Evaluation of the Safety and Pharmacokinetics of Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Combination Ophthalmic Solution

A Multi-Center, Double-Masked, Randomized, Vehicle-Controlled, Parallel-Group Study Evaluating the Safety and Pharmacokinetics of Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Combination Ophthalmic Solution, Used Two Times Daily in Healthy Adult Subjects and in Pediatric Subjects With a History or Family History of Atopic Disease (Including Allergic Conjunctivitis)

To compare the safety and tolerability of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% combination ophthalmic solution versus its vehicle in healthy adult subjects and in pediatric subjects.

Study Overview

• Status: Completed
• Conditions: Allergic Conjunctivitis
• Intervention / Treatment: Drug: Vehicle of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% ophthalmic solution; Drug: Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Ophthalmic Solution (Combo)

Detailed Description

The study will consist of 4-5 study visits to compare the safety and tolerability of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% combination ophthalmic solution versus its vehicle in healthy adult subjects and in pediatric subjects with a history or family history of atopic disease (including allergic conjunctivitis).

To characterize the plasma pharmacokinetics (PK) of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% combination ophthalmic solution following a single dose and 22-day twice daily (BID) topical ocular dosing in a subset of healthy adult subjects.

• Study Type: Interventional
• Enrollment (Actual): 512
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Chandler, Arizona, United States, 85225
      • 104- Arizona Eye Center
  • Maryland
    • Havre De Grace, Maryland, United States, 21078
      • 103- Seidenberg Protzko Eye Associates
  • Massachusetts
    • Andover, Massachusetts, United States, 01810
      • 101 - Andover Eye Associates
  • North Carolina
    • Apex, North Carolina, United States, 27502
      • 105- NC Eye Associates
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • 107 Total Eye Care, PA
  • Virginia
    • Falls Church, Virginia, United States, 22046
      • 106- Emerson Research Institute, Inc.
    • Lynchburg, Virginia, United States, 24502
      • 102 - Piedement Eye Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Study Population

Approximately 600 subjects will be screened in order to enroll approximately 501 subjects from approximately 6 sites in the United States. Of the subject total, approximately 100 pediatric subjects are anticipated to be enrolled into this study.

Description

Inclusion Criteria:

1. be at least 5 years of age at Screening Visit or Visit 1 (if Screening and Visit 1 are done on the same day), of either sex and any race (a government issued ID and/or birth certificate will be verified at the time ICF is signed);
2. provide written informed consent and sign the the Health Insurance Portability and Accountability Act (HIPAA) form. Subjects who are at least 7 years of age and less than 18 years of age will need to sign an assent form. In addition, all subjects below the age of 18 years will be required to have both parents or legal guardian sign the informed consent.
3. be willing and able to follow all instructions and attend all study visits (and be accompanied by a parent/legal guardian if the subject is under the age of 18);
4. be able to self-administer eye drops satisfactorily or have a caregiver or parent/legal guardian (if applicable, for subjects less than 18 years of age) at home1 routinely available for this purpose.
5. for subjects less than 18 years of age, have either a history or family history of atopic disease (such as atopic dermatitis, asthma, allergic conjunctivitis/rhinitis, and atopic keratoconjunctivitis).
6. (if female and of childbearing potential) agree to have urine pregnancy testing performed at Visit 1 (must be negative) and at exit visit 2; must not be lactating; and must agree to use at least 1 medically acceptable form of birth control throughout the study duration and for at least 14 days prior to Visit 1 and 1 month after discontinuing investigational product. Acceptable forms of birth control are true abstinence (when this is in line with the preferred and usual lifestyle of the subject), spermicide with barrier, oral contraceptive, injectable or implantable method of contraception, transdermal contraceptive, intrauterine device, or surgical sterilization of male partner at least 3 months prior to the first dose of investigational drug (Visit 1). Note: Women considered capable of becoming pregnant include all females who have experienced menarche and have not experienced menopause (as defined by amenorrhea for greater than 12 consecutive months) or have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy).
7. (if male and with female partner of childbearing potential) must use at least 1 medically acceptable form of birth control. Note: Acceptable forms of birth control are true abstinence (when this is in line with the preferred and usual lifestyle of the subject) or vasectomy at least 3 months prior to receiving investigational product (Visit 1). Without a vasectomy, must use condoms with spermicidal foam/gel/film/cream/suppository throughout the study duration, for at least 14 days prior to and 1 month after discontinuing investigational product;
8. have ocular health within normal limits, including a calculated visual acuity of 0.3 logMAR or better in each eye as measured using an ETDRS chart. For subjects under 10 years old who are developmentally unable to use the ETDRS chart, a best attempt at visual acuity will be made using the LEA symbols or Visual Behavior. For subjects utilizing LEA symbols, Snellen equivalent units of 20/63 or better in both eyes will be required. Subjects utilizing Visual Behavior must have a passing score;
9. (for selected healthy adult subjects agreeing to undergo PK blood draws) have a body mass index (BMI) ≥18 and ≤34 lbs/in2 and a minimum body weight of 99 lbs;
10. (for selected healthy adult subjects agreeing to undergo PK blood draws) have suitable venous access for blood sampling.

Exclusion Criteria:

1. have known contraindications or sensitivities to the use of any of the investigational product medication or components;
2. have had ocular surgical intervention within 3 months prior to Visit 1 or during the study and/or a history of refractive surgery within the past 6 months;
3. have a known history of retinal detachment, diabetic retinopathy, or active retinal disease;
4. have the presence of an active ocular infection (bacterial, viral or fungal) or positive history of an ocular herpetic infection at any visit;
5. use any of the following disallowed medications during the period indicated prior to Visit 1 and during the study:

5 days

• artificial tear products, eye whiteners (e.g., vasoconstrictors), ocular decongestants, ocular corticosteroids, ocular antihistamines, and any other topical ophthalmic agents;

  14 days

• any systemic medications which the investigator feels may confound study data or interfere with subject's study participation;

  6. have used contact lenses within 24 hours prior to each visit (Visit 1, 2, 3, and 4);

  7. have prior (within 7 days of beginning IP) or currently active significant illness that could compromise participation, in the opinion of the investigator;

  8. have prior (within 30 days of beginning investigational product) or anticipated concurrent use of an investigational product or device during the study period;

  9. have been randomized in study 909 or 910 conducted by Bausch & Lomb;

  10. be an employee or family member of employee at the investigative site;

  11. have an ocular or systemic condition or is in a situation that the investigator feels may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's study participation;

  12. have planned surgery (ocular or systemic) during the trial period or within 30 days after;

  13. have body weight below the 5th percentile for their age (subjects 12 years of age or younger only) (see Appendix 2);

  14. be a female who is currently pregnant, is planning a pregnancy, or lactating;

  15. have an abnormal blood pressure (defined as ≤ 90 or ≥ 160 (systolic) measured in mmHg or ≤ 60 or ≥ 100 (diastolic) measured in mmHg). For pediatric subjects, abnormal blood pressure is defined as ≥ 140 (systolic) measured in mmHg or ≥ 90 (diastolic) measured in mmHg;

  16. have an intraocular pressure (IOP) that is less than 5 mmHg or greater than 22 mmHg or have a normal IOP with a prior diagnosis/history of glaucoma at Visit 1;

  17. have symptoms associated with COVID-19 or have been in contact with someone diagnosed with COVID-19 within 14 days of the Screening Visit or Visit 1 (if Screening and Visit 1 are done on the same day);

  18. (for selected healthy adult subjects agreeing to undergo PK blood draws) have excessive consumption of caffeine- or xanthine-containing beverages (more than 4 cups or servings per day) within 48 hours prior to dosing at Visit 1 or for the duration of the study (see Appendix 6);

  19. (for selected healthy adult subjects agreeing to undergo PK blood draws) have a history of tobacco, nicotine, or nicotine-containing product use within 12 months prior to Visit 1;

  20. (for selected healthy adult subjects agreeing to undergo PK blood draws) have a history or current evidence of drug or alcohol abuse within 12 months prior to Visit 1;

  21. (for selected healthy adult subjects agreeing to undergo PK blood draws) have blood donation or equivalent blood loss of >450 mL within 60 days prior to Visit 1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brimonidine tartrate 0.025%/ketotifen fumarate 0.035% combination ophthalmic solution	Drug: Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Ophthalmic Solution (Combo); Brimonidine Tartrate 0.025%/Ketotifen Fumarate 0.035% Ophthalmic Solution (Combo)
Active Comparator: Vehicle ophthalmic solution	Drug: Vehicle of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% ophthalmic solution; Vehicle of brimonidine tartrate 0.025%/ketotifen fumarate 0.035% ophthalmic solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	TEAE is defined as any untoward medical occurrence or undesirable event(s) that begins or worsens following administration of the study drug, whether or not considered related to the treatment by the Investigator. A TEAE is considered serious if, in the view of the Investigator or Sponsor, it results in any of the following outcomes: death, a life-threatening TEAE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, an important medical event that jeopardized the participant and required medical intervention, or sight-threatening (possibly resulting in persistent or significant loss of vision)	Baseline up to Day 42

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drop Comfort Assessment as Assessed by the Participant	Drop comfort assessment (0-10 unit scale in which a score of 0 denotes "very comfortable" and 10 is "very uncomfortable") was performed by the participantsubjects ≥ 10 years of age	At dose installation, 30 seconds post dose installation, and 1-minute post dose installation on Day 1, Day 8 and Day 22
Plasma Concentration: Brimonidine	Blood samples will be collected to measure the concentration of brimonidine. Concentration values reported below the limit of quantification (BLQ) before the first quantifiable concentration or after the last quantifiable concentration were set to zero for concentration descriptive statistics.	Pre-Instillation and 15 min, 30 min, 1 hr, 2hr and 4hrs post-instillation on Day 1 and on Day 22.
Plasma Concentration: Ketotifen	Blood samples will be collected to measure the concentration of ketotifen. Concentration values reported below the quantification limit (BLQ) before the first quantifiable concentration or after the last quantifiable concentration were set to zero for concentration descriptive statistics.	Pre-Instillation and 15 min, 30 min, 1 hr, 2hr and 4hrs post-instillation on Day 1 and on Day 22.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Pharmacokinetics	Blood samples will be collected to measure the concentration of brimonidine and ketotifen In plasma at pre- and post-dose time points on Day 1 and on Day 22.	Day 1 and Day 22

Collaborators and Investigators

• Sponsor: Bausch & Lomb Incorporated

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2023
• Primary Completion (Actual): September 18, 2023
• Study Completion (Actual): September 18, 2023

Study Registration Dates

• First Submitted: March 21, 2023
• First Submitted That Met QC Criteria: April 4, 2023
• First Posted (Actual): April 18, 2023

Study Record Updates

• Last Update Posted (Actual): July 10, 2025
• Last Update Submitted That Met QC Criteria: June 20, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Eye Diseases; Hypersensitivity, Immediate; Hypersensitivity; Conjunctival Diseases; Conjunctivitis; Conjunctivitis, Allergic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Dermatologic Agents; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Anti-Allergic Agents; Antipruritics; Antihypertensive Agents; Histamine H1 Antagonists; Brimonidine Tartrate; Pharmaceutical Solutions; Ophthalmic Solutions; Ketotifen
• Other Study ID Numbers: 913

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No