Non-Inferiority Trial of Brimonidine Tartrate/Timolol Maleate Eye Drops Versus Combigan in Open-Angle Glaucoma or Ocular Hypertension Patients

The primary objective of this clinical trial is to confirm the **non-inferiority** of a fixed-combination generic formulation of **Brimonidine 0.2%/Timolol 0.5%** eye drops, solution in single-dose containers, compared to the marketed preservative-containing Combigan® eye drops, solution. This comparison is conducted in patients with **open angle glaucoma** or **ocular hypertension** (intraocular pressure ≥22 mmHg). The clinical relevance of this objective lies in evaluating the change in intraocular pressure (IOP) at 08:00 from the end of the study to baseline, which is crucial for determining the efficacy and tolerability of the new formulation in managing these conditions.

The clinical trial involves participants diagnosed with **open angle glaucoma** or ocular hypertension, characterized by increased intraocular pressure. The study population includes both male and female subjects, aged 18 years and older, of any race. Participants are required to have an average intraocular pressure of 22 mmHg to 35 mmHg, measured at specific times pre-treatment. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Participants must not have received treatment for open-angle glaucoma with intraocular pressure-lowering drugs for at least four weeks prior to the study. Additionally, they should not have started any new systemic medication that may alter intraocular pressure in the 30 days preceding the study. Females of reproductive age must practice effective birth control methods throughout the study. The trial includes a vulnerable population, and participants are expected to have controlled arterial blood pressure and best-corrected visual acuity of at least 20/100. The selection criteria ensure that participants can understand the trial requirements and agree to follow-up visits, providing informed consent and data protection declarations before any trial-related procedures. The study aims to confirm the clinical non-inferiority of a fixed-combination generic formulation of Brimonidine 0.2%/Timolol 0.5% eye drops compared to the marketed Combigan® eye drops in managing intraocular pressure.

The clinical trial is designed as a **non-inferiority**, observer-blind, randomized study with two parallel groups, aimed at comparing the efficacy and tolerability of a new fixed-combination generic formulation of **brimonidine tartrate** 0.2% and **timolol maleate** 0.5% eye drops, solution in single-dose containers, against the marketed preservative-containing Combigan® eye drops. The trial targets patients diagnosed with open-angle glaucoma or ocular hypertension, characterized by increased intraocular pressure (IOP) leading to potential optic nerve damage and visual field loss. The primary objective is to confirm the clinical non-inferiority of the test product by examining the change in IOP at 08:00 from the end of the study to baseline.

The trial will span approximately 12 weeks, with participant involvement expected to last the same duration. The study will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, diagnosis, and IOP measurements. Participants must have an average IOP between 22 mmHg and 35 mmHg and should not have received IOP-lowering drugs for at least four weeks prior to the study. The trial will include several follow-up visits at weeks 2, 6, and 12 to monitor changes in IOP at different times of the day (08:00, 12:00, and 16:00) and assess the average diurnal IOP change. The end-of-study visit will occur at week 12, where the primary endpoint, the change in IOP at 08:00 from baseline, will be evaluated.

Participants may be withdrawn from the study if therapeutic failure occurs, defined as a diurnal IOP of 22 mmHg or higher at any time point during or at the end of week 12. Other conditions for early termination include adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial is expected to start recruitment on March 1, 2024, and conclude by July 31, 2025. The study will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their data is protected throughout the trial.

The clinical trial involves the evaluation of two ophthalmic solutions for the treatment of **open angle glaucoma** or **ocular hypertension**. The experimental medication is a fixed-combination generic formulation of **Brimonidine 0.2%** and **Timolol 0.5%** eye drops, presented as a solution in single-dose containers. This formulation is manufactured by BECRO (CYPRUS) LTD. The pharmaceutical form is eye drops, solution in single-dose container, and it is administered via ocular use. The dosage is 2 mg/ml of Brimonidine and 5 mg/ml of Timolol, with a maximum daily dose of 0.35 mg/ml. The treatment period is up to 12 months. The active substances, **Brimonidine tartrate** and **Timolol maleate**, are of chemical origin.

The comparator treatment in this trial is the marketed product Combigan, which is also a combination of Brimonidine 0.2% and Timolol 0.5% eye drops, solution. This product is manufactured by ABBVIE DEUTSCHLAND GMBH & CO. KG and is available as a preservative-containing solution. The pharmaceutical form is eye drops, solution, and it is administered via ocular use. The dosage and maximum daily dose are identical to the experimental medication, with a maximum treatment period of 12 months. The active substances, Brimonidine tartrate and Timolol maleate, are also of chemical origin.

Both treatments are designed to be administered with the same frequency and route, ensuring consistency in the trial's methodology. Participant compliance will be monitored throughout the study to ensure adherence to the dosing schedule. The primary objective of the trial is to confirm the clinical non-inferiority of the generic formulation compared to the marketed Combigan product by examining the change in intraocular pressure (IOP) at 08:00 from the end of the study to baseline.

The efficacy of the clinical trial will be assessed by evaluating the change in **intraocular pressure (IOP)** in patients with open-angle glaucoma or ocular hypertension. The primary endpoint is the change in IOP at 08:00 from the end of treatment (week 12) to baseline (week 0) in subjects treated with the test product compared to those treated with the reference product. Secondary endpoints include changes in IOP at 12:00 and 16:00 from the end of treatment to baseline, as well as changes at these time points from week 2 and week 6 to baseline. Additionally, the average diurnal IOP change from baseline to the end of week 12, and the average decrease of diurnal IOP measured between baseline and weeks 2 and 6 will be evaluated. The proportion of withdrawals due to therapeutic failure, defined as diurnal IOP ≥22 mmHg at any time point during or at the end of week 12, will also be assessed.