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1 TITLE PAGE Clinical Study Protocol Brinzolamide 1% Ophthalmic Brinzolamide 1% Ophthalmic Suspension Study S0883 Valeant Research & Development 1 TITLE PAGE Clinical Study Protocol Brinzolamide 1% Ophthalmic Suspension A RANDOMIZED, DOUBLE-MASKED, ACTIVE-CONTROLLED, PARALLEL GROUP, MULTI-CENTER BIOEQUIVALENCE STUDY OF THE GENERIC BRINZOLAMIDE 1% OPHTHALMIC SUSPENSION COMPARED TO REFERENCE LISTED DRUG AZOPT® (BRINZOLAMIDE) OPHTHALMIC SUSPENSION 1% IN SUBJECTS WITH PRIMARY OPEN ANGLE GLAUCOMA OR OCULAR HYPERTENSION Protocol S0883 Developmental phase of study: Bioequivalence, pivotal Study design: A multi-center, randomized, double- masked, active-controlled, parallel bioequivalence study of both eyes in subjects with primary open angle glaucoma or ocular hypertension Date: Original 11 JAN 2018 Amendment 1 12 APR 2018 Sponsor representative Sponsor Valeant Pharmaceuticals North America LLC 400 Somerset Corporate Blvd, Bridgewater NJ 08807 Main office: (866) 246-8245 CONFIDENTIAL Nothing herein is to be disclosed without prior approval of the sponsor. This clinical investigation will be conducted in accordance with the protocol and in compliance with Good Clinical Practice, including the archiving of essential documents. ™/® are trademarks of Valeant Pharmaceuticals North America LLC or its affiliates. All other brand names/product names are trademarks of their respective owners. The information in the following document is confidential. The information contained herein will not be disclosed to others without written authorization from Valeant Pharmaceuticals North America LLC. Confidential 1 Amendement 1, Clinical Study Protocol 12 April 2018 Brinzolamide 1% Ophthalmic Suspension Study S0883 Valeant Research & Development Personnel Responsible for Conducting the Study A RANDOMIZED, DOUBLE-MASKED, ACTIVE-CONTROLLED, PARALLEL GROUP, MULTI-CENTER BIOEQUIVALENCE STUDY OF THE GENERIC BRINZOLAMIDE 1% OPHTHALMIC SUSPENSION COMPARED TO REFERENCE LISTED DRUG AZOPT® (BRINZOLAMIDE) OPHTHALMIC SUSPENSION 1% IN SUBJECTS WITH PRIMARY OPEN ANGLE GLAUCOMA OR OCULAR HYPERTENSION Protocol S0883 Contract Research Organization Lexitas Pharma Services 313 Foster St Durham, NC, 27701 Confidential 4 Amendement 1, Clinical Study Protocol 12 April 2018 Brinzolamide 1% Ophthalmic Suspension Study S0883 Valeant Research & Development Principal Investigator Protocol Agreement Page I agree: To assume responsibility for the proper conduct of this clinical study at this site and to conduct the study in compliance with this protocol, any future amendments, and with any other study conduct procedures provided by the sponsor. That I am aware of, and will comply with, the internationally recognized code of Good Clinical Practices (GCP) and all other applicable regulatory requirements to obtain written and dated approval from the Institutional or Central Review Board (IRB) or Independent Ethics Committee (IEC) for the study protocol, written informed consent, consent-form updates, subject-recruitment procedures (eg, advertisements), and any other written information to be provided to the subjects, before initiating this clinical study. Not to implement any changes to, or deviations from the protocol without prior agreement from the sponsor and review and documented approval from the IRB/IEC, except to eliminate an immediate hazard to the study subjects, or when change(s) involves only logistical or administrative aspects of the clinical study. To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and inspection by the appropriate regulatory authority (ies). That I am thoroughly familiar with the appropriate use of the investigational products(s), as described in this protocol, and any other information provided by the sponsor or designee, including, but not limited to, the current investigator Brochure or equivalent document and approved product label (if applicable). To provide sufficient time and adequate numbers of qualified staff and facilities for the foreseen duration of the clinical study to conduct the study properly, ethically, and safely. To ensure that all persons assisting in this study are adequately informed about the protocol, investigational product(s), and their clinical study-related duties and functions. Principal Investigator (print name) Principal Investigator (signature) Date Confidential 5 Amendement 1, Clinical Study Protocol 12 April 2018 Brinzolamide 1% Ophthalmic Suspension Study S0883 Valeant Research & Development 2 Synopsis Name of Sponsor/Company: Valeant Pharmaceuticals North America LLC Name of Investigational Product (test product): Brinzolamide 1% Suspension Name of Active Ingredient: Brinzolamide 1% Suspension Title of Study: A randomized, double-masked, active-controlled, parallel group, multicenter bioequivalence study of the generic brinzolamide 1% ophthalmic suspension compared to Reference Listed Drug Azopt® (brinzolamide) ophthalmic suspension 1% in subjects with primary open angle glaucoma or ocular hypertension. Number of clinical centers: Approximately 32 Sites, United States only Objectives: Primary: To establish that the generic brinzolamide 1% suspension is bioequivalent to brinzolamide 1% suspension (AZOPT®), the selected Reference Listed Drug. Secondary: To compare the safety and tolerability of the generic brinzolamide 1% suspension to brinzolamide 1% suspension (AZOPT®). Methodology: This repeat study will be prospective, randomized, double masked and will follow Food and Drug Administration (FDA) guidance, revised as of March 2015, for demonstrating bioequivalence of the generic brinzolamide 1% ophthalmic suspension compared to brinzolamide 1% Ophthalmic Suspension (AZOPT®) for the treatment of elevated intraocular pressure (IOP) in patients with Primary Open Angle Glaucoma (POAG) or Ocular Hypertension (OH). Number of patients planned: Approximately 624 subjects will be randomized to ensure that 560 subjects complete the 42 days (6 weeks) of dosing. Diagnosis and main criteria for inclusion: 1. Subjects must be of legal age (at least 18 years) on the date the Informed Consent Form (ICF) is signed. 2. Subjects must be able to read, understand, and provide written informed consent on the Institutional Review Board (IRB)/Ethics Committee (EC)-approved ICF and provide authorization as appropriate for local privacy regulations. 3. Subjects who are willing and able to comply with scheduled visits, treatment plan, and other study procedures. 4. Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 28 days after last dose of assigned treatment. Acceptable contraceptive methods for female subjects (need at least one): a) Hormonal methods of contraception (including oral and transdermal contraceptives, injectable progesterone, progestin subdermal implants, progesterone-releasing intrauterine devices [IUDs]) initiated at least 14 days prior to the first dose of study drug b) True abstinence: when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception c) Placement of a copper-containing IUD d) Condom with spermicidal foam/gel/film/cream/suppository e) Postmenopausal at least 12 months (365 days) prior to the first dose of study drug or permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy) f) Male partner who has had a vasectomy for at least 3 months (90 days) prior to the first dose Confidential 6 Amendement 1, Clinical Study Protocol 12 April 2018 Brinzolamide 1% Ophthalmic Suspension Study S0883 Valeant Research & Development of study drug or is surgically sterile Acceptable contraceptive methods for male subjects with partners of childbearing potential (need at least one): a) True abstinence: when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. b) Vasectomy for at least 3 months (90 days) prior to the first dose of study drug or surgically sterile c) Without a vasectomy, must use a condom with spermicidal foam/gel/film/cream/suppository 5. Female subjects who are not of childbearing potential must meet at least one of the following criteria: a) Have undergone a documented hysterectomy and/or bilateral oophorectomy, and/or tubal ligation b) Have a medically confirmed ovarian failure, or; c) Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological causes 6. Diagnosis of primary-open angle glaucoma (including pigmentary or pseudoexfoliative) or ocular hypertension and requires treatment in both eyes. 7. Adequate wash-out period prior to baseline of any ocular hypotensive medication (see Table 1). In order to minimize potential risk to patients due to intraocular pressure (IOP) elevations during the washout period, the investigator may choose to substitute a parasympathomimetic or carbonic anhydrase inhibitor in place of a sympathomimetic, alpha-agonist, beta-adrenergic blocking agent, or prostaglandin; however, all patients must have discontinued all ocular hypotensive medication for the minimum washout period provided in Table 1. 8. Baseline (Day 1/hour 0) IOP ≥22 mmHg and ≤34 mmHg in both eyes and ≤5 mmHg IOP difference between
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