Clinical trial NCT02167035
Conditions: Glaucoma Ocular Hypertension
Keywords: Open-Angle Glaucoma Ocular Hypertension
Sponsor: Cornerstone Health Care, PA
Start date: 2014-08-01; Completion date: 2018-03-01
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare Combigan Two Times Daily (BID) vs Simbrinza Three Times Daily (TID) in subjects currently being treated with Latanoprost for Open-Angle Glaucoma or Ocular Hypertension. Both of these drugs are currently FDA approved as combination therapy for patients with Open-Angle Glaucoma or Ocular Hypertension. The purpose of this clinical trial would be to assess which treatment, if either, is superior in lowering intraocular pressure (IOP). A secondary objective is to assess the tolerability of each drug.

Detailed description:

Arms: arm 1: Combigan 0.2%/0.5% one drop Two Times Daily (BID) arm 2: Simbrinza 1/0.2% one drop Three Times Daily (TID)
Interventions: intervention 1: Combigan Two Times Daily (BID) intervention 2: Simbrinza Three Times Daily (TID)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Protocol version 1.0  11/May/2016 
Page 1 
 
Phase IV Comparison of Combigan BID vs Simbrinza TID in Subjects Currently 
Treated with Latanoprost for Open-Angle Glaucoma or Ocular Hypertension 
 
Protocol Title: 
Phase IV Comparison of Combigan BID vs Simbrinza TID in 
Subjects Currently Treated with Latanoprost for Open-Angle 
Glaucoma or Ocular Hypertension 
 
Protocol Number: 
TEP001 
Study Phase: 
Phase 4 
Indication: 
Open-Angle Glaucoma or Ocular Hypertension 
Investigators: 
PI:  Michael E. Tepedino,M.D. 
Sub-I:  Robert J. DaVanzo, M.D. 
Sub-I:  Michael W. Evans, M.D. 
Sub-I:  J. Zachary Forsey, M.D. 
Sponsor: 
Cornerstone Eye Care 
1400 East Hartley Drive 
High Point, NC USA 
27262 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C #497 
San Clemente, CA 92673 
 
 
 
 


Protocol version 1.0  11/May/2016 
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Contact Information 
Title of Study:  Phase IV Comparison of Combigan BID vs Simbrinza TID in Subjects Currently Treated 
with Latanoprost for Open-Angle Glaucoma or Ocular Hypertension 
Name and degrees of Principal Investigator: Michael E. Tepedino, MD 
Department: Cornerstone Eye Care 
Mailing Address:  1400 East Hartley Drive High Point, NC  27262 
Phone #: 333-802-2255  
Fax#: 336-885-7830 
Email: tepedino@cornerstonehealthcare.com 
 
Name of Study Coordinator: April Kettering 
Department: Cornerstone Eye Care 
Mailing Address:  1400 East Hartley Drive High Point, NC  27262 
Phone #: 333-802-2255  
Fax#: 336-885-7830 
Email: april.kettering@cornerstonehealthcare.com 
 
Name of funding source:  Allergan, Inc 
Contact for IRB invoicing: April Kettering 
Department: Cornerstone Eye Care 
Mailing Address:  1400 East Hartley Drive High Point, NC  27262 
Phone #: 333-802-2255  
Fax#: 336-885-7830 
Email: april.kettering@cornerstonehealthcare.com 
Project Personnel and Conflicts of Interest 
All study investigators and study coordinators who have study-related contact with subjects or 
identifiable data from subjects are listed below.   
Role 
Name 
PI 
Michael E. Tepedino,M.D 
Sub-I 
Robert J. DaVanzo, M.D. 
Sub-I 
Michael W. Evans, M.D. 
Sub-I 
J. Zachary Forsey, M.D. 
Study Coordinator 
April Kettering, CRA 
Study Coordinator 
Chelsea Allred, COA 
 
No investigator or study staff member and/or their immediate family members has any conflict 
of interest in the design, conduct, or results of this study. 
 
 


Protocol version 1.0  11/May/2016 
Page 3 
 
Brief Summary 
Purpose 
To compare Combigan BID vs Simbrinza TID in approximately 40 subjects currently being treated with 
Latanoprost for Open-Angle Glaucoma or Ocular Hypertension.  Both of these drugs are currently FDA 
approved as combination therapy for patients with Open-Angle Glaucoma or Ocular Hypertension.  The 
purpose of this clinical trial would be to assess which treatment, if either, is superior in lowering 
intraocular pressure (IOP).  A secondary objective is to assess the tolerability of each drug. 
Participants 
Approximately 40 subjects adults, male or female, age 18 and older, of any ethnicity or race with the 
diagnosis of Open-Angle Glaucoma or Ocular Hypertension currently being treated with latanoprost for 
at least six weeks prior to screening. 
Procedures (methods): 
After acquisition of properly obtained informed consent, subjects will under the go the following 
assessments: Review of medical and ophthalmic history, demographics, review of concomitant 
medications, review of ocular symptoms, vital signs (BP, Resp, Pulse), Best Corrected Visual Acuity 
(BCVA), Intraocular Pressure (IOP) measurement, Biomicroscopy, Ophthalmoscopy, Gonioscopy, Central 
Corneal Thickness measurement (Pachymetry), urine pregnancy test (if of child-bearing potential), and 
Visual Field. 
Purpose and Rationale 
Prostaglandins, such as latanoprost, are the most common initial therapy for POAG and OHT.  Patients 
being treated for POAG and OHT with latanoprost often require adjunctive therapy to achieve target 
pressures.  Patients are often switched to a combination therapy for a number of reasons including 
improved efficacy, tolerability, and/or compliance.  Little head-to-head data exists comparing the 
current marketed combination products Combigan and Simbrinza.  This study will serve as a data 
reference comparing safety, efficacy, and tolerability of Combigan and Simbrinza. 
Subjects 
Adults, male or female, age 18 and older, of any ethnicity or race with the diagnosis of Open-Angle 
Glaucoma or Ocular Hypertension currently being treated with latanoprost for at least six weeks prior to 
screening.  Subjects will be identified from Investigator’s current patient population. 
 
 


Protocol version 1.0  11/May/2016 
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Inclusion and Exclusion Criteria 
Inclusion Criteria: 
 
Open-angle glaucoma or ocular HTN 
 
Currently treated with Latanoprost for min of 6 weeks 
 
IOP must be  10 mmHg and ≤ 34 mmHg at screening visit while on Latanoprost  
 
Male or Female 18 yrs and older 
 
BCVA 20/100 or better OU 
 
Pachymetry >470 and < 640 
 
Women of childbearing potential must have a negative urine pregnancy test at the 
screening/baseline visit 
 
Patient willing and capable of providing informed consent 
Exclusion Criteria: 
 
C/D >0.8 
 
Visual field loss, which in the opinion of the investigator is functionally significant 
 
Current use of ocular steroids 
 
Concurrent significant active ocular disease History: (within 3 months prior to Screening) of 
ocular laser, intraocular, filtering or refractive surgery or planned ocular surgery of any kind 
during study participation 
 
Change,  within prior 30 days or anticipated change,  in any systemic medication that is known 
to affect IOP 
 
Uncontrolled systemic disease 
 
Significant ocular hyperemia at baseline 
 
Prior glaucoma procedure within 3 months 
 
Females who are pregnant, nursing, or planning a pregnancy or who are of childbearing 
potential and not using a reliable method of contraception 
 
Known allergy or sensitivity to any study medication 
 
Asthma or any other known medical condition that the investigator feels would put patient at 
increased risk from any of the study medications 
 
Current enrollment in an investigational drug or device study or participation in such a study 
within 30 days prior to Screening 
Full Description of the Study Design, Methods and Procedures 
This research study will compare two currently FDA approved and marketed combination treatments for 
open-angle glaucoma and/or ocular hypertension.  The main objective of the study is to assess which 
drug is superior in lowering the intraocular pressure of the subjects.  The secondary objective is to 
compare the tolerability of each drug in regards to the following known side effects: Oral effects (bad 
taste, dry mouth) and Ocular comfort effects (itching, burning, stinging, burning on instillation, blurred 
vision). 


Protocol version 1.0  11/May/2016 
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Subjects will be discontinued from their current Latanoprost regimen and randomized 1:1 to either 
Combigan 0.2/0.5% BID or Simbrinza 1/0.2% TID.  Duration of treatment for each arm will be 90 days.  
Subjects will discontinue Latanoprost at Visit 1 and begin either Combigan 0.2/0.5% BID or Simbrinza 
1/0.2% TID on the evening of Visit 1 (approximately 8pm). Both are ophthalmic drops and will be placed 
in the eye by the subject according to the appropriate dosing scheduled (Combigan BID, Simbrinza TID). 
The following data will be collected by the Investigator and designated study team members: 
Relevant (as determined by the Investigator) 
 
 
Medical History 
 
Ophthalmic History 
 
Demographics 
 
Concomitant Medications 
 
Ocular Symptoms 
 
Vital Signs (BP, Resp, Pulse) 
 
Best Corrected Visual Acuity (BCVA) 
 
Intraocular Pressure (IOP) 
 
Biomicroscopy (Slit Lamp Exam) 
 
Ophthalmoscopy 
 
Gonioscopy 
 
Central Corneal Thickness (Pachymetry) 
 
Urine Pregnancy Test (if child-bearing potential) 
 
Visual Field 
All ophthalmic exams are routine Open-Angle Glaucoma/Ocular Hypertension assessments.  
Participation in the study may require earlier and will require more frequent performance of 
assessments. 
A detailed description of each visit is listed below: 
Visit 1 (Day 0):  ICF, Med/Oph Hx, Con-Meds, Ocular Symptoms Assessment, Vitals (BP, RES, HR), BCVA, 
IOP (8am, 10am, and 4 pm), Biomicroscopy, Ophthalmoscopy (non-dilated if a dilated exam has been 
performed within 6 months.  Dilated if no dilated exam within 6 months), Gonioscopy (if not performed 
within 12 months), Visual Field (if not performed within 12 months), Central Corneal Thickness (if not 
performed within 12 months), Urine Pregnancy test (women of childbearing potential only), IP 
dispensing 
Visit 2 (Day 7 +/- 2 days):  PHONE CALL ONLY- Med/Oph Hx , Con-Meds, Adverse Events, Ocular 
Symptoms Assessment 
Visit 3 (Day 30 +/- 3 days): Med/Oph Hx, Con-Meds, Ocular Symptoms Assessment, BCVA, IOP (8am, 
10am, and 4pm), Biomicroscopy, IP dispensing, Adverse Event 


Protocol version 1.0  11/May/2016 
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Visit 4 (Day 90 +/- 3days):  Med/Oph, Hx Con-Meds, Ocular Symptoms Assessment, Vitals (BP, RES, HR), 
BCVA, IOP (8am, 10am, and 4pm), Biomicroscopy, Ophthalmoscopy (non-dilated if a dilated exam has 
been performed within 6 months.  Dilated if no dilated exam within 6 months), Central Corneal Thickness 
(if not performed within 12 months), Gonioscopy, Adverse Event 
Unscheduled:  Con-Meds, Ocular Symptoms Assessment, Vitals (BP, RES, HR), BCVA, IOP (8am, 10am, 
and 4pm), Biomicroscopy, Ophthalmoscopy (non-dilated if a dilated exam has been performed within 6 
months.  Dilated if no dilated exam within 6 months), Central Corneal Thickness (if not performed within 
12 months), Adverse Event 
The patient and one study coordinator will be unmasked.  The investigator will be masked.  The 
investigator and a masked coordinator will complete all ophthalmic exams to avoid bias.  Open label 
drug will be dispensed in a site provided non-see-through pouch to avoid risk of unmasking.  
Randomization will be conducted by assigning arm to individual subject numbers prior to beginning of 
enrollment.  This master list will be held by unmasked personnel and kept in a secure location.  As 
subjects enroll, they will be assigned a number in sequential order. 
Adverse Experiences 
Adverse Events  
 Adverse events occurring during the study will be recorded on an adverse event case report form.  If 
adverse events occur, the first concern will be the safety of the study participants.  
Definitions 
Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this treatment.  An 
adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product.  In addition, during the 
screening period, adverse events will be assessed regardless of the administration of a pharmaceutical 
product.   
Note:  Adverse events must be collected once informed consent has been obtained, regardless of 
whether or not the subject has been administered study drug. 
Adverse events will be assessed, documented, and recorded in the CRF throughout the study (ie, after 
informed consent has been obtained).  At each visit, the investigator will begin by querying for adverse 
events by asking each subject a general, non-directed question such as “How have you been feeling 


Protocol version 1.0  11/May/2016 
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since the last visit?”  Directed questioning and examination will then be done as appropriate.  All 
reported adverse events will be documented on the appropriate case report form.   
Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the following 
outcomes:  death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth 
defect.  Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in this definition.   
Pre-planned surgeries or procedures for pre-existing, known medical conditions for which a subject 
requires hospitalization is not reportable as a serious adverse event. 
Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity assessment for a 
clinical adverse event must be completed using the following definitions as guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
Not applicable 
In some cases, an adverse event may be an ‘all or nothing’ finding which 
cannot be graded. 
 
Relationship to Study Drug  
A determination will be made by the investigator of the relationship (if any) between an adverse event 
and the study drug, as applicable.  A causal relationship is present if a determination is made that there 
is a reasonable possibility that the adverse event may have been caused by the drug.   
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate case report form. 
All adverse events that are drug-related and unexpected (not listed as treatment-related in the current 
Investigator's Brochure) must be reported to the governing Institutional Review Board/Independent 
Ethics Committee (IRB/IEC) as required by the IRB/IEC, local regulations, and the governing health 


Protocol version 1.0  11/May/2016 
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authorities.  Any adverse event that is marked ‘ongoing’ at the exit visit must be followed-up as 
appropriate. 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed consent) must be 
immediately reported to Allergan but no later than 15 calendar days after learning of a serious adverse 
event.  Serious adverse events  must be recorded on the Serious Adverse Event Form provided by 
Allergan.  All subjects with a  serious adverse event must be followed up and the outcomes reported.  In 
the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the  Serious Adverse Event form. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and medical 
judgments from colleagues who assisted in the treatment and follow-up of the subject. 
3. Provide Allergan with a complete, written description of the adverse event(s) on the Serious 
Adverse Event form describing the event chronologically, including any treatment given (eg, 
medications administered, procedures performed) for the adverse event(s).  Summarize 
relevant clinical information about the event:  signs, symptoms, diagnosis, clinical course and 
relevant clinical laboratory tests, etc.  Include any additional or alternative explanation(s) for the 
causality which includes a statement as to whether the event was or was not related to the use 
of the investigational drug. 
4. Promptly inform the governing IRB/IEC of the serious adverse event as required by the IRB/IEC, 
local regulations, and the governing health authorities. 
 
Benefits to Subjects and/or Society 
This study may or may not benefit the individual subjects.  A potential benefit to subjects may be better 
control of the subject’s IOP.  The potential benefit to society is the knowledge of possible superiority of 
one drug over the other to reduce IOP.  This is especially of interest as Combigan requires BID dosing 
while Simbrinza require TID dosing.  The other potential benefit to society is the knowledge of 
comparative tolerability and ocular discomfort associated with each drug. 
Full Description or Risks and Measures to Minimize Risks 
See package inserts for each drug for full list of risks. 
Most common side effects: 


Protocol version 1.0  11/May/2016 
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Combigan: 5 to 15% experience allergic conjunctivitis, conjunctival folliculitis, conjunctival hyperemia, 
eye pruritis, ocular burning and stinging 
Simbrinza: 3 to 5% experience blurred vision, eye irritation, dysgeusia, dry mouth, eye allergy  
Data Monitoring and Analysis 
For safety purposes the Principal Investigator will review the study data on each subject enrolled. 
For statistical analysis, summary tables will be provided for baseline variables (demographics, 
dispensing, medical history).  IOP is the primary endpoint- Summarized by treatment for each visit.  All 
safety endpoints will be presented descriptively. 
Collect or Receive Identifiers 
Names, telephone numbers, social security numbers and any elements of dates (other than year) for 
dates directly related to an individual, including birth date, admission date, discharge date, date of 
death.  For ages over 89: all elements of dates (including year) indicative of such age, except that such 
ages and elements may be aggregated into a single category of age 90 and older will be collected or 
received. 
Identifiers in Research Data 
The collected or received identifiers listed above will not be linked or maintained with the research data. 
Confidentiality of the Data 
Paper records will be kept in a secure location accessible to only research personnel.   
 Whenever feasible, identifying information will be removed from study related documents. 
Data Sharing 
The collected or received identifiers will not be shared with anyone outside the immediate research 
team.   
 
 
 
 
 
 


Protocol version 1.0  11/May/2016 
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Appendix 
Patient Questionnaire 
Patient Diary 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
Cover Page 
 
Study Title: Phase IV Comparison of Combigan BID vs Simbrinza TID in 
Subjects Currently Treated with Latanoprost for Open-Angle 
Glaucoma or Ocular Hypertension 
 
 
NCT # 02167035 
 
10MAY2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan 
Analysis Populations  
There are four populations included in this analysis: (1) Safety Population, (2) Intent-to-treat Population 
(ITT), (3) Modified Intent-to-treat Population (mITT) and (4) Per-protocol Population (PP).  
 
The ‘Safety Population’ included all enrolled subjects.  
 
The ‘Intent-to-treat Population’ included all enrolled subjects randomized to masked study medication.  
 
The ‘Modified Intent-to-treat Population’ included all ITT subjects who attended Visits 1, 2 and 3 
(minimally).  
 
The ‘Per-protocol Population’ included all randomized subjects that completed all scheduled study visits 
without a major protocol violation/deviation.  
 
Analysis Assumptions and Conditions  
 
Summary tables (descriptive statistics and/or frequency distributions) were provided for all baseline 
variables and efficacy variables. Continuous variables were described by descriptive statistics (n, mean, 
standard deviation, range and median). Frequency distributions (counts and percentages) of subjects 
within each category were provided for categorical variables.  
 
No replacement of missing values was performed for this study.  
 
Select Specific Variables Discussion  
 
Intraocular Pressure (IOP)  
 
Study Eye Definition: Study eye was determined to be the eye which qualified for study inclusion 
according to the inclusion and exclusion criteria; if both eyes qualified then the eye with the worse IOP 
at baseline (10:00 AM time point) was denoted as the study eye. If both eyes had the same IOP at 
baseline, then the right eye was denoted as the study eye.  
 
Diurnal Calculation: A diurnal value was determined only when all three (3) time point’s worth of IOP 
study eye data were present (8:00 AM, 10:00 AM and 4:00 PM) for any given subject at any given visit.  
 
Ocular Symptoms/Tolerability Questionnaire  
 
 Scoring: Individual categorical responses for symptom severity were converted to numeric responses using the 
following conversion parameters. All “N/A” and blank responses were not used when calculating the Ocular 
Symptoms/Tolerability Questionnaire mean scores, etc. 
Questions 1-10 Response 
Converted Numeric Response 
None 
0 
Mild 
1 
Moderate 
2 
Severe 
3