Sponsor's prerogative since initial purpose for study shifted according to business strategy.

Objectives: To evaluate the non-inferiority in the intraocular pressure decrease of the preservative-free ophthalmic solution PRO-122, manufactured by Laboratorios Sophia S.A. de C.V., versus concomitant therapy in subjects with uncontrolled primary open-angle glaucoma and/or IOP.

Hypothesis: The mean (average) value of the IOP final absolute reduction in the experimental group (PRO-122) is not lower, considering a lower limit of 1 mmHg, compared to the IOP mean absolute reduction of the standard group (concomitant therapy).

Methodology: A non-inferiority, phase III, double-blind, randomized, controlled, parallel, clinical trial

Number of patients: 51 subjects divided into 3 groups (17 subjects per group)

Diagnosis and main inclusion criterion:

Diagnosis: Primary open-angle glaucoma or ocular hypertension

Main criteria:

• Patients of either sex
• Average intraocular pressure (IOP) ≤ 36 mm/Hg
• Previous management with ocular hypotensive medications ≥ 2 months, without achieving control (target IOP)
• Age ≥ 18 years
• Informed consent

Test product, dosage and route of administration:

• PRO-122. Preservative-free ophthalmic solution of timolol 0.5% / brimonidine 0.2% / dorzolamide 2% Manufactured by Laboratorios Sophia, S.A. de C.V., Zapopan, Jalisco, Mexico. + Placebo + Placebo
• Dosage: 1 drop every 12 hours
• Route of administration: ophthalmic

Treatment duration: 90 days

Evaluation criteria:

Efficiency (non-inferiority):

• IOP decrease

Safety:

• Best corrected visual acuity

• Cup-to-disc ratio

• Visual fields determined by computerized perimetry

• Central corneal thickness determined by pachymetry

• Ocular surface integrity, including:

  • Conjunctival hyperemia
  • Chemosis
  • Fluorescein staining

• Density of goblet cells

• Adverse events

Tolerability:

• Ocular comfort index

Statistical methodology:

The data will be expressed with measures of central tendency: mean and standard deviation for quantitative variables. The qualitative variables will be presented in frequencies and percentages. Statistical analysis will be done by means of a Kruskal-Wallis test for quantitative variables. The difference between qualitative variables will be analyzed using an square chi An alpha ≤ 0.05 would be considered as significant.

Inclusion Criteria:

• Signed informed consent
• Age greater or equal to 18 years
• Both sexes
• Women of childbearing age with birth control method
• Diagnosis of Primary open-angle glaucoma (according to the Guidelines of the Preferred Practice Pattern of the American Academy of Ophthalmology) or ocular hypertension (OHT)
• Intraocular pressure (IOP) not controlled with dual therapy according to the principal investigator (PI) judgment.
• IOP on the selection visit at 9 am, after the washing period, from 21 - 36 mmHg in at least one eye.

Exclusion Criteria:

General criteria

• Pregnant, breastfeeding or planning to get pregnant women.
• Women of childbearing age and who do not intake a hormonal contraceptive method, intrauterine device or bilateral tubal obstruction.
• Participation in another clinical research study greater or equal 30 days before the screening visit.
• People who cannot comply with their attendance at appointments or with all the - Protocol requirements

Medical and therapeutic criteria:

• Anterior chamber angle grade less than 2 of Shaffer rating.
• Excavation of optic nerve greater than 0.80 horizontal or vertical (ratio cup-disc)
• Serious loss of central visual field in any eye (sensitivity less or equal to 10 decibels in greater or equal to 2 of 4 points of the visual field test close to the fixation point)
• People not able to safely suspend ocular hypotensives drug products for the washout period according to the PI judgement.
• Chronic, recurrent, or active ocular inflammatory diseases (e.g. uveitis, scleritis, keratitis, herpetic) in any eye.
• Eye trauma less or equal to 6 months prior to the study
• Eye infection / inflammation less or equal to 3 months prior to the study
• Clinically significant or progressive retinal disease (e.g. degenerations, diabetic retinopathy, retinal detachment)
• Ability Visual 20/200 or worse in any of the eyes.
• Subject with only one eye
• Eye diseases that contraindicate the use of Beta-blocker (BB) Alpha-adrenergic agonist (AA) or Carbonic anhydrase inhibitors (CAIs)
• Intraocular surgery less or equal to 6 months prior to the study
• Laser intraocular surgery less or equal to 3 months prior to the study
• Any abnormality preventing reliable applanation tonometry
• Unstable or uncontrolled cardiovascular disease
• Chronic pulmonary disease (e.g. bronchial asthma)
• Any condition or illness that do not fit the subject for the study according to the PI judgment.
• Use of high doses of salicylate (1 g daily) less or equal to4 weeks before the eligibility visit
• In treatment with psychotropic medications that increase the adrenergic response
• Known hypersensitivity to BB medications (e.g. timolol), AA (e.g. brimonidine) and CAI (e.g. dorzolamide), sulfonamide derivatives, or any of the components of the study drugs
• Concomitant use of monoamine oxidase inhibitors
• Systemic or topical use of corticosteroids

Blinding will be performed by the personnel assigned by the Laboratorios Sophia S.A. de C.V. Clinical Operations Management. The blinding will consist in the elimination of the primary label (commercial) for Krytantek Ofteno® and the triple concomitant therapy and the placement of a label identical to those of the other interventions. Since the bottles in which Krytantek Ofteno® and the concomitant therapies are different in color and cap shape to the ones used for the placebo and the PRO-122, a masking will be performed in the primary packaging, which shall be identical for all three interventions.