Prospective, Randomized Phase III Study Comparing Two Models of a Travoprost Intraocular Implant to Timolol Maleate Ophthalmic Solution, 0.5%
Phase: PHASE3
Conditions: Glaucoma, Open-Angle, Ocular Hypertension
Sponsor: Glaukos Corporation

CLINICAL PROTOCOL 
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Protocol No.: 
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Phase 3 Study
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CONFIDENTIAL 
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PROSPECTIVE, RANDOMIZED PHASE 3 STUDY 
COMPARING TWO MODELS OF A TRAVOPROST 
INTRAOCULAR IMPLANT TO TIMOLOL 
MALEATE OPHTHALMIC 
SOLUTION, USP, 0.5% 
PROTOCOL #GC-012 
REVISION #:  REV 4  
DATE:  JULY 26, 2022 
Sponsor: 
GLAUKOS CORPORATION 
229 Avenida Fabricante │ San Clemente, CA 92672 │ (949) 367-9600 
NCT03868124

CLINICAL PROTOCOL 
Date: 
 
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Phase 3 Study 
GC-012 
 
 
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Table of Contents 
1 
INTRODUCTION ..........................................................................................11 
2 
OBJECTIVE ...................................................................................................12 
3 
CLINICAL HYPOTHESIS ............................................................................12 
4 
STUDY DESIGN ...........................................................................................12 
4.1 
Discussion of Study Design ................................................................... 15 
5 
STUDY MEASURES ....................................................................................15 
5.1 
Efficacy Measures .................................................................................. 15 
5.2 
Safety Measures ..................................................................................... 15 
6 
MATERIALS .................................................................................................16 
6.1 
Study Medications .................................................................................. 16 
6.1.2  CONTROL ARTICLE:  TIMOLOL MALEATE OPHTHALMIC ....... 18 
7 
METHODS .....................................................................................................19 
7.1 
Subjects .................................................................................................. 19 
7.2 
Eligibility Requirements ........................................................................ 19 
7.3 
Procedures .............................................................................................. 26 
7.4 
Concomitant Therapies .......................................................................... 44 
7.5 
Post-Treatment Management of IOP and Rescue Medications ............. 44 
8 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ...............48 
9 
STATISTICAL ANALYSES .........................................................................48 
9.1 
Sample Size ............................................................................................ 48 
9.2 
Analysis Populations .............................................................................. 49 
9.3 
General Statistical Methods ................................................................... 50 
9.4 
Safety Analyses ...................................................................................... 50 
9.5 
Efficacy Endpoints ................................................................................. 51 
9.6 
Interim Analyses .................................................................................... 53 
10  ADVERSE EVENTS .....................................................................................53 
10.1  Serious Adverse Event ........................................................................... 56 
10.2  Unexpected Adverse Event .................................................................... 56 
10.3  Suspected, Unexpected, Serious, Adverse Event (SUSAR) .................. 57 
10.4  Adverse Events Follow-up ..................................................................... 57 

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11  MAINTAINING THE MASK........................................................................57 
12  INFORMED CONSENT ................................................................................58 
13  INSTITUTIONAL REVIEW .........................................................................58 
14  CONFIDENTIALITY/PUBLICATION OF THE STUDY ...........................58 
15  STATEMENT OF COMPLIANCE ...............................................................59 
16  RECORD KEEPING ......................................................................................59 
16.1  Source Documents.................................................................................. 59 
16.2  Data Collection ....................................................................................... 60 
16.3  Study Supply Accountability ................................................................. 60 
16.4  Record Retention .................................................................................... 60 
17  REFERENCES ...............................................................................................61 
 
List of Figures 
Figure 1. Glaukos Travoprost Intraocular Implant ............................................... 17 
Figure 2. Glaukos Travoprost Intraocular Implant and Inserter ........................... 17 
Figure 3. Post-Treatment Management of IOP and Rescue Medications ............. 47 
 
List of Appendices 
APPENDIX A:  SCHEDULE OF VISITS AND MEASUREMENTS ................ 62 
APPENDIX B:  OBLIGATIONS OF THE INVESTIGATOR ............................ 63 
APPENDIX C:  DECLARATION OF HELSINKI .............................................. 65 
 
 
 
 

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SYNOPSIS 
 
This randomized, controlled, double-masked (subject and observer) clinical trial 
intends to randomize approximately 558 male and female subjects over 18 years 
old who have been diagnosed with open-angle glaucoma (OAG) or ocular 
hypertension (OHT).  All subjects are required to meet eligibility criteria at Visit 
1 (Screening) and unmedicated IOP inclusion criteria at Visit 2 (Baseline).  The 
purpose of this study is to evaluate the IOP-lowering effect of each of two 
investigational implanted medication treatments, as compared to a control topical 
medication treatment.  After completing Visit 2 (Baseline), subjects will be 
randomized in a 1:1:1 allocation to one of three study treatment arms:  model  
G2TR-
 implant (test) arm, model G2TR-
 implant (test) arm, and topical 
timolol (control) arm.  Postoperatively, there are 16 follow-up visits over a 
three-year period.  Specular microscopy photos will be collected at selected sites. 
 
 
IND Study Phase: 
3 
 
Test Article(s): 
Travoprost Intraocular Implant, high elution rate 
(Model G2TR-
), 
 
Travoprost Intraocular Implant, low elution rate 
(Model G2TR
), 
 
 
Concurrent Control: Timolol Maleate Ophthalmic Solution, USP, 0.5% 
(timolol) 
 
 
STUDY OBJECTIVE 
To compare the safety and initial efficacy of intraocular implants containing 
travoprost at two different elution rates versus Timolol Maleate Ophthalmic 
Solution, USP, 0.5% (timolol) in reducing elevated intraocular pressure in 
subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT).  
 
 
STUDY TREATMENTS 
There are three treatment groups in this study, with medications administered as 
follows: 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation/Term 
Definition 
α-agonists 
α-adrenergic receptor agonists 
ALT 
Argon laser trabeculoplasty 
AE 
Adverse Event 
BAK 
Benzalkonium chloride 
β-blockers 
β-adrenergic receptor antagonists 
BSCVA 
Best Spectacle Corrected Visual Acuity 
CAI 
Carbonic Anhydrase Inhibitor 
CI 
Confidence Interval 
CRF 
Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IOP 
Intraocular Pressure 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MA 
Medical Affairs 
MLT 
MicroPulse Laser Trabeculoplasty 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeters of mercury 
OAG 
Open-Angle Glaucoma 
OHT 
Ocular Hypertension 
PAS 
Peripheral Anterior Synechia 
PGA 
Prostaglandin analogue 
PP 
Per Protocol 
ROCK 
Rho Kinase Inhibitors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SLT 
Selective Laser Trabeculoplasty 
TEAE 
Treatment Emergent Adverse Event 
VA 
Visual acuity 
 
 
 

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1 
INTRODUCTION 
Glaucoma is a group of eye diseases characterized by progressive, irreversible 
and largely asymptomatic vision loss caused by optic nerve damage, which is 
most commonly associated with elevated levels of intraocular pressure. 
Glaucoma is a chronic condition that progresses slowly over long periods of 
time and can have a devastating impact on a patient's vision and quality of 
life.  Reducing intraocular pressure currently is the only proven treatment for 
glaucoma.  
Treatment for open-angle glaucoma (OAG) traditionally has started with 
topical ocular hypotensive medical therapy.  Development of more effective 
medications has increased the popularity of this approach as initial treatment 
compared to more invasive incisional or drainage device surgery. 
Furthermore, the more benign medication treatments preserve the ocular 
tissues in the event that more invasive surgical approaches are eventually 
required. 
The various topical ocular medications available to reduce IOP include 
miotics, β-adrenergic receptor antagonists (β-blockers), carbonic anhydrase 
inhibitors (CAIs), α-adrenergic receptor agonists (α-agonists), and 
prostaglandin analogues (PGAs).  The PGAs are a class of ocular hypotensive 
agents that have been proven effective in lowering IOP in subjects with OAG 
or OHT.  Other advantages of this class of medications is that the systemic 
side effects associated with α-agonists (e.g., dry mouth, drowsiness) 
and  β- blockers (e.g., depression, fatigue, bradycardia) do not appear to be 
associated with PGAs.  Furthermore, the ocular side effects typically 
associated with a-agonists (e.g., allergic reactions), and cholinergic agents 
(e.g., reduced vision), do not seem to manifest with the use of PGAs. 
However, PGAs have been shown to be associated with side effects such as 
ocular hyperemia, iris hyperchromia, periorbital atrophy, increased eyelash 
growth, general ocular surface discomfort and headache.1-5 These side effects 
and other factors including cost, compliance, and the difficulty of proper 
instillation, can sometimes hinder the proper use of topical medications.6,7 
Some patients may possess or develop an intolerance to topical medications or 
the preservatives in their formulations. 
The Travoprost Intraocular Implant was developed to remove or minimize the 
issue of patient compliance with topical hypotensive medication.  This clinical 
protocol will evaluate two versions of the Travoprost Intraocular Implant:  
Model G2TR-
 and Model G2TR
.  The implants are identical except 
that they are designed to elute travoprost at two different elution rates.  

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For the purposes of this protocol, Model G2TR-
 is the high elution rate 
implant and Model G2TR-
 is the low elution rate implant.  
These implants have the potential for providing important benefits to patients. 
The long duration of drug therapy provided by the implants avoids the 
problem of compliance with topical ocular hypotensive medications.  
 
  
Earlier versions of both models of the implant have been investigated in 
clinical trials conducted in 
 (Phase 1/2) as well as the United States 
(Phase 2).  The results from the U.S. Phase 2 trial have demonstrated that the 
Model G2TR-
 and G2TR-
 implants have long-term IOP-lowering 
effects and are also generally well-tolerated by study subjects.  These results 
support the continued evaluation of the implant models in a Phase 3 trial.   
2 
OBJECTIVE 
The objective of this study is to evaluate the safety and efficacy of intraocular 
implants that elute travoprost at two different elution rates.  Specifically, the 
Travoprost Intraocular Implant Model G2TR-
(high elution rate) and the 
Travoprost Intraocular Implant Model G2TR-
(low elution rate).  Both 
implants will be compared to Timolol Maleate Ophthalmic Solution, USP, 
0.5% (timolol) for reducing intraocular pressure in subjects with open-angle 
glaucoma (OAG) or ocular hypertension (OHT). 
3 
CLINICAL HYPOTHESIS 
The following are the hypotheses for the study: 
‐ 
Intraocular implants containing travoprost are at least as effective as 
timolol in achieving lowered intraocular pressure (IOP) in subjects with 
OAG or OHT. 
‐ 
Intraocular implants containing travoprost are well-tolerated. 
4 
STUDY DESIGN 
This is a prospective, randomized, double-masked, active-controlled, parallel-
group, multi-center clinical trial comparing the efficacy and safety of the 
Model G2TR
 Travoprost Intraocular Implant and the Model G2TR-
 
Travoprost Intraocular Implant to topical timolol in subjects with OAG or 
OHT.  Approximately 558 subjects will be randomized in this study and will 
be followed through 3 years postoperative.  
 
 
  
 
 
 
 

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sites), ophthalmoscopy findings (including cup-to-disc ratio), and visual field 
evaluation. Note:  See APPENDIX A for a schedule of visits and assessments. 
6 
MATERIALS 
6.1 
Study Medications 
Subjects randomized to the implant groups in the study will undergo surgery 
to receive the implants using the test articles described below in Section 6.1.1, 
before receiving their placebo eye drops. 
 
 
 
Subjects randomized to the control group will undergo a sham procedure 
(pretend surgery) using a needleless syringe (as described in Section 6.1.4, 
Other Articles: Sham Procedure)
 
  
During the study period, bottles of study medication will be dispensed to all 
subjects at Visit 3 (Operative Day 0), Visit 8 (Month 3), 
 
 
 
 
6.1.1 TEST ARTICLES:  MODELS G2TR-
 AND G2TR-
 
TRAVOPROST INTRAOCULAR IMPLANTS 
The Travoprost Intraocular implant is a 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 1. Glaukos Travoprost Intraocular Implant 
 
The Travoprost Intraocular Implant is provided sterile and pre-loaded 
onto an inserter in a blister tray, pouch and unit carton.  Each tray lid is 
labeled with the required product identification information.  The surgeon 
should use the provided pre-loaded inserter to implant the product. 
 
The inserter (Figure 2) is a sterile, single-use insertion system, pre-loaded 
with one implant, and designed to deliver the implant through the 
trabecular meshwork to the implant site.  
 
Figure 2. Glaukos Travoprost Intraocular Implant and Inserter 
 
 
Each unique product is packaged in a pouch and outer carton labeled with 
the study number, unique kit number, and instructions (including storage 
conditions).   
 

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7 
METHODS 
7.1 
Subjects 
Approximately 558 subjects diagnosed with OAG or OHT will be randomized 
at approximately 
 primarily in the United States and international 
sites.  After signing informed consent, prospective subjects will be evaluated 
to determine whether they meet Visit 1 (Screening) criteria.  Subjects who 
qualify at Visit 1 (Screening) must meet all other eligibility requirements at 
Visit 2 (Baseline).  
 
    
 
7.2 
Eligibility Requirements 
7.2.1 INCLUSION CRITERIA  
7.2.1.1 
Visit 1 (Screening) Inclusion Criteria 
At the Visit 1 (Screening), all subjects must meet the following 
criteria: 
1) Subject status as follows: 
a. male or female, 18 years of age or older 
b. 
 
 
 
 
 
 
 
2) Diagnosis of either OAG (i.e. primary, pseudoexfoliation, or 
pigmentary glaucoma) or OHT.  
 
Subjects with OAG should have the following: 
a. Diagnosis of OAG 
 
b. Vertical C/D ratio ≤ 0.8 
 
c. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.2.2  EXCLUSION CRITERIA 
7.2.2.1 
Visit 1 (Screening) Exclusion Criteria  
Subjects who meet any of the following criteria in the study eye at 
Visit 1 (Screening) are not eligible to participate in the study: 
1)
 
 
 
 
 
 
 
 
 
 

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2) 
 
 
 
 
 
3) Corneal status as follows: 
a. any active inflammation 
 
 
 
 
 
 
 
  
 
 
 
 
4) 
 
 
  
 
 
 
6) Retinal or optic nerve disorders, 
 
 
 
 
 
 
 

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7) Other ocular status as follows: 
a. clinically significant sequelae from trauma (e.g., chemical 
 
 
 
 
 
 
 
 
 
 
 
 
 
8) 
 
 
 
9) 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 

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i. known allergy, hypersensitivity or contraindication to the study 
 
 
 
 
 
 
7.2.2.2 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7.2.3 CRITERIA FOR EARLY STUDY EXIT  
Subjects may voluntarily withdraw from the study at any time.  The 
investigator may elect to discontinue any subject for reasons unrelated to 
the study product.  Details of a subject’s exit from the study should be 
recorded in the subject’s clinical records.  Subjects exited after signing the 
informed consent form and prior to study completion will be handled as 
follows: 
 
7.2.3.1 
Prior to Randomization 
Subjects will be ineligible for the study if they fail to meet Visit 1 
(Screening) criteria, baseline criteria or randomization criteria as 
outlined in Section 7.2, if they withdraw consent, or if study 
randomization goals have been met. 
 
7.2.3.2 
After Randomization 
Subjects may be exited (discontinued) from the study in the event of a 
condition that may cause them harm if participation were to be 
continued.  Subjects may also withdraw voluntarily. 
 
7.2.3.3 
Lost to Follow-up 
Subjects who miss postoperative study visits and cannot be contacted 
within a reasonable timeframe via letter or telephone, will be 
considered lost to follow-up.  The site will make at least three attempts 
to contact the subject via telephone.  If unsuccessful, the site will send 
a registered letter with return receipt to the subject.  The letter will 
request the subject to contact and return to the study site.  If the subject 
does not contact the site within a week after the letter was received, 
he/she will be considered lost to follow-up, and the site will send a 
second registered letter (with return receipt) to notify the subject of 
study exit due to lack of response to the telephone calls and first 
registered letter.  A Study Exit CRF may then be completed for the 
subject. 
 
All attempts to contact the subject (including telephone call logs, 
copies of registered letters and registered letter receipts) must be 
documented and maintained with the subject’s study source 
documentation. 
 

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7.2.4 STUDY TERMINATION 
The study may be terminated by Glaukos at any time following 
appropriate notification to the study sites and subjects. 
 
7.3 
Procedures 
Study visits and assessments are listed below; a table overview of study 
procedures by visit is provided in APPENDIX A Schedule of Visits. 
 
7.3.1 DURATION OF STUDY 
Following any required washout period, the treatment period will be three 
years in duration. 
 
7.3.2 METHODS TO MONITOR SUBJECT COMPLIANCE  
In order to obtain reliable efficacy and safety data, it is critical that each study 
subject complies with the dosing schedule specified in this protocol.  The 
following precautions will be taken to assure subject compliance during the 
study: 
a. For all 8 AM IOP measurements post-randomization, 
 
 
b. Subjects will receive instructions regarding the proper instillation of study 
medication and the dosing regimen. 
 
7.3.3 ENROLLMENT  
All subjects must give written informed consent before undergoing any 
study-related change in their treatment or any study related procedures. 
 
 
 
 
 
 
7.3.4 PREOPERATIVE PROCEDURES 
7.3.4.1 
Visit 1 (Screening) 
1) 
Written informed consent. 
2) 
Assign subject number.  

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3) 
Demographics, medical and surgical history, current ocular and 
systemic conditions, prescription medications, and medications 
known or suspected to lower IOP. 
4) 
Measure best spectacle corrected visual acuity through manifest 
refraction (Snellen) in each eye. 
5) 
Provide adequate and interpretable visual field usi
 
 (if not performed within the previous six 
months). 
6) 
Conduct slit-lamp biomicroscopy (including crystalline lens). 
7) 
Measure IOP (can be measured at any time) using the two-person 
methodology. 
8) 
Pachymetry (ultrasonic). 
9) 
Conduct a gonioscopic examination. 
10) Conduct a dilated ophthalmoscopy/fundus examination. 
11) Assess optic nerve abnormality (ophthalmoscopy). 
12) Assess vertical C/D ratio.  
13) Review screening inclusion and exclusion criteria.  Do not 
continue screening any subject who does not meet the screening 
eligibility requirements  
Remind the subject of the following: 
i. Visit 2 (Baseline) is a day-long exam that begins before 
8:00 AM and to plan accordingly 

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If the subject is ineligible for the study, complete the appropriate CRF. 
7.3.5 TREATMENT PROCEDURES 
7.3.5.1 
Visit 3 (Operative Day 0) 
1) Assess any adverse events. 
2) Prepare subject for surgery. 
3) Administer an additional drop of antibiotic 30 minutes 
preoperatively.  
4) Visually confirm Shaffer grade angle and target implant location.  
5) Obtain a randomization assignment from online electronic data 
capture system.  NOTE:  This step should be done immediately 
prior to the operative procedure in order to ensure the 
randomization is successfully assigned.     
6) Obtain the corresponding unique randomization kit to be used in 
surgery. 
7) Administer anesthetic (general, retrobulbar, peribulbar or topical 
for implant subjects; topical for sham procedure subjects). 
8) Perform surgery as per randomization assignment:  implant either 
G2TR
 or G2TR-
, OR perform sham procedure using 
syringe. 
9) Record clinical data from the surgical procedure on the Operative 
Day 0 CRF, noting any intra-operative AEs and post-operative 
AEs. 
 
Postoperatively: 
10) Obtain the unique masked study medication kit to be used after 
surgery (topical study medication).  Dispense the masked study 
medications to the subject, and instruct the subject to use one drop 
of the masked study medication in the study eye at approximately 
8:00 PM that evening (7:00 PM to 9:00 PM). 
11) Schedule the subject to return for Visit 4 (Day 1-2) to collect a 
standard IOP measurement at either 8:00 AM (± 30 minutes), 
10:00 AM (± 30 minutes), OR 4:00 PM (± 30 minutes). 
 
 
  Remind the subject to bring all study medications to the 
visit. 
12) Dispense other postoperative medications and instruct the subject 
as follows: 

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• 
 
 
 
 
 
 
 
 
 
7.3.5.2 
Visit 4 (Day 1-2 Exam, 1-2 days postoperative) 
1) For 8:00 AM IOP visits:  Confirm that the subject has not instilled 
their 8:00 AM masked study medication. 
2) Update subject’s medical status and concomitant medications. 
3) Assess any adverse events. 
4) Assess subject dosing compliance. 
5) Measure pinhole visual acuity (Snellen). 
6) Conduct slit-lamp biomicroscopy.  
7) Measure standard IOP at either 8:00 AM (± 30 minutes), 10:00 
AM (± 30 minutes), OR 4:00 PM (± 30 minutes) and record the 
time using the two-person methodology. 
8) For 8:00 AM IOP visits: 
 
 
9) Instruct the subject to instill the masked study drop at 
 
 
 
10) Schedule the subject to return for Visit 5 (Day 10).  Remind the 
subject of the following: 
i. Visit 5 (Day 10) is a day-long exam that begins before 8:00 
AM and to plan accordingly 
ii. Instill the masked study medication the evening before Visit 
5 (Day 10), but not on the morning of Visit 5 (Day 10) 
iii. Bring all study medications to the visit. 
 
7.3.5.3 
Visit 5 (Day 10 Exam, 10 ± 3 days postoperative) 
1) Confirm that the subject has not instilled their 8:00 AM masked 
study medication. 
2) Update subject’s medical status and concomitant medications. 

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6) Conduct slit-lamp biomicroscopy & ocular assessments 
(conjunctiva and iris).  
7) Measure standard IOP at either 8:00 AM (± 30 minutes), 10:00 
AM (± 30 minutes), OR 4:00 PM (± 30 minutes) and record the 
time using the two-person methodology . 
8) For 8:00 AM visits:  Instill one drop of masked study medication 
immediately after the IOP measurement. 
9) Conduct a gonioscopic examination. 
10) 
 
 
 
 
 
11) Schedule the subject to return for Visit 7 (Week 6).  Remind the 
subject of the following: 
i. Visit 7 (Week 6) is a day-long exam that begins before 
8:00 AM and to plan accordingly. 
ii. Instill the masked study medication the evening before Visit 
7 (Week 6), but not on the morning of Visit 7 (Week 6). 
iii. Bring all study medications to the visit. 
 
7.3.5.5 
Visit 7 (Week 6 Exam, 42 ± 5 days postoperative) 
1) Confirm that the subject has not instilled their 8:00 AM masked 
study medication. 
2) Update subject’s medical status and concomitant medications. 
3) Assess any adverse events. 
4) Assess subject dosing compliance. 
 
: 
5) Measure corrected visual acuity 
.  
 
 
  
6) Conduct slit-lamp biomicroscopy & ocular assessments 
(conjunctiva and iris).  
7) Measure diurnal IOP at 8:00 AM (within ±30 minutes) using the 
two-person methodology. 
8) Immediately after the 8:00 AM measurement, instill one drop of 
masked study medication. 
9) Conduct a gonioscopic examination. 

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10) Measure diurnal IOP at 10:00 AM (± 30 minutes) using the two-
person methodology. 
11) Measure diurnal IOP at 4:00 PM (± 30 minutes) using the two-
person methodology. 
12) Instruct the subject to instill the masked study drop at 
approximately 8:00 PM (7:00 PM to 9:00 PM) later that evening 
 
 
13) Schedule the subject to return for Visit 8 (Month 3).  Remind the 
subject of the following: 
i. Visit 8 (Month 3) is a day-long exam that begins before 8:00 
AM and to plan accordingly. 
ii. Instill the masked study medication the evening before Visit 
8 (Month 3), but not on the morning of Visit 8 (Month 3). 
iii. Bring all study medications to the visit. 
 
7.3.5.6 
Visit 8 (Month 3 Exam, 91 ± 14 days postoperative) 
1) Confirm that the subject has not instilled their 8:00 AM masked 
study medication. 
2) Update subject’s medical status and concomitant medications. 
3) Assess any adverse events. 
4) Assess subject dosing compliance. 
 
5) Measure corrected visual acuity 
  
 
 
 
6) Conduct slit-lamp biomicroscopy & ocular assessments 
(conjunctiva and iris).  
7) Measure diurnal IOP at 8:00 AM (within ±30 minutes) using the 
two-person methodology . 
8) Immediately after the 8:00 AM measurement, instill one drop of 
masked study medication. 
9) Conduct a gonioscopic examination. 
10) Assess optic nerve abnormality (ophthalmoscopy). 
11) 
 
 

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12) Measure diurnal IOP at 10:00 AM (± 30 minutes) using the two-
person methodology.
12) Measure diurnal IOP at 4:00 PM (± 30 minutes) using the two-
person methodology.
13) Dispense replacement masked study medication to the subject and
14) Schedule the subject to return for Visit 9 (Month 6) to collect a
standard IOP measurement at either 8:00 AM, 10:00 AM, OR
4:00 PM.  If Visit 9 (Month 6) is scheduled for an 8:00 AM IOP
measurement, instruct the subject to instill the masked study
medication the evening before Visit 9 (Month 6), but not on the
morning of Visit 9 (Month 6).  Remind the subject to bring all
study medications to the visit.

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9.2 
Analysis Populations 
9.2.1 SAFETY POPULATION (SP) 
The safety analysis population will contain all subjects who are randomized 
and receive any level of treatment.  Subjects will be grouped according to 
their actual treatment received, not according to their randomization 
assignment (as randomized). 
9.2.2 INTENT-TO-TREAT (ITT) POPULATION  
This subset includes all subjects who are randomized.  All baseline 
characteristics will be summarized based on ITT.  Subjects in the ITT will be 
analyzed according to original treatment assignment, regardless of actual 
treatment received.  The primary analyses will be based on this ITT 
population. 
9.2.3 PER-PROTOCOL (PP) POPULATION  
The Per Protocol Population is a subset of ITT.  It includes all the ITT 
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randomization schedule and do not have the major protocol deviations likely 
to impact the primary efficacy endpoints. 
 
 
 
9.3 
General Statistical Methods 
9.4 
Safety Analyses 
No formal statistical testing will be conducted for the safety analyses.  No 
imputation will be performed for the missing values.  All summaries will be 
based on the available data of the safety population.   
Descriptive statistics will be calculated as described in Section 9.3 at each 
visit for the 3 treatment groups separately.  For each reported adverse event in 
each treatment group, the percentage of eyes will be reported.  The sections 
below describe specific data handling for adverse events, and best spectacle 
corrected visual acuity (BSCVA). 
Other safety outcomes such as slit lamp examination, intraocular pressure, 
dilated fundus examination, and endothelial cell count (from specular 
microscopy at selected sites) will be summarized descriptively at each visit for 
the Safety Population.  Line listings for abnormal findings for individual eyes 

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9.5.4 ANALYSIS OF KEY SECONDARY EFFICACY 
ENDPOINTS 
 
9.5.5 SENSITIVITY ANALYSES 
Various sensitivity analyses will be performed, as specified in the statistical 
analysis plan, to determine robustness of results to underlying assumptions of 
missing data and data after intercurrent events. 
 
9.5.6 SUBGROUP ANALYSES 
Subgroup analyses will be performed, as specified in the statistical analysis 
plan, to investigate consistency of results across identified subgroups.  
 
9.5.7 OTHER EFICACY ANALYSES 
The same analyses as described above for primary (Section 9.5.3) and 
secondary (Section 9.5.4) efficacy will be performed for IOP evaluations at 
9.6 
Interim Analyses 
No interim analyses are planned. 
10 ADVERSE EVENTS   
An Adverse Event (AE) is defined as any untoward and unintended medical 
occurrence (e.g., sign, symptom, disease, syndrome, intercurrent illness) that 
occurs in a study subject, regardless of the suspected cause during the study. 
Adverse events will be clearly documented on the study source document and 
monitored throughout the course of the study.   
Events occurring after signing the informed consent but prior to the implant or 
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observed during or after the implant or sham procedure until the final study 
visit, are to be recorded as AEs.  
Any clinically significant change in a subject's condition after receiving any of 
the study treatments, regardless of causality, is to be considered an adverse 
event, unless the change is determined to be a continuation of a pre-existing 
condition that is documented in the subject's medical history.  If an adverse 
event occurs, an AE form must be completed.   
An AE includes any of the following: 
 An exacerbation or an unexpected increase in frequency or intensity of a 
pre-existing condition, including intermittent or episodic conditions 
 New conditions or illnesses detected or diagnosed after the implant or 
sham procedure 
 A suspected interaction with any of the study treatments 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
any of the study treatments or a concomitant medication 
 Any clinically significant laboratory finding that was not present prior to 
receiving any of the study treatments 
An AE does NOT include any of the following: 
 Anticipated day-to-day fluctuations of any pre-existing conditions, 
including the disease under study (OAG and OHT). 
 Medical or surgical procedure, (e.g., colonoscopy or hernia repair).  The 
condition that led to the procedure may be an AE, if not present in medical 
history. 
 Hospitalizations where an untoward medical occurrence did not occur 
(social or convenience admission to the hospital). 
 Pre-existing conditions or diseases that were present before receiving any 
of the study treatments that do not worsen or that are chronic but stable 
 Changes in a chronic condition or disease that are consistent with natural 
disease progression.  (These medical conditions should be adequately 
documented).   
 Lack of efficacy of the study treatment for the condition being 
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AEs will be graded on a 3-point scale and reported in detail as indicated on 
the CRF: 
Mild: 
easily tolerated, causing minimal discomfort and not 
interfering with normal everyday activities 
Moderate: 
sufficiently discomforting to interfere with normal 
everyday activities 
Severe:  
incapacitating and/or preventing normal everyday activities 
 
The relationship of each AE to study treatment should be determined by the 
investigator using the following explanations: 
 
Definitely Unrelated: 
the event is clearly related to other factors such as the 
subject’s clinical state, therapeutic interventions, or 
concomitant medications administered to the subject 
 
Unlikely Related: 
the event is most likely produced by other factors such as 
the subject’s clinical state, therapeutic interventions, or 
concomitant medications administered to the subject; and 
does not follow a known response pattern to the study 
medication 
 
Possibly Related: 
the event follows a reasonable temporal sequence from 
the time of drug administration; and/or follows a known 
response pattern to the study medication; but could have 
been produced by other factors such as the subject’s 
clinical state, therapeutic interventions, or concomitant 
medications administered to the subject 
 
Probably Related: 
the event follows a reasonable temporal sequence from 
the time of drug administration; and/or follows a known 
response pattern to the study medication; and is not likely 
to have been produced by other factors such as the 
subject’s clinical state, therapeutic interventions, or 
concomitant medications administered to the subject 
 
Definitely Related: the event follows a reasonable temporal sequence from 
the time of drug administration; and follows a known 
response pattern to the study medication; and cannot be 
reasonably explained by other factors such as the 
subject’s clinical state, therapeutic interventions, or 
concomitant medications administered to the subject 
 

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10.1 
Serious Adverse Event 
Serious adverse events are defined as any findings that suggest a significant 
hazard, contraindication, side effect, or precaution.  Any adverse event is 
considered a serious adverse event if it results in any of the following 
outcomes: 
‐ 
Death 
‐ 
Life- or sight-threatening 
‐ 
Required admission to the hospital or prolongation of an existing 
hospitalization (emergency room visits that do not result in admission 
to the hospital should be evaluated for one of the other serious 
outcomes) 
‐ 
A persistent or significant disability/incapacity 
‐ 
A congenital anomaly/birth defect 
 
The terms “mild,” “moderate,” and “severe” are measures of intensity; thus a 
severe AE is not necessarily serious.  For example, nausea of several hours 
duration may be rated as severe, but may not be clinically serious. 
 
Important medical events that may not result in death, be life-threatening, or 
require admission to the hospital may be considered a serious adverse drug 
experience when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above.  A life-threatening event is any 
event that places the subject at substantial risk of death from the event as it 
occurred; it does not refer to an event that hypothetically might have caused 
death if it were more severe.  A sight-threatening event is any event that 
places the subject at risk of permanently losing vision in either eye as a direct 
result of the event. 
 
Serious adverse events must be reported to Glaukos immediately (preferably 
within 24 hours of knowledge of the event). 
Email:  
 
When new significant information (including the outcome of the event) is 
obtained, the investigator should inform Glaukos as soon as possible.  
Depending on the nature of the AE, Glaukos may request copies of the 
ophthalmic and medical records of the subject.  If the subject was hospitalized 
for a study-treatment related serious adverse event, a copy of the discharge 
summary must be forwarded to Glaukos as soon as possible. 
 
10.2 
Unexpected Adverse Event 
An adverse event is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been 

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observed, or is not consistent with the risk information described in the 
general investigational plan or protocol.   
Unexpected adverse events must be reported to Glaukos immediately 
(preferably within 24 hours of knowledge of the event).   
 
Email: i
 
When new significant information (including the outcome of the event) is 
obtained, the investigator should inform Glaukos as soon as possible.  
Depending on the nature of the AE, Glaukos may request copies of the 
ophthalmic and medical records of the subject.  If the subject was hospitalized 
for a study-treatment related unexpected adverse event, a copy of the 
discharge summary must be forwarded to Glaukos as soon as possible. 
 
10.3 
Suspected, Unexpected, Serious, Adverse Event (SUSAR) 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is any AE for 
which there is evidence to suggest a causal relationship between the 
Travoprost Intraocular Implant and the AE, and which is assessed as both 
unexpected and serious.  An unexpected adverse reaction, i.e. any untoward 
and unintended response to any of the study treatments, is one for which the 
nature and severity is inconsistent with the applicable reference safety 
information (e.g., Investigator’s Brochure).  
 
10.4 
Adverse Events Follow-up 
Adverse events will be followed and documented until the time of complete 
resolution, or resolution with sequelae, or exit from the study with an 
assessment of the outcome.  
 
11 MAINTAINING THE MASK 
This will be a masked study, in which the treatments will be unknown to the 
subject and the site staff performing certain measurements.  All surgical study 
kits will be packaged in boxes labeled with the study number and unique kit 
number.  All medication study kits will be packaged in boxes labeled with the 
study number and unique kit number.  The study medications dispensed at a 
given site will be contained in bottles that are similar in size and cap color and 
packaged in identical study kit boxes.  Both the bottles and the kit boxes will 
be labeled with the study number and unique kit number and dosing 
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Glaukos must be informed of all instances where a subject's treatment was 
unmasked and the reasons for unmasking.  In case of a medical emergency 
where it is necessary to know which study medication a subject received, the 
investigator may obtain the subject's treatment assignment.   
 
 
12 INFORMED CONSENT 
The investigator or designee will discuss the purpose and pertinent details of 
the study with each subject.  The Informed Consent Form must be approved 
by the governing Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC).  Prior to undergoing any study related change in their 
treatment or any study related procedures, a subject must understand, sign, 
and date the appropriate IRB-approved Informed Consent Form.  The signed 
and dated Informed Consent Form will be retained with the study records, and 
a copy of the signed Informed Consent will be given to the subject. 
 
13 INSTITUTIONAL REVIEW 
This study must be reviewed and approved by an appropriate Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC).  A copy of the 
letter indicating IRB approval must be provided to Glaukos (or designee) prior 
to study initiation.  Updates must be provided to the IRB by the investigator at 
least annually or as required by the IRB. 
 
14 CONFIDENTIALITY/PUBLICATION OF THE STUDY 
The existence of this clinical study is confidential, and it should not be 
discussed with persons outside of the study.  Additionally, the information in 
this document and regarding this study contains trade secrets and 
commercially sensitive information that is confidential and may not be 
disclosed unless such disclosure is required by federal or state law or 
regulations.  Subject to the foregoing, this information may be disclosed only 
to those persons involved in the study who have a need to know, but all such 
persons must be instructed not to further disseminate this information to 
others.  These restrictions of disclosure will apply equally to all future 
information supplied to you that is indicated as confidential. 
 
The data generated by this clinical study are the property of Glaukos (the 
Sponsor) and should not be disclosed without the prior written permission of 
Glaukos.  These data may be used by Glaukos now and in the future for 
presentation or publication at Glaukos' discretion or for submission to 
governmental regulatory agencies.  Glaukos reserves the right of prior review 
of any publication or presentation of data from this study. 
 

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In signing this protocol, the investigator agrees to the release of the data from 
this study, and acknowledges the above publication policy. 
15 STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the protocol, good clinical 
practices (GCP), and all applicable laws and regulations. 
 
The clinical investigator must maintain all information supplied by Glaukos in 
confidence, and when this information is submitted to an institutional review 
board (IRB), independent ethics committee (IEC) or another group, it will be 
submitted with a designation that the material is confidential. 
 
The clinical investigator must ensure that all persons assisting with the trial 
are adequately informed about the protocol, the investigational product(s), and 
their trial-related duties and functions. 
 
16 RECORD KEEPING 
16.1 
Source Documents 
The clinical investigator must maintain detailed source documents on all study 
subjects.  Source documents include subject medical records, hospital charts, 
clinic charts, investigator subject study files, as well as the results of 
diagnostic tests (e.g., laboratory tests, visual field test printouts). 
The following minimum information should be entered into the subject's 
medical record: 
‐ 
The date the subject entered the study and the subject number 
‐ 
The study protocol number and the name of Glaukos 
‐ 
The date that informed consent was obtained 
‐ 
Evidence that the subject meets study eligibility requirements (e.g., 
medical history, study procedures and/or evaluations) 
‐ 
The dates of all study related subject visits 
‐ 
Evidence that required procedures and/or evaluations were completed 
‐ 
Use of any concurrent medications 
‐ 
Documentation of study medication accountability, including a copy of 
study medication labels 
‐ 
Occurrence and status of any adverse events 
‐ 
The date the subject exited the study, and a notation as to whether the 
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16.2 
Data Collection 
The clinical investigator must maintain detailed records on all enrolled 
subjects.  Data for enrolled subjects will be collected with an electronic data 
capture system.  The electronic database, which is Title 21 CFR Part 11 
compliant, will be managed by a data management vendor.  Access to the 
database will be granted to authorize study personnel based on their role after 
training; and the access will be password-protected.  The data clarification 
process will be managed within the electronic data capture system by either 
system-generated or manually generated electronic queries.  Accuracy of data 
will be verified by source data verification at regular intervals, and all 
corrections to data will be made in the database.  CRF forms are completed 
for all enrolled subjects, regardless of their final study status (e.g., subject 
discontinuation, study termination). 
16.3 
Study Supply Accountability 
The principal investigator is responsible for ensuring that an inventory is 
conducted upon receipt of the clinical supplies and that the clinical study 
supplies are received and stored as instructed.  The receipt of clinical supplies 
should be completed, signed, and returned as directed by Glaukos (or 
designee).  A copy must be maintained at the site for the investigator's 
records.  The principal investigator will keep a current record of the inventory 
and dispensing of all study medications.  This record will be made available to 
the Glaukos monitor (or designee) for the purpose of accounting for all 
clinical supplies.  Any significant discrepancy and/or deficiency must be 
recorded with an explanation.  All supplies sent to the investigator must be 
accounted for and in no case will study medications be used in any 
unauthorized situation.  It is the responsibility of the principal investigator to 
return or destroy any used and unused supplies to the Glaukos monitor (or 
designee) at the conclusion of the study. 
16.4 
Record Retention 
All records relating to the conduct of this study are to be retained by the 
investigator until notified by Glaukos that the records may be destroyed. 
The investigator will allow representatives of Glaukos' monitoring team (or 
designee), the governing institutional review board, the Food and Drug 
Administration (FDA), and other applicable regulatory agencies to inspect all 
study records, CRFs, and corresponding portions of the subject's office and/or 
hospital medical records at regular intervals throughout the study.  These 
inspections are for the purpose of verifying adherence to the protocol, 
completeness, and exactness of the data being entered onto the CRF, and 
compliance with FDA or other regulatory agency regulations. 
 

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Visits with Diurnal IOPs are in Red 
 
 

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APPENDIX B:  OBLIGATIONS OF THE INVESTIGATOR 
In summary, the clinical investigator has agreed to the following obligations: 
‐ 
Obtaining informed consent from every subject prior to enrollment in the 
study and maintaining records of consent as part of the study records. 
‐ 
Obtaining approval from the Institutional Review Board (IRB) before 
enrolling any subject; submitting verification of the approval to the 
Sponsor; submitting periodic progress reports (at least annually) and final 
report to IRB. 
‐ 
Approving the protocol and conducting the study according to the protocol 
and applicable regulations; informing the Sponsor of all deviations from 
the protocol. 
‐ 
Informing the IRB of all protocol amendments/modifications; sending the 
Sponsor a copy of the letter from the IRB approving the 
amendment/modification. 
‐ 
Reporting to the Sponsor and the IRB any adverse experiences that occur 
in the course of the investigation. 
‐ 
Keeping careful and accurate records of all clinical study data (study 
records must be considerably more exact and complete than those kept in 
ordinary medical practice); maintaining records of all materials submitted 
to the IRB and of all action by the IRB regarding the study. 
‐ 
Making study records available for inspection by the Sponsor and 
representatives of the Food and Drug Administration; keeping records 
until notified by the Sponsor that they may be destroyed. 
‐ 
Maintaining proper control and documentation of all test and control 
articles. 
‐ 
Submitting the following records and reporting to the Sponsor (See I, II, 
and III). 
 
I. Prior to Beginning the Study 
‐ 
A signed Form FDA-1572 or Statement of Investigator. 
‐ 
A current curriculum vitae (CV) if not submitted to Glaukos previously or if 
updated. 
‐ 
CVs for all sub-investigators listed on the 1572. 
‐ 
A letter from the Institutional Review Board (IRB) indicating that the protocol 
was approved, including the name and address of the IRB. 
‐ 
A copy of the consent form approved by IRB. 
‐ 
A list of current members of the IRB. 
 

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II. While the Study is in Progress 
‐ 
Acknowledgment of receipt of the test and control articles; 
documentation of disposition of all test and control articles. 
‐ 
Original Case Report Forms for each subject enrolled in the study. 
‐ 
Information regarding all deviations from the protocol. 
‐ 
Information regarding all adverse medical events occurring to a 
subject while enrolled in the study. 
‐ 
Annual progress report (if study is ongoing for more than one year). 
Letter from the IRB indicating approval of the annual progress report. 
 
III. Once the Study is Completed 
‐ 
Disposition of all used and/or unused test and control articles, as well as 
documentation of all drug accountability. 
‐ 
A final study report (if requested). 
 
 
 
 

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APPENDIX C:  DECLARATION OF HELSINKI 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
 
Ethical principles for medical research involving human subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, 
October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of 
Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and 
data. 
The Declaration is intended to be read as a whole and each of its 
constituent paragraphs should be applied with consideration of all other 
relevant paragraphs. 
 
2.         Consistent with the mandate of the WMA, the Declaration is addressed 
primarily to physicians.  The WMA encourages others who are involved in 
medical research involving human subjects to adopt these principles. 
 
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the 
words, “The health of my patient will be my first consideration,” and the 
International Code of Medical Ethics declares that, “A physician shall act 
in the patient’s best interest when providing medical care.” 
 
4.         It is the duty of the physician to promote and safeguard the health, well-
being and rights of patients, including those who are involved in medical 

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research. The physician’s knowledge and conscience are dedicated to the 
fulfilment of this duty. 
 
5.         Medical progress is based on research that ultimately must include studies 
involving human subjects. 
 
6.         The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures 
and treatments).  Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, 
accessibility and quality. 
 
7.         Medical research is subject to ethical standards that promote and ensure 
respect for all human subjects and protect their health and rights. 
 
8.         While the primary purpose of medical research is to generate new 
knowledge, this goal can never take precedence over the rights and 
interests of individual research subjects. 
 
9.         It is the duty of physicians who are involved in medical research to protect 
the life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects.  The 
responsibility for the protection of research subjects must always rest with 
the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
 
10.       Physicians must consider the ethical, legal and regulatory norms and 
standards for research involving human subjects in their own countries as 
well as applicable international norms and standards.  No national or 
international ethical, legal or regulatory requirement should reduce or 
eliminate any of the protections for research subjects set forth in this 
Declaration. 
 
11.       Medical research should be conducted in a manner that minimises possible 
harm to the environment. 
 
12.       Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training 
and qualifications.  Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other 
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13.       Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
 
14.       Physicians who combine medical research with medical care should 
involve their patients in research only to the extent that this is justified by 
its potential preventive, diagnostic or therapeutic value and if the 
physician has good reason to believe that participation in the research 
study will not adversely affect the health of the patients who serve as 
research subjects. 
 
15.       Appropriate compensation and treatment for subjects who are harmed as a 
result of participating in research must be ensured. 
 
Risks, Burdens and Benefits 
16.       In medical practice and in medical research, most interventions involve 
risks and burdens. 
Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the 
research subjects. 
 
17.       All medical research involving human subjects must be preceded by 
careful assessment of predictable risks and burdens to the individuals and 
groups involved in the research in comparison with foreseeable benefits to 
them and to other individuals or groups affected by the condition under 
investigation. 
Measures to minimise the risks must be implemented.  The risks must be 
continuously monitored, assessed and documented by the researcher. 
 
18.       Physicians may not be involved in a research study involving human 
subjects unless they are confident that the risks have been adequately 
assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there 
is conclusive proof of definitive outcomes, physicians must assess whether 
to continue, modify or immediately stop the study. 
 

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Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically 
considered protection. 
 
20.       Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research 
cannot be carried out in a non-vulnerable group.  In addition, this group 
should stand to benefit from the knowledge, practices or interventions that 
result from the research. 
 
Scientific Requirements and Research Protocols 
21.       Medical research involving human subjects must conform to generally 
accepted scientific principles, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation.  The welfare of 
animals used for research must be respected. 
 
22.       The design and performance of each research study involving human 
subjects must be clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations 
involved and should indicate how the principles in this Declaration have 
been addressed.  The protocol should include information regarding 
funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating 
and/or compensating subjects who are harmed as a consequence of 
participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements 
for post-trial provisions. 
 

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Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, 
guidance and approval to the concerned research ethics committee before 
the study begins.  This committee must be transparent in its functioning, 
must be independent of the researcher, the sponsor and any other undue 
influence and must be duly qualified.  It must take into consideration the 
laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards but 
these must not be allowed to reduce or eliminate any of the protections for 
research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies.  The 
researcher must provide monitoring information to the committee, 
especially information about any serious adverse events.  No amendment 
to the protocol may be made without consideration and approval by the 
committee.  After the end of the study, the researchers must submit a final 
report to the committee containing a summary of the study’s findings and 
conclusions. 
 
Privacy and Confidentiality 
24.       Every precaution must be taken to protect the privacy of research subjects 
and the confidentiality of their personal information. 
 
Informed Consent 
25.       Participation by individuals capable of giving informed consent as 
subjects in medical research must be voluntary.  Although it may be 
appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
 
26.       In medical research involving human subjects capable of giving informed 
consent, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, 
institutional affiliations of the researcher, the anticipated benefits and 
potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study.  The potential 
subject must be informed of the right to refuse to participate in the study 
or to withdraw consent to participate at any time without reprisal.  Special 
attention should be given to the specific information needs of individual 
potential subjects as well as to the methods used to deliver the 
information. 

CLINICAL PROTOCOL 
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Protocol No.: 
July 26, 2022 
Phase 3 Study 
GC-012 
 
 
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After ensuring that the potential subject has understood the information, 
the physician or another appropriately qualified individual must then seek 
the potential subject’s freely-given informed consent, preferably in 
writing.  If the consent cannot be expressed in writing, the non-written 
consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being 
informed about the general outcome and results of the study. 
 
27.       When seeking informed consent for participation in a research study the 
physician must be particularly cautious if the potential subject is in a 
dependent relationship with the physician or may consent under duress.  In 
such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
 
28.       For a potential research subject who is incapable of giving informed 
consent, the physician must seek informed consent from the legally 
authorised representative.  These individuals must not be included in a 
research study that has no likelihood of benefit for them unless it is 
intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of 
providing informed consent, and the research entails only minimal risk 
and minimal burden. 
 
29.       When a potential research subject who is deemed incapable of giving 
informed consent is able to give assent to decisions about participation in 
research, the physician must seek that assent in addition to the consent of 
the legally authorised representative.  The potential subject’s dissent 
should be respected. 
 
30.       Research involving subjects who are physically or mentally incapable of 
giving consent, for example, unconscious patients, may be done only if the 
physical or mental condition that prevents giving informed consent is a 
necessary characteristic of the research  group.  In such circumstances the 
physician must seek informed consent from the legally authorised 
representative.  If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent 
provided that the specific reasons for involving subjects with a condition 
that renders them unable to give informed consent have been stated in the 
research protocol and the study has been approved by a research ethics 
committee.  Consent to remain in the research must be obtained as soon as 
possible from the subject or a legally authorised representative. 

CLINICAL PROTOCOL 
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Protocol No.: 
July 26, 2022 
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GC-012 
 
 
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31.       The physician must fully inform the patient which aspects of their care are 
related to the research.  The refusal of a patient to participate in a study or 
the patient’s decision to withdraw from the study must never adversely 
affect the patient-physician relationship. 
 
32.       For medical research using identifiable human material or data, such as 
research on material or data contained in biobanks or similar repositories, 
physicians must seek informed consent for its collection, storage and/or 
reuse.  There may be exceptional situations where consent would be 
impossible or impracticable to obtain for such research.  In such situations 
the research may be done only after consideration and approval of a 
research ethics committee. 
 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must 
be tested against those of the best proven intervention(s), except in the 
following circumstances: 
• 
Where no proven intervention exists, the use of placebo, or no 
intervention, is acceptable; or 
• 
Where for compelling and scientifically sound methodological 
reasons the use of any intervention less effective than the best 
proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention 
• 
and the patients who receive any intervention less effective than 
the best proven one, placebo, or no intervention will not be subject 
to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country 
governments should make provisions for post-trial access for all 
participants who still need an intervention identified as beneficial in the 
trial.  This information must also be disclosed to participants during the 
informed consent process. 
 
 

CLINICAL PROTOCOL 
Date: 
 
Phase: 
 
Protocol No.: 
July 26, 2022 
Phase 3 Study 
GC-012 
 
 
CONFIDENTIAL 
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Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a 
publicly accessible database before recruitment of the first subject. 
 
36.       Researchers, authors, sponsors, editors and publishers all have ethical 
obligations with regard to the publication and dissemination of the results 
of research.  Researchers have a duty to make publicly available the 
results of their research on human subjects and are accountable for the 
completeness and accuracy of their reports.  All parties should adhere to 
accepted guidelines for ethical reporting.  Negative and inconclusive as 
well as positive results must be published or otherwise made publicly 
available.  Sources of funding, institutional affiliations and conflicts of 
interest must be declared in the publication.  Reports of research not in 
accordance with the principles of this Declaration should not be accepted 
for publication. 
 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do 
not exist or other known interventions have been ineffective, the 
physician, after seeking expert advice, with informed consent from the 
patient or a legally authorised representative, may use an unproven 
intervention if in the physician’s judgement it offers hope of saving life, 
re-establishing health or alleviating suffering.  This intervention should 
subsequently be made the object of research, designed to evaluate its 
safety and efficacy.  In all cases, new information must be recorded and, 
where appropriate, made publicly available.