A Phase 1, Double-Masked, Vehicle-Controlled Study to Assess Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of Palovarotene Ophthalmic Solution in Healthy Adult Subjects
Overview
- Phase
- Phase 1
- Intervention
- Palovarotene
- Conditions
- Dry Eye Disease
- Sponsor
- Clementia Pharmaceuticals Inc.
- Enrollment
- 48
- Locations
- 1
- Primary Endpoint
- Number and severity of treatment-emergent ocular adverse events (TEAEs)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
Dry eye disease (DED) is a keratoconjunctive disorder that "is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. The goal of this study is to assess the safety, tolerability, and pharmacokinetics (PK) of multiple ascending doses of palovarotene ophthalmic solution in healthy adult subjects.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Healthy, adult, male or female, 18 to 55 years of age, inclusive, at screening.
- •Continuous non-smoker who had not used nicotine containing products for at least 3 months prior to the first dosing and throughout the study, based on subject self-reporting.
- •Body mass index (BMI) ≥18.0 and ≤32.0 kg/m2 at screening.
- •Medically healthy as deemed by the Investigator or delegate and determined by medical history, physical examination, vital signs, 12-lead ECGs, and clinical laboratory results obtained within 28 days before the start of the study.
- •Tolerate topical administration to the eye.
- •Best corrected visual acuity is equal or better than 70 Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in both eyes.
Exclusion Criteria
- •Mentally or legally incapacitated or had significant emotional problems at the time of the screening visit or expected during the conduct of the study.
- •History or presence of clinically significant medical (systemic or ophthalmic) or psychiatric condition or disease in the opinion of the Investigator or delegate.
- •History of any illness that, in the opinion of the Investigator or delegate, might have confounded the results of the study or posed an additional risk to the subject by their participation in the study.
- •History or presence of alcoholism or drug abuse within the past 18 months prior to the first dosing.
- •History or presence of hypersensitivity or idiosyncratic reaction to the study drug, systemic retinoids such as isotretinoin or related compounds (e.g., topical tretinoins, vitamin A), fluorescein, or parabens or to the inactive ingredients in the study formulation.
- •History of any ocular surgery or laser within the past 6 months prior to screening.
- •History of herpes simplex keratitis.
- •History or presence of:
- •Any chronic eye disease other than refractive error, incipient cataract, strabismic amblyopia, or anisometropic amblyopia.
- •Acute eye disease (such as infection, corneal abrasion, or allergy) within the past 6 months from screening.
Arms & Interventions
Dose 1
Subjects were randomized in a 3:1 ratio to receive one dose regimen of either active treatment or placebo (vehicle). Advancement of the study from the once daily (QD) dosing regimen to the twice daily (BID) dosing regimen, and dose escalation to the next dose regimen
Intervention: Palovarotene
Dose 1
Subjects were randomized in a 3:1 ratio to receive one dose regimen of either active treatment or placebo (vehicle). Advancement of the study from the once daily (QD) dosing regimen to the twice daily (BID) dosing regimen, and dose escalation to the next dose regimen
Intervention: Vehicle
Dose 3
Subjects were randomized in a 3:1 ratio to receive one dose regimen of either active treatment or placebo (vehicle). Advancement of the study from the once daily (QD) dosing regimen to the twice daily (BID) dosing regimen, and dose escalation to the next dose regimen
Intervention: Palovarotene
Dose 2
Subjects were randomized in a 3:1 ratio to receive one dose regimen of either active treatment or placebo (vehicle). Advancement of the study from the once daily (QD) dosing regimen to the twice daily (BID) dosing regimen, and dose escalation to the next dose regimen
Intervention: Palovarotene
Dose 2
Subjects were randomized in a 3:1 ratio to receive one dose regimen of either active treatment or placebo (vehicle). Advancement of the study from the once daily (QD) dosing regimen to the twice daily (BID) dosing regimen, and dose escalation to the next dose regimen
Intervention: Vehicle
Dose 3
Subjects were randomized in a 3:1 ratio to receive one dose regimen of either active treatment or placebo (vehicle). Advancement of the study from the once daily (QD) dosing regimen to the twice daily (BID) dosing regimen, and dose escalation to the next dose regimen
Intervention: Vehicle
Outcomes
Primary Outcomes
Number and severity of treatment-emergent ocular adverse events (TEAEs)
Time Frame: from baseline until the end of study (up to 25 days)
Change in Corneal Fluorescein Staining
Time Frame: from baseline until the end of study (up to 25 days)
Change in intraocular pressure
Time Frame: from baseline until the end of study (up to 25 days)
Change in ocular safety measurements as determined by Best-Corrected Visual Acuity (BCVA)
Time Frame: from baseline until the end of study (up to 25 days)
Secondary Outcomes
- Average concentration at steady state (Cavg)(Day 7 and Day 10)
- Time to reach Cmax at steady state (Tmax)(Day 7 and Day 10)
- Apparent first-order terminal elimination half-life (t½)(Day 7 and Day 10)
- Plasma concentration (predose) observed at the end of a dosing interval (Ctrough)(Day 5 and Day 6 (prior to the morning), Day 7 ((prior to the morning), Day 8, Day 9, Day 10)
- Area under the concentration-time curve during a dosing interval (AUCtau)(Day 7 and Day 10)
- Area under the concentration-time curve, from time 0 to the last observed non-zero concentration (AUC0-t)(Day 10)
- Maximum observed concentration at steady state (Cmax,ss)(Day 7 and Day 10)
- Apparent total plasma clearance after topical administration (CL/F)(Day 7 and Day 10)
- Apparent first-order terminal elimination rate (k el)(Day 7 and Day 10)
- Apparent volume of distribution (Vss/F)(Day 7 and Day 10)