 ophthalmic solution Stage 1 Cohort 1B: AGN-242428 Vehicle AGN-242428 Vehicle Administration of matching placebo (vehicle) ophthalmic solution Stage 1 Cohort 1B: AGN-231868 High Dose AGN-231868 Administration of AGN-231868 ophthalmic solution Stage 1 Cohort 1B: AGN-231868 Vehicle AGN-231868 Vehicle Administration of matching placebo (vehicle) ophthalmic solution Stage 2 Cohort 2: AGN-242428 High Dose AGN-242428 Administration of AGN-242428 ophthalmic solution Stage 2 Cohort 2: AGN-242428 Vehicle AGN-242428 Vehicle Administration of matching placebo (vehicle) ophthalmic solution Stage 2 Cohort 2: AGN-231868 High Dose AGN-231868 Administration of AGN-231868 ophthalmic solution Stage 2 Cohort 2: AGN-231868 Vehicle AGN-231868 Vehicle Administration of matching placebo (vehicle) ophthalmic solution Stage 2 Cohort 2: Lifitegrast Ophthalmic Solution Lifitegrast 5% Ophthalmic Solution Administration of Lifitegrast ophthalmic solution
- Primary Outcome Measures
Name Time Method Stage 2: Number of Participants With Adverse Events Day 1 to Day 42 An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment.
Stage 2: Percentage of Participants With Potentially Clinically Significant (PCS) Clinical Laboratory Values Day 42 The percentage of participants who have PCS postbaseline clinical laboratory values at Day 42 (Visit 6).
Stage 2: Percentage of Participants Who Met Criteria for PCS Vital Sign Values (Blood Pressure, Pulse Rate, Weight, Respiration Rate, and Temperature) Day 42 The percentage of participants who met PCS criteria at least once postbaseline for vital sign values at Day 42 (Visit 6) (sitting systolic and diastolic blood pressure, pulse rate, weight, respiration rate, and temperature). The numerator for the incidence is the number of participants with non-PCS baseline and at least one post-baseline value meeting the specific criterion at the visit. The denominator is the number of participants with non-PCS baseline and at least one post-baseline assessment at the visit. If a participant did not have a baseline value, but met the criterion post-baseline, then the participant is counted in the numerator.
Stage 1: Number of Participants With Adverse Events Day 1 to Day 15 An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment.
Stage 1: Maximum Tear Drug Concentration (Cmax) After Single and Repeat Dose Administration Day 2 and Day 15 (Predose and up to 12 hours postdose) Following single dose administration, the tear Cmax (Visit 3) was calculated. Following repeat dose administration twice daily for 14 days, the tear Cmax (Visit 5) was calculated.
Stage 1: Area Under the Plasma Concentration Versus Time Curves After Single and Repeat Dose Administration Day 2 and Day 15 (Predose and up to 12 hours postdose) Following single dose administration, the area under the plasma concentration versus time curves from time 0 to time of the last measurable concentration (AUC0-tlast; Visit 3) was calculated. Following repeat dose administration twice daily for 14 days, the area under the plasma concentration versus time curves from time 0 to the end of the dosing interval (AUC0-τ; Visit 5) was calculated. For Visit 3 and Visit 5, tlast was 12 hours post-dose.
Stage 1: Area Under the Tear Concentration Versus Time Curves After Single and Repeat Dose Administration Day 2 and Day 15 (Predose and up to 12 hours postdose) Following single dose administration, the area under the tear concentration versus (vs) time curves from time 0 to time of the last measurable concentration (AUC0-tlast; Visit 3) was calculated. Following repeat dose administration twice daily for 14 days, the area under the tear concentration versus time curves from time 0 to the end of the dosing interval (AUC0-τ; Visit 5) was calculated. For Visit 3 and Visit 5, tlast was 12 hours post-dose.
Stage 1: Terminal Elimination Half-life of the Study Drugs (T1/2) in Plasma After Single Dose Administration Day 2 (Predose and up to 12 hours postdose). Following single dose administration, the plasma T1/2 (Day 2; Visit 3) was calculated.
Stage 1: Terminal Elimination Half-life of the Study Drugs (T1/2) in Plasma After Repeat Dose Administration Day 15 (Predose and up to 12 hours postdose) Following repeat dose administration twice daily for 14 days, plasma T1/2 (Day 15; Visit 5) was calculated.
Stage 1: Maximum Plasma Drug Concentration (Cmax) After Single and Repeat Dose Administration Day 2 and Day 15 (Predose and up to 12 hours postdose) Following single dose administration, the plasma Cmax (Visit 3) was calculated. Following repeat dose administration twice daily for 14 days, the plasma Cmax (Visit 5) was calculated.
Stage 1: Time of Maximum Plasma Drug Concentration (Tmax) After Single and Repeat Dose Administration Day 2 and Day 15 (Predose and up to 12 hours postdose) Following single dose administration, the plasma Tmax (Visit 3) was calculated. Following repeat dose administration twice daily for 14 days, the plasma Tmax (Visit 5) was calculated.
Stage 1: Time of Maximum Tear Drug Concentration (Tmax) After Single and Repeat Dose Administration Day 2 and Day 15 (Predose and up to 12 hours postdose) Following single dose administration, the tear Tmax (Visit 3) was calculated. Following repeat dose administration twice daily for 14 days, the tear Tmax (Visit 5) was calculated.
Stage 1: Terminal Elimination Half-life of the Study Drugs (T1/2) in Tear After Single and Repeat Dose Administration Day 2 and Day 15 (Predose and up to 12 hours postdose) Following single dose administration, the tear T1/2 (Visit 3) was calculated. Following repeat dose administration twice daily for 14 days, tear T1/2 (Visit 5) was calculated.
Stage 1: Minimum Plasma Drug Concentration at Steady State (Cmin,ss) After Repeat Dose Administration Day 15 (Predose and up to 12 hours postdose) Following repeat dose administration twice daily for 14 days, the plasma Cmin,ss (Visit 5) was calculated.
Stage 1: Mean Accumulation Index of Drug Concentration (AI) After Repeat Dose Administration Day 15 (up to 12 hours) / Day 1 (up to 12 hours) Following repeat dose administration, the mean plasma and tear AI(area under curve \[AUC\]) was calculated. AI(AUC) is reported as the ratio of exposure (AUC) at steady state (Day 15) to the exposure after a single daily dose (Day 1). Values greater than one are indicative of drug accumulation with repeat dosing.
Stage 1: Mean Drop Tolerability Questionnaire Scores Day 15 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. Higher mean scores indicate higher levels of comfort with the assigned intervention.
Stage 1: Percentage of Participants Who Met Criteria for Potentially Clinically Significant (PCS) Clinical Laboratory Values Day 1 to Day 15 The percentage of participants with non-PCS baseline value and met PCS criterion at least once postbaseline for clinical laboratory values.
Stage 1: Minimum Tear Drug Concentration at Steady State (Cmin,ss) After Repeat Dose Administration Day 15 (Predose and up to 12 hours postdose) Following repeat dose administration twice daily for 14 days, the tear Cmin,ss (Visit 5) was calculated.
Stage 1: Percentage of Participants Who Met Criteria for PCS Vital Sign Values (Blood Pressure, Pulse Rate, Weight, Respiration Rate, and Temperature) Day 1 to Day 15 The percentage of participants who met PCS criteria at least once postbaseline for vital sign values (sitting systolic and diastolic blood pressure, pulse rate, weight, respiration rate, and temperature)
Stage 1: Percentage of Participants Who Met Criteria for PCS Electrocardiogram (ECG) Values Day 1 to Day 15 The percentage of participants with PCS postbaseline (but not at baseline) ECG values for QRS interval, PR interval, and QTc (Fridericia)
Stage 1: Mean Change From Baseline in Intraocular Pressure (IOP) Day 1 to Day 15 At least 2 measurements were taken by qualified study site personnel using a Goldmann applanation tonometer affixed to a slit lamp with the participant seated.
Stage 1: Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) Day 1 to Day 15 BCVA was quantified using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity protocol.
Stage 1: Biomicroscopy: Percentage of Participants With Any Severity Increase From Baseline Day 1 to Day 15 The number of participants with any ophthalmoscopy findings of any severity increase from baseline at one or more visit.
Stage 1: Percentage of Participants With Any Clinically Significant Postbaseline Findings During Dilated Fundus Examination Day 1 to Day 15 The fundus (posterior pole; periphery, when dilated) was evaluated for pathology. Ophthalmoscopy with clinically significant findings (per investigator assessment) postbaseline are reported.
Stage 2: Percentage of Participants Who Met Criteria for PCS Electrocardiogram (ECG) Values Day 42 The percentage of participants who have PCS ECG at Visit 6 (but not baseline) pre and post-controlled adverse environment (CAE). The numerator for the incidence is the number of participants with non-PCS baseline and at least one post-baseline value meeting the specific criterion at the visit. The denominator is the number of participants with non-PCS baseline and at least one post-baseline assessment at the visit. If a participant did not have a baseline value, but met the criterion post-baseline, then the participant is counted in the numerator.
Stage 2: Mean Change From Baseline in Intraocular Pressure (IOP) Day 1, Day 42 At least 2 IOP measurements were taken by qualified study site personnel using a Goldmann applanation tonometer affixed to a slit lamp with the participant seated. Average intraocular pressure = mean of the 2 (or 3) measures in the study eye and non-study eye. Total fluorescein scores and Schirmer values were used to determine the study eye, and if both eyes qualified, the right eye was designated by default.
Stage 2: Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) Day 1, Day 42 BCVA was quantified using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity protocol in the study eye and the non-study eye. Total fluorescein scores and Schirmer values were used to determine the study eye, and if both eyes qualified, the right eye was designated by default.
Stage 2: Slit-lamp Biomicroscopy: Percentage of Participants With Any Clinically Significant Finding Postbaseline Day 1 to Day 42 Percentage of participants with a clinically significant finding postbaseline, post-CAE. A clinically significant finding is defined as more than one severity grade increase (worsening) from baseline or positive status change from absence at baseline to presence at postbaseline (not associated with a severity grade) in one or both eyes.
Stage 2: Percentage of Participants With Any Clinically Significant Postbaseline Findings During Dilated Fundus Examination Day 1 to Day 42 The fundus (posterior pole; periphery, when dilated) was evaluated for pathology. Ophthalmoscopy with clinically significant findings (per investigator assessment) postbaseline are reported.
Stage 2: Drop Tolerability Questionnaire Score (Post-controlled Adverse Environment) Day 42 (Post-CAE) Acute overall tolerability attributes of study interventions on an 8-question visual analog scale (VAS) Drop Tolerability Questionnaire. Participants completed questionnaires after exposure to a controlled adverse environment (CAE) for approximately 90 minutes. Visual scale ranges from 0 = not at all comfortable to 100 = very comfortable. Higher mean scores indicate higher levels of comfort with the assigned intervention.
- Secondary Outcome Measures
Name Time Method Stage 2: Trough Plasma Concentration (Ctrough) and Plasma Concentration at 0.5 Hours Postdose (C0.5h) Day 42 Trough plasma concentration (Ctrough) and plasma concentration at 0.5 hours postdose (C0.5h), following twice daily dosing for up to 6 weeks
Stage 2: Trough Tear Concentration (Ctrough) and Tear Concentration at 0.5 Hours Postdose (C0.5h) Day 42 Trough tear concentration (Ctrough) and tear concentration at 0.5 hours postdose (C0.5h), following twice daily dosing for up to 6 weeks
Trial Locations
- Locations (11)
Duplicate_Alpine Research Organization, Inc. /ID# 240508
🇺🇸Clinton, Utah, United States
Cornea and Cataract Consultants of Arizona /ID# 232769
🇺🇸Phoenix, Arizona, United States
The Eye Research Foundation /ID# 232696
🇺🇸Newport Beach, California, United States
Vision Institute Central /ID# 239910
🇺🇸Colorado Springs, Colorado, United States
The Eye Care Institute /ID# 232683
🇺🇸Louisville, Kentucky, United States
Andover Eye Associates /ID# 232689
🇺🇸Andover, Massachusetts, United States
Vita Eye Clinic /ID# 232721
🇺🇸Shelby, North Carolina, United States
Scott and Christie and Associates /ID# 232746
🇺🇸Cranberry Township, Pennsylvania, United States
Total Eye Care, PA /ID# 232657
🇺🇸Memphis, Tennessee, United States
Advancing Vision Research /ID# 232660
🇺🇸Smyrna, Tennessee, United States
Piedmont Eye Center /ID# 232698
🇺🇸Lynchburg, Virginia, United States