Randomized, Parallel Arm, Double-Masked, Placebo-Controlled Study of the Safety and Efficacy of 0.75% Phentolamine Ophthalmic Solution to Reverse Pharmacologically Induced Mydriasis in Healthy Pediatric Subjects

Molecule Phentolamine ophthalmic solution 0.75%
Therapeutic focus Reversal of pharmacologically-induced mydriasis
Phase 3
Status Completed
Participants 23
Completion Date April 28, 2022

https://clinicaltrials.gov/study/NCT05223478.

Trial Design1,2

*Stratification was 1:1 between 3–5 and 6–11 years old; †Mydriatic agent randomization: 3:1:1. A: 2.5% phenylephrine;2  B: 1% tropicamide;2  C: Paremyd®† (1% hydroxyamphetamine/0.25% tropicamide).3,4 †Paremyd is a registered trademark of Akorn, Inc.
h, hour; max, maximum; min, minute; POS, phentolamine ophthalmic solution; US, United States.
1. https://clinicaltrials.gov/study/NCT05223478; 2. MIRA-4 Ocuphire Pharma, Inc. Data on file; 3. RYZUMVI™ (phentolamine ophthalmic solution). Prescribing Information. Available at: https://www.ryzumvi.com/files/prescribing-information.pdf; 4. PAREMYD® (hydroxyamphetamine hydrobromide/ tropicamide ophthalmic solution). Prescribing Information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2001/19261s8lbl.pdf.

Inclusion Criteria

  • Males or premenstrual females 3 to 11 years of age
  • Ability to comply with all protocol-mandated procedures independently and to attend all scheduled office visits
  • Parent/legal guardian willing to give written informed consent to participate in this study. Children aged 7 to 11 years to provide signed assent form, as well as a separate parental/legal guardian consent
https://clinicaltrials.gov/study/NCT05223478.

Exclusion Criteria1,2

Ophthalmic:*

  • Clinically significant ocular disease as deemed by the Investigator (e.g., amblyopia, congenital cataract, congenital glaucoma) that might interfere with the study
  • Unwilling or unable to discontinue use of contact lenses at screening until study completion
  • Unwilling or unable to suspend use of topical medication at screening until study completion
  • Ocular trauma or ocular surgery within the 6 months prior to screening
  • Use of any topical prescription or over-the-counter (OTC) ophthalmic medications within 7 days of screening
  • Recent or current evidence of ocular infection or inflammation (such as current evidence of clinically significant blepharitis, conjunctivitis, or keratitis). Subjects must be symptom-free for at least 7 days prior to screening
  • Closed or very narrow-angle that in the Investigator's opinion is potentially occludable if the subject’s pupil is dilated
  • History of any traumatic (surgical or nonsurgical) or nontraumatic condition affecting the pupil or iris
  • Known allergy, hypersensitivity, or contraindication to any component of the phentolamine ophthalmic solution or to any component of the mydriatic agents or vehicle formulation
*In either eye.2
1. MIRA-4 Ocuphire Pharma, Inc. Data on file; 2. https://clinicaltrials.gov/study/NCT05223478.

Exclusion Criteria1,2

Systemic:

  • Known hypersensitivity or contraindication to alpha- and/or beta-adrenoceptor antagonists
  • Clinically significant systemic disease (e.g., uncontrolled diabetes, cancer, hepatic, renal, endocrine, or cardiovascular disorders) that in the opinion of the Investigator could interfere with the study
  • Subjects with learning disabilities that in the opinion of the Investigator could interfere with the study
  • Initiation of treatment with or any changes to the current dosage, drug, or regimen of any systemic adrenergic or cholinergic drugs within 7 days prior to screening or during the study
  • Participation in any investigational study within 30 days prior to screening
1. MIRA-4 Ocuphire Pharma, Inc. Data on file; 2. https://clinicaltrials.gov/study/NCT05223478.

Efficacy Endpoints

  • Percentage of subjects returning to ≤0.2 mm from baseline (-1 hour) photopic pupil diameter (PD) at 0 min, 90 min, 3 hours, and 24 hours1,2
  • Mean change in PD (mm) from maximum pupil dilation (0 min) at 90 min, 3 hours, and 24 hours1,2
  • Time (hours) to return to ≤0.2 mm from baseline (-1 hour) photopic PD (time-savings analysis)1,2
This study is primarily for safety and not powered to evaluate efficacy. In accordance with the Sponsor Pediatric Safety Plan for the indication of reversal of pharmacologically induced mydriasis, the sample size of 20 subjects is adequate to evaluate safety in the pediatric population.2
1. https://clinicaltrials.gov/study/NCT05223478; 2. MIRA-4 Ocuphire Pharma, Inc. Data on file.

Safety Endpoints

The primary safety measures were conjunctival hyperemia, impairment in visual acuity (BCDVA), vital signs (HR and BP), and AEs.

Safety analyses include:

  • Change from baseline (-1 hour) in conjunctival hyperemia grading (CCLRU images) at each time point (0 min, 90 min, 3 hours, and 24 hours) for the study eye and fellow eye
  • Change from baseline (-1 hour) in BCDVA at 0 min, 90 min, 3 hours, and 24 hours for the study eye and fellow eye
  • Change from baseline (-1 hour) in vital signs (HR and BP) at 3 hours and 24 hours
This study is primarily for safety and not powered to evaluate efficacy. In accordance with the Sponsor Pediatric Safety Plan for the indication of reversal of pharmacologically induced mydriasis, the sample size of 20 subjects is adequate to evaluate safety in the pediatric population.
AE, adverse event; BCDVA, best-corrected distance visual acuity; BP, blood pressure; CCLRU, Cornea and Contact Lens Research Unit; HR, heart rate.
MIRA-4 Ocuphire Pharma, Inc. Data on file.

Baseline Characteristics

*Data presented as mean (SD), unless otherwise specified;1,2 †For BCDVA, the number of letters read is from the 4-meter distance only, so that 55 letters read is equivalent to a Snellen acuity of 20/20.2 ‡Paremyd is a registered trademark of Akorn, Inc.
BCDVA, best-corrected distance visual acuity; PD, pupil diameter; POS, phentolamine ophthalmic solution; SD, standard deviation.
1. https://clinicaltrials.gov/study/NCT05223478; 2. MIRA-4 Ocuphire Pharma, Inc. Data on file.

Efficacy Outcome Measures – Secondary Endpoints

*The mITT population included all randomized subjects who received 1 drop of study medication in the study eye and then had at least 1 scheduled post-treatment PD measurement during visit 1 in the study eye.2
mITT, modified intention-to-treat; PD, pupil diameter; POS, phentolamine ophthalmic solution.
1. https://clinicaltrials.gov/study/NCT05223478; 2. MIRA-4 Ocuphire Pharma, Inc. Data on file.

Efficacy Outcome Measures – Secondary Endpoints

The mITT population included all randomized subjects who received 1 drop of study medication in the study eye and then had at least 1 scheduled post-treatment PD measurement during visit 1 in the study eye.2
mITT, modified Intention-to-Treat; PD, pupil diameter; POS, phentolamine ophthalmic solution; SD, standard deviation.
1. https://clinicaltrials.gov/study/NCT05223478; 2. MIRA-4 Ocuphire Pharma, Inc. Data on file.

Efficacy Outcome Measures – Secondary Endpoints

The mITT population included all randomized subjects who received 1 drop of study medication in the study eye and then had at least 1 scheduled post-treatment PD measurement during visit 1 in the study eye.
mITT, modified Intention-to-Treat; PD, pupil diameter; POS, phentolamine ophthalmic solution; SD, standard deviation.
MIRA-4 Ocuphire Pharma, Inc. Data on file.

Efficacy Outcome Measures – Secondary Endpoints

The mITT population included all randomized subjects who received 1 drop of study medication in the study eye and then had at least 1 scheduled post-treatment PD measurement during visit 1 in the study eye.2
mITT, modified Intention-to-Treat; PD, pupil diameter; POS, phentolamine ophthalmic solution; SD, standard deviation.
1. https://clinicaltrials.gov/study/NCT05223478; 2. MIRA-4 Ocuphire Pharma, Inc. Data on file.

Safety Outcome Measures – Primary Endpoint

  • At baseline (-1 hr), mean (SD) conjunctival hyperemia score was 0.4 (0.50) in study eyes treated with 0.75% POS and 0.8 (0.39) in study eyes treated with placebo2
*Graded with a CCLRU card 4-point grading scale. The safety population included all randomized subjects who received at least 1 drop of study medication.2
CCLRU, Cornea and Contact Lens Research Unit; NS, not significant; POS, phentolamine ophthalmic solution; SD, standard deviation.
1. https://clinicaltrials.gov/study/NCT05223478 ; 2. MIRA-4 Ocuphire Pharma, Inc. Data on file.

Safety Outcome Measures – Primary Endpoint

*Graded with a CCLRU card 4-point grading scale: None (0) = Normal. Appears white with a small number of conjunctival blood vessels easily observed; Mild (+1) = Prominent, pinkish-red color of both the bulbar and palpebral conjunctiva; Moderate (+2) = Bright, scarlet-red color of the bulbar and palpebral conjunctiva; Severe (+3) = Beefy-red with petechiae, dark red bulbar and palpebral conjunctiva with evidence of subconjunctival hemorrhage. The safety population included all randomized subjects who received at least 1 drop of study medication.
CCLRU, Cornea and Contact Lens Research Unit; POS, phentolamine ophthalmic solution.
MIRA-4 Ocuphire Pharma, Inc. Data on file.

Safety Outcome Measures – Primary Endpoint

Change from baseline (-1 hour) in BCDVA and vital signs2

  • BCDVA: One study eye in the POS 0.75% group lost ≥5 letters in BCDVA at 0 min; no other study eyes lost ≥5 letters in either treatment group at any time point
  • Vital signs: Mean SBP, DBP, and HR were relatively unchanged, remained within normal limits throughout the duration of the study, and were similar between treatment groups
*Data presented as n (%).1
AE, adverse event; BCDVA, best-corrected distance visual acuity; DBP, diastolic blood pressure; HR, heart rate; POS, phentolamine ophthalmic solution; SAE, serious adverse event​; SBP, systolic blood pressure.
1. https://clinicaltrials.gov/study/NCT05223478; 2. MIRA-4 Ocuphire Pharma, Inc. Data on file.