Clinical trial NCT03284853
Conditions: Open Angle Glaucoma Ocular Hypertension
Sponsor: Aerie Pharmaceuticals
Start date: 2017-09-05; Completion date: 2020-11-06
Enrollment: 436 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is intended to test the effectiveness and safety of Netarsudil / Latanoprost 0.02% / 0.005% Ophthalmic Solution, relative to GANFORT® for lowering of intraocular pressure (IOP) in patients with elevated intraocular pressure

Detailed description:

Arms: arm 1: PG324 Ophthalmic Solution (netarsudil 0.02% / latanoprost 0.005%) one drop daily to each eye for 180 days. arm 2: GANFORT® (bimatoprost 0.03%/timolol 0.5%) Ophthalmic solution one drop daily to each eye for 180 days.
Interventions: intervention 1: Netarsudil/Latanoprost 0.02%/0.005% intervention 2: GANFORT®
Intervention descriptions: intervention 1: Topical sterile ophthalmic solution intervention 2: Topical sterile ophthalmic solution

Protocol documents:
Prot_000.pdf: 
A prospective, double-masked, randomized, multicenter, active-
controlled, parallel-group, 6-month study assessing the safety 
and ocular hypotensive efficacy of PG324 Ophthalmic Solution 
compared to GANFORT® (bimatoprost 0.03%/timolol 0.5%) 
Ophthalmic Solution in subjects with elevated intraocular 
pressure (MERCURY 3) 
 
 
NCT03284853 
 
 
27 May 2020 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
 Aerie Pharmaceuticals Ireland Ltd. 
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CLINICAL STUDY PROTOCOL: PG324-CS303 
Study Title: 
A prospective, double-masked, randomized, multicenter, active-
controlled, parallel-group, 6-month study assessing the safety and 
ocular hypotensive efficacy of PG324 Ophthalmic Solution 
compared to GANFORT® (bimatoprost 0.03%/timolol 0.5%) 
Ophthalmic Solution in subjects with elevated intraocular pressure 
(MERCURY 3) 
Study Number: 
EudraCT Number: 
PG324-CS303 
2015-001528-41 
Study Phase: 
3 
Product Name: 
PG324 (netarsudil/latanoprost 0.02%/0.005%) Ophthalmic 
Solution 
Indication: 
Reduction of elevated intraocular pressure in subjects with open-
angle glaucoma or ocular hypertension 
Investigators: 
Multi-center 
Sponsor: 
Aerie Pharmaceuticals Ireland Ltd. 
Sponsor Contact: 
 
Medical Monitor: 
Version 
Original Protocol (Rev 0): 
Amendment 1 (Rev 1) 
Amendment 2 (Rev 2) - UK Specific 
Amendment 3 (Rev 3) 
Amendment 4 (Rev 4) 
Amendment 5 (Rev 5) - Hungary Specific 
Amendment 6 (Rev 6) 
Date 
05 December 2016 
27 January 2017 
07 April 2017 
05 June 2017 
19 March 2018 
06 August 2018 
27 May 2020 
Confidentiality Statement 
This document contains Aerie Pharmaceuticals Ireland Ltd. (Aerie) information that 
is confidential, a trade secret and/or proprietary in nature. It is loaned to you for your 
confidential use on behalf of Aerie and is not to be photocopied, disclosed or 
transmitted to any other person or party who is not covered by a Confidential 
Disclosure Agreement with Aerie. As the Principal Investigator you are responsible 
for the safekeeping and return of this document to Aerie upon request. You will be 
sent updated information and/or amendments as they become available. 




PG324 Ophthalmic Solution 
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Aerie Medical Monitor 
 
 
 
 
 
Clinical Laboratory 
 
 
 
Biostatistics  
 
 
 
Data Management 
 
 
 
 
 
 
 


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Amendment #1: 27 January 2017 
Changes made include the addition of a patient-reported outcome (PRO) tool (health survey 
questionnaire, SF-36 v.2) and clarification of storage conditions throughout the duration of 
the study. Modified text is shown here in bold type. Specifically: 
General / Throughout the document  
• Any corrections to dates and version number, due to the amendment to the 
protocol, were made, along with other miscellaneous typographical errors not 
previously addressed. 
• Language has been added to clarify that any activity conducted by the Sponsor 
may be carried out by a designee, if specified and documented. 
• List of Abbreviations has been updated. 
• Reference in support of the SF-36 PRO tool has been added. 
• An updated version of the PRO tool, NEI-VFQ-25 added to the appendices 
(Appendix 7), replacing the previous version. 
• A copy of the additional PRO tool, SF-36 v.2, added to the Appendices 
(Appendix 8). 
Synopsis, Sections 2.2, 6.5.1, 7.1.1, 7.1.21 Appendix 1, Appendix 2 
• Wherever PRO tools are discussed or described (previously just the Self-
Administered National Eye Institute (NEI) Visual Functioning Questionnaire 25 
(VFQ-25)), the Short Form Health Survey Questionnaire 36 (SF-36 v.2) has been 
added. 
• Clarifying language added that the PRO tool scores for PG324-treated subjects will 
be compared to GANFORT®-treated subjects’ scores. 
Section 5.10 Handling and Storage of Investigational Product 
• Storage conditions for PG324 have been updated such that IP should be kept at 2°C 
to 8°C/ 36°F to 46°F, in accordance with the drug label, throughout the study, 
including after it has been provided to the subject. 
Section 7.1.12 Visit 6, Month 3 08:00 hours and Appendix 1 and Appendix 2 
• Pachymetry added for consistency with other studies. 
Section 8.5.4.4 
• New section added detailing the analysis planned for PRO tool, SF-36 v.2. 
Appendix 7 
• Copy of NEI-VFQ-25 added to replace previous version. 
Appendix 8 
• Copy of SF-36 v2 added. 
None of these changes impact patient safety or exposure to investigational product. 
 
 


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Amendment #2: 07 April 2017 (Country Specific - UK) 
Changes made to the Protocol include: 
• Any corrections to dates and version number, due to the amendment to the 
protocol. 
• Amendment of the investigator requirements in case of emergency unmasking. 
• Amendment to the Safety Section with specific reference to reactions not listed in the 
AR-13324 Ophthalmic Solution (Netarsudil Ophthalmic Solution) / PG324 
Ophthalmic Solution Investigator Brochure and/or in Section 4.8 of Ganfort® SmPC.  
• Clarification to contraception guidance section with specific reference to sexual 
abstinence. 
• Amendment to the Protocol Deviation section to clarify that Protocol deviations are 
not acceptable and clarification of Sponsor responsibilities for the assessment and 
reporting to the MRHA if any non-compliances considered as a serious breach of 
GCP and the protocol, and other minor clarifications.  
• Administrative changes to numeration errors in the summary of changes section for 
Amendment #1: 27 January 2017. 
Modified or added text is shown here in bold type. Specifically: 
Section 5.5.1 Operational Measures at study sites 
WAS: “If the investigator feels it is necessary to unmask a subject’s treatment assignment in 
the event of an emergency situation, the Investigator should promptly contact the Sponsor’s 
medical monitor or Sponsor representative to discuss the rationale for proposal to unmask the 
subject. A decision will be made as to whether or not the treatment for the subject should be 
unmasked, preferably after consultation with the Sponsor’s Medical Monitor or designee. 
The treatment assignment will be revealed on a subject-by-subject basis, thus leaving the 
masking on remaining subject intact. 
In an emergency situation in which treatment of an adverse event requires immediate 
unmasking, and the investigator is unable to promptly contact the Sponsor or Sponsor 
representative’s Medical Monitor, the Investigator may unmask the treatment. The 
investigator will perform the unmasking through the IWRS or other randomization system. In 
case of such unmasking in an emergency situation, the investigator should contact the 
Sponsor/Sponsor representative immediately thereafter and document the unmasking in 
writing, recording the date, time and reason for unmasking the study drug treatment in the 
source documentation”. 


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IS: “If the investigator feels it is necessary to unmask a subject’s treatment assignment in the 
event of an emergency situation, the investigator will perform the unmasking through the 
IWRS or other randomization system. The treatment assignment will be revealed on a 
subject-by-subject basis, thus leaving the masking on remaining subjects intact. 
In case of such unmasking in an emergency situation, the investigator should contact the 
Sponsor/Sponsor representative immediately thereafter and document the unmasking in 
writing, recording the date, time and reason for unmasking the study drug treatment in the 
source documentation”. 
Section 7.2.1 Adverse Event Definitions 
WAS: “Unexpected adverse event or unexpected suspected adverse reaction.  An adverse 
event or suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been observed.”   
IS: “Unexpected adverse event or unexpected suspected adverse reaction.  An adverse event 
or suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in Section 8.4 of 
the Investigator’s Brochure ‘Reference Safety Information’ or is not listed at the specificity 
or severity that has been observed”. 
Section 7.2.5 Expectedness 
WAS: “An AE or suspected adverse reaction is considered “unexpected” if it is not listed in 
the Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed”.   
IS: “An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Section 8.4 of the Investigator’s Brochure ‘Reference Safety Information’ or is not listed at 
the specificity or severity that has been observed”.   
Section 7.2.6 Serious Adverse Events (SAE’s) or Serious Unexpected Suspected Adverse 
Reaction Safety reports (SUSARs) 
WAS: “An investigator must immediately report to the Sponsor representative any SAE or 
serious unexpected suspected adverse reactions within 24 hours of occurrence or being 
informed of the event, whether or not considered drug related including those listed in the 
protocol or Investigator Brochure and must include an assessment of whether there is a 
reasonable possibility that the drug caused the event. Study endpoints that are serious adverse 
events (e.g., all-cause mortality) must be reported in accordance with the protocol unless 
there is evidence suggesting a causal relationship between the drug and the event (e.g., death 
from anaphylaxis. 
This requirement applies to occurrences observed during the course of the study and within 
30 days of last administration of the study medication. In addition, in the case of immediately 
life-threatening AEs or AEs with fatal outcome, or adverse events that are serious, 
unexpected (i.e., not in the Clinical Investigator’s Brochure) and judged related to the IP, the 


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Investigator must inform the Sponsor or Sponsor representative by phone within 24 hours of 
observation or occurrence of the SAE”. 
IS: “An investigator must immediately report to the Sponsor representative any SAE’s within 
24 hours of occurrence or being informed of the event, whether or not considered drug 
related including those listed in the protocol or investigator brochure and must include an 
assessment of whether there is a reasonable possibility that the drug caused the event. 
A reaction will be considered unexpected if it is not listed in the Reference Safety 
Information Section 8.4 in the AR-13324 Ophthalmic Solution (Netarsudil Ophthalmic 
Solution) / PG324 Ophthalmic Solution Investigator Brochure and/or in Section 4.8 of the 
GANFORT® SmPC (see Appendix 3). Study endpoints that are serious adverse events (e.g., 
all-cause mortality) must be reported in accordance with the protocol unless there is evidence 
suggesting a causal relationship between the drug and the event (e.g., death from 
anaphylaxis). 
This requirement applies to occurrences observed during the course of the study and within 
30 days of last administration of the study medication. In addition, in the case of immediately 
life-threatening AEs or AEs with fatal outcome, or adverse events that are serious, 
unexpected (i.e., not in the Clinical Investigator’s Brochure Reference Safety Information 
Section 8.4 and /or in Section 4.8 of the GANFORT® SmPC) and judged related to the IP, 
the Investigator must inform the Sponsor or Sponsor representative by phone within 24 hours 
of observation or occurrence of the SAE”. 
Section 7.2.6 Pregnancy Testing, Prevention and Reporting  
WAS: “sexual abstinence” 
IS: “sexual abstinence: sexual abstinence is only considered to be an acceptable method 
of contraception when defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject.   Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception. 
Male subjects 
WAS: “Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use an effective method of contraception from time of randomization 
and for 3 months following the last dose of study medication”. 
 
 


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Male subjects 
IS: “Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use a condom as an effective method of contraception from time of 
randomization and for 3 months following the last dose of study medication”. 
Section 11.6 Protocol Deviations 
WAS: “Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study regulatory acceptability or subject 
safety. Therefore, adherence to the criteria as specified in the protocol is essential. 
If a protocol deviation is identified by the investigator or through site monitoring activities an 
immediate submission to the IEC/CEC may be required e.g. 24 or 48 hours.  If per country 
requirements, the protocol deviation is not required to be reported immediately but is still 
required to be notified to the IEC/CEC, the specific protocol deviation will be added to the 
annual progress report”.   
IS: “Protocol Waivers or any deviations from the protocol inclusion and exclusion are not 
allowed because they can potentially jeopardize the scientific integrity of the study regulatory 
acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol 
is essential. 
If a protocol deviation is identified by the investigator or through site monitoring activities an 
immediate submission to the IEC/CEC may be required e.g. 24 or 48 hours.  The Sponsor 
will assess any protocol deviation and decide whether any of these non-compliances 
should be reported to the relevant competent authority as a serious breach of GCP and 
the protocol. If per the relevant competent authorities’ requirements, the protocol 
deviation is not required to be reported immediately but is still required to be notified to the 
IEC/CEC, the specific protocol deviation will be added to the annual progress report.” 
 
 


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Amendment #3: 05 June 2017 
Changes to the protocol have been made in accordance with observations made by the: 
German Federal Institute for Drugs and Medical Devices (BfArM) 23 March 2017: 
• New text added to include details of European Medicines Agency (EMA) scientific 
advice in the protocol as per BfArM request. 
• New text added to include rational for the IOP limits used for non-inferiority analysis 
as discussed with regulatory agencies. 
• Expanded rationale for selection of dose selection of netarsudil 0.02% ophthalmic 
solution. 
• New text added to document regarding validation status of NEI visual functioning 
questionnaire-25 (VFQ-25). 
• Inclusion of footnotes from the Clinical Trials Facilitation Group (CTFG) regarding 
highly effective contraception. 
• New text added to clarify how the IMPs under investigation differ and their influence 
on unmasking. 
• Inclusion of guidance for study subjects if a dose of study medication is missed. 
• Schedule of events includes IMP dispensation and collection. 
• Clarification of investigator responsibilities according to German requirements. 
 27 March 17: 
• Addition of risks associated with the washout period, weekly monitoring of subjects 
during the washout period and not exceeding a maximum of 8-week washout. 
• Only patients capable of giving their consent can participate in the study. 
 
April 2017: 
• Addition of inclusion criteria to indicate all subjects included in France are 
beneficiaries or members of a French social security system. 
• Addition of exclusion criteria regarding vulnerable individuals. 
• Addition of pregnancy test at Month 3. 
• Clarification to the Study Objectives. 
 
• Clarification of the selection the upper limit of intra ocular pressure (IOP) of 
25mmHg on treatment and 36mmHg off treatment required for subject inclusion.  
• Addition of exclusion of patients previously treated with GANFORT®. 
• Updated the exclusion criteria to include all contraindications as per Section 4.3 of 
the GANFORT® SmPC.  
• Inclusion of the reference justification for the washout period for beta blockers, 
muscarinic agonists and carbonic anhydrase inhibitors in Section 5.7.1 Prior Therapy 
Washout Period. 


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• Introduction of drug interactions indicated in the GANFORT® SmPC and the role of 
the investigator in judging the soundness of treating a study patient despite the 
concomitant administration of a drug on this list. 
• Justification the 30-day period after the study refraining from breast feeding. 
• Inclusion of urine pregnancy test for visits at Qualifying visit # 2, Week 2, Week 6, 
Month 3, Month 4 and Month 5, in addition to Month 6. Note: The pregnancy test 
at Qualifying visit #1 has been removed as the Sponsor has added a urine 
pregnancy test at Screening Visit. 
• Included direction to investigators with respect to monitoring patients with interim 
visits during the washout period. 
General/Throughout the Document 
Any corrections to dates and version number due to the amendment of the protocol were 
made, along with other miscellaneous typographical errors identified. 
Appendix 2: Procedures 
Language has been amended to clarify tonometer validation on at least a monthly basis must 
be documented. 
Appendix 3: Marketed Product Medication Information - GANFORT® 
Existing Summary of Product Characteristics replaced with extract from updated SmPC 
EPAR version 01 June 2017.  
Modified or added text is shown here in bold type, deleted text is indicated by strikethrough. 
For completeness, changes made in Amendment 2 that address questions raised by the 
Competent Authorities/Ethics Committees listed above are also included and, shown in bold 
italic type. Specifically: 
Synopsis: Section 2.1 – Primary Objectives; Section 2.2 – Secondary Objectives 
WAS: 
Primary Objectives: 
To evaluate: 
• The ocular hypotensive efficacy of PG324 Ophthalmic Solution relative to 
GANFORT® Ophthalmic solution over a 3-month period. 
• The ocular hypotensive safety of PG324 Ophthalmic Solution relative to GANFORT® 
Ophthalmic solution over a 6-month period. 
Secondary Objectives: 
To evaluate: 
• Change in Self-Administered National Eye Institute (NEI) Visual Functioning 
Questionnaire 25 (VFQ-25) score from baseline to study exit for PG324 compared to 
GANFORT®. 


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• Change in self-administered Short Form Health Survey Questionnaire 36 (SF-36 v2) 
score from baseline to study exit for PG324 compared to GANFORT®. 
IS: 
Primary Objectives: 
To evaluate: 
• The ocular hypotensive efficacy of PG324 Ophthalmic Solution relative to 
GANFORT® Ophthalmic solution over a 3-month period. 
• The ocular hypotensive safety of PG324 Ophthalmic Solution relative to 
GANFORT® Ophthalmic solution over a 6-month period. 
Secondary Objectives: 
To evaluate: 
• The ocular hypotensive safety of PG324 Ophthalmic Solution relative to 
GANFORT® Ophthalmic solution over a 6-month period. 
• Change in Self-Administered National Eye Institute (NEI) Visual Functioning 
Questionnaire 25 (VFQ-25) score from baseline to study exit for PG324 compared to 
GANFORT®. 
• Change in Self-Administered Short Form Health Survey Questionnaire 36 (SF-36 v2) 
score from baseline to study exit for PG324 compared to GANFORT®. 
Synopsis: Section 4.2 – Inclusion Criteria; Section 4.3 – Exclusion Criteria 
WAS: 
Inclusion Criteria: 
10. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception from time of randomization and for 
3 months following the last dose of study medication. 
Exclusion Criteria: 
4. Treatment-naïve subjects. 
5. Known hypersensitivity to any component of the investigational formulations to be used 
(e.g., benzalkonium chloride etc.) or to fluorescein. 
15. Known hypersensitivity or contraindication to β-adrenoceptor antagonists (e.g. Chronic 
obstructive pulmonary disease or bronchial asthma; abnormally low blood pressure or heart 
rate; second or third-degree heart block or congestive heart failure; severe diabetes). 
18. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable and highly effective form of birth control. An adult woman is 
considered to be of childbearing potential unless she is one year post-menopausal or three 
months post-surgical sterilization. 
 
 


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IS: 
Inclusion Criteria: 
10. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception from time of randomization and for 
3 months following the last dose of study medication. 
11. In France, a subject will be eligible for inclusion in this study only if either affiliated 
to or as a beneficiary of a social security number. 
Exclusion Criteria: 
4. Treatment-naïve subjects. 
5. PRIOR TREATMENT WITH GANFORT® TOPICAL EYE DROPS 
6. Known hypersensitivity to any component of the investigational formulations to be used 
(e.g., benzalkonium chloride etc.) or to fluorescein. 
Systemic 
15. Known hypersensitivity or contraindication to GANFORT® (Appendix 3 Marketed 
Product Medication Information Section 4.3) and to β-adrenoceptor antagonists 
(e.g. Chronic obstructive pulmonary disease or bronchial asthma; abnormally low blood 
pressure or heart rate; second or third-degree heart block or congestive heart failure; 
cardiac failure, cardiac shock and severe diabetes).  
20. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable and highly effective form of birth control. An adult woman is 
considered to be of childbearing potential unless she is one year post-menopausal (1 year 
without menses with appropriate clinical profile, e.g. age appropriate, > 45 years in the 
absence of HRT. In questionable cases the subject must have FSH value > 40mIU/mL 
and an estradiol value < 40pg/mL [< 140pmol/L]) or three months post-surgical 
sterilization. 
21. Vulnerable subjects such as minors, adults under legal protection or unable to 
express their consent (e.g. hospitalized persons in coma), persons deprived of liberty 
(prisoners from jails), or persons subject to psychiatric care. 
Section 1.2 – Findings from non-clinical and clinical studies 
WAS: 
Clinical 
“The investigations of this concentration (0.02%) and 2 other concentrations (0.01% and 
0.04%) in a Phase 2 dose response study (Clinical Study Report AR-13324-CS201) was used 
in order to define the appropriate concentration of netarsudil ophthalmic solution for the 
Phase 2 clinical studies of PG324.  


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A Phase 3 clinical study (AR-13324-CS302) evaluating the safety and efficacy netarsudil 
0.02% has been completed. As several different concentrations of netarsudil had already been 
evaluated with regard to efficacy and safety during netarsudil clinical development, no 
separate Phase 1 pharmacokinetic studies were conducted with the FDC. Based on the results 
obtained from the netarsudil program, it was decided to conduct a Phase 2 study with PG324 
0.02%. The Phase 2 study (study PG324-CS201) has been completed. Two Phase 3 studies 
(PG324-CS301 and PG324-CS302) are currently ongoing.”  
IS: 
Clinical 
“The investigation of the efficacy of the 3 doses of netarsudil (0.01%, 0.02% and 0.04%) 
were evaluated over 7 days. The 0.02% and 0.04% doses showed similar reduction of 
IOP, which was higher relative to the 0.01% dose. It was therefore concluded that the 
top of the dose response curve was reached at the 0.02% netarsudil concentration and 
this was selected as the appropriate concentration of netarsudil ophthalmic solution for 
further development. 
A Phase 3 clinical study (AR-13324-CS302) evaluating the safety and efficacy netarsudil 
0.02% has been completed. This study compared netarsudil 0.02% Q.D. and BID and 
Timolol 0.5% BID, and concluded that netarsudil 0.02% Q.D. was safe, generally well 
tolerated and provided IOP lowering that was non-inferior to timolol in subjects with 
OAG and OHT. Netarsudil 0.02% BID provided slightly larger IOP reductions but had 
a less favorable safety profile and therefore netarsudil 0.02% Q.D. was recommended 
as the dose for clinical use.  
As several different concentrations of netarsudil had already been evaluated with regard to 
efficacy and safety during netarsudil clinical development, no separate Phase 1 
pharmacokinetic studies were conducted with the FDC PG324. Based on the results obtained 
from the netarsudil program, it was decided to conduct a four arm Phase 2 study comparing 
two doses of PG324 (either 0.01% or 0.02% AR-13324 in combination with 0.005% 
latanoprost) against AR-13324 0.02% and latanoprost. The Phase 2 study (study PG324-
CS201) has been completed demonstrating superiority of the PG324 combinations over 
0.02% AR-13324 and 0.005% latanoprost alone. PG324 0.02% showed better IOP 
lowering than 0.01% and was selected for further development in Phase 3.  
Two pivotal Phase 3 studies (PG324-CS301 and PG324-CS302) are currently ongoing 
comparing PG324 with its components to demonstrate superiority and safety. In 
addition to these 2 pivotal studies a supportive study will be conducted comparing 
PG324 to a fixed dose combination therapy containing a prostaglandin analogue (PGA). 
Following review of the study through scientific advice procedure with the EMA, Aerie 
Pharmaceuticals has agreed to GANFORT® as the comparator. In addition, the EMA 
has reviewed and accepted the masking procedures as documented in this protocol.” 
 
 


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Section 4.1 – Study Population 
WAS: 
“A total of approximately 472 subjects will be enrolled in this study at approximately 40 sites 
in approximately 6 EU countries comprising a total of 236 subjects per each treatment arm 
for each of the two treatment arms. Subjects enrolled to this study will be those at least 18 
years of age with diagnosed OAG or OHT, each of whom meets all the inclusion criteria and 
none of the inclusion criteria.” 
IS: 
“A total of approximately 472 subjects will be enrolled in this study at approximately 46 sites 
in approximately 6 EU countries comprising a total of 236 subjects per each treatment arm 
for each of the two treatment arms. Subjects enrolled to this study will be those at least 18 
years of age with diagnosed OAG or OHT, who are currently using topical IOP- lowering 
medication. Inclusion criterion 4 specifies that subjects must present with medicated 
IOP at screening of > 18mmHg and < 25mmHg in both eyes and, in the opinion of the 
investigator, require a change in IOP therapy. The low limit IOP is based on the 
guidelines issued by the 
 with respect to initiating 
alternative therapy. The upper limit IOP is selected to exclude subjects who may require 
more aggressive therapy than a FDC to prevent glaucoma progression. Inclusion 
criterion 5 states that following a washout period from current IOP therapy, patients 
must present with an unmedicated IOP of > 20mmHg and < 36mmHg in both eyes at 2 
qualification visits at 08:00 hour, 2-7 days apart and at the second qualification visit, 
have IOP > 17mmHg and < 36mmHg in both eyes at 10:00 and 16:00 hours. The upper 
limit was chosen to exclude subjects who require a more aggressive therapy than a FDC 
to prevent glaucomatous damage. 
Subjects MUST meet all the inclusion criteria and none of the exclusion criteria.” 
Section 5.1 – Description of Treatments 
WAS: 
5.1.1 Investigational Product 
“PG324 Ophthalmic Solution is a sterile, isotonic, buffered aqueous solution containing 
netarsudil 0.02%, latanoprost 0.005%, boric acid, mannitol, water for injection, and 
preserved with benzalkonium chloride (0.02%). The product formulation is adjusted to 
approximately pH 5. 
5.1.2 Comparator 
GANFORT® (bimatoprost 0.03% / timolol maleate 0.5% ophthalmic solution) is a sterile, 
buffered aqueous solution containing sodium chloride, sodium phosphate dibasic 
heptahydrate, and citric acid monohydrate and preserved with benzalkonium chloride 
(0.005%).” 
 
 


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IS: 
5.1.1 Investigational Product  
“PG324 Ophthalmic Solution is a sterile, isotonic, buffered aqueous solution containing 
netarsudil 0.02%, latanoprost 0.005%, boric acid, mannitol, water for injection, and 
preserved with benzalkonium chloride (0.02%). The product formulation is adjusted to 
approximately pH 5. PG324 is a colorless to slightly yellowish solution (PG324 Safety 
data sheet). 
5.1.2 Comparator 
GANFORT® (bimatoprost 0.03% / timolol maleate 0.5% ophthalmic solution) is a sterile, 
buffered aqueous solution containing sodium chloride, sodium phosphate dibasic 
heptahydrate, and citric acid monohydrate and preserved with benzalkonium chloride 
(0.005%).  GANFORT® is a colorless to slightly yellow solution (GANFORT® SmPC).” 
5.2 
Treatment of Subjects 
WAS: 
“Subjects will be randomized to receive IP (PG324 Q.D. or the active comparator 
(GANFORT® Q.D.). All treatments will be both eyes (OU). Subjects will instill 1 drop of 
study drug into each eye, one time per day in the evening between 20:00 and 22:00 hours. 
Doses will be administered by the study subjects.  For subjects deemed unable to administer 
the doses, a guardian or alternative person will be asked to administer the medication. 
All subjects will administer study treatment for approximately 180 days.” 
IS: 
“Subjects will be randomized to receive IP (PG324 Q.D. or the active comparator 
(GANFORT® Q.D.). All treatments will be both eyes (OU). Subjects will instill 1 drop of 
study drug into each eye, one time per day in the evening between 20:00 and 22:00 hours 
(including days when the subject is scheduled to visit the study site). Doses will be 
administered by the study subjects.  For subjects deemed unable to administer the doses, a 
guardian or alternative person will be asked to administer the medication. All subjects will 
administer study treatment for approximately 180 days”. 
5.3 
Selection of Timing of Dose for Each Subject 
WAS: 
“The dose of PG324 selected for this study is based on the positive outcomes seen for PG324 
in the PG324-CS201 clinical study. Each IP dose is being administered Q.D. OU in the 
evening (between 20:00 and 22:00 hours) in this study to allow for estimated peak and trough 
levels of both netarsudil and latanoprost to be present in ocular tissue at the observation times 
selected in the clinic for the following morning and the subsequent afternoon. The treatment 
period is selected on the basis of non-clinical safety studies and regulatory requirements for 
studies of ophthalmic glaucoma medications.” 
 
 


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IS: 
“The dose of PG324 selected for this study is based on the positive outcomes seen for PG324 
in the PG324-CS201 clinical study. Each IP dose is being administered Q.D. OU in the 
evening (between 20:00 and 22:00 hours including days when the subject is scheduled to 
visit the study site) in this study to allow for estimated peak and trough levels of both 
netarsudil and latanoprost to be present in ocular tissue at the observation times selected in 
the clinic for the following morning and the subsequent afternoon. The treatment period is 
selected on the basis of non-clinical safety studies and regulatory requirements for studies of 
ophthalmic glaucoma medications.” 
Section 5.5 – Masking 
WAS: 
“Treatment assignments will be masked to the Investigator, the clinical study team, Sponsor/ 
Sponsor representative working on behalf of the Sponsor, personnel involved in day to day 
study management, Monitors, Data Managers, and Statisticians), and the subjects for the 
duration of the study.  
Masking of treatment assignment of study supplies is planned to be achieved via both IP 
packaging/labelling operations and as instructed in the study Pharmacy Manual.” 
IS: 
“The 
 through the scientific advice procedure has agreed to 
the masking procedures documented in this section.  
To minimize unmasking due to the differences in bottle closure cap colour, clinical 
supplies will be packaged in identical outer containers labeled appropriately for clinical 
trial use as detailed in Section 5.9 of this document. 
Differences in the physical characteristics of the PG324 and GANFORT® are minimal 
and should not pose a significant risk to the masking of the study. Both are essentially 
colourless liquids of equivalent viscosity which in individual eye drops are 
indistinguishable to subjects taking part in the study. 
Treatment assignments will be masked to the Investigator, the clinical study team, Sponsor/ 
Sponsor representative working on behalf of the Sponsor, personnel involved in day to day 
study management, Monitors, Data Managers, and Statisticians), and the subjects for the 
duration of the study.  
Masking of treatment assignment of study supplies is planned to be achieved via both IP 
packaging/labelling operations and as instructed in the study Pharmacy Manual.” 
 
 


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Section 5.6 – Concomitant Medications 
WAS: 
“Contact lens wear during the study is acceptable. However, subjects must remove their 
contact lenses at least 30 minutes before instillation of study medication, and not place them 
in their eye(s) until 30 minutes after instillation. 
Use of all medications should be documented on the appropriate CRF.  Investigators are 
encouraged to contact the Sponsor/Sponsor representative for any questions regarding 
allowed medications. Judgment of continued study participation by the subject, and inclusion 
of this subject’s subsequent visits in the safety and efficacy analysis will be made by the 
Sponsor.” 
IS: 
“Contact lens wear during the study is acceptable. However, subjects must remove their 
contact lenses at least 30 minutes before instillation of study medication, and not place them 
in their eye(s) until 30 minutes after instillation. 
As detailed in the GANFORT® SmPC Section 4.5 (Appendix 3) there is a potential for 
additive effects resulting in hypotension, and/or marked bradycardia when ophthalmic 
solution containing beta-blockers (timolol) is administered concomitantly with oral 
calcium channel blockers, guanethidine, beta-adrenergic blocking agents (prohibited 
see above), parasympathomimetics, anti-arrhythmics (including amiodarone) and 
digitalis glycosides.  
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been 
reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, 
fluoxetine, paroxetine) and timolol.  
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline 
(epinephrine which is prohibited) has been reported occasionally.  
Beta-adrenergic blocking agents and epinephrine are not permitted to be used 
concomitantly during the subject’s participation in the study. Concomitant use of the 
other medications is at the discretion of the investigator who must assess if the subject 
should participate in the study based on the potential interactions listed in Section 4.5 of 
the GANFORT® SmPC. 
Use of all medications should be documented on the appropriate CRF.  Investigators are 
encouraged to contact the Sponsor/Sponsor representative for any questions regarding 
allowed medications. Judgment of continued study participation by the subject, and inclusion 
of this subject’s subsequent visits in the safety and efficacy analysis will be made by the 
Sponsor.” 
 
 


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Section 5.7.1 – Prior Washout Period 
WAS: 
“Subjects must undergo a minimum washout period as specified in Table 1.  
For prostaglandins the minimum washout period should be not less than 4 weeks and it may 
be extended if deemed necessary in investigator opinion. 
If washout is to be extended beyond 8 weeks (56 days) for logistical or other reasons, the 
Sponsor should be contacted. (Stewart 2001).” 
Table 1 reference – Hughes 2005. 
IS: 
“Subjects must undergo a minimum washout period as specified in Table 1.  
For prostaglandins the minimum washout period should be not less than 4 weeks and it may 
be extended if deemed necessary in investigator opinion. 
Washout should not extend beyond 8 weeks (56 days). If for logistical or other reasons 
the period needs to be extended beyond 8 weeks (56 days), the Sponsor should be 
contacted.  
The risks associated with a wash period are increase in IOP requiring immediate 
intervention. Therefore, the investigator must monitor the subject regularly during the 
washout period, ideally every week.” 
Table 1 references – Stewart 2001, Hughes 2005, and 
 
November 2011 
Section 5.8 – Treatment Compliance 
WAS: 
“All subjects will be instructed on the importance of following the once-daily dosing 
regimen. Dosing should occur in the evening between 20:00 and 22:00 hours. As no 
commercially available method is readily available for direct, single-container monitoring of 
treatment adherence with multi-dose ophthalmic products, no formal measure of treatment 
compliance is planned.  Subjects should be reminded at all visits to dose every evening. In 
addition, subjects will be provided with a paper and electronic dosing reminder.” 
IS: 
“All subjects will be instructed on the importance of following the once-daily dosing 
regimen. Dosing should occur in the evening between 20:00 and 22:00 hours. As no 
commercially available method is readily available for direct, single-container monitoring of 
treatment adherence with multi-dose ophthalmic products, no formal measure of treatment 
compliance is planned.  Subjects should be reminded at all visits to dose every evening. In 
addition, subjects will be provided with a paper and electronic dosing reminder. 


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If a dose of study medication is missed the subject should take the next dose as planned. 
The dose of study medication should not exceed one drop daily.” 
Section 6.1 – Informed Consent 
WAS: 
“Prior to any study procedures, the study will be discussed with each subject and subjects 
wishing to participate must give written informed consent…At the end of the interview, the 
subject should be given time to reflect. Subjects and/or legally authorized representative then 
will be required to sign and date the informed consent form.”   
IS: 
“Prior to any study procedures, the study will be discussed with each subject and subjects 
wishing to participate must give written informed consent…At the end of the interview, the 
subject should be given time to reflect. Subjects and/or legally authorized representative 
then will be required to sign and date the informed consent form.” 
Section 7.1.1 – Visit 1 (Screening visit) 
WAS: 
“The following procedures will be performed:   
• Heart rate and blood pressure 
• Best Corrected Visual Acuity” 
IS: 
“The following procedures will be performed:   
• Confirm eligibility per inclusion and exclusion criteria 
• Heart rate and blood pressure 
• Urine pregnancy test: All females of childbearing potential must have a 
negative urine pregnancy prior to commencement of washout period 
• Best corrected visual acuity” 
Section 7.1.1.1 – Evaluation of eye-drop instillation performance 
WAS: 
“Subjects (or legally authorized representative for subjects deemed unable to administer) will 
be provided a bottle of commercially available, multi-dose, non-medicated artificial tears in a 
room with access to water and soap…If the subject (guardian or alternative person) cannot 
demonstrate proper delivery of the eye drop, or if staff member feels that the individual will 
be unable to do so consistently, then the subject will be excluded from further study 
participation.” 


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IS: 
“Subjects (or guardian or care giver for subjects deemed unable to administer) will be 
provided a bottle of commercially available, multi-dose, non-medicated artificial tears in a 
room with access to water and soap…If the subject (guardian or alternative person) cannot 
demonstrate proper delivery of the eye drop, or if staff member feels that the individual will 
be unable to do so consistently, then the subject will be excluded from further study 
participation.” 
Section 7.1.1.2 – Washout 
WAS: 
“As noted in Section 5.7.1, as current use of at least one ocular hypotensive medication is an 
inclusion criterion, a washout period is required for those who meet other qualifications for 
enrollment.  The investigator is encouraged to have interim visits during the washout period 
for IOP measurement for individuals for whom the washout period may be a risk for further 
glaucomatous progression.” 
IS: 
“As noted in Section 5.7.1, as current use of at least one ocular hypotensive medication is an 
inclusion criterion, a washout period is required for those who meet other qualifications for 
enrollment.  The investigator must perform interim visits, ideally at weekly intervals, 
during the washout period for IOP measurement.” 
Section 7.1.2 Visit 2 (Qualifying visit #1 for 08.00 hours IOP and safety measurements) 
WAS: 
The following procedures will be performed 
• Heart rate and blood pressure 
• Pregnancy test: All females of childbearing potential must have a negative urine 
pregnancy test result within 7 days prior to randomization 
• Symptomology: Individuals will be asked “How are you feeling”……. 
IS: 
• Heart rate and blood pressure 
• Symptomology: Individuals will be asked “How are you feeling”….. 
Section 7.1.3 - Visit 3.0 (Qualifying visit #2 for 08.00 hours IOP and safety  
measurements) 
WAS: 
The following procedures will be performed 
• Heart rate and blood pressure 
• Symptomology: Individuals will be asked “How are you feeling”……. 


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IS: 
• Heart rate and blood pressure 
• Urine pregnancy test: All females of childbearing potential must have a negative 
urine pregnancy test result within 7 days prior to randomization 
• Symptomology: Individuals will be asked “How are you feeling”….. 
Section 7.1.6 – Visit 4.0 (Week 2); Section 7.1.9 – Visit 5.0 (Week 6); Section 7.1.12 – 
Visit 6.0 (Month 3); Section 7.1.15 – Visit 7.0 (Month 4); Section 7.1.18 – Visit 8.0 
(Month 5)  
WAS: 
“Subjects will return to the Investigator’s office. The subject will be questioned about any 
missed doses and any changes in their health or concomitant medication use. Subjects will be 
examined and each examination will include: 
• Heart rate and blood pressure 
• Symptomatology: Individuals will be asked “How are you feeling?”” 
IS: 
“Subjects will return to the Investigator’s office. The subject will be questioned about any 
missed doses and any changes in their health or concomitant medication use. 
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure  
• Urine pregnancy test (female subjects of childbearing potential as applicable) 
• Symptomatology: Individuals will be asked “How are you feeling?”” 
Section 7.2.3 Severity 
WAS: 
“For example, a change in severity may go from mild to severe or from severe to moderate. 
In either case, the start and stop dates should be recorded.” 
IS: 
“For example, a change in severity may go from mild to severe or from severe to moderate. 
In both cases, the start and stop dates should be recorded.” 
Section 7.2.6 – Serious Adverse Events (SAEs) or Serious Unexpected Suspected 
Adverse Reaction Safety Reports (SUSARs) 
WAS: 
“Highly acceptable contraceptive methods when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows (Clinical Trials 
Facilitation Group 2014): 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 


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- 
oral 
- 
intravaginal 
- 
transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation.  
- 
oral 
- 
injectable 
- 
implantable  
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS) 
• bilateral tubal occlusion 
• vasectomised partner  
Sexual abstinence: sexual abstinence is only considered to be an acceptable method of 
contraception when defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the trial and the preferred and usual 
lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception.   
Female subjects who are lactating must discontinue nursing prior to the first dose of IP and 
must refrain from nursing throughout the treatment period and for 30 days following the last 
dose of IP. 
Male subjects 
Men with a female partner of childbearing potential must have either had a prior vasectomy 
or agree to use a condom as an effective method of contraception from time of 
randomization and for 3 months following the last dose of study medication. A combination 
of male condom with either cap, diaphragm or sponge with spermicide (double barrier 
methods) are also considered acceptable,…..” 
IS: 
“Highly acceptable contraceptive methods when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows (Clinical Trials 
Facilitation Group 2014): 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation. Due to lack of systemic absorption of netarsudil and 
no systemic effects seen with latanoprost, PG324 is not expected to lower the 
effectiveness of hormonal contraception 
- 
oral 
- 
intravaginal 
- 
transdermal 


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• progestogen-only hormonal contraception associated with inhibition of ovulation. 
Due to lack of systemic absorption of netarsudil and no systemic effects seen 
with latanoprost, PG324 is not expected to lower the effectiveness of hormonal 
contraception  
- 
oral 
- 
injectable 
- 
implantable (considered to have low user dependency) 
• intrauterine device (IUD)  
• intrauterine hormone-releasing system (IUS) (considered to have low user 
dependency) 
• bilateral tubal occlusion (considered to have low user dependency) 
Vasectomised partner (is considered as having lower user dependency and highly effective 
birth control method providing that the partner is the sole sexual partner of the women of 
childbearing potential and that the vasectomized partner has received a medical 
assessment of the surgical success). 
Sexual abstinence: sexual abstinence is only considered to be an acceptable method of 
contraception when defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the trial and the preferred and usual lifestyle of 
the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method 
(LAM) are not acceptable methods of contraception. 
Female subjects who are lactating must discontinue nursing prior to the first dose of IP and 
must refrain from nursing throughout the treatment period and for 30 days following the last 
dose of IP. 
Male subjects 
Men with a female partner of childbearing potential must have either had a prior vasectomy 
or agree to use a condom as an effective method of contraception from time of randomization 
and for 3 months following the last dose of study medication.  A combination of male 
condom with either cap, diaphragm or sponge with spermicide (double barrier 
methods) are also considered acceptable, but not highly effective, birth control methods. 
A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) is also considered acceptable,…..” 
Section 8.1 – Primary Hypotheses 
WAS: 
“Clinical non-inferiority will be concluded if the upper limit of the 95% CIs around the 
difference (PG324 Q.D. - GANFORT® Q.D.) is ≤ 1.5mmHg at all time points and ≤ 1.0 
mmHg at the majority of time points through Month 3.” 


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IS: 
“Clinical non-inferiority will be concluded if the upper limit of the 95% CIs around the 
difference (PG324 Q.D. - GANFORT® Q.D.) is ≤ 1.5mmHg at all time points and ≤ 1.0 
mmHg at the majority of time points through Month 3. 
The non-inferiority (NI) margin specified in the protocol was based on advice received 
from EMA through the scientific advice procedure (EMA/CHMP/SAWP/588765/2016) 
on 15 September 2016. In addition to the 1.5 mmHg margin at all time points specified 
in the draft protocol submitted to EMA for comment, advice was given that in 
accordance with the European Glaucoma Society’s (EGS) Glaucoma Guideline a 
difference of 1 mmHg in IOP was considered to also be clinically relevant and therefore 
a NI margin no larger than this at the majority of time points should be included in the 
protocol.  
As agreed with the USA FDA at the end of Phase 2 meeting for netarsudil (AR-13324) 
in accordance with the agency’s draft guidance paragraph 16 (recommended Sep 2008; 
Revised Feb 2014, Dec 2014, Mar 2015).” 
Section 13 REFERENCES 
WAS: 
7. Collaborative Normal-Tension Glaucoma Study Group.  The effectiveness of 
intraocular pressure reduction in the treatment of normal-tension glaucoma.  Am J 
Ophthalmol 1998; 126:498-505. 
8. Ferris FL, Freidlin V, Kassoff A, et al. Relative letter and position difficulty on 
visusal acuity charts from the early Treatment Diabetic Retinopathy Study. Am J 
Ophthalmol 1993; 116:735-40. 
IS: 
7. Collaborative Normal-Tension Glaucoma Study Group.  The effectiveness of 
intraocular pressure reduction in the treatment of normal-tension glaucoma.  Am J 
Ophthalmol 1998; 126:498-505. 
8. European Glaucoma Society, Tip of the Month, November 2011, Ann Hoste, 
Antwerp. 
9. Ferris FL, Freidlin V, Kassoff A, et al. Relative letter and position difficulty on visual 
acuity charts from the early Treatment Diabetic Retinopathy Study. Am J Ophthalmol 
1993; 116:735-40. 
Appendix 1 – Schedule of Visits and Examinations 
WAS: 
“Urine Pregnancy Test at Visit 2 (Qualification #1) and Visit 9.0 (Month 6 [Day 180])” 
IS: 
“Urine Pregnancy Test at Visit 1 (Screening visit), Visit 3.0 (Qualifying Visit #2), Visit 4.0 


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(Day 15), Visit 5.0 (week 6) Visit 6.0 (Month 3 [Day 90]), Visit 7.0 (Month 4 [Day 120]), 
Visit 8.0 (Month 5 [Day150]), and Visit 9.0 (Month 6 [Day 180])” 
WAS: 
9. Collect used kit(s) dispensed during the previous visit 
IS: 
9. Collect used kit(s) dispensed during the previous visit 
10. Per Section 5.2 and 5.3, subjects are required to administer IP on all days of the 
study, including days of study visits 
Appendix 2 – Procedures: 
Procedures:  Biomicroscopy and measurement of Intraocular pressure (IOP) 
WAS: “Tonometer calibration on at least a monthly basis will be documented.” 
IS: “Tonometer validation on at least a monthly basis will be documented.” 
Procedures: Self-Administered NEI Visual Functioning Questionnaire-25 (VFQ-25) 
WAS: 
“Translations of the NEI Visual Functioning Questionnaire -25 (VFQ-25), if available, will 
be provided for participating centers in non-English-speaking countries.” 
IS: 
“Translations of the NEI Visual Functioning Questionnaire -25 (VFQ-25), if available, will 
be provided for participating centers in non-English-speaking countries.” 
The NEI Visual Functioning Questionnaire-25 (VFQ-25) is a validated VFQ-25 and 
reliable 25-item version of the 51-item National Eye Institute Visual Function 
Questionnaire (NEI-VFQ). It is especially useful in settings such as clinical trials, where 
interview length is a critical consideration (Mangione 2001).” 
Appendix 5 – Investigator’s Obligations 
WAS: 
“The Investigator is obligated to: 
A. In the event of a serious adverse experience, whether related to the use of the study 
medication or device or not…” 
IS: 
“An Investigator for the PG324-CS303 study must be a physician duly qualified to 
practice medicine. The Investigator is obligated to: 


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A. Questioning (evaluation of) examination regarding, as well as collection and 
documentation of, adverse events and efficacy parameters. In the event of a serious 
adverse experience, whether related to the use of the study medication or device or not…” 
 
 


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Amendment #4: 19 March 2018 
Changes have been made to the protocol based on feedback from Investigators. The changes 
made reflect current clinical practice. The changes are as follows: 
1. Changes to the following inclusion and exclusion criteria have been made based on 
feedback from Investigators to reflect current clinical practice and facilitate patient 
screening: 
a. Revision to medicated IOP required for a subject to enter screening from 
> 18mmHg and < 25mmHg in both eyes to ≥ 17mmHg in at least one eye and 
< 28mmHg in both eyes. 
b. Clarification of the GANFORT® exclusion criteria. 
c. Revision of the criteria regarding prior systemic medications (including 
corticosteroids) that affect IOP. 
d. Clarification of the use of topical steroids. 
2. Changes to Section 5.6 Concomitant medications to clarify the use of steroids by 
various routes. 
3. To allow investigators at their discretion record images of ocular events. 
4. Removal of the requirement at Visits 7, 8, and 9 to measure IOP at 08:00 and 16:00. 
All assessments previously required to be performed at 08:00 and 16:00 visits will 
now be performed at one 10:00 visit. 
5. Increase window for 08:00 IOP assessments to +/- 1 hour. 
In addition to the feedback from investigators the following changes have been made: 
1. From the time that the subject gives written consent events that occur will be recorded 
as adverse events and not as previously stated as medical history until the time of 
randomization. 
2. Updated references to ICH E6 (R2) throughout. 
3. Abbreviation QD changed to Q.D. throughout. 
4. To clarify that Investigational Product will be administered to both eyes for the 
duration of the study. 
5. 
 has changed name to 
. 
arch has been updated to 
the new company name 
 throughout. 
 
 


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Other changes have been made to correct typographical errors and inconsistences. 
Modified or added text is shown below in bold type, deleted text is indicated by 
strikethrough. 
Synopsis, Section 4.2 – Subject Inclusion Criteria, Section 4.3 – Subject Exclusion 
Criteria 
Primary Objectives 
WAS: 
“To evaluate: 
• The ocular hypotensive efficacy of PG324 Ophthalmic Solution relative to 
GANFORT® Ophthalmic Solution over a 3-month period”. 
IS: 
“To evaluate: 
• The ocular hypotensive efficacy of PG324 Ophthalmic Solution relative to 
GANFORT® Ophthalmic Solution at 08,00, 10:00 and 16:00 hours at Week 2, 
Week 6 and Month 3”. 
Study Design 
WAS: 
“Procedures conducted at each of Study Visits 3-9 will include safety measures and efficacy 
measurements, including IOP assessments at the following time points at a study visit: 08:00, 
10:00, and 16:00 hours; …” 
IS: 
“Procedures conducted at each of Study Visits 3-9 will include safety measures and efficacy 
measurements, including IOP assessments at the following time points at study visits 3-6: 
08:00, 10:00, and 16:00 hours, and 10:00 hours only at visits 7-9; …” 
Inclusion Criteria 
WAS: 
4. 
Medicated intraocular pressure > 18mmHg and < 25mmHg in both eyes at screening 
visit. 
5. 
Unmedicated (post-washout) IOP > 20mmHg and < 36mmHg in both eyes at 2 
qualification visits at 08:00 hour, 2-7 days apart. At the second qualification visit, have IOP > 
17mmHg and < 36mmHg in both eyes at 10:00 and 16:00 hours. Note: For purposes of 
determining eligibility of subjects to be enrolled the non–integral IOP mean number will be 
used. Any non-integral mean IOP number should not be rounded.  
IS: 
4. 
Medicated intraocular pressure ≥ 17mmHg in at least one eye and < 28mmHg in 
both eyes at the screening visit.  


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5. 
Unmedicated (post-washout) IOP > 20mmHg in at least one eye and < 36mmHg in  
both eyes at 2 qualification visits at 08:00 hour, 2-7 days apart. At the second qualification 
visit, have IOP > 17mmHg in at least one eye and < 36mmHg in both eyes at 10:00 and 
16:00 hours. Note: For purposes of determining eligibility of subjects to be enrolled the non–
integral IOP mean number will be used. Any non-integral mean IOP number should not be 
rounded. If only one eye qualifies at second qualification visit it MUST be the same eye 
that qualified on the first visit and this will be the study eye for the duration of the 
study. 
Exclusion Criteria 
WAS: 
3. 
Intraocular pressure…Note: fixed dose combination medications, for the purpose of 
this exclusion criterion, count as one medication. 
IS: 
3. 
Intraocular pressure… Note: fixed dose combination medications, for the purpose of 
this exclusion criterion, count as one medication. However, subjects currently taking 2 
fixed dose combination products are excluded.” 
WAS: 
5. 
Prior treatment with GANFORT® topical eye drops. 
IS: 
5.   Prior treatment with GANFORT® topical eye drops where the subjects IOP did not 
achieve the target IOP and was considered either a therapeutic failure or to have 
insufficient response. Subjects currently (immediately prior to screening visit) being 
treated with GANFORT® are excluded from the study.” 
WAS: 
10. Recent or current evidence of ocular infection or inflammation in either eye.  Current 
evidence of clinically significant blepharitis, conjunctivitis, keratitis, current evidence or 
history of herpes simplex or zoster keratitis in either eye at screening, in either eye at 
screening. 
IS: 
10. Recent or current evidence of ocular infection or inflammation in either eye.  Current 
evidence of clinically significant blepharitis, conjunctivitis, keratitis, current evidence or 
history of herpes simplex or zoster keratitis in either eye at screening.  
WAS: 
11. Use of ocular medication in either eye of any kind within 30 days of screening and 
throughout the study, with the exception of a) ocular hypotensive medications (which must 
be washed out according to the provided schedule), b) lid scrubs (which may be used prior to, 
but not after, screening), c) lubricating drops for dry eye (which may be used throughout the 
study), as prescribed by the Investigator. 


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IS: 
11. Use of ocular medication in either eye of any kind within 30 days of screening and 
throughout the study, with the exception of a) ocular hypotensive medications which must 
be the same medication for 30 days prior to screening (which must be washed out 
according to the provided schedule), b) lid scrubs (which may be used prior to, but not after, 
screening), c) lubricating drops for dry eye (which may be used throughout the study), as 
prescribed by the Investigator. 
WAS: 
18. 
Systemic medication that could have a substantial effect on IOP within 30 days prior 
to screening, or anticipated during the study, including any corticosteroid-containing drug 
regardless of route of administration. 
19. 
Women of childbearing potential… 
IS: 
18. Systemic medication including corticosteroid containing drugs that could have a 
substantial effect on IOP which HAVE NOT been maintained at a consistent dose and 
regime within 30 days prior to screening and are anticipated to change in dose and/or 
regimen during the study.” 
19. 
Use of topical steroid containing medications on the face or in or around the eyes 
will exclude the subject (see Section 5.6 concomitant medications). 
20. 
Women of childbearing potential…” 
Efficacy Assessments 
WAS: 
Secondary efficacy outcomes will be comparison of PG324 Ophthalmic Solution relative to 
GANFORT® for: 
• Mean diurnal IOP within a treatment group at each post-treatment visit 
• Mean change from diurnally adjusted baseline IOP at each post-treatment time point 
• Mean change from baseline in diurnal IOP at each post-treatment visit 
• Mean percent change from diurnally adjusted baseline IOP at each post-treatment 
time point 
• Mean percent change from baseline in diurnal IOP at each post-treatment visit 
• Mean percent change from diurnally adjusted baseline IOP at each post-treatment 
time point 
• Mean percent change from baseline in diurnal IOP at each post-treatment visit 
IS: 
Secondary efficacy outcomes will be comparison of PG324 Ophthalmic Solution relative to 
GANFORT® for: 
• Mean diurnal IOP within a treatment group at each post-treatment visit 
• Mean change from diurnally adjusted baseline IOP at each post-treatment time point 


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• Mean change from baseline in diurnal IOP at each post-treatment visit 
• Mean percent change from diurnally adjusted baseline IOP at each post-treatment 
time point 
• Mean percent change from baseline in diurnal IOP at each post-treatment visit 
Section 1.2 – Findings from Non-clinical and Clinical Studies 
WAS: 
“Two pivotal Phase 3 studies (PG324-CS301 and PG324-CS302) are currently ongoing…” 
IS: 
“Two pivotal Phase 3 studies (PG324-CS301 and PG324-CS302) have been completed…” 
Section 1.3 – Risks and Benefits to Human Subjects 
WAS: 
“(Clinical Study Reports AR-13324-CS101, AR-13324-CS102, AR-13324-CS201, 
AR-13324-CS202, AR-13324-CS301, PG324-CS201 and AR-13324-CS302)” 
IS: 
“(Clinical Study Reports AR-13324-CS101, AR-13324-CS102, AR-13324-CS201, 
AR-13324-CS202, AR-13324-CS301, PG324-CS201 and AR-13324-CS302, 
AR-13324-CS304, PG324-CS301 and PG324-CS302)” 
Section 3.1 – Overall Study Design and Plan 
WAS: 
“Subsequent visits at Month 4, Month 5 and Month 6 will focus primarily on safety and will 
include IOP measurements at 08:00, 10:00 and 16:00 hours.” 
IS: 
“Subsequent visits at Month 4, Month 5 and Month 6 will focus primarily on safety and will 
include IOP measurements at 10:00 hours.” 
Section 4.1 – Study Population 
WAS: 
“A total of approximately 472 subjects will be enrolled in this study at approximately 40 sites 
in approximately 6 EU countries”. 
IS: 
“A total of approximately 472 subjects will be enrolled in this study at approximately 60 
sites in approximately 12 EU countries”. 
 
 


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Section 5.6 – Concomitant Medications 
WAS: 
• “Any corticosteroid containing systemic drug is disallowed during the study regardless 
of route of administration”. 
IS: 
• “Routine (e.g. daily) and intermittent use of topical medication containing steroids 
on the face or topical eye drops containing steroids is NOT permitted at any time 
during the study.” 
WAS: 
“Systemic therapy with agents other than corticosteroids that could have an effect on IOP is 
to be consistent in dose, regimen and agent within the 30 days prior to screening and 
throughout the study.” 
IS: 
“Systemic therapy with agents including corticosteroids that could influence IOP is to be 
consistent in dose, regimen and agent within the 30 days prior to screening and throughout 
the study…  
Intermittent use of topical steroids for certain skin conditions (but not on the face) may 
be permitted following consultation with and approval from the Medical Monitor if 
dosing has been intermittent for 90 days prior to screening and no alteration to the 
dosing regimen is anticipated during the 6-month study participation.” 
Section 5.7.1 
WAS: 
“Prior Therapy Washout period” 
Subjects must undergo a minimum washout period as specified in Table 1. 
For prostaglandins the minimum washout period should be not less than 4 weeks and it may 
be extended if deemed necessary in investigator opinion.” 
IS: 
“Prior Therapy Washout period” 
To qualify subjects must have been taking the same  IOP lowering medication for 30 
days prior to screening. Subjects must undergo a minimum washout period as specified in 
Table 1. For prostaglandins the minimum washout period should be not less than 4 weeks 
and it may be extended if deemed necessary in investigator opinion.” 
WAS: 
“If for logistical or other reasons, the period needs to be extended beyond 8 weeks (56 days), 
the Sponsor should be contacted.” 


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IS: 
“If for logistical or other reasons, the washout period needs to be extended beyond 8 weeks 
(56 days), the Sponsor should be contacted. Washout period can start at any time 
following the screening visit but the period between the screening (visit 1) and 
qualification 1 (visit 2) MUST not exceed 56 days.” 
Section 5.11.5 – Actions after Discontinuation 
WAS: 
“For the subject who chooses to withdraw consent or who is non-compliant, every possible 
effort should be made by the Investigator to assure there is a final visit that includes all 
examinations listed for Visit 9.0 (Exit) and dilated ophthalmoscopy.” 
IS: 
“For the subject who chooses to withdraw consent or who is non-compliant, every possible 
effort should be made by the Investigator to assure there is a final visit that includes all 
examinations listed for Visit 9.0 (Exit) and dilated ophthalmoscopy. 
Subjects should not take part in another clinical trial within 30 days of withdrawing or 
completing the study.” 
Section 7.1.1 – Visit 1 (Screening Visit) 
WAS: 
• Pregnancy test: women of childbearing potential must have a negative urine pregnancy 
prior to commencement of washout period. 
IS: 
• Pregnancy test: women of childbearing potential must have a negative urine pregnancy 
test prior to commencement of washout period. 
WAS: 
• “Dilated ophthalmoscopy: Medicated IOP must be > 18mmHg and < 25mmHg in both 
eyes at screening visit.” 
IS: 
• Dilated ophthalmoscopy (including cup:disc ratio): Medicated IOP must be                  
≥ 17mmHg in at least one eye and < 28mmHg in both eyes at screening visit.  
WAS:  
For subjects who are unable or unwilling to have blood drawn for clinical labs at Visit 1 
(Screening), the blood sample may be drawn at Visit 2 (Qualification Visit #1) so long as the 
results of the clinical labs are available for that subject prior to Visit 3 (Qualification Visit 
#2). 
 
 


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IS: 
For subjects who are unable or unwilling to have blood drawn for clinical labs at Visit 1 
(Screening), the blood sample may be drawn at Visit 2 (Qualification Visit #1) or during the 
washout period at a visit where interim IOP measurements are being performed so long 
as the results of the clinical labs are available for that subject prior to Visit 3 (Qualification 
Visit #2). 
Section 7.1.1.2  
WAS: 
As noted in Section 5.7.1, as current use of at least one ocular hypotensive medication is an 
inclusion criterion, a washout period is required for those who meet other qualifications for 
enrollment.  The investigator must perform interim visits, ideally at weekly intervals, during 
the washout period for IOP measurement. 
IS: 
As noted in Section 5.7.1, as current use of at least one ocular hypotensive medication is an 
inclusion criterion, a washout period is required for those who meet other qualifications for 
enrollment.  The investigator must perform interim visits, ideally at weekly intervals, during 
the washout period for IOP measurement. 
In addition, all women of childbearing potential will have a pregnancy test performed 
during the washout period if the washout period extends beyond 4 weeks. 
Section 7.1.2 – Visit 2 (Qualifying Visit 1, 08:00) and Section 7.1.3 (Qualifying Visit 2, 
08:00). 
WAS: 
“Any change in the individual’s Visit 1 health status should be recorded on the Medical 
History page of the eCRF (e.g., the subject has been diagnosed with cancer)” 
IS: 
“Any change should be recorded on the Adverse Event page of the CRF.” 
Addition of the following bullet: 
• Recording of any AEs. 
Section 7.1.2 – Visit 2 (Qualifying Visit #1, 08:00), Section 7.1.3 – Visit 3.0 (Qualifying 
Visit #2, 08:00), Section 7.1.6 – Visit 4.0 (Day 15, 08:00), Section 7.1.9 – Visit 5.0 (Day 
43, 08:00), Section 7.1.12 – Visit 6.0 (Day 90, 08:00) 
WAS: 
• A non-dilated eye examination will be performed, including pupil size, IOP 
measurements and biomicroscopy. IOP must be measured within 30 minutes of the 
nominal time (i.e., 07:30 to 08:30 hours). 


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IS: 
• A non-dilated eye examination will be performed, including pupil size, IOP 
measurements and biomicroscopy. IOP must be measured within 60 minutes of the 
nominal time (i.e., 07:00 to 09:00 hours). 
Section 7.1.3 – Visit 3.0 (Qualifying Visit #2, 08:00), 7.1.4 – Visit 3.1 (Day 1, 10:00) and 
7.1.5 – Visit 3.2 (Day 1, 16:00),  
WAS: 
“Individuals who screen fail due to IOP being > 36mmHg in both eyes (exclusion criterion) 
MAY NOT return for additional qualification visits.” 
IS: 
“Individuals who screen fail due to IOP being > 36mmHg in either eye (exclusion criterion) 
MAY NOT return for additional qualification visits.” 
Section 7.1.2 – Visit 2 (Qualifying Visit #1, 08:00 hours IOP and safety measurements) 
WAS: 
“For further evaluation in the study, at this time, unmedicated (post-washout) IOP must be 
> 20mmHg and < 36mmHg in both eyes. This is the first of the four qualifying IOPs for 
randomization. 
Individuals who screen fail due to IOP being > 36mmHg in both eyes (exclusion criterion) 
MAY NOT return for additional qualification visits.” 
IS: 
“For further evaluation in the study, at this time, unmedicated (post-washout) IOP must be 
> 20mmHg in at least one eye and < 36mmHg in both eyes. This is the first of the four 
qualifying IOPs for randomization. 
 “Individuals who screen fail due to IOP being > 36mmHg in either eye (exclusion criterion) 
MAY NOT return for additional qualification visits.” 
Addition of the following bullet: 
• 
Pregnancy test: Women of childbearing potential (who have a washout period 
that extends beyond 4 weeks) 
Section 7.1.3 – Visit 3.0 (Qualifying Visit #2, Day 1, for IOP and safety measurements at 
08:00 hours) 
WAS: 
“For further evaluation in the study, at this time, (08.00 hours) unmedicated (post-washout) 
IOP must be > 20mmHg and < 36mmHg in both eyes. This is the first of the four qualifying 
IOPs for randomization. 


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Individuals who screen fail due to IOP being > 36mmHg in both eyes (exclusion criterion) 
MAY NOT return for additional qualification visits.” 
IS: 
“For further evaluation in the study, at this time (08.00 hours), unmedicated (post-washout) 
IOP must be > 20mmHg in at least one eye and < 36mmHg in both eyes. This is the 
second of the four qualifying IOPs for randomization.” 
Individuals who screen fail due to IOP being > 36mmHg in either eye (exclusion criterion) 
MAY NOT return for additional qualification visits. 
If one eye qualifies at the second qualification visit, it MUST be the same eye as in 
previous qualification visit (Visit 2 qualifying visit #1) and this will be the study eye for 
the duration of the study.’’ 
Section 7.1.4 – Visit 3.1 (Day 1, for IOP and safety measurements at 10:00 hours) 
WAS: 
“For further evaluation in the study, at this time, (10.00 hours, Day 1) unmedicated (post-
washout) IOP must be > 17mmHg and < 36mmHg in both eyes. This is the third of the four 
qualifying IOPs for randomization. 
Individuals who screen fail due to IOP being > 36mmHg in both eyes (exclusion criterion) 
MAY NOT return for additional qualification visits.” 
IS: 
“For further evaluation in the study, at this time, unmedicated (post-washout) IOP must be 
> 17mmHg in at least one eye and < 36mmHg in both eyes. This is the third of the four 
qualifying IOPs for randomization. 
Individuals who screen fail due to IOP being > 36mmHg in either eye (exclusion criterion) 
MAY NOT return for additional qualification visits. If one eye qualifies it MUST be the 
same eye as Visit 2.0 and Visit 3.0.” 
Section 7.1.5 – Visit 3.2 (Day 1, for IOP and safety measurements at 16:00 hours) 
WAS: 
For further evaluation in the study, at this time, (16.00 hours, Day 1) unmedicated (post-
washout) IOP must be > 17mmHg and < 36mmHg in both eyes. This is the fourth of the four 
qualifying IOPs for randomization. 
Individuals who screen fail due to IOP being > 36mmHg in both eyes (exclusion criterion) 
MAY NOT return for additional qualification visits. 
 
 


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IS: 
For further evaluation in the study, at this time (16.00 hours Day 1), unmedicated (post-
washout) IOP must be > 17mmHg in at least one eye and < 36mmHg in both eyes. This is 
the fourth of the four qualifying IOPs for randomization. 
Individuals who screen fail due to IOP being > 36mmHg in either eye (exclusion criterion) 
MAY NOT return for additional qualification visits. If one eye qualifies it MUST be the 
same eye as Visit 2.0, Visit 3.0 and Visit 3.1. 
Section 7.1.4 Visit 3.1 (QUAL 2, IOP 10:00), Section 7.1.7 Visit 4.1 (W2 IOP 10:00), 
Section 7.1.10 Visit 5.1 (W6 IOP 10:00) Section 7.1.13 Visit 6.1 (M3 IOP 10:00) 
WAS: 
A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 30 minutes of the nominal time (i.e., 09:30 to 
10:30 hours).  
IS: 
A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 30 minutes of the nominal time (i.e., 09:30 to 
10:30 hours). PLEASE NOTE, the minimum time between IOP measurements is 60 
minutes. For example, if the previous IOP measurement was taken at 09:00, the IOP at 
this visit should not be measured before 10:00. 
Section 7.1.5 Visit 3.2 (day 1, for IOP and safety measurements at 16.00 hours) 
WAS: 
Subjects will be: 
Instructed to administer their masked medication OU at home between 20.00-22.00 hours 
beginning with their first dose on the evening of this study visit.  
IS: 
Subjects will be: 
Instructed to administer their masked medication to both eyes (OU) at home between 20:00 
– 22:00 hours beginning with their first dose on the evening of this study visit or no later 
than within 48 hours of randomization.  
Section 7.1.5 – Visit 3.2 (Day 1, 16:00) 
WAS: 
“As noted in Section 4.2, subjects must qualify in both eyes based upon IOP and ocular 
history for a subject who qualifies…In each subject, BOTH eyes will be treated.” 
 
 


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IS: 
“For subjects that qualify in both eyes based upon IOP and ocular history for a subject who 
qualifies…In all subjects, BOTH eyes will be treated.” 
Sections 7.1.6 – Visit 4.0 (Day 15, 08:00), Section 7.1.9 – Visit 5.0 (Day 43, 08:00), 
Section 7.1.12 – Visit 6.0 (Day 90, 08:00), Section 7.1.15 – Visit 7.0 (Month 4, 10:00), 
Section 7.1.16 – Visit 8.0 (Month 5, 10:00) and Section 7.1.17 – Visit 9.0 (Month 6, 
10:00) 
WAS: 
• “Urine pregnancy test (women of childbearing potential as applicable).” 
IS: 
• “Urine pregnancy test for women of childbearing potential.” 
Section 7.1.6 – Visit 4.0 (Day 15, 08:00) to Section 7.1.17 – Visit 9.0 (Month 6, 10:00) (all 
on-treatment visits) 
WAS: 
• “Recording of any AEs.” 
IS: 
• “Recording of any AEs. At the investigator’s discretion photography of any ocular 
events.” 
Section 7.1.15 – Visit 7.0 (Month 4, 10:00), Section 7.1.16 – Visit 8.0 (Month 5, 10:00), 
Section 7.1.17 – Visit 9.0 (Month 6, 10:00) 
WAS: 
• A non-dilated eye examination will be performed, including pupil size, IOP 
measurements and biomicroscopy. IOP must be measured within 30 minutes of the 
nominal time (i.e., 07:30 to 08:30 hours). 
IS: 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 30 minutes of the nominal time (i.e., 09:30 
to 10:30 hours). 
Visit 7 (Month 4), Visit 8 (Month 5), Visit 9 (Month 6) 
WAS: 
• Sections 7.1.15 – 7.1.17 (Month 4 [Day 120] 08:00 – 16:00) 
• Sections 7.1.18 – 7.1.20 (Month 5 [Day 150] 08:00 – 16:00) 
• Sections 7.1.21 – 7.1.23 (Month 6 [Day 180] 08:00 – 16:00) 
 
 


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IS: 
• Section 7.1.15 (Month 4 [Day 120], 10:00) 
• Section 7.1.16 (Month 5 [Day 150], 10:00) 
• Section 7.1.17 (Month 6 [Day 180], 10:00) 
• Section 7.1.18 (Unscheduled Visits) 
• Section 7.1.19 (Instructions for Completion of Case Report Forms) 
Sections 7.1.15 Visit 7.0 (Month 4) and 7.1.16 Visit 8 (Month 5) 
Added text as follows: 
TO: 
“Two new subject kits, from the assigned safety extension subject packer, each containing 1 
bottle will be dispensed to the subject by the unmasked site staff, along with dosing and 
storage instructions. Subjects will be: 
• Instructed to continue to administer their masked medication to both eyes (OU) at home 
between 20:00 – 22:00 hours (taking the daily evening dose on that day). 
• Instructed to return to the office with their study medication on Month 5 or Month 6 (Day 
180).” 
Delete text: 
WAS: 
“Subjects are allowed to leave the investigator’s office, and eat and drink without restrictions. 
However, individuals are not to consume alcohol or engage in strenuous exercise” 
Section 7.1.19 – Instructions for completion of Case Report Forms 
WAS: 
“At each subject visit, the appropriate CRFs must be completed. Whenever a CRF is used, be 
sure to provide all information requested including subject identification number and initials, 
name or number of Investigator, date(s), etc.” 
IS: 
“At each subject visit, the appropriate CRFs must be completed. Whenever a CRF is used, be 
sure to provide all information requested including subject identification number and initials, 
name or number of Investigator, date(s), etc.” 
Section 7.2.1 Adverse Event Definitions 
WAS: 
“Note: If an event occurs during the washout period (prior to subject enrollment and the 
commencement of study medication), it should be recorded as part of the Medical History 
and not as an adverse event. As noted in section 7.1.2, any change in their Visit 1 (Screening) 


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health status should be recorded on the Medical History page of the eCRF (e.g., the subject 
has been diagnosed with cancer)” 
IS: 
“Note: If an event occurs during the washout period (prior to subject enrollment and 
the commencement of study medication), it should be recorded as an adverse event.” 
Section 7.2 – Performing Adverse Events Assessments 
WAS: 
“Adverse events should be documented from the time the subject receives the first dose of 
Investigational Product until 30 days after the last dose of study drug. 
… 
Documentation of adverse events/adverse reactions include start date and stop date, severity, 
action(s) taken, seriousness and outcome.” 
IS: 
“Adverse events should be documented from the time the subject signs the informed 
consent until 30 days after the last dose of Investigational Product. 
… 
Documentation of adverse events/adverse reactions include start date and stop date, severity, 
action(s) taken, seriousness and outcome. Investigators at their discretion may also take 
photographs of ocular events to provide additional documentation of adverse events. 
These images can only be shared with the sponsor if the subject has provided 
permission to do so by signing the appropriate consent documentation.” 
Section 7.2.1 – Adverse Event Definition 
WAS: 
“Note: If an event occurs during the washout period (prior to subject enrollment and the 
commencement of study medication), it should be recorded as part of the Medical History 
and not as an adverse event.” 
IS: 
“Note: If an event occurs during the washout period (prior to subject enrollment and the 
commencement of study medication), it should be recorded as an adverse event.” 
Section 7.2.2 – Timing for Reporting of Adverse Events 
WAS: 
“AEs should be documented from the time the subject receives the first dose of 
investigational product until subject participation in the study has been completed.” 
IS: 
“AEs should be documented from the time the subject signs and dates the subject consent 
form until subject participation in the study has been completed.” 


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Section 7.2.3 – Severity 
WAS: 
“For example, a change in severity may go from mild to severe or from severe to moderate.  
In either case, the start and stop dates should be recorded.” 
IS: 
“For example, a change in severity may go from mild to severe or from severe to moderate.  
In both cases, the start and stop dates should be recorded.” 
Section 7.2.6 – Serious Adverse Events (SAEs) or Serious Unexpected Suspected 
Adverse Reaction Safety Reports (SUSARs) 
WAS: 
Procedurally, for this study, the Investigator will report the event to INC Drug Safety. An 
SAE report should be completed and faxed or emailed directly to INC Drug Safety as 
indicted below, using the study-specific SAE fax coversheet.  
IS: 
Procedurally, for this study, the Investigator will report the event to 
 Drug 
Safety. An SAE report should be completed and faxed or emailed directly to 
th 
Drug Safety, using the study-specific SAE fax coversheet. The SAE fax/email cover page 
is included in attachment 1 of the Safety Management Plan (SMP) together with all 
relevant fax numbers and email addresses. 
Removed phone numbers for all countries. 
Section 13.2 Internal References 
Added completed clinical study reports. 
IS: 
8. 
AR-13324-CS304 Clinical Study Report: A double masked, randomized, multi-
center, active controlled, parallel 6-month study with a 3-month interim analysis 
assessing the ocular hypotensive efficacy and safety of AR-13324 Ophthalmic 
Solution, 0.02% QD compared to Timolol Maleate Ophthalmic Solution, 0.5% BID 
in patients with elevated intraocular pressure (2017) 
10. 
PG324-CS301 Clinical Study Report: A prospective, double-masked, randomized, 
multi-center, active-controlled, parallel-group 12-month study assessing the safety 
and ocular hypotensive efficacy of PG324 Ophthalmic Solution compared to AR-
13324 Ophthalmic Solution, 0.02% and Latanoprost Ophthalmic Solution, 0.005% in 
subjects with elevated intraocular pressure (2018) 
11. 
PG324-CS302 Clinical Study Report: A prospective, double-masked, randomized, 
multi-center, active-controlled, parallel-group, 3-month study assessing the safety and 


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ocular hypotensive efficacy of PG324 Ophthalmic Solution compared to AR-13324 
Ophthalmic Solution, 0.02% and Latanoprost Ophthalmic Solution, 0.005% in 
subjects with elevated intraocular pressure (2018) 
Appendix 1 – Schedule of Visits and Examinations 
• Updated table and footers to reflect changes identified in section 7 of this protocol; added 
cup-to-disc ratio exam 
Appendix 2 – Procedures 
Procedures: Visual Acuity 
IS: 
• “If the individual is unreliable on two visual fields, the Investigator should consider that 
this individual is not appropriate for study entry. 
• Complete visual field reports will be provided to the Sponsor, with subject names 
removed.” 
Procedures: Photography 
IS: 
“At the investigator’s discretion images of treatment emergent events may be taken. 
Events such as corneal verticillata or conjunctival hemorrhage can be imaged using a 
slit lamp mounted camera system using the investigator’s normal practice. Subjects 
must confirm by checking the relevant section on the patient information and consent 
form that images can be taken and shared with the sponsor. 
Images should be stored electronically ideally in an uncompressed JPEG format 
identifying the subject by site and subject identification number only and date image 
acquired.”  
 
 


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Amendment #5: 06 August 2018 (Country Specific – Hungary) 
Changes to the protocol have been made in accordance with observations made by the 
 
. The changes are as follows: 
• An amendment to the study title to clarify that PG324 is a fixed dose 
combination of netarsudil and latanoprost. 
Study Title 
WAS: 
A prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, 
6-month study assessing the safety and ocular hypotensive efficacy of PG324 Ophthalmic 
Solution compared to GANFORT® (bimatoprost 0.03%/timolol 0.5%) Ophthalmic Solution 
in subjects with elevated intraocular pressure (MERCURY 3) 
IS: 
A prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, 
6-month study assessing the safety and ocular hypotensive efficacy of PG324 (netarsudil 
0.02%/ latanoprost 0.005%) Ophthalmic Solution compared to GANFORT® (bimatoprost 
0.03%/timolol 0.5%) Ophthalmic Solution in subjects with elevated intraocular pressure 
(MERCURY 3) 
• Any corrections to dates and version number, due to the amendment to the 
protocol  
 
 


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Amendment #6: 27 May 2020 
Changes have been made primarily to reflect updates that will be made to the statistical 
analysis plan (SAP), and a decision to stop screening activities when the study was >90% 
enrolled.  The decision to stop screening was not the result of any safety concerns, but a 
Sponsor administrative decision. 
Synopsis: 
•
Study Population: Sample size updated FROM 472 TO “up to 440”; and FROM
236/arm TO “up to 220 per arm”
•
Statistical Methods: Primary efficacy analysis population changed FROM per protocol
(PP) TO intent-to-treat (ITT); ADDED “To account for the potential of additional
variability in the primary efficacy outcome due to multiple imputations of missing
data, up to 220 subjects per arm will be randomized.”
Section 3.1; Section 4.1 and Figure 1: Sample size updated FROM 472 TO “up to 440” 
Section 5.6: Corrected typographical error so systemic use of beta-adrenergic blocking 
agents are NOT prohibited provided the dose is stable 
Section 5.11.7: Study is completed when… changed FROM planned enrollment has been 
completed, and all the enrolled subjects have completed the study TO …when the last visit 
of the last subject has completed at the last site of all the countries taking part in the 
study. 
Updated reference to GANFORT® SmPC listed concomitant medications due to recent 
updates to the SmPC coming into effect; REMOVED beta adrenergic blocking agents as a 
prohibited concomitant medication 
Section 8.2: Primary efficacy analysis population changed FROM per protocol (PP) TO 
intent-to-treat (ITT); ADDED; “…to account for the potential of additional variability 
in the primary efficacy outcome due to multiple imputations of missing data, up to 220 
subjects per arm will be randomized.” 
Section 8.5.3: Primary efficacy analysis population changed FROM per protocol (PP) TO 
intent-to-treat (ITT) 
Section 11.3: For source data verification…..data will be changed FROM 100% TO 80% 
source verified 
Appendix 3 UPDATED to latest version of GANFORT® SmPC  
Other changes have been made to correct typographical errors and inconsistences. 


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SYNOPSIS 
Sponsor: 
Aerie Pharmaceuticals Ireland Ltd. 
Name of Finished Product: PG324 Ophthalmic Solution   
Name of Active Ingredients: netarsudil and latanoprost 
Study Title: 
A prospective, double-masked, randomized, multicenter, active-controlled, parallel-group,6-month study assessing 
the safety and ocular hypotensive efficacy of PG324 Ophthalmic Solution compared to GANFORT® (bimatoprost 
0.03%/timolol 0.5%) Ophthalmic Solution in subjects with elevated intraocular pressure (MERCURY 3) 
Study Number: PG324-CS303 
Study Phase: Phase 3 
Primary Objectives: 
To evaluate: 
• 
The ocular hypotensive efficacy of PG324 Ophthalmic Solution relative to GANFORT® Ophthalmic 
Solution at 08,00,10:00 and 16:00 hours at Week 2, Week 6 and Month 3. 
Secondary Objectives: 
To evaluate: 
• 
The ocular and systemic safety of PG324 Ophthalmic Solution relative to GANFORT® Ophthalmic 
Solution over a 6-month period. 
• 
Change in Self-Administered National Eye Institute (NEI) Visual Functioning Questionnaire 25 (VFQ-25) 
score from baseline to study exit for PG324 compared to GANFORT®. 
• 
Change in Self-Administered Short Form Health Survey Questionnaire 36 (SF-36 v2) score from baseline 
to study exit for PG324 compared to GANFORT®. 
Study Design: 
This will be a 6-month, double-masked, randomized, multicenter, active-controlled, parallel-group efficacy and 
safety trial for reduction of elevated intraocular pressure (IOP) with PG324 Ophthalmic Solution compared to 
GANFORT® Ophthalmic solution, in subjects at least 18 years of age with open angle glaucoma (OAG) or ocular 
hypertension (OHT). 
All investigational products (IP) will be dosed in both eyes once daily/ Q.D. (PM). Subjects eligible to be enrolled 
in this study will be those with a diagnosis of either open angle glaucoma (OAG) or ocular hypertension (OHT) that 
are on treatment with a topical ocular hypotensive medication. Subjects who agree to participate in this study and 
are enrolled in the study will attend a total of 9 study visits:  Screening Visit, Qualification Visit #1, Qualification 
Visit #2/Day 1 (baseline), Week 2 (Day 15), Week 6 (Day 43), Month 3 (Day 90), Month 4 (Day 120), Month 5 
(Day 150) and Month 6 (Day 180). 
Subjects will be required to washout of their pre-study ocular hypotensive medication for a prescribed period (up to 
4 weeks or longer), depending on the medication, prior to attending Qualification Visit #1. Subjects eligible to be 
enrolled in this study must meet all inclusion criteria and none of the exclusion criteria at each of the Screening 
Visit and Qualification Visits #1 and #2. Subjects will receive a baseline eye examination including IOP 
measurements at the Screening Visit and Qualification Visits #1 and #2 and, if deemed eligible, will be enrolled at 
Qualification Visit #2 and assigned to 1 of 2 IPs in a 1:1 ratio according to a computer-generated randomization 
list. Randomization will take place using interactive web-based response system (IWRS) methodology and will 
stratify subjects by site and by maximum baseline IOP (< 25mmHg vs ≥ 25mmHg).  
Randomized subjects will dose the assigned IP in both eyes Q.D. in the evening beginning on Day 1 and up to and 
including the evening prior to the Month 6 study visit. Procedures conducted at each of Study Visits 3-9 will 
include safety measures and efficacy measurements, including IOP assessments at the following time points at 
study visits 3-6:  08:00, 10:00, and 16:00 hours, and 10:00 hours only at visits 7-9; IOP assessments at visits 7 
(Month 4), 8 (Month 5) and 9 (Month 6) will not be part of the primary efficacy analysis of this study. Following 
completion of the Month 6 study visit procedures, subjects will exit the study. For subjects who discontinue early, 
every possible effort will be made to assure there is a final visit that includes all examinations listed for Visit 9.0 
(Month 6) and dilated ophthalmoscopy. 
 


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Inclusion criteria: 
Subjects have to meet all of the following criteria at screening and qualification visits to enter into the study: 
 
1. Must be 18 years of age or older.  
2. Diagnosis of OAG or OHT in both eyes (OAG in one eye and OHT in the fellow eye is acceptable).  
3. Subjects insufficiently controlled and/or subjects considered in need for combination therapy by the 
investigators. 
4. Medicated intraocular pressure ≥ 17mmHg in at least one eye and < 28mmHg in both eyes at the screening 
visit. 
5. Unmedicated (post-washout) IOP > 20mmHg in at least one eye and < 36mmHg in both eyes at 2 
qualification visits at 08:00 hour, 2-7 days apart.  At the second qualification visit, have IOP > 17mmHg in 
at least one eye and < 36mmHg in both eyes at 10:00 and 16:00 hours. Note: For purposes of determining 
eligibility of subjects to be enrolled the non–integral IOP mean number will be used.  Any non-integral 
mean IOP number should not be rounded. If only one eye qualifies at the second qualification visit it 
MUST be the same eye that qualified on the first visit and this will be the study eye for the duration of the 
study.  
6. Best corrected visual acuity +1.0 logMAR or better by ETDRS in each eye (equivalent to 20/200 or better 
Snellen visual acuity in each eye). 
7. Be able and willing to give signed informed consent and follow study instructions. 
8. Women must be either of non-childbearing potential, or women with childbearing potential and men with 
reproductive potential must be willing to practice acceptable methods of birth control during the study.  
9. Women of childbearing potential must have a negative urine pregnancy test within 7 days of first dose of 
study treatment and agree to use highly effective contraception during the study and for 3 months after the 
last dose of study medication. 
10. Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use 
effective form of contraception from time of randomization and for 3months following the last dose of 
study medication. 
11. In France, a subject will be eligible for inclusion in this study only if either affiliated to or as a beneficiary 
of a social security number. 
Exclusion criteria: 
Subjects meeting any of the following criteria during screening or qualification evaluations (e.g., at the time of  
randomization) will be excluded from entry into the study: 
 
Ophthalmic: 
1. Clinically significant ocular disease (e.g. corneal edema, uveitis, or severe keratoconjunctivitis sicca) which 
might interfere with interpretation of the study efficacy endpoints or with safety assessments, including 
subjects with glaucomatous damage so severe that washout of ocular hypotensive medications for 4 weeks 
or longer if needed is not judged safe as it would put the subject at risk for further vision loss. 
2. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle closure glaucoma, or 
narrow angles (i.e., Grade 2 Shaffer (Chan Ry 1981) or less; extreme narrow angle with complete or partial 
closure). Note: Previous laser peripheral iridotomy is NOT acceptable. 
3. Intraocular pressure ≥ 36mmHg (unmedicated) in either eye (individuals who are excluded for this criterion 
are not allowed to attempt requalification), or use of more than two ocular hypotensive medications within 
30 days of screening.  Note: fixed dose combination medications, for the purpose of this exclusion 
criterion, count as one medication. However, subjects currently taking 2 fixed dose combination products 
are excluded. 
4. Treatment-naïve subjects. 
5. Prior treatment with GANFORT® topical eye drops where the subjects IOP did not achieve the target IOP 
and was considered either a therapeutic failure or to have insufficient response. Subjects currently 
(immediately prior to screening visit) being treated with GANFORT® are excluded from the study. 
6. Known hypersensitivity to any component of the investigational formulations to be used (e.g., 
benzalkonium chloride etc.)  or to fluorescein.  
7. Previous glaucoma intraocular surgery, including SLT or ALT in either eye.  
8. Refractive surgery in either eye (e.g., radial keratotomy, PRK, LASIK, corneal cross-linking, keratoplasty). 


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9. Ocular trauma within the six months prior to screening, or ocular surgery or non-refractive laser treatment 
within the three months prior to screening. 
10. Recent or current evidence of ocular infection or inflammation in either eye.  Current evidence of clinically 
significant blepharitis, conjunctivitis, keratitis, current evidence or history of herpes simplex or zoster 
keratitis in either eye at screening. 
11. Use of ocular medication in either eye of any kind within 30 days of screening and throughout the study, 
with the exception of a) ocular hypotensive medications which must have been the same medication for 30 
days prior to screening (which must be washed out according to the provided schedule), b) lid scrubs 
(which may be used prior to, but not after, screening), c) lubricating drops for dry eye (which may be used 
throughout the study) as prescribed by the Investigator. 
12. Mean central corneal thickness greater than 620μm at screening. 
13. Any abnormality preventing reliable Goldmann applanation tonometry of either eye (e.g., keratoconus). 
 
Systemic: 
14. Clinically significant abnormalities in laboratory tests at screening. 
15. Known hypersensitivity or contraindication to GANFORT® (Appendix 3 Marketed Product Medication 
Information Section 4.3) and to β-adrenoceptor antagonists (e.g. Chronic obstructive pulmonary disease or 
bronchial asthma; abnormally low blood pressure or heart rate; second or third-degree heart block or 
congestive heart failure; cardiac failure, cardiac shock and severe diabetes).  
16. Clinically significant systemic disease which might interfere with the study. 
17. Participation in any investigational study within 30 days prior to screening. 
18. Systemic medication including corticosteroid containing drugs that could have a substantial effect on IOP 
which HAVE NOT been maintained at a consistent dose and regime within 30 days prior to screening and 
are anticipated to change in dose and/or regimen during the study.  
19. Use of topical steroid containing medications on the face or in or around the eyes will exclude the subject 
(see section 5.6 concomitant medications). 
20. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using a 
medically acceptable and highly effective form of birth control.  An adult woman is considered to be of 
childbearing potential unless she is one year post-menopausal (1 year without menses with appropriate 
clinical profile, e.g. age appropriate, > 45 years in the absence of HRT. In questionable cases the subject 
must have FSH value > 40mIU/mL and an estradiol value < 40pg/mL (< 140pmol/L)) or three months post-
surgical sterilization. 
21. Vulnerable subjects such as minors, adults under legal protection or unable to express their consent 
(e.g. hospitalized persons in coma), persons deprived of liberty (prisoners from jails), or persons subject to 
psychiatric care. 
Study Population: 
A total of up to 440 subjects will be enrolled in this study at approximately 60 clinical sites, comprising a total of up 
to 220 subjects per treatment arm for each of 2 treatment arms.  Subjects will be at least 18 years of age diagnosed 
with OAG or OHT, each of whom meets all inclusion criteria and none of the exclusion criteria. 
Investigational Product, Dose, and Mode of Administration: 
• 
PG324 Ophthalmic Solution, 1 drop once daily (Q.D.) each evening (PM) in both eyes (OU). 
• 
GANFORT®, 1 drop once daily (Q.D.) each evening (PM), in both eyes (OU). 
Duration of Treatment: 
All subjects will administer Investigational Product for approximately 180 days. 
Efficacy Assessments: 
Efficacy will be evaluated by: 
• 
IOP measurements at 08:00, 10:00, and 16:00 hours at baseline and at Week 2 (Day 15), Week 6 (Day 
43), and Month 3 (Day 90) by Goldmann Applanation Tonometry. 
The primary efficacy outcome will be comparison of PG324 Ophthalmic Solution relative to GANFORT® for: 
• 
Mean IOP within a treatment group at the following time points: 08:00, 10:00, and 16:00 hours at the 
Week 2, Week 6, and Month 3 study visits. 
Secondary efficacy outcomes will be comparison of PG324 Ophthalmic Solution relative to GANFORT® for: 
• 
Mean diurnal IOP within a treatment group at each post-treatment visit. 
• 
Mean change from diurnally adjusted baseline IOP at each post-treatment time point. 


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•
Mean change from baseline in diurnal IOP at each post-treatment visit.
•
Mean percent change from diurnally adjusted baseline IOP at each post-treatment time point.
•
Mean percent change from baseline in diurnal IOP at each post-treatment visit.
•
Percentages of subjects achieving pre-specified mean, mean change, and percent mean change in diurnal
IOP levels
Other secondary efficacy analyses may be carried out as described in the study Statistical Analysis Plan. 
Safety Assessments: 
The primary safety measures in both eyes of enrolled subjects will be: 
•
Ocular symptoms/adverse events.
•
Pachymetry and gonioscopy.
•
ETDRS corrected visual acuity.
•
Objective findings of biomicroscopic examinations (i.e., anterior segment examinations including
evaluation of cornea, conjunctiva, lids, and lens).
•
Visual field and cup-disc ratio measurements.
•
Dilated ophthalmoscopy.
Other safety assessments will be: 
•
Systemic safety assessments as measured by heart rate, blood pressure, and clinical laboratory evaluations
(including hematology and clinical chemistry).
•
Pregnancy testing (for women of childbearing potential).
•
Change in Self-Administered NEI Visual Functioning Questionnaire-25 (VFQ-25) score from baseline to
study exit (Mangione 2001).
•
Change in Self-Administered Short Form Health Survey Questionnaire 36 (SF-36 v.2) score from
baseline to study exit (Ware 2000).
Statistical Methods: 
The primary analysis of the primary efficacy outcome will employ a linear model with IOP at the given visit 
(Week 2, Week 6 and Month 3) and time point (08:00, 10:00 and 16:00 hours) as the response, baseline IOP as a 
covariate, and treatment as a main effect factor, using the intent-to-treat (ITT) population with Monte Carlo 
Markov chain multiple imputation techniques used to impute missing data. Each time point within each visit will 
be modeled separately.  The least squares mean differences (PG324 Q.D. – GANFORT® Q.D.) will be presented 
as well as 2-sided 95% confidence intervals (CIs) and p-values. Inference will be made on the upper limit of the 
2-sided 95% confidence interval. Clinical non-inferiority will be concluded if the upper limit of the 95% CIs
around the difference (PG324 Q.D. ̶ GANFORT® Q.D.) is ≤ 1.5mmHg at all time points and ≤ 1.0mmHg at the
majority of time points through month 3.
Assuming no difference between PG324 Ophthalmic Solution Q.D. and GANFORT® Q.D., a two-tailed alpha of 
0.05 (2-sided 95% CI) at each of 9-time points, a common SD of 3.5mmHg, and a correlation between time points 
of 0.60 or less 200 ITT subjects per arm are necessary to have 85% power to show clinical non-inferiority 
(as defined above) of PG324 Ophthalmic Solution Q.D. to GANFORT® Q.D. in the mean change from baseline 
IOP.  To account for the potential of additional variability in the primary efficacy outcome due to multiple 
imputations of missing data, up to 220 subjects per arm will be randomized   
Date of Original Protocol:  05 December 2016 
Date of Version (Protocol Amendment 1): 27 January 2017 
Date of Version (Protocol Amendment 2) – UK Specific: 07 April 2017 
Date of Version (Protocol Amendment 3): 05 June 2017 
Date of Version (Protocol Amendment 4): 19 March 2018 
Date of Version (Protocol Amendment 5) – Hungary Specific: 06 August 2018 
Date of Version (Protocol Amendment 6): 27 May 2020 
Prepared in:  Microsoft Word 2016 


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TABLE OF CONTENTS 
SYNOPSIS ....................................................................................................................... 45 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 53 
1. 
INTRODUCTION ................................................................................................... 55 
1.1 
Investigational Product ...................................................................................... 55 
1.2 
Findings from Non-Clinical and Clinical Studies ............................................ 56 
1.3 
Risks and Benefits to Human Subjects ............................................................. 57 
2. 
STUDY OBJECTIVES ........................................................................................... 58 
2.1 
Primary Objectives ............................................................................................. 58 
2.2 
Secondary Objectives .......................................................................................... 58 
3. 
STUDY DESIGN ..................................................................................................... 58 
3.1 
Overall Study Design and Plan .......................................................................... 59 
3.2 
Rationale for Study Design and Dosing Regimen ............................................ 60 
3.3 
Expected Duration of Subject Participation ..................................................... 60 
4. 
STUDY POPULATION SELECTION .................................................................. 60 
4.1 
Study Population ................................................................................................. 60 
4.2 
Subject Inclusion Criteria .................................................................................. 61 
4.3 
Subject Exclusion Criteria ................................................................................. 62 
5. 
STUDY TREATMENTS ......................................................................................... 64 
5.1 
Description of Treatments .................................................................................. 64 
5.1.1 
Investigational Product ................................................................................ 64 
5.1.2 
Comparator ................................................................................................... 64 
5.2 
Treatment of Subjects ......................................................................................... 64 
5.3 
Selection of Timing of Dose for Each Subject .................................................. 64 
5.4 
Method of Assigning Subjects to Treatment .................................................... 65 
5.5 
Masking ................................................................................................................ 65 
5.5.1 
Operational Measures at Study Sites .......................................................... 65 
5.6 
Concomitant Medications .................................................................................. 66 
5.7 
Restrictions .......................................................................................................... 68 
5.7.1 
Prior Therapy Washout period ................................................................... 68 
5.7.2 
Fluid and Food Intake .................................................................................. 69 
5.7.3 
Subject Activity Restrictions ........................................................................ 69 
5.8 
Treatment Compliance ....................................................................................... 69 
5.9 
Packaging and Labeling ..................................................................................... 69 
5.10 
Handling and Storage of Investigational Product ............................................ 70 
5.11 
Investigational Product Retention at Study Site .............................................. 70 
5.11.1 
Receipt and Disposition of Study Medication ............................................. 70 
5.11.2 
Return of Study Medication ......................................................................... 71 
5.11.3 
Completed subject ......................................................................................... 71 
5.11.4 
Non-completing subject ................................................................................ 71 
5.11.5 
Actions After Discontinuation ..................................................................... 72 
5.11.6 
Study and Site Closure Discontinuation of the Entire Study .................... 72 
5.11.7 
Completed study ............................................................................................ 72 
5.11.8 
Procedure After the Completion of the Study ............................................ 73 


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5.12 
Method and timing for Assessing, Recording, and Analyzing of Efficacy 
parameters ........................................................................................................... 73 
6. 
STUDY PROCEDURES ......................................................................................... 73 
6.1 
Informed Consent ............................................................................................... 73 
6.2 
Demographics and Medical History .................................................................. 73 
6.3 
Dispensing Investigational Product ................................................................... 74 
6.4 
Appropriateness of Measurements .................................................................... 74 
6.5 
Efficacy Assessments .......................................................................................... 74 
6.5.1 
Specification of the Efficacy and Safety Parameters ................................. 74 
7. 
STUDY ACTIVITIES ............................................................................................. 75 
7.1 
Study Visits .......................................................................................................... 75 
7.1.1 
Visit 1 (Screening Visit) ................................................................................ 75 
7.1.2 
Visit 2 (Qualifying Visit #1, for 08:00 hours IOP and safety 
measurements) ............................................................................................... 77 
7.1.3 
Visit 3.0 (Qualifying Visit #2, Day 1, for IOP and safety measurement 
at 08:00 hours) ............................................................................................... 78 
7.1.4 
Visit 3.1 (Day 1, for IOP and safety measurement at 10:00 hours) .......... 79 
7.1.5 
Visit 3.2 (Day 1, for IOP and safety measurements at 16:00 hours) ........ 79 
7.1.6 
Visit 4.0 (Week 2 [Day 15], for IOP and safety measurements at 08:00 
hours) ............................................................................................................. 80 
7.1.7 
Visit 4.1 (Week 2 [Day 15], for IOP and safety measurements at 10:00 
hours) ............................................................................................................. 81 
7.1.8 
Visit 4.2 (Week 2 [Day 15], for IOP and safety measurements at 16:00 
hours) ............................................................................................................. 81 
7.1.9 
Visit 5.0 (Week 6 [Day 43], for IOP and safety measurements at 08:00 
hours) ............................................................................................................. 82 
7.1.10 
Visit 5.1 (Week 6 [Day 43], for IOP and safety measurements at 10:00 
hours) ............................................................................................................. 82 
7.1.11 
Visit 5.2 (Week 6 [Day 43], for IOP and safety measurements at 16:00 
hours) ............................................................................................................. 83 
7.1.12 
Visit 6.0 (Month 3 [Day 90], for IOP and safety measurements at 
08:00 hours) ................................................................................................... 83 
7.1.13 
Visit 6.1 (Month 3 [Day 90], for IOP and safety measurements at 
10:00 hours) ................................................................................................... 84 
7.1.14 
Visit 6.2 (Month 3 [Day 90], for IOP and safety measurements at 
16:00 hours) ................................................................................................... 85 
7.1.15 
Visit 7.0 (Month 4 [Day 120], for IOP and safety measurements at 
10:00 hours) ................................................................................................... 85 
7.1.16 
Visit 8.0 (Month 5 [Day 150], for IOP and safety measurements at 
10:00 hours) ................................................................................................... 86 
7.1.17 
Visit 9.0 (Month 6 [Day 180] for IOP and safety measurements at 
10:00 hours) ................................................................................................... 87 
7.1.18 
Unscheduled Visits ........................................................................................ 88 
7.1.19 
Instructions for Completion of Case Report Forms .................................. 88 
7.2 
Adverse Events Assessments and Ocular Safety .............................................. 88 


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7.2.1 
Adverse Event Definitions ............................................................................ 89 
7.2.2 
Timing for Reporting of Adverse Events .................................................... 90 
7.2.3 
Severity ........................................................................................................... 91 
7.2.4 
Relationship ................................................................................................... 92 
7.2.5 
Expectedness .................................................................................................. 92 
7.2.6 
Serious Adverse Events (SAEs) or Serious Unexpected Suspected 
Adverse Reaction Safety Reports (SUSARs) .............................................. 93 
7.2.7 
Follow-up of Subjects After Adverse Events .............................................. 96 
8. 
STATISTICAL METHODS ................................................................................... 97 
8.1 
Primary Hypotheses ............................................................................................ 97 
8.2 
Sample Size Considerations ............................................................................... 97 
8.3 
Analysis Populations ........................................................................................... 98 
8.4 
Statistical Methods to be Employed .................................................................. 98 
8.4.1 
General Considerations ................................................................................ 98 
8.5 
Interim analyses .................................................................................................. 99 
8.5.1 
Analysis of Baseline Data ............................................................................. 99 
8.5.2 
Subject Disposition ........................................................................................ 99 
8.5.3 
Analysis of Efficacy ....................................................................................... 99 
8.5.4 
Analysis of Safety ........................................................................................ 101 
8.6 
Procedure for Accounting for Missing, Unused or Spurious Data .............. 103 
8.7 
Procedure for Reporting Deviations from the Statistical Plan ..................... 103 
8.8 
Data Listings ...................................................................................................... 103 
9. 
ACCESS TO SOURCE DOCUMENTATION ................................................... 103 
10. STUDY MONITORING ....................................................................................... 103 
11. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE ....................................................................................... 104 
11.1 
GCP compliance ................................................................................................ 104 
11.2 
Subject Confidentiality ..................................................................................... 104 
11.3 
Study Monitoring .............................................................................................. 105 
11.4 
Case Report Forms and Study Records .......................................................... 106 
11.5 
Independent Ethics Committee/Competent Ethics Committee (IEC/ CEC) 107 
11.6 
Protocol Deviations ........................................................................................... 107 
11.7 
Informed Consent Requirements .................................................................... 108 
12. DATA HANDLING AND RECORD KEEPING ................................................ 108 
12.1 
Data Generation and Analysis ......................................................................... 109 
12.2 
Archiving of Data .............................................................................................. 109 
12.3 
Records Retention ............................................................................................. 109 
12.4 
Amendments to the Protocol ............................................................................ 109 
13. REFERENCES ...................................................................................................... 110 
13.1 
Published References ........................................................................................ 110 
13.2 
Internal References ........................................................................................... 111 
TABLE OF TABLES 
Table 1 
Ocular Hypotensive Medication Washout Period ............................... 69 
Table 2 
Comparison of Snellen ration and logMAR units .............................. 116 


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TABLE OF FIGURES 
Figure 1 
Study Design ............................................................................................ 58 
LIST OF APPENDICES 
Appendix 1 
Schedule of Visits and Examinations ................................................... 113 
Appendix 2 
Procedures ............................................................................................. 115 
Appendix 3 
Marketed Product Medication Information – GANFORT® ............. 124 
Appendix 4 
Sponsor’s Obligations ........................................................................... 137 
Appendix 5 
Investigator’s Obligations ..................................................................... 138 
Appendix 6 
Declaration of Helsinki ......................................................................... 141 
Appendix 7 
Self-Administered National Eye Institute Visual Functioning  
Questionnaire-25 (VFQ-25) .................................................................. 144 
Appendix 8 
Health Survey Questionnaire Short Form 36 Questions (SF-36) ..... 155 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Description 
AE 
Adverse Event 
ALT 
Argon laser trabeculoplasty 
AM 
Morning 
AR-13324 
Netarsudil mesylate (drug substance) / netarsudil ophthalmic solution (drug product) 
BID 
Twice-daily 
BOCF 
Baseline observation carried forward 
BP 
Blood pressure 
CEC 
Competent Ethics Committee 
CFR 
Code of Federal Regulations 
CTFG 
Clinical Trials Facilitation Group 
CI 
Confidence Interval 
CRF 
Case Report Form 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
EU 
European Union 
FDA 
Food and Drug Administration 
FDC 
Fixed-dose combination 
GCP 
Good Clinical Practice 
HR 
Heart rate 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
IWRS 
Interactive web-based response system 
LASIK 
Laser-Assisted In-Situ Keratomileusis 
LDPE 
Low-density polyethylene 
LOCF 
Last observation carried forward 
logMAR 
Logarithm of the minimum angle resolvable 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
Millimeters of mercury 
mL 
Milliliter 
NEI 
National Eye Institute 
OAG 
Open-angle glaucoma 
OHT 
Ocular hypertension 
OTC 
Over-the-counter 
OU 
Both Eyes 
PG324 
Fixed-dose combination of netarsudil and latanoprost 
PM 
Evening 
PP 
Per protocol 
PRK 
Photorefractive keratectomy 
PRO 
Patient-reported outcome 


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PT 
Preferred term 
Q.D. 
Once-daily 
ROCK 
Rho kinase 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SF-36 v.2 
Short Form (Health Survey Questionnaire, 36 questions, version 2) 
SLT 
Selective laser trabeculoplasty 
SOC 
System/Organ/Class 
SSAR 
Serious Suspected Adverse Reaction 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
US 
United States 
VA 
Visual Acuity 
VFQ 
Visual Function Questionnaire (NEI, 25 questions) 
 
 
 


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1. INTRODUCTION 
1.1 
Investigational Product 
Glaucoma is a progressive optic neuropathy that causes characteristic loss of visual fields and 
can eventually lead to blindness.  A major risk factor for glaucomatous visual field loss is 
elevated intraocular pressure (AGIS 2000).  
The need for improved efficacy of glaucoma medications is supported by several clinical 
studies.  Studies such as the Early Manifest Glaucoma Trial (Heijl 2002), the Ocular 
Hypertension Treatment Study (Kass 2002; Kass 2010), and the Collaborative Normal 
Tension Glaucoma Study Group (Collaborative Normal-Tension Glaucoma Study Group 
1998) support the general conclusion that every millimeter of reduction in IOP is significant 
for delaying disease progression.  This conclusion holds true not only for high risk ocular 
hypertensive and glaucoma subjects with elevated IOPs but also for glaucoma subjects with 
IOPs in the normal range.  Thus, the goal for treating subjects should be to lower IOP to the 
point that it prevents further damage to the optic nerve and achieve this without sacrificing 
safety or convenience.  For many individuals with glaucoma, current IOP-lowering 
medications are not sufficiently effective as monotherapy to achieve target IOP and the 
majority of glaucoma patients often need more than one drug to reach their target IOP 
(Lichter 2001).  Increasing complexity of the dosing regimen often leads to decreased 
compliance with dosing.  Fixed-dose combination (FDC) products such as Simbrinza® 
Ophthalmic Solution help simplify dosing regimens by providing two medications in a single 
bottle, but some FDC products marketed in the EU require twice-daily dosing.  An FDC 
product that would provide the same efficacy as co-administration of two medications with 
the convenience of once daily (Q.D.) dosing may allow for better compliance from these 
patients. 
Inhibitors of Rho kinase (ROCK) have emerged as a new class of IOP-lowering agents and 
are currently being tested in the clinic (Chen 2011; Kopczynski 2014).  Netarsudil mesylate 
(AR-13324) is a novel Rho kinase and norepinephrine transporter inhibitor developed at 
Aerie Pharmaceuticals, Inc. for topical ophthalmic use for lowering IOP.  In both rabbit and 
monkey studies, netarsudil produces large reductions in IOP with a longer duration of action 
than reported for previously characterized Rho kinase inhibitors.  Netarsudil Ophthalmic 
Solution has been shown to provide significant IOP lowering when dosed once-daily in the 
evening (AR-13324-CS202), and reduces IOP potentially through several mechanisms: 
increasing trabecular outflow (Wang 2014), decreasing aqueous humor production 
(Wang 2015), and reducing episcleral venous pressure (Kiel 2015).  The ability to reduce 
aqueous production may be related to netarsudil in vitro inhibitory activity against 
monoamine transporters, including the norepinephrine transporter. 
Prostaglandin analogues are highly effective at lowering IOP when dosed once daily in the 
evening, primarily acting on uveoscleral outflow.  Because netarsudil lowers IOP through 
different mechanisms of action than prostaglandin analogues, netarsudil should provide 
additional IOP-lowering efficacy when used in combination with a prostaglandin analogue.  
An FDC of netarsudil and latanoprost, PG324 (PG324 Ophthalmic Solution), was therefore 


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tested as a topical solution to include the known latanoprost mechanism of increasing 
uveoscleral outflow.  Based on this rationale, a fixed-dose combination of AR-13324 
(0.01% or 0.02%) and latanoprost (0.005%) dosed Q.D. (PM) was investigated in a 
double-masked, parallel-group study (Lewis 2015; PG324-CS201). In this study 
PG324 0.02% provided clinically relevant and statistically superior ocular hypotensive 
efficacy relative to its individual active components at the same concentrations.  The only 
safety finding of note was transient asymptomatic conjunctival hyperemia which was of mild 
severity approximately 80% of the time when it occurred. 
The present investigation is designed to evaluate PG324 in a controlled study compared to a 
fixed dose combination of bimatoprost and timolol (GANFORT®, Bimatoprost 0.03% and 
timolol maleate 0.5% ophthalmic solution, GANFORT®) in a study of 6 months duration. 
1.2 
Findings from Non-Clinical and Clinical Studies 
Non-Clinical 
Proof of concept for netarsudil in lowering IOP was established in primary pharmacology 
studies in 2 species, rabbits and monkeys.  Safety pharmacology (central nervous system and 
cardiovascular) of netarsudil was investigated in rats and dogs. Pharmacokinetics/bio 
distribution of netarsudil was assessed after systemic and ocular administration of netarsudil. 
Ocular toxicity was investigated in studies up to 6 months in rabbits and up to 9 months in 
monkeys. Repeated dose toxicity of systemically administered netarsudil was investigated in 
studies up to 28 days in rats and dogs. The non-clinical program for netarsudil also included a 
standard range of genotoxicity tests. 
PG324 is a FDC of one approved drug (latanoprost) and one unapproved drug at an advanced 
stage of development (netarsudil), which has undergone non-clinical testing as summarized 
above. In primary pharmacology studies in 2 species, rabbits and monkeys, the topically 
applied FDC product PG324 was effective in lowering IOP. The non-clinical programs for 
PG324 further included a 3-month ocular toxicity study in rabbits. In this study, the addition 
of latanoprost had no unexpected consequences of toxicological significance. 
Clinical 
The clinical development of netarsudil ophthalmic solution monotherapy is significant as it 
relates to clinical development of PG324 in a number of respects, including 
pharmacokinetics, tolerability and dose-response investigations. The assessment of the ocular 
and systemic safety of netarsudil 0.02% in Phase 1 clinical study (AR-13324-CS101) and 
Phase 1 Clinical study (Clinical Study Report AR-13324-CS102) has been completed. The 
investigation of the efficacy of the 3 doses of netarsudil (0.01%, 0.02% and 0.04%) were 
evaluated over 7 days (AR-13324-CS201). The 0.02% and 0.04% doses showed similar 
reduction of IOP, which was higher relative to the 0.01% dose. It was therefore concluded 
that the top of the dose response curve was reached at the 0.02% netarsudil concentration and 
this was selected as the appropriate concentration of netarsudil ophthalmic solution for 
further development. 


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A Phase 3 clinical study (AR-13324-CS302) evaluating the safety and efficacy netarsudil 
0.02% has been completed. This study compared netarsudil 0.02% Q.D. and BID and 
Timolol 0.5% BID, and concluded that netarsudil 0.02% Q.D. was safe, generally well 
tolerated and provided IOP lowering that was non-inferior to timolol in subjects with OAG 
and OHT. Netarsudil 0.02% BID provided slightly larger IOP reductions but had a less 
favourable safety profile and therefore netarsudil 0.02% Q.D. was recommended as the dose 
for clinical use.  
As several different concentrations of netarsudil had already been evaluated with regard to 
efficacy and safety during netarsudil clinical development, no separate Phase 1 
pharmacokinetic studies were conducted with the FDC PG324. Based on the results obtained 
from the netarsudil program, it was decided to conduct a four arm Phase 2 study comparing 
two doses of PG324 (either 0.01% or 0.02% AR-13324 in combination with 0.005% 
latanoprost) against AR-13324 0.02% and latanoprost. The Phase 2 study (PG324-CS201) 
has been completed demonstrating superiority of the PG324 combinations over 0.02% 
AR-13324 and 0.005% latanoprost alone. PG324 0.02% showed better IOP lowering than 
0.01% and was selected for further development in Phase 3.  
Two pivotal Phase 3 studies (PG324-CS301 and PG324-CS302) have been completed 
comparing PG324 with its components to demonstrate superiority and safety. In addition to 
these 2 pivotal studies a supportive study will be conducted comparing PG324 to a fixed dose 
combination therapy containing a prostaglandin analogue (PGA). Following review of the 
study through scientific advice procedure with the EMA, Aerie Pharmaceuticals have agreed 
to GANFORT® as the comparator. In addition, the EMA has reviewed and accepted the 
masking procedures as documented in this protocol. 
Detailed information on nonclinical and clinical studies completed with netarsudil and 
PG324 is provided in the Investigator’s Brochure.  
1.3 
Risks and Benefits to Human Subjects 
As no other FDCs of this class are approved, and only early stage clinical experience is 
available, the risks and benefits are not well understood at this time.  Given the 
pharmacology of this class of agents and the results of previous Phase 1, Phase 2, and Phase 
3 clinical studies by the Sponsor (Clinical Study Reports AR-13324-CS101, 
AR-13324-CS102, AR-13324-CS201, AR-13324-CS202, AR-13324-CS301, PG324-CS201, 
AR-13324-CS302, AR-13324-CS304, PG324-CS301 and PG324-CS302), it is expected that 
adverse events seen in clinical trials individually with latanoprost and netarsudil-containing 
ophthalmic formulations may be observed with PG324.  The reader should refer to the 
Investigator’s Brochure for more detailed information on potential risks due to use of 
netarsudil and PG324 ophthalmic solutions.   
The major potential benefit from exposure to PG324 is reduction in IOP in subjects with 
open angle glaucoma or ocular hypertension.  A sequela of reduced IOP could be slowing of 
disease progression and preservation of vision in subjects for longer times when measured 
over periods of months to years. 


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2. STUDY OBJECTIVES  
2.1 
Primary Objectives 
The primary objective of this study is to evaluate: 
• The ocular hypotensive efficacy of PG324 Ophthalmic Solution relative to GANFORT® 
ophthalmic solution at 08:00, 10:00 and 16:00 hours at Week 2, Week 6 and Month 3 
2.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate: 
• The ocular and systemic safety of PG324 Ophthalmic Solution relative to GANFORT® 
ophthalmic solution during a 6-month treatment period 
• Change in Self-Administered NEI Visual Functioning Questionnaire- 25 (VFQ-25) score 
from baseline to study exit for PG324 compared to GANFORT® 
• Change in Self-Administered Short Form Health Survey Questionnaire 36 (SF-36 v2) 
score from baseline to study exit for PG324 compared to GANFORT® 
3. STUDY DESIGN 
Figure 1 
Study Design 
 
 
 
      
 
 
 
 
 
 
 
                                                 
                          
 
 
 
 
 
 
Screening Visit 
(Visit 1) 
Subjects with OAG or OHT 
PG324 
Ophthalmic Solution  
1 drop Q.D. in both 
eyes  
each evening 
GANFORT® 
Ophthalmic Solution 
1 drop Q.D. in both 
eyes 
each evening 
 
Randomize 1:1 
 
N = ≤440 
 
Stratification 
- By site 
- Maximum IOP  
(< 25mmHg vs ≥ 25mmHg) 
Primary Analysis 
The ocular hypotensive efficacy of PG324 relative to 
GANFORT® for mean IOP at specified time points within a 
treatment group at the Week 2, Week 6, and Month 3.  
Post Randomization Visits  
Week 2, Week 6,  
Month 3, Month 4, Month 5 and Month 6  
(Treatment Period - 180 Days) 
Washout Period           
of Prior Ocular 
Hypotensive Medication  
Qualification #2 Visit 3 
(08:00) – Visit 3.0 
(10:00) – Visit 3.1 
(16:00) – Visit 3.2 
Qualification #1 Visit 2 
(08:00) 


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3.1 
Overall Study Design and Plan 
This is a 6-month, double-masked, randomized, multicenter, active-controlled, parallel-group 
efficacy and safety trial for reduction of elevated IOP with PG324 Ophthalmic Solution 
compared to GANFORT® Ophthalmic Solution, in subjects at least 18 years of age with 
OAG or OHT. 
Subjects eligible to be enrolled in this study will be those with a diagnosis of either OAG or 
OHT that are on treatment with a topical ocular hypotensive medication. Up to 440 subjects 
will be enrolled in this study. 
Participating subjects who have signed a consent form will attend up to 9 study visits. 
The study duration for an enrolled subject will be approximately 180 days from Visit 1 
(Screening) to the last visit (Visit 9 [Day 180 ± 7 days]). Visit 1 will occur up to 
approximately 4 weeks prior to Visit 2 [Qualification Visit #1], depending on the washout 
period required for previous IOP medication. Eligible subjects who have met all the inclusion 
criteria and none of the exclusion criteria will be enrolled and assigned masked study 
medication at Qualification Visit # 2.  Eligible subjects will be randomized in a 1:1 ratio to 
receive PG324 or GANFORT® stratified by investigative site and maximum baseline IOP < 
25mmHg vs ≥ 25mmHg. 
Randomized subjects will dose the assigned investigational product (IP) as a single drop in 
both eyes once daily (Q.D.) in the evening (between 20:00 and 22:00 hours) beginning on 
Day 1 and up to and including the evening prior to the Month 6 study visit. Significant effort 
will be made to ensure adequate masking of all IP for both subjects and clinical staff. For 
subjects deemed unable to self-administer, a guardian or an alternative person will be asked 
to administer the medication. 
Enrolled subjects will return on Week 2, Week 6, Month 3, Month 4, Month 5 and Month 6 
for efficacy and/or safety assessments. Efficacy assessments for the first 3 months of the 
study will focus on careful monitoring of IOP at each study visit at 3 different times (08:00, 
10:00 and 16:00 hours) during each study visit.  These data will be used to evaluate the 
primary efficacy endpoint of mean IOP at 08:00, 10:00 and 16:00 hours at the Week 2, Week 
6 and Month 3 study visits.   
Subsequent visits at Month 4, Month 5 and Month 6 will focus primarily on safety and will 
include IOP measurements at 10:00 hours. 
At each study visit, multiple ocular and systemic safety assessments will be conducted 
including some or all of the following: systemic safety assessments (heart rate, blood 
pressure and clinical laboratory evaluations [including hematology,]) pregnancy testing (for 
women of childbearing potential) ocular symptoms/ adverse events, ETDRS corrected visual 
acuity, objective findings of biomicroscopic evaluations (i.e. anterior segment evaluations 
including evaluation of cornea, conjunctiva and lens), visual field and cup disc ratio 
measurements, dilated ophthalmoscopic examination and Quality of Life assessments. 


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For subjects who discontinue early, every possible effort will be made to assure there is a 
final visit that includes all examinations listed for Visit 9.0 (Month 6) and dilated 
ophthalmoscopy. 
3.2 
Rationale for Study Design and Dosing Regimen 
In order to further evaluate the non-inferiority of the FDC PG324 relative to the ocular 
hypotensive efficacy of an approved FDC product in subjects with elevated IOP and to 
generate additional safety data for PG324, a parallel group, double-masked, 2 arm study 
design was selected.  
As the intended route of administration for PG324 Ophthalmic Solution is topical ocular, this 
is the route to be used in this study. The dosage regimen selected for this study is based on 
study PG324-CS201 (Bacharach 2015) the treatment period and dosing frequency is selected 
on the basis of preclinical safety studies with PG324 and regulatory requirements for 
demonstration of ocular hypotensive efficacy.  
3.3 
Expected Duration of Subject Participation 
Each subject is planned to undergo a washout period of their current ocular hypotensive 
medications, followed by approximately 180 days of treatment with IP. A temporary study 
treatment interruption may be permitted at the request of the Investigator on a case-by-case 
basis and following consultation with the Sponsor/Sponsor representative.  
4. STUDY POPULATION SELECTION 
4.1 
Study Population 
A total of approximately 440 subjects will be enrolled in this study at approximately 60 sites 
in approximately 12 EU countries comprising a total of up-to 220 subjects per each treatment 
arm for each of the two treatment arms. Subjects enrolled to this study will be those at least 
18 years of age with diagnosed OAG or OHT, who are currently using topical IOP-lowering 
medication. Inclusion criterion 4 specifies that subjects must present with medicated IOP at 
screening of ≥ 17mmHg in at least one eye and < 28mmHg in both eye and, in the opinion of 
the investigator, require a change in IOP therapy. The lower limit IOP is based on the 
guidelines issued by the European Glaucoma Society and current clinical practice in Europe 
with respect to initiating alternative therapy. The upper limit IOP is selected to exclude 
subjects who may require more aggressive therapy than a FDC to prevent glaucoma 
progression. Inclusion criterion 5 states that following a washout period from current IOP 
therapy, patients must present with an unmedicated IOP of > 20mmHg in at least one eye and 
< 36mmHg in both eyes at 2 qualification visits at 08:00 hour, 2-7 days apart and at the 
second qualification visit, have IOP > 17mmHg in at least one eye and < 36mmHg in both 
eyes at 10:00 and 16:00 hours. The upper limit was chosen to exclude subjects who require a 
more aggressive therapy than a FDC to prevent glaucomatous damage. 
Subjects MUST meet all the inclusion criteria and none of the exclusion criteria. 


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Planned enrollment numbers are higher than statistically required for demonstrating efficacy 
(approximately 200 intent-to-treat subjects per arm for 85% power) to account for the 
potential of additional variability in the primary efficacy outcome due to multiple 
imputations of missing data, up to 220 subjects per arm will be randomized. Over-enrollment 
is to be undertaken only after communication between the investigational site and the 
Sponsor representative. 
4.2 
Subject Inclusion Criteria  
Subjects must qualify in at least one eye.  See Section 8.4 for more information on statistical 
analysis of the study eye. ALL TREATMENTS WILL BE DOSED TO BOTH EYES. 
(OU) 
Subjects have to meet all of the following criteria at screening and qualification visits to enter 
into the study: 
1. Must be 18 years of age or older.  
2. Diagnosis of OAG or OHT in both eyes (OAG in one eye and OHT in the fellow eye is 
acceptable).  
3. Subjects insufficiently controlled and/or subjects considered in need for combination 
therapy by the investigators. 
4. Medicated intraocular pressure ≥ 17 mmHg in at least one eye and < 28mmHg in both 
eyes   at screening visit.  
5. Unmedicated (post-washout) IOP >20mmHg in at least one eye and < 36mmHg in both 
eyes at 2 qualification visits at 08:00 hour, 2-7 days apart.  At the second qualification 
visit, have IOP >17mmHg in at least one eye and < 36mmHg in both eyes at 10:00 and 
16:00 hours. Note: For purposes of determining eligibility of subjects to be enrolled, 
the non-integral IOP mean number will be used. Any non-integral mean IOP 
number should not be rounded. If only one eye qualifies at the second qualification visit 
it MUST be the same eye that qualified on the first visit and this will be the study eye for 
the duration of the study. 
6. Best corrected visual acuity +1.0 logMAR or better by ETDRS in each eye (equivalent to 
20/200 or better Snellen visual acuity in each eye). 
7. Be able and willing to give signed informed consent and follow study instruction. 
8. Women must be either of non-childbearing potential, or women with childbearing 
potential and men with reproductive potential must be willing to practice acceptable 
methods of birth control during the study. 


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9. Women of childbearing potential must have a negative urine pregnancy test within 7 days 
of first dose of study treatment and agree to use highly effective contraception during the 
study and for 3 months after the last dose of study medication. 
10. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use an effective form of contraception from time of randomization 
and for 3 months following the last dose of study medication. 
11. In France, a subject will be eligible for inclusion in this study only if either affiliated to or 
as a beneficiary of a social security number. 
4.3 
Subject Exclusion Criteria 
Individuals with the following characteristics will be excluded from the study: 
Ophthalmic: 
1. Clinically significant ocular disease (e.g., corneal edema, uveitis, or severe 
keratoconjunctivitis sicca) which might interfere with interpretation of the study efficacy 
endpoints or with safety assessments, including subjects with glaucomatous damage so 
severe that washout of ocular hypotensive medications for 4 weeks or longer if needed is 
not judged safe as it would put the subject at risk for further vision loss.  
2. Pseudoexfoliation or pigment dispersion component glaucoma, history of angle closure 
glaucoma, or narrow angles i.e. Grade 2 Shaffer (Chan 1981) or less extreme narrow 
angle with complete or partial closure. Note: Previous laser peripheral iridotomy is NOT 
acceptable. 
3. Intraocular pressure ≥ 36mmHg (unmedicated) in either eye (individuals who are 
excluded for this criterion are not allowed to attempt requalification), or use of more than 
two ocular hypotensive medications within 30 days of screening.  Note: fixed dose 
combination medications, for the purpose of this exclusion criterion, count as one 
medication. However, subjects currently taking 2 fixed dose combination products are 
excluded. 
4. Treatment-naïve subjects. 
5. Prior treatment with GANFORT® topical eye drops where the subjects IOP did not 
achieve the target IOP and was considered either a therapeutic failure or to have 
insufficient response. Subjects currently (immediately prior to screening visit) being 
treated with GANFORT® are excluded from the study. 
6. Known hypersensitivity to any component of the investigational formulations to be used 
(e.g., benzalkonium chloride) or to fluorescein. 
7. Previous glaucoma intraocular surgery, including SLT or ALT in either eye. 


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8. Refractive surgery in either eye (e.g., radial keratotomy, PRK, LASIK, corneal 
cross-linking, keratoplasty). 
9. Ocular trauma within the six months prior to screening, or ocular surgery or non-
refractive laser treatment within the three months prior to screening. 
10. Recent or current evidence of ocular infection or inflammation in either eye.  Current 
evidence of clinically significant blepharitis, conjunctivitis, keratitis, current evidence or 
history of herpes simplex or zoster keratitis in either eye at screening. 
11. Use of ocular medication in either eye of any kind within 30 days of screening and 
throughout the study, with the exception of a) ocular hypotensive medications which 
must have been the same medication for 30 days prior to screening (which must be 
washed out according to the provided schedule), b) lid scrubs (which may be used prior 
to, but not after, screening), c) lubricating drops for dry eye (which may be used 
throughout the study), as prescribed by the Investigator. 
12. Mean central corneal thickness greater than 620μm at screening. 
13. Any abnormality preventing reliable Goldmann applanation tonometry of either eye 
(e.g., keratoconus). 
Systemic: 
14. Clinically significant abnormalities in laboratory tests at screening. 
15. Known hypersensitivity or contraindication to GANFORT® (Appendix 3 Marketed 
Product Medication Information Section 4.3) and to β-adrenoceptor antagonists (e.g. 
Chronic obstructive pulmonary disease or bronchial asthma; abnormally low blood 
pressure or heart rate; second or third-degree heart block or congestive heart failure, 
cardiac failure, cardiac shock and severe diabetes). 
16. Clinically significant systemic disease which might interfere with the study. 
17. Participation in any investigational study within 30 days prior to screening. 
18. Systemic medication including corticosteroid containing drugs that could have a 
substantial effect on IOP which HAVE NOT been maintained at a consistent dose and 
regime within 30 days prior to screening, and are anticipated to change in dose and/or 
regime during the study. 
19. Use of topical steroid containing medications on the face or in or around the eyes will 
exclude the subject (see Section 5.6 Concomitant Medications). 
20. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable and highly effective form of birth control.  An adult woman 
is considered to be of childbearing potential unless she is one year post-menopausal (1 


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year without menses with appropriate clinical profile, e.g. age appropriate, > 45 years in 
the absence of HRT. In questionable cases the subject must have FSH value > 40mIU/mL 
and an estradiol value < 40pg/mL (< 140pmol/L)) or three months post-surgical 
sterilization. 
21. Vulnerable subjects such as minors, adults under legal protection or unable to express 
their consent (e.g. hospitalized persons in coma), persons deprived of liberty (prisoners 
from jails), or persons subject to psychiatric care. 
5. STUDY TREATMENTS 
5.1 
Description of Treatments 
5.1.1 
Investigational Product  
PG324 Ophthalmic Solution is a sterile, isotonic, buffered aqueous solution containing 
netarsudil 0.02%, latanoprost 0.005%, boric acid, mannitol, water for injection, and 
preserved with benzalkonium chloride (0.02%). The product formulation is adjusted to 
approximately pH 5. PG324 is a colorless to slightly yellowish solution (PG324 Safety data 
sheet). 
5.1.2 
Comparator 
GANFORT® (bimatoprost 0.03% / timolol maleate 0.5% ophthalmic solution) is a sterile, 
buffered aqueous solution containing sodium chloride, sodium phosphate dibasic 
heptahydrate, and citric acid monohydrate and preserved with benzalkonium chloride 
(0.005%).  GANFORT® is a colorless to slightly yellow solution (GANFORT® SmPC). 
5.2 
Treatment of Subjects 
Subjects will be randomized to receive IP (PG324 Q.D. or the active comparator 
(GANFORT® Q.D.). All treatments will be both eyes (OU). Subjects will instill 1 drop of 
study drug into each eye, one time per day in the evening between 20:00 and 22:00 hours 
(including days when the subject is scheduled to visit the study site). Doses will be 
administered by the study subjects.  For subjects deemed unable to administer the doses, a 
guardian or alternative person will be asked to administer the medication. All subjects will 
administer study treatment for approximately 180 days. 
5.3 
Selection of Timing of Dose for Each Subject 
The dose of PG324 selected for this study is based on the positive outcomes seen for PG324 
in the PG324-CS201 clinical study. Each IP dose is being administered Q.D. OU in the 
evening (between 20:00 and 22:00 hours including days when the subject is scheduled to 
visit the study site) in this study to allow for estimated peak and trough levels of both 
netarsudil and latanoprost to be present in ocular tissue at the observation times selected in 
the clinic for the following morning and the subsequent afternoon. The treatment period is 


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selected on the basis of non-clinical safety studies and regulatory requirements for studies of 
ophthalmic glaucoma medications. 
5.4 
Method of Assigning Subjects to Treatment  
A randomization code for allocating the treatments will be prepared by an independent 
biostatistician, who is not involved in the day-to-day conduct of the study. Subjects will be 
randomized in a 1:1 ratio to receive PG324 or GANFORT® stratified by Investigative site 
and maximum baseline IOP < 25mmHg and ≥ 25mmHg.  
5.5 
Masking 
The European Medicines Agency through the scientific advice procedure has agreed to the 
masking procedures documented in this section.  
To minimize unmasking due to the differences in bottle closure cap color, clinical supplies 
will be packaged in identical outer containers labeled appropriately for clinical trial use as 
detailed in Section 5.9 of this document. 
Differences in the physical characteristics of the PG324 and GANFORT® are minimal and 
should not pose a significant risk to the masking of the study. Both are essentially colorless 
liquids of equivalent viscosity which in individual eye drops are indistinguishable to subjects 
taking part in the study. 
Treatment assignments will be masked to the Investigator, the clinical study team, Sponsor/ 
Sponsor representative working on behalf of the Sponsor, personnel involved in day to day 
study management, Monitors, Data Managers, and Statisticians), and the subjects for the 
duration of the study.  
Masking of treatment assignment of study supplies is planned to be achieved via both IP 
packaging/labelling operations and as instructed in the study Pharmacy Manual.  
5.5.1 
Operational Measures at Study Sites 
Study related site personnel will be instructed that the subject kits are not to be opened at the 
clinical site by staff involved in IOP measurements or safety assessments both at the time of 
IP dispensation as well as upon collection of the returned IP by the subjects at the defined 
visits. Study site staff member(s) not responsible for performing intraocular measurements 
and safety assessments will be assigned to accept and confirm receipt of IP shipments, to 
manage any temperature excursions, to dispense IP to the subjects at the defined visits and 
collect unused or returned IP, and to ensure the IP is stored as instructed by the label. 
The unmasked staff will also maintain the drug accountability records. 
An unmasked monitor will be assigned to each site. During pre-study activities at each 
selected site it will be confirmed that unmasked staff is available to accept and document 
receipt of IP. The unmasked monitor will confirm IP storage and dispensing facilities are 
appropriate for the study and will ensure the unmasked site staff is adequately trained and the 


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training is documented. The unmasked monitor will confirm that unmasked site staff has the 
facilities to maintain study documentation that may unmask the masked site staff in a 
separate and limited access location. The unmasked monitor will be responsible for 
responding to study related questions from unmasked site staff for the duration of the study. 
Throughout the course of the study and during unmasked monitoring visits, the unmasked 
monitor will check the integrity of the treatment masking and will communicate all 
unmasked monitoring activities in a separate monitoring report. The unmasked monitor will 
confirm access to the IP remains limited to unmasked site staff only (e.g. pharmacist) 
involved in the day to day management and storage of IP and dispensing and collection of 
returned/used or expired IP. The unmasked monitor will perform drug accountability of IP, 
storage of IP and dispensing and collection of returned/used IP.  
Treatment assignment(s) will be unmasked and made available to the Investigator and the 
Sponsor’s Medical Monitor/Designee during the study only in case of medical emergency or 
occurrence of adverse events that in the opinion of the investigator warrant unmasking.  In 
the absence of medical need, the randomization code/treatment assignment(s) will not be 
available to the above study personnel until after the study is completed and the database is 
locked. All medical management (including the Medical Director and Medical Scientist who 
will review the line listings and AE’s for the study) will remain masked for the duration of 
the study.  
If the Investigator feels it is necessary to unmask a subject’s treatment assignment in the 
event of an emergency situation, the Investigator will perform the unmasking through the 
IWRS or other randomization system.  The treatment assignment will be revealed on a 
subject-by-subject basis, thus leaving the masking on remaining subjects intact. 
In the case of such unmasking in an emergency situation, the Investigator should contact the 
Sponsor/Sponsor representative immediately thereafter and document the unmasking in 
writing, recording the date, time, and reason for unmasking the study drug treatment in the 
source documentation. 
Once the subject is unmasked there is no requirement for the Medical Monitor to be informed 
of the treatment assignment. Individual unmasking by the Investigator will result in 
withdrawal of the subject from the study and should only be performed for the specific 
subject requiring unmasking in their treatment group. 
5.6 
Concomitant Medications 
As noted in Section 5.7.1, subjects are required to undergo a washout of their current ocular 
hypotensive medications.  Intermittent use of over-the-counter (OTC) artificial tear lubricant 
products is acceptable, with a minimum of 10 minutes between OTC products and study 
medication.  However, concurrent therapy with any form of ocular hypotensive medications 
(prescription or OTC) is not allowed during the study. 
 


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Disallowed ocular medications include: 
• Miotics. 
• Epinephrine-related compounds. 
• Carbonic anhydrase inhibitors (ocular or systemic). 
• α-adrenoceptor agonists. 
• β adrenoceptor antagonists 
• Muscarinic agonists (e.g., pilocarpine). 
• Prostaglandin analogues. 
• Routine (e.g. daily) and intermittent use if topical medication containing steroids on the 
face or topical eye drops containing steroids is NOT permitted at any time during the 
study. 
Systemic therapy with agents including corticosteroids that could influence IOP is to be 
consistent in dose, regimen and agent within the 30 days prior to screening and throughout 
the study. For example, a subject can be treated with a systemic β-adrenoceptor antagonist as 
long as the particular agent and its dose and regimen had been consistent for the 30 days prior 
to screening, and there is no reason to believe that alteration would be necessary at some 
point later during the study. Subjects should be cautioned to avoid use of alcohol or the use 
of any drugs such as cannabis or marijuana during the study visit days. 
Intermittent use of topical steroids for certain skin conditions (but not on the face) may be 
permitted following consultation with and approval from the Medical Monitor if dosing has 
been intermittent for 90 days prior to screening and no alteration to the dosing regimen is 
anticipated during the 6-month study participation. 
Contact lens wear during the study is acceptable. However, subjects must remove their 
contact lenses at least 30 minutes before instillation of study medication, and not place them 
in their eye(s) until 30 minutes after instillation. 
As detailed in the GANFORT® SmPC Section 4.5 (Appendix 3) there is a potential for 
additive effects resulting in hypotension, and/or marked bradycardia when ophthalmic 
solution containing beta-blockers (timolol) is administered concomitantly with oral calcium 
channel blockers, guanethidine, beta-adrenergic blocking agents, parasympathomimetics, 
anti-arrhythmics (including amiodarone) and digitalis glycosides.  
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported 
during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) 
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Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline 
(epinephrine which is prohibited) has been reported occasionally.  
Epinephrine is not permitted to be used concomitantly during the subject’s participation in 
the study. Concomitant use of the other medications is at the discretion of the investigator 
who must assess if the subject should participate in the study based on the potential 
interactions listed in Section 4.5 of the GANFORT® SmPC. 
Use of all medications should be documented on the appropriate CRF.  Investigators are 
encouraged to contact the Sponsor/Sponsor representative for any questions regarding 
allowed medications. Judgment of continued study participation by the subject, and inclusion 
of this subject’s subsequent visits in the safety and efficacy analysis will be made by the 
Sponsor. 
All medications which the subject has taken within 30 days prior to screening and during the 
study will be recorded in the CRF. The name of the drug, dose, route of administration, 
duration of treatment and indication will be recorded for each medication. For combination 
products (e.g., Contac®), the brand name is required.  For non-combination products, the 
generic name is desired. The use of routine ophthalmic diagnostic pharmaceutical agents 
(e.g., fluorescein and local anesthetic) will be allowed, and individual documentation not 
required. Any change in dosing parameters should also be recorded in the CRF. 
5.7 
Restrictions 
5.7.1 
Prior Therapy Washout period 
To qualify subjects must have been taking the same IOP lowering medication for 30 days 
prior to screening. Subjects must undergo a minimum washout period as specified in 
Table 1. For prostaglandins the minimum washout period should be not less than 4 weeks 
and it may be extended if deemed necessary in investigator opinion. 
Washout should not extend beyond 8 weeks (56 days). If for logistical or other reasons, the 
washout period needs to be extended beyond 8 weeks (56 days), the Sponsor should be 
contacted. Washout period can start at any time following the screening visit but the period 
between the screening (Visit 1) and qualification 1 (Visit 2) MUST not exceed 56 days. 
The main risk associated with a wash period is an increase in IOP requiring immediate 
intervention. Therefore, the investigator must monitor the subject regularly during the 
washout period, ideally every week. 
 
 


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Table 1 
Ocular Hypotensive Medication Washout Period 
Medication class 
Minimum washout period 
Prostaglandin analogues 
4 weeks 
β-adrenoceptor antagonists 
4 weeks 
Adrenergic agonists (including α-agonists such as brimonidine and apraclonidine) 
2 weeks 
Muscarinic agonists (e.g., pilocarpine), Carbonic anhydrase inhibitors (topical or 
oral) 
5 days 
Stewart 2001, Hughes 2005 and European Glaucoma Society November 2011. 
5.7.2 
Fluid and Food Intake 
There are no general restrictions on fluid or food intake for subjects participating in this 
study. 
5.7.3 
Subject Activity Restrictions 
On days which diurnal IOP measurements are made, subjects may not engage in strenuous 
activity. Otherwise, there are no restrictions on subject activities during their participation in 
this study. 
5.8 
Treatment Compliance 
All subjects will be instructed on the importance of following the once-daily dosing regimen. 
Dosing should occur in the evening between 20:00 and 22:00 hours. As no commercially 
available method is readily available for direct, single-container monitoring of treatment 
adherence with multi-dose ophthalmic products, no formal measure of treatment compliance 
is planned.  Subjects should be reminded at all visits to dose every evening. In addition, 
subjects will be provided with a paper and electronic dosing reminder.  
If a dose of study medication is missed the subject should take the next dose as planned. 
The dose of study medication should not exceed one drop daily in both eyes. 
5.9 
Packaging and Labeling 
The container-closure systems for the two products are both multi-dose ophthalmic dropper 
dose bottles. The commercial label from the comparator will be removed and replaced with 
an investigational label which will be similar in appearance for both treatment groups. 
The labeled bottles will be packaged in identical appearing subject kits to ensure adequate 
masking.   
The container-closure systems for the IP are both multi-dose ophthalmic dropper dose bottle.  
All clinical trial material packers (containing subject kits) and subject kits containing the 
bottles will be identical in appearance. A clinical trial material packer, which contains subject 
kits sufficient for the intended dosing period(s), will be packaged and provided to the site for 


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dispensation to the subjects. Subject packers therefore contain sufficient kits for an individual 
subject that will be distributed during this study. 
Clinical supplies of PG324 and GANFORT® will be in a dropper dose bottle containing a 
volume of no less than 2.5 mL. The container-closure system used for PG324 in this clinical 
study is a clear, multi-dose low density polyethylene (LDPE) dropper dose ophthalmic 
bottle with a white polypropylene cap. The container-closure system used for GANFORT® 
in this clinical study is a white, multi-dose LDPE dropper dose ophthalmic bottle with a blue 
polystyrene cap (which is the presentation of the commercial product). Each packaged unit 
will be labeled with an investigational label with the minimal information required per the 
regulatory requirements of EU Guidelines to Good Manufacturing Practice. Once open, IP 
may only be used for 28 days. 
5.10 
Handling and Storage of Investigational Product 
Investigational Product must be dispensed or administered according to the procedures 
prescribed in this protocol. Only subjects enrolled in the study may receive IP, in accordance 
with all the applicable regulatory requirements. Only authorized staff is allowed to dispense 
these medications. 
Under normal conditions of handling and administration, IP is not expected to pose 
significant safety risk to site staff. Adequate precautions must be taken to avoid direct contact 
with IP.  
Investigational Product will be stored in a secure area under the appropriate physical 
conditions for the product. Access to the IP will be limited to authorized site staff only. 
The IP will be stored as directed on the drug label (2°C to 8°C/ 36°F to 46°F).  Temperature 
of the IP storage location at the site is to be monitored using a calibrated monitoring device 
and documented. 
At time of dispensing, the subject will be instructed to store the bottle(s) as directed on the 
drug label (2°C to 8°C/ 36°F to 46°F). The bottle(s) must be protected from light, and is 
recommended to be stored in the carton provided at all times; further, the bottle must be used 
for no longer than 28 days once opened.   
5.11 
Investigational Product Retention at Study Site 
5.11.1 
Receipt and Disposition of Study Medication 
Investigational Product will be shipped to the Investigator’s site from a central depot.  
The unmasked study site personnel at the Investigator’s site (see Section 5.5.1) will verify 
study medication shipment records by comparing the shipping documentation 
accompanying the study medication to the study medication actually received at the 
Investigator’s site. If a discrepancy is noted, the appropriate individual at the Sponsor or 
designee must be notified immediately. The responsible person (e.g., unmasked pharmacist) 


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at the Investigator’s institution has to account for all used, partially used and unused IP. The 
unmasked staff will also maintain the drug accountability records. 
5.11.2 
Return of Study Medication 
When the site is closed, the study is completed or is terminated by the Sponsor; all study 
material including used and unused study IP will be returned to the Sponsor’s designee.  
All IP medication accounting procedures must be completed before the study is considered to 
be concluded. The responsible person at the Investigator’s institution has to account for all 
used, partially used and unused IP. The unmasked monitor will complete a study drug 
returns form or equivalent that will be signed by the Investigator or designee prior to 
returning the used and unused IP to the Sponsor’s designee. 
5.11.3 
Completed subject 
A completed subject is defined as one who completes all 6 months (180 days) of planned 
participation. 
5.11.4 
Non-completing subject 
A non-completing subject is defined as one who exits the study by their own volition or at 
the discretion of the Investigator and/or the Sponsor Safety Officer/designee.  Any subject 
may decide to voluntarily withdraw from the study at any time without prejudice.  In the 
event that discontinuation of treatment is necessary, the Investigator will make every attempt 
to complete all subsequent safety assessments listed for Visit 9.0 (Day 180) as well as dilated 
ophthalmoscopy. 
Per Section 5.5.1, unmasking of a subject by the investigator will result in withdrawal of the 
subject from the study. 
The subject may also be discontinued from the study for the following reasons: 
• Lack of efficacy (as demonstrated by IOP measurements and investigator decision that 
there is a risk of additional glaucomatous damage if the subject continues in the study). 
• Adverse Events (adverse events including, in the opinion of the investigator, clinically 
relevant laboratory abnormalities and intercurrent diseases reported by the subject or 
observed by the investigator with documentation on the case report form [CRF]). 
• Withdrawal of consent. 
• Non-compliance (e.g., non-adherence to scheduled follow-up visits or non-compliance 
with dosing of medication and/or scheduled follow-up visits). 
• Lost to Follow-up.    
• Disallowed concurrent medication.  


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• Investigator Decision.  
• Protocol Deviation.  
• Death. 
• Other. 
5.11.5 
Actions After Discontinuation 
All subjects who discontinue IP due to a report of an AE must be followed-up and provided 
appropriate medical care until their signs and symptoms have remitted or stabilized or until 
abnormal laboratory findings have returned to acceptable or pre-study limits. At any time 
after completion of study treatment, the investigator may report any AE that they believe 
possibly related to study treatment or important for the clinical understanding of an AE. 
For the subject who chooses to withdraw consent or who is non-compliant, every possible 
effort should be made by the Investigator to assure there is a final visit that includes all 
examinations listed for Visit 9.0 (Exit) and dilated ophthalmoscopy. 
Subjects should not take part in another clinical trial within 30 days of withdrawing or 
completing the study. 
5.11.6 
Study and Site Closure Discontinuation of the Entire Study 
The entire study may be discontinued at a given site (by the Investigator or the Sponsor/ 
Sponsor representative or at all sites (by the Sponsor). Aerie reserves the right to temporarily 
or permanently terminate the study at any time for reasons including but not limited to safety 
issues, ethical issues, or severe non-compliance. If Aerie determines that such action is 
required, Aerie or its representative will discuss the reasons for taking such action with the 
investigator or head of the medical institution (where applicable). When feasible, Aerie will 
provide advance notice to the investigator or head of the medical institution of the impending 
action. If a study is terminated or suspended for any reasons, Aerie or its representative will 
promptly inform all investigators, heads of institutions (where applicable and /or the 
institutions conducting the study. Aerie or Sponsor representative on behalf of Aerie will also 
promptly inform the relevant regulatory authorities/ IEC/ CECs of the suspension/termination 
with the reasons for such actions where required. 
5.11.7 
Completed study 
The study is completed when the last visit of the last subject has completed at the last site of 
all the countries taking part in the study.  The Sponsor representative will be in 
communication with investigational sites regarding study completion. 


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5.11.8 
Procedure After the Completion of the Study 
When the study is completed, the Investigator will provide the governing IEC/ CEC with a 
brief report. 
5.12 
Method and timing for Assessing, Recording, and Analyzing of Efficacy 
parameters 
As detailed in subsequent sections and Appendix 1 describing each visit, IOP will be 
measured at a screening visit, at 2 qualification visits after washout of ocular hypotensive 
medications as required, and frequently throughout the study. 
6. STUDY PROCEDURES 
Please see Appendix 1 for schedule of visits and examinations and Appendix 2 for 
detailed description of study procedures 
6.1 
Informed Consent 
Prior to any study procedures, the study will be discussed with each subject and subjects 
wishing to participate must give written informed consent. The verbal explanation of the 
study will cover all the elements specified in the written information provided for the subject. 
The Investigator will inform the subject of the aims, methods, anticipated benefits and 
potential hazards of the study, including any discomfort it may entail. The subject must be 
given every opportunity to clarify any points he/she does not understand and, if necessary, 
may ask for more information. At the end of the interview, the subject should be given time 
to reflect. Subjects then will be required to sign and date the informed consent form.   
The informed consent form must have received approval/favorable review by a properly 
constituted IRB/IEC/CEC prior to use. A copy of the signed and dated consent document will 
be given to each subject. The original signed and dated informed consent document must be 
maintained in the study files at the Investigator’s site.   
The Investigator or staff is responsible for ensuring that no subject is subject to any 
study-related examination or activity before the subject has given written informed consent.  
It should be emphasized that the subject is at liberty to withdraw consent to participate at any 
time, without penalty or loss of benefits to which the subject is otherwise entitled. Subjects 
who refuse to give, or withdraw, written informed consent may not be included or continued 
in this study, and should be notified that discontinuation from the study will not impact on 
their subsequent care.   
6.2 
Demographics and Medical History 
Demographic data and any ongoing medication use will be collected and recorded. Any 
medications the subject took but discontinued within the 30 days prior to screening also will 
be recorded. Significant medical history will be collected and any current underlying medical 


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conditions, including those that began within the last 30 days and which may have resolved 
before screening, additionally must be recorded.   
6.3 
Dispensing Investigational Product  
Study related personnel will be cautioned that any unused or unused subject kits are not to be 
opened at the clinical site by the site staff involved in the efficacy or safety measurements. 
Study staff responsible for dispensing IP will be listed on the Delegation of Responsibilities 
Log. When a subject meets all criteria for selection and has completed all screening 
assessments, the subject will be assigned to a treatment group according to the IWRS. The 
responsible unmasked study staff will account for used and unused investigation product 
packers and their kit contents by maintaining an IP accountability log.  
6.4 
Appropriateness of Measurements 
The ophthalmic and systemic measures used in this study are consistent with standard of 
care.  In particular, IOP as measured by Goldmann applanation tonometry, the primary 
efficacy assessment in this study, is accepted worldwide as a standard for testing of 
pharmacologically active agents intended to reduce IOP. 
6.5 
Efficacy Assessments 
6.5.1 
Specification of the Efficacy and Safety Parameters 
The primary efficacy outcome will be the comparison of PG324 Ophthalmic Solution relative 
to GANFORT® for mean IOP within a treatment group at the following time points: 08:00, 
10:00, and 16:00 hours at the Week 2, Week 6, and Month 3 study visits. 
Secondary efficacy outcomes will be comparison of PG324 Ophthalmic Solution relative to 
GANFORT® for: 
• Mean diurnal IOP within a treatment group at each post-treatment visit. 
• Mean change from diurnally adjusted baseline IOP at each post-treatment time point. 
• Mean change from baseline in diurnal IOP at each post-treatment visit. 
• Mean percent change from diurnally adjusted baseline IOP at each post-treatment time 
point. 
• Mean percent change from baseline in diurnal IOP at each post-treatment visit. 
• Percentages of subjects achieving pre-specified mean, mean change, and percent mean 
change in diurnal IOP levels. 
 


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Assessment of Safety 
The primary safety measures will be visual acuity, goniometry, pachymetry, objective 
biomicroscopic and ophthalmoscopic examination, and adverse events. 
Other safety measures will be systemic safety as measured by pregnancy testing, heartrate, 
blood pressure, and clinical laboratory evaluations. 
Change in Self-Administered NEI Visual Functioning Questionnaire-25 (VFQ-25), and Short 
Form Health Survey Questionnaire (SF-36 v.2) scores from baseline to study exit. 
Other secondary efficacy analyses, including those for the entire subject population, will be 
carried out as described in the study Statistical Analysis Plan. 
7. STUDY ACTIVITIES  
The schedule of study visits and procedures is shown in Appendix 1. 
7.1 
Study Visits 
7.1.1 
Visit 1 (Screening Visit) 
This visit may occur at any time of the day. 
A member of the Investigator’s staff will interview the individual as to their qualifications 
for participation in the study. 
Individuals will be asked to review the informed consent, discuss issues as needed, and to 
sign the form.  A signed written informed consent must be obtained from the subject prior to 
any study specific procedures or assessments.  
Significant medical and ophthalmic history including systemic and ocular medication use 
will be taken, and demographic measures recorded (see Section 6.2).  
The following procedures will be performed:   
• Confirm eligibility per inclusion and exclusion criteria. 
• Heart rate and blood pressure. 
• Pregnancy test: women of childbearing potential must have a negative urine pregnancy 
test prior to commencement of washout period. 
• Best corrected visual acuity. 
• Central corneal thickness will be measured by ultrasound pachymetry (taken at Screening 
or within 1 week prior to the Screening visit). 


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• Intraocular pressure (before pupil dilation).  
• Biomicroscopy 
• Dilated ophthalmoscopy (including cup:disc ratio): Medicated IOP must be ≥ 17mmHg in 
at least one eye and < 28mmHg in both eyes at screening visit.  
• Visual fields and gonioscopy may be taken up to 3 months prior to randomization. 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• The subject will complete both the Self-Administered NEI Visual Functioning 
Questionnaire-25 (VFQ-25) and the Self-Administered Health Survey Questionnaire 
(SF-36 v.2). 
Blood samples will be taken for clinical chemistry and hematology (Appendix 2). The results 
of blood work should be reviewed after this study visit (if available) in order to determine 
eligibility of the subject prior to undertaking the examination at Visit 2 (Qualification Visit 
#1). 
For subjects who are unable or unwilling to have blood drawn for clinical labs at Visit 1 
(Screening), the blood sample may be drawn at Visit 2 (Qualification Visit #1) or during the 
washout period at a visit where interim IOP measurements are being performed so long 
as the results of the clinical labs are available for that subject prior to Visit 3 (Qualification 
Visit #2). 
The investigator will evaluate the results of these examinations for possible enrollment of the 
individual into the study. 
All individuals who are qualified for enrollment should undergo a washout period as noted in 
Section 5.7.1. 
7.1.1.1 
Evaluation of eye-drop instillation performance 
Subjects (or guardian or carer for subjects deemed unable to administer) will be provided a 
bottle of commercially available, multi-dose, non-medicated artificial tears in a room with 
access to water and soap. Medication instiller will be asked to instill a drop of the artificial 
tear in each eye under the observation of a member of the investigator’s staff. The staff will 
observe the subject, guardian or alternative person to assure that they instill 1 drop of the 
artificial tear into each eye, without touching the tip of the bottle to their eye or face 
(Stone 2009). The staff member may work with the individual to improve their delivery 
technique to meet this standard. If the subject (guardian or alternative person) cannot 
demonstrate proper delivery of the eye drop, or if staff member feels that the individual will 
be unable to do so consistently, then the subject will be excluded from further study 
participation. 


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7.1.1.2 
Washout Period 
As noted in Section 5.7.1, as current use of at least one ocular hypotensive medication is an 
inclusion criterion, a washout period is required for those who meet other qualifications for 
enrollment.  The investigator must perform interim visits, ideally at weekly intervals, during 
the washout period for IOP measurement. 
In addition, all women of childbearing potential will have a pregnancy test performed 
during the washout period if the washout period extends beyond 4 weeks. 
7.1.2 
Visit 2 (Qualifying Visit #1, for 08:00 hours IOP and safety measurements) 
After the washout, individuals will return to the Investigator’s office in the early morning. 
The subject will be questioned regarding any changes in their health or concomitant 
medication use.  Any change should be recorded on the Adverse Event page of the CRF. 
Inclusion/exclusion criteria will be reviewed again for the qualified individual. Results of the 
clinical laboratory tests from Visit 1 need to be available and reviewed by the Investigator. 
For subjects who were unable or unwilling to have blood drawn for clinical labs at Visit 1, 
the blood sample may be drawn at Visit 2 (Qualification Visit #1) or during the washout 
period at a visit where interim IOP measurements are being performed so long as the results 
of the clinical labs are available for that subject prior to Visit 3 (Qualification Visit #2). 
The following procedures will be performed: 
• Heart rate and blood pressure. 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. 
• Best corrected visual acuity. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 60 minutes of the nominal time (i.e., 07:00 
to 09:00 hours). 
• Urine Pregnancy test: women of childbearing potential (who have a washout period that 
extends beyond 4 weeks). 
For further evaluation in the study, at this time, unmedicated (post-washout) IOP must be 
> 20mmHg in at least one eye and < 36mmHg in both eyes. This is the first of the four 
qualifying IOPs for randomization.  Individuals who do NOT meet this requirement may 
return for up to 2 additional qualification visits within 1 week of failing this qualification 
visit. 


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Individuals who screen fail due to IOP being ≥ 36mmHg in either eye (exclusion criterion) 
may not return for additional qualification visits. 
Qualified individuals will be scheduled to return 2-7 days later for the second qualification 
visit. 
7.1.3 Visit 3.0 (Qualifying Visit #2, Day 1, for IOP and safety measurement at 08:00 
hours) 
Within 2 to 7 days after Visit 2, individuals will return to the Investigator’s office for the next 
08:00 hour IOP measurement. The results of the clinical laboratory tests need to be 
available, and reviewed by the Investigator. In order for the individual to be enrolled, the 
tests cannot be indicative of any clinically significant disease in the opinion of the 
investigator. The subject will be questioned regarding any changes in their health or 
concomitant medication use.  Any change should be recorded on the Adverse Event of the 
CRF. Inclusion/exclusion criteria will be reviewed again for the qualified individual. 
The following procedures will be performed: 
• Heart rate and blood pressure. 
• Urine pregnancy test: women of childbearing potential must have a negative urine 
pregnancy test result within 7 days prior to randomization. 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. 
• Best Corrected Visual Acuity. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy.  IOP must be measured within 60 minutes of the nominal time 
(i.e., 07:00 to 09:00 hours). 
For further evaluation in the study, at this time (08:00 hours) unmedicated IOP must be 
> 20mmHg in at least one eye and < 36mmHg in both eyes. This is the second of the four 
qualifying IOPs for randomization. If one eye qualifies at the second qualification visit, 
it MUST be the same eye as in previous qualification visit (Visit 2 qualifying visit# 1) 
and this will be the study eye for the duration of the study.’’ 
Qualified individuals will continue with the measurements of IOP at 10:00 hours and 16:00 
hours. 
Individuals who do not meet this requirement may return for up to 2 additional qualification 
visits within 1 week of failing this qualification visit. Individuals returning at an unscheduled 
visit within 1 week are required to only re-measure IOP in both eyes. 


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Upon return for an unscheduled qualification visit, such individuals’ IOP measurements 
would need to qualify at 08:00, 10:00 and 16:00 hours. Individuals who screen fail due to 
IOP being ≥ 36mmHg in either eye (exclusion criterion) may not return for additional 
qualification visits. 
Individuals are allowed to leave the investigator’s office between assessments, and eat and 
drink with no restrictions. However, individuals are not to consume alcohol or engage in 
strenuous exercise. 
7.1.4 
Visit 3.1 (Day 1, for IOP and safety measurement at 10:00 hours) 
Inclusion/exclusion criteria will be reviewed again for the qualified individual. Qualified 
individuals will be examined. Each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• A non-dilated eye examination will be performed, including IOP measurements and bio 
microscopy. IOP must be measured within 30 minutes of the nominal time (i.e., 09:30 to 
10:30 hours). Please note, the minimum time between IOP measurements is 60 minutes. 
For example if the previous IOP measurement was taken at 09:00, the IOP at this visit 
should not be measured before 10:00. 
At this and any other in-office visit, any subject complaining of visual function issues will 
have visual function assessed as judged appropriate by the investigator. 
For further evaluation in the study, at this time (10:00 hours, Day 1) unmedicated IOP must 
be > 17mmHg in at least one eye and < 36mmHg in both eyes. This is the third of the four 
qualifying IOPs for randomization. If one eye qualifies it must be the same eye as 
Visit 2.0 and Visit 3.0.   
Qualified individuals will continue with the qualification visit. Individuals who do not meet 
this requirement may return for up to 2 additional qualification visits within 1 week of failing 
this qualification visit. Individuals returning at an unscheduled visit within 1 week are 
required to only re-measure IOP in both eyes. Upon return, such individuals would need to 
qualify at 08:00, 10:00 and 16:00 hours. Individuals who screen fail due to IOP being 
≥ 36mmHg in either eye (exclusion criterion) may not return for additional qualification 
visits. 
Individuals are allowed to leave the investigator’s office between assessments, and eat and 
drink with no restrictions.  However, individuals are not to consume alcohol or engage in 
strenuous exercise. 
7.1.5 
Visit 3.2 (Day 1, for IOP and safety measurements at 16:00 hours) 
Inclusion/exclusion criteria will be reviewed again for the qualified individual. Qualified 
individuals will be examined. Each examination will include: 


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• Symptomatology: Individuals will be asked “How are you feeling?” 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy.  IOP must be measured within 30 minutes of the nominal time 
(i.e., 15:30 to 16:30 hours). 
For further evaluation in the study, at this time (16:00 hours, Day 1) unmedicated IOP must 
be > 17mmHg in at least one eye and < 36mmHg in both eyes. This is the fourth of the four 
qualifying IOPs for randomization. If one eye qualifies it must be the same eye as Visit 
2.0, Visit 3.0. and Visit 3.1.  
Individuals who do NOT meet this requirement may return for up to 2 additional 
qualification visits within 1 week of failing the first qualification visit. Individuals returning 
at an unscheduled visit within 1 week are required to only re-measure IOP in both eyes. 
Upon return, such individuals would need to qualify at 08:00, 10:00 and 16:00 hours. 
Individuals who screen fail due to IOP being ≥ 36mmHg in either eye (exclusion criterion) 
may not return for additional qualification visits. 
For subjects that qualify in both eyes based upon IOP and ocular history, the study eye will be 
the eye with the higher IOP at 08:00 hours on Visit 3. If both eyes have the same IOP at 08:00 
hours on Visit 3, then the right eye will be the study eye. In all subjects, both eyes will be 
treated. 
At this point, eligible subjects will be randomized. The first IP kit(s) containing 1 bottle from 
the assigned subject packer will be dispensed within 48 hours of the randomization visit to 
the subject, along with dosing and storage instructions by unmasked site staff.  
Subjects will be: 
• Instructed to administer their masked medication in both eyes (OU) at home between 
20:00 – 22:00 hours beginning with the first dose on the evening of this study visit or no 
later than within 48 hours of randomization.  
• Instructed to return to the office with their study medication on Week 2 (Day 15). 
For post randomization assessments a window of ±3 days for scheduled visits up to Month 5 
is permitted. A window of ±7 days for Month 6 is permitted.  
7.1.6 
Visit 4.0 (Week 2 [Day 15], for IOP and safety measurements at 08:00 hours) 
Subjects will return to the Investigator’s office. The subject will be questioned about any 
missed doses any changes in their health or concomitant medication use. Subjects will be 
examined and each examination will include: 
• Heart rate and blood pressure. 


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• Urine pregnancy test for women of childbearing potential. 
• Symptomatology: Individuals will be asked “How are you feeling”? 
• Recording of any AEs. At the investigator’s discretion photography of any ocular events. 
• Best Corrected Visual Acuity. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 60 minutes of the nominal time 
(i.e., 07:00 to 09:00 hours). 
• All used/returned IP kits will be collected for destruction by the unmasked site staff. 
After randomization, any new or worsening of symptoms beyond those collected at baseline 
are to be entered as adverse events. 
Subjects are allowed to leave the investigator’s office between assessments, and eat and drink 
without restrictions. However, individuals are not to consume alcohol or engage in strenuous 
exercise. 
7.1.7 
Visit 4.1 (Week 2 [Day 15], for IOP and safety measurements at 10:00 hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular events. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 30 minutes of the nominal time 
(i.e., 09:30 to 10:30 hours). Please note, the minimum time between IOP measurements is 
60 minutes. For example, if the previous IOP measurement was taken at 09:00, the IOP at 
this visit should not be measured before 10:00. 
Subjects are allowed to leave the investigator’s office between assessments, and eat and drink 
without restrictions. However, individuals are not to consume alcohol or engage in strenuous 
exercise. 
7.1.8 
Visit 4.2 (Week 2 [Day 15], for IOP and safety measurements at 16:00 hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular events. 


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• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 30 minutes of the nominal time 
(i.e., 15:30 to 16:30 hours). 
• Two new subject kits, each containing 1 bottle from the originally assigned subject 
packer, will be dispensed to the subject by the unmasked site staff, along with dosing and 
storage instructions. 
Subjects will be: 
• Instructed to continue to administer their masked medication in both eyes (OU) at home 
between 20:00 - 22:00 hours (taking the daily evening dose on that day).   
• Instructed to return to the office with their used study medication on Week 6 (Day 43). 
7.1.9 
Visit 5.0 (Week 6 [Day 43], for IOP and safety measurements at 08:00 hours) 
Subjects will return to the Investigator’s office. The subject will be questioned regarding any 
missed doses and any changes in their health or concomitant medication use. 
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure. 
• Urine pregnancy test for women of childbearing potential. 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular events. 
• Best Corrected Visual Acuity. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy.  IOP must be measured within 60 minutes of the nominal time (i.e., 07:00 
to 09:00 hours). 
All used/returned IP kits will be collected for destruction by the unmasked site staff. 
Any new or worsening of symptoms beyond those collected at baseline are to be entered as 
adverse events. 
Subjects are allowed to leave the investigator’s office, and eat and drink without 
restrictions. However, individuals are not to consume alcohol or engage in strenuous exercise. 
7.1.10 
Visit 5.1 (Week 6 [Day 43], for IOP and safety measurements at 10:00 hours) 
Subjects will be examined and each examination will include: 


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Symptomatology: Individuals will be asked “How are you feeling” Recording of any AEs. At 
the investigator’s discretion photography of any ocular events. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 30 minutes of the nominal time (i.e. 09:30 
to 10:30 hours). Please note, the minimum time between IOP measurements is 
60 minutes. For example if the previous IOP measurement was taken at 09:00, the IOP at 
this visit should not be measured before 10:00. 
Subjects are allowed to leave the investigator’s office, and eat and drink without restrictions. 
However, individuals are not to consume alcohol or engage in strenuous exercise. 
7.1.11 
Visit 5.2 (Week 6 [Day 43], for IOP and safety measurements at 16:00 hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular events. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 30 minutes of the nominal time (i.e., 15:30 
to 16:30 hours). 
Three new subject kits, each containing 1 bottle from the originally assigned subject packer, 
will be dispensed to the subject by the unmasked site staff, along with dosing and storage 
instructions. 
Subjects will be: 
• Instructed to continue to administer their masked medication in both eyes (OU) at 
home between 20:00 - 22:00 hours (taking the daily evening dose on that day). 
• Instructed to return to the office with their study medication on Month 3 (Day 90). 
7.1.12 
Visit 6.0 (Month 3 [Day 90], for IOP and safety measurements at 08:00 
hours) 
Subjects will return to the Investigator’s office. The subject will be questioned about any 
missed doses and any changes in their health or concomitant medication use. 
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure.  
• Urine pregnancy test for women of childbearing potential. 


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• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular 
events. 
• Best corrected visual acuity. 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy.  
IOP must be measured within 60 minutes of the nominal time 
(i.e., 07:00 to 09:00 hours). 
• Pachymetry at the study visit or within one week of the study visit. 
• Visual fields (may be assessed up to one week prior to this visit, or later in the 
morning or afternoon of this series of Day 90 visits so long as it occurs after the 08:00 
hour IOP measurement at that visit). See Appendix 2 for further details when dilation 
is required due to subject small pupils. 
• All used/returned IP kits will be collected for destruction by the unmasked site staff. 
Any new or worsening of symptoms beyond those collected at baseline are to be entered as 
adverse events. 
Subjects are allowed to leave the investigator’s office, and eat and drink without restrictions. 
However, individuals are not to consume alcohol or engage in strenuous exercise. 
7.1.13 
Visit 6.1 (Month 3 [Day 90], for IOP and safety measurements at 10:00 
hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular 
events. 
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy. IOP must be measured within 30 minutes of the nominal time 
(i.e., 09:30 to 10:30 hours). Please note, the minimum time between IOP 
measurements is 60 minutes. For example if the previous IOP measurement was taken 
at 09:00, the IOP at this visit should not be measured before 10:00. 
Subjects are allowed to leave the investigator’s office, and eat and drink without restrictions. 
However, individuals are not to consume alcohol or engage in strenuous exercise. 


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7.1.14 
Visit 6.2 (Month 3 [Day 90], for IOP and safety measurements at 16:00 
hours) 
Subjects will be examined and each examination will include: 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular 
events.  
• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy.  IOP must be measured within 30 minutes of the nominal time 
(i.e., 15:30 to 16:30 hours). 
• A dilated ophthalmoscopy examination (including cup:disc ratio). 
Two new subject kits, from the assigned safety extension subject packer, each containing 1 
bottle will be dispensed to the subject by the unmasked site staff, along with dosing and 
storage instructions. 
Subjects will be: 
• Instructed to continue to administer their masked medication in both eyes (OU) at 
home between 20:00 - 22:00 hours (taking the daily evening dose on that day). 
• Instructed to return to the office with their study medication on Month 4 (Day 120). 
7.1.15 
Visit 7.0 (Month 4 [Day 120], for IOP and safety measurements at 10:00 
hours) 
Subjects will return to the Investigator’s office. The subject will be questioned about any 
missed doses and any changes in their health or concomitant medication use. 
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure. 
• Urine pregnancy test for women of childbearing potential. 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular 
events. 
• Best corrected visual acuity. 


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• A non-dilated eye examination will be performed, including IOP measurements and 
biomicroscopy.  IOP must be measured within 30 minutes of the nominal time 
(i.e., 09:30 to 10:30 hours). 
• All used/returned IP kits will be collected for destruction by the unmasked site staff. 
Any new or worsening of symptoms beyond those collected at baseline are to be entered as 
adverse events. 
Two new subject kits, from the assigned safety extension subject packer, each containing 1 
bottle will be dispensed to the subject by the unmasked site staff, along with dosing and 
storage instructions. Subjects will be: 
• Instructed to continue to administer their masked medication in both eyes (OU) at 
home between 20:00 – 22:00 hours (taking the daily evening dose on that day). 
• Instructed to return to the office with their study medication on Month 5 (Day 150). 
7.1.16 
Visit 8.0 (Month 5 [Day 150], for IOP and safety measurements at 10:00 
hours) 
Subjects will return to the Investigator’s office. The subject will be questioned about any 
missed doses and any changes in their health or concomitant medication use. 
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure. 
• Urine pregnancy test for women of childbearing potential. 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Recording of any AEs. At the investigator’s discretion photography of any ocular 
events. 
• Best corrected visual acuity. 
• A non-dilated eye examination will be performed, IOP measurements and 
biomicroscopy.  IOP must be measured within 30 minutes of the nominal time 
(i.e., 09:30 to 10:30 hours). 
• All used/returned IP kits will be collected for destruction by the unmasked site staff. 
Any new or worsening of symptoms beyond those collected at baseline are to be entered as 
adverse events. 


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Two new subject kits, from the assigned safety extension subject packer, each containing 1 
bottle will be dispensed to the subject by the unmasked site staff, along with dosing and 
storage instructions. Subjects will be: 
• Instructed to continue to administer their masked medication in both eyes (OU) at 
home between 20:00 – 22:00 hours (taking the daily evening dose on that day). 
• Instructed to return to the office with their study medication on Month 6 (Day 180). 
7.1.17 
Visit 9.0 (Month 6 [Day 180] for IOP and safety measurements at 10:00 
hours) 
Subjects will return to the Investigator’s office. The subject will be questioned about any 
missed doses and any changes in their health or concomitant medication use. 
Subjects will be examined and each examination will include: 
• Heart rate and blood pressure. 
• Symptomatology: Individuals will be asked “How are you feeling?” 
• Blood samples will be taken for clinical chemistry and hematology (samples may be 
taken at any time point throughout Visit 9). 
• Recording of any AEs. At the investigator’s discretion photography of any ocular 
events. 
• Best corrected visual acuity. 
• A non-dilated eye examination will be performed, including IOP and biomicroscopy.  
IOP must be measured within 30 minutes of the nominal time 
(i.e., 09:30 to 10.30 hours). 
• Central corneal thickness will be measured by ultrasound Pachymetry. 
• Visual fields (may be assessed up to one week prior to this visit, or later in the 
morning or afternoon of this series of Day 180 visit so long as it occurs after the IOP 
measurement at that visit). See Appendix 2 for further details when dilation is 
required due to subject small pupils. 
• The subject will complete both the Self-Administered VFQ-25 Questionnaire and the 
Self-Administered Health Survey Questionnaire (SF-36 v.2).   
• Urine pregnancy test for women of childbearing potential. 
• A dilated ophthalmoscopy examination (including cup:disc ratio). 


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• All used/returned IP kits will be collected for destruction by the unmasked site staff. 
Any new or worsening of symptoms beyond those collected at baseline are to be 
entered as adverse events. 
Subjects will be thanked for their participation, will exit the study and are released to the 
normal care of their Physician. 
7.1.18 
Unscheduled Visits 
An unscheduled visit may be any visit to the Investigator other than the specific visits 
requested in the protocol as possibly required for the subject’s ophthalmic condition. 
The Investigator will perform all procedures necessary to evaluate the study participant at 
these visits and record any adverse events in the CRF. 
As noted in Section 5.11.5, every possible effort should be made by investigators to ensure 
that non-completing subjects have a final visit that includes all examinations listed for 
Visit 9.0 / Exit (Day 180) as well as dilated ophthalmoscopy.  
7.1.19 
Instructions for Completion of Case Report Forms 
The initial point of entry of study data should be the subject record source documentation. 
Then, data should be transcribed to the CRF as follows: 
At each subject visit, the appropriate CRFs must be completed. Whenever a CRF is used, be 
sure to provide all information requested including subject identification number and name or 
number of Investigator, date(s), etc. All applicable questions should be answered and all data 
requested should be provided. Those areas that require a response but are not filled in 
correctly are considered incomplete or erroneous entries, and will have to be corrected.  
Providing all the necessary data the first time saves office time for the Investigator during 
subsequent audits. 
For this study, electronic CRFs will be used. Security and authorization procedures consistent 
with the system must be used. 
7.2 
Adverse Events Assessments and Ocular Safety  
Performing Adverse Events Assessments 
Qualified study staff responsible for assessing adverse events (AEs) will be listed on the Site 
Signature/Delegation of Responsibilities Log. This includes assessment of AE severity and 
relationship to investigational product.  AE information may be volunteered by the subject or 
solicited by study personnel through non-leading questions. 
All adverse events (AEs) occurring during the study, regardless of the assumption of causal 
relationship, must be documented on the respective eCRF. Adverse events should be 


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documented from the time the subject signs the informed consent until 30 days after the last 
dose of Investigational Product.  
If a subject has an ongoing AE at the time of study completion, the ongoing AE must be 
followed-up and provided appropriate medical care until the event has resolved or stabilized.  
Documentation of adverse events/adverse reactions includes start date and stop date, severity, 
action(s) taken, seriousness and outcome. Investigators at their discretion may also take 
photographs of ocular events to provide additional documentation of adverse events. These 
images can only be shared with the sponsor if the subject has provided permission to do so 
by signing the appropriate consent documentation. 
7.2.1 
Adverse Event Definitions 
The following definitions of terms apply to this section: 
• Adverse event. Any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
• Life-threatening adverse event or life-threatening suspected adverse reaction. An 
adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the Investigator or Sponsor, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had 
it occurred in a more severe form, might have caused death. 
• Serious adverse event (SAE) or serious suspected adverse reaction (SSAR). An adverse 
event or suspected adverse reaction is considered ‘‘serious’’ if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: Death, a 
life-threatening adverse event, patient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may 
jeopardize the patient and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in patient hospitalization, or the development 
of drug dependency or drug abuse. 
• Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘‘reasonable possibility’’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. Suspected adverse reaction implies 
a lesser degree of certainty about causality than adverse reaction, which means any 
adverse event caused by a drug. 


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• Unexpected adverse event or unexpected suspected adverse reaction. An adverse event 
or suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in Section 8.4 
of the Investigator’s Brochure ‘Reference Safety Information’ or is not listed at the 
specificity or severity that has been observed.  For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the Investigator’s Brochure 
referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the Investigator’s Brochure listed only cerebral vascular accidents. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the Investigator brochure as occurring with a 
class of drugs or as anticipated from the pharmacological properties of the drug, but are 
not specifically mentioned as occurring with the particular drug under investigation. 
Note: Any medical condition present prior to administration of the masked study medication 
which remains unchanged or improved should not be recorded as an adverse event at 
subsequent visits. 
Note: If an event occurs during the washout period (prior to subject enrollment and the 
commencement of study medication), it should be recorded as an adverse event.  
Note: In the present study, Investigators are asked to use the verbatim term “conjunctival 
hyperemia” on the study AE form to describe observations of conjunctival redness if the 
ocular redness observation is increased from Visit 1 (screening) observations and clinically 
meaningful. Investigators are also asked to note all observations of conjunctival hyperemia 
on the biomicroscopy eCRF as well as on the study AE form. 
7.2.2 
Timing for Reporting of Adverse Events 
The AEs occurring during the study must be documented, regardless of the assumption of a 
causal relationship. AEs should be documented from the time the subject signs and dates the 
patient consent form until subject participation in the study has been completed. If a subject 
has one or more ongoing AEs at the time of study completion, the subject must be followed 
and provided appropriate medical care until the sign(s) and/or symptoms(s) of the AE have 
remitted or stabilized in the opinion of the Investigator. 
When recording an AE, the following information should be provided on the study AE 
eCRF: 
1. Action Taken with Study Drug: 
• None 
• Investigational Product Discontinued 
• Investigational Product Interrupted 


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2. Other Action Taken: 
• None 
• Non-Drug Therapy 
• New OTC or Rx Drug Added 
• Hospitalized less than 24 hours 
• Hospitalized greater than or equal to 24 hours 
3. Outcome of an adverse event is coded as: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Unknown/Lost to follow-up 
7.2.3 
Severity 
Severity of an adverse event is defined as a qualitative assessment of the level of discomfort 
or the degree of intensity of an adverse event as determined by the Investigator or reported to 
him/her by the subject. The assessment of severity is made irrespective of study medication 
relationship or seriousness of the event and should be evaluated according to the following 
scale: 
• 
1 = Mild: present and noticeable, but not distressing, and no disruption of normal daily 
activities. 
• 
2 = Moderate: bothersome, discomfort sufficient to possibly reduce or affect normal daily 
activity. 
• 
3 = Severe: incapacitating, with inability to work or perform normal daily activity. 
A change in severity for a reported AE will require a stop date for the previous severity and a 
new start and stop date for the new severity. For example, a change in severity may go from 
mild to severe or from severe to moderate. In both cases, the start and stop dates should be 
recorded.   


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Please note: a severe AE is not the same as a serious AE.  Seriousness of an AE (NOT 
severity) serves as a guide for defining regulatory reporting obligations (see Section 7.2.6 for 
further information on serious AEs [SAEs]). 
7.2.4 
Relationship 
The study medication relationship for each adverse event/adverse reaction should be 
determined by the Investigator using these explanations: 
• 
Not Related:  The event is clearly related to other factors such as subject’s clinical 
condition; therapeutic interventions, concomitant disease or therapy administered to the 
subject and does not follow a known response pattern to the product. 
• 
Unlikely Related: The event is most probably caused by other etiologies such as 
participant’s underlying condition, therapeutic intervention, or concomitant therapy; or 
the delay between administration and the onset of the AE is incompatible with a causal 
relationship. Therefore, there is not a reasonable possibility that the AE was caused by 
the study medication. 
• 
Possibly Related:  The event follows a reasonable, temporal sequence from the time of 
study medication 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 therapy administered to the subject. 
• 
Related:  The event follows a reasonable, temporal sequence from the time of study 
medication administration and/or follows a known response pattern to the study 
medication and cannot be reasonably explained by other factors such as subject’s clinical 
state, therapeutic interventions or concomitant therapy administered to the subject, and 
either occurs immediately following study medication administration, or improves on 
stopping the study medication, or reappears on repeat exposure, or there is a positive 
reaction at the application site. 
7.2.5 
Expectedness 
For netarsudil, the most frequently reported AE in 3 Phase 2 and one Phase 3 studies 
(Clinical Study Reports AR-13324-CS201, AR-13324-CS202, PG324-CS201, 
AR-13324-CS301, and AR-13324-CS302, AR-13324-CS304) has been conjunctival 
hyperemia. Other AEs seen in significantly greater frequency with netarsudil than in active 
control treatment arms in these studies include instillation site erythema or pain, eyelid 
erythema, conjunctival hemorrhage, conjunctival vascular disorder, blurred vision, corneal 
deposits, eye irritation, increased lacrimation, and foreign body sensation. 
The very common ocular AE’s seen with GANFORT® in clinical trials as reported in the 
GANFORT® prescribing information has been conjunctival hyperemia (Appendix 3). 
Common systemic effects are headache and dizziness. Common Ocular side effects seen with 
GANFORT® are superficial punctuate keratitis, corneal erosion, burning sensation, eye 


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pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, 
eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus, visual acuity 
worsened, blepharitis, eyelid oedema, eye irritation, epiphora, growth of eyelashes. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Section 8.4 of the Investigator’s Brochure ‘Reference Safety Information’ or is not listed at 
the specificity or severity that has been observed. “Unexpected,” as used in this definition, 
also refers to adverse events or suspected adverse reactions that are mentioned in the 
Investigator’s Brochure as occurring with this class of drugs or as anticipated from the 
pharmacological properties of PG324 or GANFORT®, and are not specifically mentioned as 
occurring with the IP. The AEs that are both unexpected and serious should be reported in an 
expedited fashion to the Sponsor (see Section 7.2.6 for further details). 
7.2.6 Serious Adverse Events (SAEs) or Serious Unexpected Suspected Adverse 
Reaction Safety Reports (SUSARs) 
An investigator must immediately report to the Sponsor representative any SAE or serious 
unexpected suspected adverse reactions within 24 hours of occurrence or being informed of 
the event, whether or not considered drug related including those listed in the protocol or 
investigator brochure and must include an assessment of whether there is a reasonable 
possibility that the drug caused the event. A reaction will be considered unexpected if it is 
not listed in the Reference Safety Information Section 8.4 in the AR-13324 Ophthalmic 
Solution (Netarsudil Ophthalmic Solution)/PG324 Ophthalmic Solution Investigator 
Brochure and /or in Section 4.8 of the GANFORT® SmPC.  Study endpoints that are serious 
adverse events (e.g., all-cause mortality) must be reported in accordance with the protocol 
unless there is evidence suggesting a causal relationship between the drug and the event 
(e.g., death from anaphylaxis). In that case, the Investigator must immediately report the 
event to the Sponsor.  The investigator must record non-serious adverse events and report 
them to the Sponsor. In case of incomplete information, the Investigator must provide follow-
up information as soon as possible, again using the SAE report form. 
This requirement applies to occurrences observed during the course of the study and within 
30 days of last administration of the study medication. In addition, in the case of 
immediately life-threatening AEs or AEs with fatal outcome, or adverse events that are 
serious, unexpected (i.e., not in the Clinical Investigator’s Brochure and/or in Section 4.8 of 
the GANFORT® SmPC [see Appendix 3]) and judged related to the IP, the Investigator 
must inform the Sponsor or Sponsor representative by phone within 24 hours of observation 
or occurrence of the SAE. 
SAEs must be reported to the IEC/ CEC according to the IEC/ CEC requirements. Prompt 
notification of SAE’s by the investigator to Sponsor/ Sponsor representative is essential so 
that legal obligations and ethical responsibilities towards the safety of the subjects are met.  
Sponsor/ Sponsor representative has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a product under clinical 
investigation. The Sponsor or Sponsor representative will comply with country specific 


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regulatory requirements relating the safety reporting to the regulatory authority, Independent 
Ethics Committee (IEC/ CEC) and Investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Sponsor /Sponsor representative and are 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (e.g. summary or listing of SAEs) from Sponsor/ Sponsor 
representative will file it with the IB and will notify the IEC/ CEC, if appropriate according to 
local requirements. 
Procedurally, for this study, the Investigator will report the event to 
 Drug 
Safety. An SAE report should be completed and faxed or emailed directly to 
lth 
Drug Safety, using the study-specific SAE fax coversheet. The SAE fax/email cover page is 
included in attachment 1 of the Safety Management Plan (SMP) together with all relevant fax 
numbers and email addresses. The SAE report should include the essential elements. The 
investigator should not wait to receive additional information to document fully the event 
before notification of a SAE, though additional information may be requested. Where 
applicable, information from relevant laboratory results, hospital case records, and autopsy 
reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the investigator at 
any time after cessation of study drug administration and linked by the investigator to this 
study, should be reported to the study monitor. 
The sponsor and/or 
 will promptly notify all relevant investigators and the 
regulatory authorities of findings that could adversely affect the safety of subjects, impact on 
the conduct of the study or alter the Institutional Review Board/Independent Ethics 
Committee (IEC/ CEC) approval/favourable opinion of the study. In addition, 
, 
on behalf of the sponsor, will expedite the reporting to all concerned investigators, to the 
IEC/ CECs where required, and to the regulatory authorities of all adverse reactions that are 
both serious and unexpected. 
Pregnancy, Testing Prevention and Reporting 
For Female Subjects 
The need for a screening pregnancy test depends on whether a woman is of childbearing 
potential or non-childbearing potential. 
A woman of non-childbearing potential (i.e. physiologically incapable of becoming pregnant) 
is defined as any woman who has had a hysterectomy, bilateral oophorectomy (ovariectomy) 
or bilateral tubal ligation, or is post-menopausal. 


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A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, > 45 years in the absence of hormone replacement 
therapy (HRT). In questionable cases the subject must have follicle stimulating hormone 
(FSH) value > 40mIU/mL and an estradiol value < 40pg/mL (< 140 pmol/L) 
A woman of childbearing potential is defined as any woman who does not meet the criteria 
of the non-childbearing potential as described in the previous paragraph. 
If a woman is of childbearing potential, she must have a urine pregnancy test performed 
within 7 days prior to the first dose of study treatment. Subjects with positive pregnancy test 
result must be excluded from the study. Subjects with negative pregnancy test must agree to 
use a highly effective contraception method described below from time of randomization and 
for 3 months following the last dose of study medication.  
Highly acceptable contraceptive methods when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows 
(Clinical Trials Facilitation Group 2014): 
• combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation. Due to lack of systemic absorption of netarsudil and no systemic 
effects seen with latanoprost, PG324 is not expected to lower the effectiveness of 
hormonal contraception: 
- 
oral 
- 
intravaginal 
- 
transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation. Due to 
lack of systemic absorption of netarsudil and no systemic effects seen with latanoprost, 
PG324 is not expected to lower the effectiveness of hormonal contraception:  
- 
oral 
- 
injectable 
- 
implantable (considered to have low user dependency) 
• intrauterine device (IUD). 
• intrauterine hormone-releasing system (IUS) (considered to have low user dependency). 
• bilateral tubal occlusion (considered to have low user dependency). 
• vasectomised partner (is considered as having lower user dependency and highly 
effective birth control method providing that the partner is the sole sexual partner of the 


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women of childbearing potential and that the vasectomized partner has received a 
medical assessment of the surgical success). 
• sexual abstinence: sexual abstinence is only considered to be an acceptable method of 
contraception when defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatments. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the trial and the preferred and usual 
lifestyle of the subject.   Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception. 
Female subjects who are lactating must discontinue nursing prior to the first dose of IP and 
must refrain from nursing throughout the treatment period and for 30 days following the last 
dose of IP. 
Male subjects 
Men with a female partner of childbearing potential must have either had a prior vasectomy 
or agree to use a condom as an effective method of contraception from time of randomization 
and for 3 months following the last dose of study medication. A combination of male 
condom with either cap, diaphragm or sponge with spermicide (double barrier methods) are 
also considered acceptable, but not highly effective, birth control methods. 
Pregnancy Reporting 
Pregnancies occurring in subjects enrolled in the study or in their partners must be reported 
and followed to outcome. While pregnancy itself is not considered to be an AE or SAE, 
pregnancy reports are tracked by 
 Drug Safety. Premature terminations 
including miscarriage, spontaneous abortion, or elective termination of a pregnancy for 
medical reasons will be reported as an SAE. Other pregnancy complications should be 
reported as SAE’s, if they meet the serious criteria. Should the pregnancy result in a 
congenital anomaly or birth defect, a separate SAE must be submitted. Furthermore, all 
neonatal deaths that occur within 30 days of the birth should be reported as SAE’s without 
regard to causality. 
The investigator must complete the Pregnancy Report Form and fax or email the form to 
 Drug Safety within one business day of the pregnancy. Following delivery or 
termination of the pregnancy, the Pregnancy Report Form is to be completed and sent by fax 
or email to 
 Drug Safety. 
7.2.7 
Follow-up of Subjects After Adverse Events 
If an adverse event/adverse reaction occurs, the Investigator will institute support and/or 
treatment as deemed appropriate. If a serious or non-serious adverse event/adverse reaction 
is unresolved at the time of the last visit, efforts will be made to follow up until the adverse 


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event/adverse reaction is resolved or stabilized, the subject is lost to follow-up, or there is 
other resolution to the event. 
8. STATISTICAL METHODS 
8.1 
Primary Hypotheses 
• H0: The difference between study eyes treated with PG324 Ophthalmic Solution Q.D. and 
study eyes treated with GANFORT® Q.D. (PG324 Q.D. - GANFORT® Q.D.), in the mean 
IOP at the following time points: 08:00, 10:00, and 16:00 hours at Week 2, Week 6, and 
Month 3 Visits, is > 1.5mmHg for at least one time point over all visits or is > 1.0mmHg 
for a majority of time points over all visits. 
• H1: The difference between study eyes treated with PG324 Ophthalmic Solution Q.D. and 
study eyes treated with GANFORT® Q.D., 0.5% (PG324 Q.D. - GANFORT® Q.D.), in 
the mean IOP at the following time points: 08:00, 10:00, and 16:00 hours at Week 2, 
Week 6, and Month 3 Visits, is ≤ 1.5mmHg for all time points over all visits and 
≤ 1.0 mmHg at a majority of time points over all visits. 
Clinical non-inferiority will be concluded if the upper limit of the 95% CIs around the 
difference (PG324 Q.D. - GANFORT® Q.D.) is ≤ 1.5mmHg at all time points and 
≤ 1.0 mmHg at the majority of time points through Month 3.  
The non-inferiority (NI) margin specified in the protocol was based on advice received from 
EMA through the scientific advice procedure (EMA/CHMP/SAWP/588765/2016) on 
15 September 2016. In addition to the 1.5 mmHg margin at all time points specified in the 
draft protocol submitted to EMA for comment, advice was given that in accordance with the 
European Glaucoma Society’s (EGS) Glaucoma Guideline a difference of 1 mmHg in IOP 
was considered to also be clinically relevant and therefore a NI margin no larger than this at 
the majority of time points should be included in the protocol.  
As agreed with the USA FDA at the End of Phase 2 meeting for netarsudil (AR-13324) in 
accordance with the agency’s draft guidance paragraph 16 (recommended Sep 2008; Revised 
Feb 2014, Dec 2014, Mar 2015). 
8.2 
Sample Size Considerations  
Assuming no difference between PG324 Ophthalmic Solution Q.D. and GANFORT® Q.D., a 
two-tailed alpha of 0.05 (2-sided 95% CI) at each of 9-time points, a common standard 
deviation (SD) of 3.5mmHg, and a correlation between time points of 0.60 or less, 200 
intent-to-treat subjects per arm are necessary to have 85% power to show clinical non-
inferiority (as defined above) of PG324 Ophthalmic Solution Q.D. to GANFORT® Q.D. in 
the mean change from baseline IOP.  To account for the potential of additional variability in 
the primary efficacy outcome due to multiple imputations of missing data, approximately up 
to 220 subjects per arm will be randomized. 


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8.3 
Analysis Populations 
Randomized Population: The randomized population will include all subjects who were 
randomized to treatment.  Baseline variables and demographic characteristics will be 
summarized for this population. 
Intent-to-Treat Population (ITT): The ITT population will include all randomized subjects 
who have received at least one dose of study medication. This population will be the 
primary population for efficacy analyses and will be used to summarize all efficacy 
variables and will summarize subjects as randomized. 
Per-protocol population: The PP population is a subset of the ITT population, which will 
include those subjects (and their visits) who do not have major protocol deviations likely to 
seriously affect the primary outcome of the study as judged by a masked evaluation prior to 
the unmasking of the study treatment. This population will be the secondary population for 
efficacy analyses and will be used to summarize a subset of efficacy variables. If the PP and 
ITT populations are exactly the same, then additional efficacy analyses on the PP population 
will not be performed. The PP population will summarize subjects as treated. 
Safety Population: The safety population will include all randomized subjects who have 
received at least one dose of study medication. This population will be used to summarize 
safety variables and will summarize subjects as treated. 
8.4 
Statistical Methods to be Employed  
8.4.1 
General Considerations 
All continuous study assessments will be summarized by treatment and time point 
(as applicable) using descriptive statistics (n, mean, median, standard deviation, minimum, 
and maximum). All categorical study assessments will be summarized by treatment and time 
point (as applicable) using frequency counts and percentages. 
Hypothesis testing, unless otherwise indicated, will be performed at a 2-sided 0.05 
significance level. Where applicable, 2-sided 95% CIs will be reported. All p-values will be 
displayed to four decimal places, with p-values less than 0.0001 presented as '<0.0001' and 
p-values greater than 0.9999 presented as ‘>0.9999’. Difference between PG324 and 
GANFORT® will be calculated as PG324 - GANFORT®. 
All study data will be listed by treatment, subject and time point (as applicable). 
For diurnally-adjusted IOP, baseline will refer to the time-relevant measure at Visit 3.0 
through 3.2 (e.g., IOP at 08:00 hours at Visit 3.0 will be the baseline for 08:00 hours at 
Visit 4.0, Visits 5.0 and 6.0, IOP at 10:00 hours at Visit 3.1 will be the baseline for 10:00 
hours at Visit 4.1, Visits 5.1 and 6.1, etc.). For all other variables, baseline is defined as the 
last measurement prior to the first dose of study medication. 


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The unit of analysis for efficacy will be the study eye.  If the Subject qualifies in both eyes, 
the study eye will be the eye with the higher IOP at 08:00 hours on Visit 3. If both eyes have 
the same IOP at 08:00 hours on Visit 3, then the right eye will be the study eye. 
Statistical methods will be more fully described in a separate Statistical Analysis Plan.  
8.5 
Interim analyses 
When all subjects have completed 3 months of treatment, select individuals from the 
Sponsor/Designee will unmask the study to analyze the 3-month efficacy and safety data.  
This is the time for primary analysis of the study. Efforts will be made to keep the 
investigators masked as to individual subject assignments as the subjects continue to be 
evaluated for safety and efficacy for the following 3 months.   
8.5.1 
Analysis of Baseline Data 
Demographic and baseline characteristics such as age, gender, or disease status will be 
summarized and listed. Medical history, history of ocular surgery and procedures, glaucoma 
history and washout period will also be summarized and listed. 
8.5.2 
Subject Disposition 
Subject enrollment, discontinuation of IP, and withdrawal from the study will be summarized 
and listed. 
8.5.3 
Analysis of Efficacy 
The primary efficacy outcome will be comparison of PG324 Ophthalmic Solution relative to 
GANFORT® for: 
• Mean IOP within a treatment group at the following time points: 08:00, 10:00, and 16:00 
hours at the Week 2, Week 6, and Month 3 study visits. 
Secondary efficacy outcomes will be comparison of PG324 Ophthalmic Solution relative to 
GANFORT® for: 
• Mean diurnal IOP within a treatment group at each post-treatment visit. 
• Mean change from diurnally adjusted baseline IOP at each post-treatment time point. 
• Mean change from baseline in diurnal IOP at each post-treatment visit. 
• Mean percent change from diurnally adjusted baseline IOP at each post-treatment time 
point. 
• Mean percent change from baseline in diurnal IOP at each post-treatment visit. 


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• Percentages of subjects achieving pre-specified mean, mean change, and percent mean 
change in diurnal IOP levels. 
Note that each subject will have one eye designated as the study eye. Only the study eyes will 
be evaluated for the primary efficacy measure; however, both eyes will be treated. 
The primary analysis of the primary outcome will employ a linear model with IOP at the 
given visit and time point as the response, baseline IOP as a covariate, and treatment as a 
main effect factor, using the intent-to-treat population with Monte Carlo Markov chain 
multiple imputation techniques used to impute missing data. Each time point within each 
visit will be modeled separately.  The least squares mean differences (PG324 Q.D. – 
GANFORT® Q.D.) will be presented as well as 2-sided 95% confidence intervals (CIs) and 
p-values.  
If the upper limits of the 95% confidence intervals are < 1.5mmHg at all time points and 
< 1.0mmHg at a majority of time points (at least 5 of 9), then the null hypothesis will be 
rejected in favour of the alternative hypothesis and PG324 Q.D. will be considered to be 
clinically non-inferior to GANFORT® Q.D. Results will be presented in both tabular and 
graphical form. 
Analyses will be performed primarily on the ITT population using multiple imputation 
techniques to impute missing data and secondarily using: observed data only, last observation 
carried forward (LOCF) where LOCF will be performed using time-relevant measures; and 
baseline observation carried forward (BOCF) using time-relevant measures to determine the 
robustness of results. Additionally, the above analyses will be repeated on the PP population 
to determine robustness of results. Additional imputation techniques may be designated in the 
formal statistical analysis plan.   
Secondary analyses of the primary endpoint will be completed using individual 2-sample 
t-tests and 95% t-distribution confidence intervals at each time point (08:00, 10:00, and 16:00 
hours at Week 2, Week 6, and Month 3 Visits) using the ITT and PP populations.     
Similar analyses will be completed on the secondary endpoints: change from baseline IOP 
measures at each time point and visit, mean diurnal IOP and change from baseline mean 
diurnal IOP measures.  Note that the linear model analysis including baseline IOP as a 
covariate will only be completed for the IOP values at the given visit and time point and will 
not be presented for change from baseline as inference is identical between the mean IOP 
response variable and the mean change from baseline IOP response in such a model. 
Additionally, for the individual IOP values at each time point, mixed model repeated 
measures will be run with baseline as the covariate; treatment, visit, time point, treatment by 
visit, treatment by time point, visit by time point, and treatment by visit by time point as the 
fixed effect factors; and subject as the random effect, repeated measure.  An unstructured 
covariance structure will be used to model the within subject, between visit and time point 
variances. This model allows for different variances and covariances within and between 
time points and visits. The treatment by visit, treatment by time point, visit by time point, and 


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treatment by visit by time point interactions allow for a different rate of change in IOP in the 
different treatment arms among visits and time points. This model will be run including the 
Week 2, Week 6, and Month 3 visits. 
Percent change from diurnally adjusted baseline IOP at each time point will be analyzed 
using 2-sample t-tests, between PG324 Q.D. and GANFORT® Q.D. at each time point and 
visit, including 95% t-distribution confidence intervals on the difference (PG324 Q.D. - 
GANFORT® Q.D.). 
Mean diurnal IOP values will be constructed by averaging the 3 diurnal IOP measurements 
on each of Week 2, Week 6, and Month 3 visits. Mean diurnal baseline IOP will be 
constructed as the average of the 3 Day 1 IOP measurements. Mean change from mean 
baseline diurnal IOP will be created by taking the average of the 3-time points on each of 
Week 2, Week 6, and Month 3 visits and subtracting the single mean baseline diurnal IOP 
measurement.  
Sub-group analyses based upon pre-study characteristics such as site, demographics, or 
pre-study ocular hypotensive medications may be completed to further investigate the 
efficacy measures.   
Analyses of IOP will also include summarizing the number and percentage of study eyes 
achieving mean diurnal IOP reduction from baseline of ≥ 4 to ≥ 12 mmHg in 2 mmHg 
increments and percent reduction from baseline of ≥ 5% to ≥ 40% in 5% increments at Week 2, 
Week 6, and Month 3.  Additionally, the number and percentage of study eyes attaining a mean 
diurnal IOP of ≤ 22 mmHg to ≤ 14 mmHg in 1mmHg increments will be summarized at Week 2, 
Week 6, and Month 3.  Fisher’s exact test (2-sided p-values) will be used to test the pair wise 
differences between treatment groups for each category at each visit.  These analyses will be 
presented for both the ITT and PP populations with observed data only. Additional sub-group 
analyses based upon pre-study characteristics such as site, demographics, or pre-study ocular 
hypotensive medications will be completed to further investigate efficacy measures. 
8.5.4 
Analysis of Safety 
8.5.4.1 
Ocular and Systemic Safety Assessments 
Slit lamp biomicroscopy and dilated ophthalmoscopy measures will be summarized at each 
measured time point using discrete summary statistics. 
Visual acuity data will be summarized at each time point using both continuous summaries 
(logMAR), including change from baseline, and discrete summaries, including change from 
baseline in the number of lines and the proportion of subjects with a worsening of ≥ 3 lines 
from baseline. 
Vital signs will be summarized at each visit and for change from baseline to each visit using 
continuous summary statistics by treatment group and visit. 


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Clinical laboratory results will be summarized using both continuous summaries, including 
change from baseline, and discrete summaries, including frequency and percent of subjects 
with an abnormal value and shift tables from baseline.  Additionally, laboratory data will be 
presented in data listings.  
8.5.4.2 
Adverse Events 
Verbatim descriptions of AEs will be mapped to MedDRA thesaurus terms and be presented 
in a data listing. Treatment emergent AEs, those that occur after the first dose of study 
medication, will be summarized by treatment group using frequency and percent for each 
system organ class (SOC) and preferred term (PT) within each SOC. These summaries will 
also be presented for relation to IP and by severity. Fisher’s exact test will be used to test the 
difference in proportions of subjects with each AE between treatment groups (SOC and PT). 
8.5.4.3 
NEI Visual Functioning Questionnaire-25 (VFQ-25) 
The VFQ-25 measurements will be summarized for the Screening, Month 6 and Month 
6/Early Discontinuation visits, including change from Screening to Month 6 and change from 
Screening to Month 6/Early Discontinuation using continuous summary statistics for the total 
score, subscale scores, and each individual question score using observed data only.  
Imputation of missing individual question scores will be detailed in the formal statistical 
analysis plan and will follow methodology used in developing the instrument. One-sample t-
tests will be used to primarily analyze the mean change from Screening to Month 6 and 
Month 6/Early Discontinuation within a treatment group; additionally, the non-parametric 
Wilcoxon signed-rank test will be used secondarily to analyze the change from Screening to 
Month 6 and Month 6/ Early Discontinuation. Two-sample t-tests will be used to primarily 
analyze the difference in the mean scores between treatments at Screening, Month 6, Month 
6/ Early Discontinuation and change from Screening to Month 6 and Month 6/Early 
Discontinuation; additionally, the non-parametric Wilcoxon rank-sum test will be used 
secondarily to analyze the differences in scores between treatments. 
8.5.4.4 
Medical Outcome Short Form (36) Health Survey (SF-36 v.2) 
The SF-36 measurements will be summarized for the Screening, Month 6, and Month 6/ 
Early Discontinuation visits, including change from Screening to Month 6 and change from 
Screening to Month 6/Early Discontinuation using continuous summary statistics for the total 
score, physical and mental health composite summary scores, domain scores, and each 
individual question score using observed data only. Imputation of missing individual 
question scores in calculating domain scores will be detailed in the formal statistical analysis 
plan and will follow methodology detailed in the instrument’s manual. One-sample t-tests 
will be used to primarily analyze the mean change from Screening to Month 6 and Month 6/ 
Early Discontinuation within a treatment group; additionally, the non-parametric Wilcoxon 
signed-rank test will be used to secondarily analyze the change from Screening to Month 6 
and Month 6/ Early Discontinuation. Two-sample t-tests will be used to primarily analyze the 
difference in the mean scores between treatments at Screening, Month 6, Month 6/ Early 
Discontinuation and change from Screening to Month 6 and Month 6 /Early Discontinuation; 


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additionally, the non-parametric Wilcoxon rank-sum test will be used to secondarily analyze 
the differences in scores between treatments. 
8.6 
Procedure for Accounting for Missing, Unused or Spurious Data 
Analyses will be performed primarily using multiple imputation techniques to impute missing 
data and secondarily using: observed data only, last observation carried forward (LOCF) 
where LOCF will be performed using time-relevant measures; and baseline observation 
carried forward (BOCF) using time-relevant measures to determine the robustness of results.     
Any missing, unused, or spurious data will be noted in the final statistical report. 
8.7 
Procedure for Reporting Deviations from the Statistical Plan 
Any deviations from the statistical plan will be described and a justification given in the final 
statistical report. 
8.8 
Data Listings 
Data listings will be prepared for all data on the database. 
9. ACCESS TO SOURCE DOCUMENTATION  
The Investigator will permit study-related monitoring visits, audits, IEC/ CEC review, and 
regulatory inspection(s) by providing direct access to source data and documents. 
10. STUDY MONITORING 
The progress of the study will be monitored by on-site, written, and telephone 
communications between personnel at the Investigator’s site and the masked and unmasked 
Study Monitor. The Investigator will allow the Sponsor or designee to inspect all CRFs; 
subject records (source documents); signed consent forms; records of study medication 
receipt, storage, preparation, and disposition; and regulatory files related to this study. 
The monitor and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents and to allocate their time and the time of their 
staff to monitor to discuss findings and any issues 
Sponsor/designee will monitor the study to ensure: 
• Data are authentic, accurate and complete. 
• Safety and rights of the subjects are being protected. 
• Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP and all applicable regulatory requirements. 


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11. ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
Publication and Disclosure Policy 
Study information for this protocol will be posted on publicly available clinical trial registers 
before enrollment of Subjects begins. Where required by applicable regulatory requirements, 
an investigator signatory will be identified for the approval of the clinical study report. 
The investigator will be provided reasonable access to statistical tables, figures and relevant 
reports and will have the opportunity to review the complete study results at a 
mutually-agreeable location. Aerie will also provide the investigator with the full summary 
of the study results. The investigator is encouraged to share the summary results with the 
study subjects, as appropriate. 
Aerie will provide the Investigator with the randomization codes for their site only after the 
completion of the full statistical analysis. 
The results summary will be posted no later than 8 months after the final primary completion 
date, the date the final subject examined or received an intervention for the purposes of final 
collection of data for the primary outcome. In addition, a manuscript will be submitted to a 
peer reviewed journal for publication no later than 18 months after the last subject’s last visit 
when manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register for not publishing.  
11.1 
GCP compliance 
The proposed study is subject to all applicable governmental rules and regulations 
concerning the conduct of clinical trials on human subjects.  This includes, but is not 
necessarily limited to: the approval of IEC/ CECs, the Helsinki Declaration (Appendix 6), US 
FDA Law, EU Clinical Trials Directive2001/20/EC and EC local laws and regulations, ICH 
E6 (GCP) R2 guidelines, obtaining prospective informed consent, monitoring of the conduct 
of the study and the completeness of the CRFs by the Sponsor or its designee(s); and 
appropriate record retention by the Investigator. Applicable IEC/ CEC, Investigator/Sponsor 
obligations, study monitoring and protocol change procedures are detailed in Appendix 4 
and Appendix 5.  
11.2 
Subject Confidentiality 
The Investigator and his/her staff will maintain all personal subject data collected and 
processed for the purposes of this study using adequate precautions to ensure confidentiality, 
in accordance with local, state and federal laws and regulations.  
Monitors, auditors and other authorized representatives of Aerie, the IEC/ CEC approving 
this study, and government regulatory authorities (e.g., FDA and other EU regulatory 
agencies) may be granted direct access to the study subject’s original medical and study 
records for verification of the data or clinical study procedures. Access to this information 


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will be permitted to representatives of the aforementioned organizations to the extent 
permitted by law.  
A report of this study’s results may be published or sent to the appropriate health authorities 
in any country in which the study drug may ultimately be marketed, but subject identities will 
not be disclosed in these documents. 
11.3 
Study Monitoring 
Clinical research associates hired or contracted by the Sponsor will be responsible for 
monitoring the study sites and study activities. Clinical research associates will contact and 
visit the Investigator regularly.  The actual frequency of monitoring visits depends on subject 
enrollment and on study site performance. Among others, the following items will be 
reviewed: 
• Study progress 
• Compliance with the protocol 
• Completion of CRFs 
• Dispensing, storage, and accountability of IP, including intentional or inadvertent 
unmasking of IP 
• Source data verification 
• AE and SAE reporting 
• Essential documents contained within the regulatory binder 
For source data verification (i.e., comparison of CRF entries with subject records), data will 
be 80% source verified and will include as a minimum:  
• Subject identification  
• Informed consent (procedure, signature, and date)  
• Selection criteria 
• Primary efficacy and safety parameters (i.e., AEs) 
Member(s) of the Sponsor or their designee will meet with the Investigator prior to the 
initiation of the study in order to assess the adequacy of the Investigator's subject population, 
facilities, and equipment, and to familiarize the Investigator with the protocol. 
A member of the Sponsor or their designee in the role of Study Monitor will subsequently 
meet with the Investigator after several of the subjects have initiated the study in order to 


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ensure that the subjects are being properly selected, that adequate supplies for the study have 
been provided and that the assignment of medication is properly recorded. In addition, the 
Study Monitor will verify that the Investigator follows the approved protocol and all 
approved amendments, if any, by reviewing the Investigator’s regulatory documents, source 
documents, Informed Consent Forms, and Case Report Forms of study subjects. 
The Study Monitor will meet with the Investigator when all subjects have completed the 
Final Visit of the study, in order to collect, unused study medications, and unused supplies 
and materials. 
Interim monitoring visits and telephone consultations will be done by the Study Monitor as 
necessary, to ensure the proper progression and documentation of the study. 
11.4 
Case Report Forms and Study Records 
The initial point of entry of study data should be the subject source documentation.  
The location and nature of the source documentation for all data collected in the study will be 
identified in the study files at the investigator’s site. In cases where no source documents will 
be used (i.e., data will be recorded directly onto the CRF without first being recorded on 
another document, such as a flowsheet, laboratory report, or other typical form of data 
reporting for later transcription to the CRF), the original data will be included in the CRF.  
Source document information should be legible. Recorded data should only be corrected by 
drawing a single line through the incorrect entry and writing the revision next to the corrected 
data. The person who has made the correction should place his or her initials as well as the 
date of the correction next to the correction. Data may not be obliterated by erasure, 
redaction, or with correction fluid. 
Study data will be transcribed and recorded via an electronic data capture (EDC) system as 
electronic CRFs (eCRFs). Security and authorization procedures consistent with the EDC 
system must be used. At each subject visit, the appropriate eCRFs must be completed.  
Whenever an eCRF is used, be sure to provide all information requested including subject 
identification number and initials, name or number of Investigator, date(s), etc.  All 
applicable questions should be answered and all data requested should be provided.  Those 
areas that require a response but are not filled in correctly are considered incomplete or 
erroneous entries, and will have to be corrected.   
Each authorized study staff member will receive a unique access account in order to use the 
EDC system. Access accounts will not be shared among study staff. Authorized users will 
make entries and/or changes to eCRFs via a secure internet access. Each completed set of 
eCRFs will be reviewed by the Investigator who will then electronically sign and date the 
eCRF confirming that data for the subjects are complete and accurate. 
The study records must include a copy of each Investigator's CV and medical license, and 
statement of Investigator qualifications. The name of each sub-investigator working under 
the supervision of the investigator is also required to be filed in the study records. In addition, 


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each eCRF, subject charts/source documents, Investigator’s Brochure, protocol, protocol 
amendments, correspondence with the Sponsor/designee  and the IEC/ CEC, IP storage, 
receipts, returns and dispensing records, Delegation of Responsibilities Log, site training 
records, records of site monitoring, any unmasking documentation, AE and SAE reporting, 
IEC/ CEC approvals, advertisements, written information provided to subjects, and subject 
completed ICFs will be included in the study records.  
If the Investigator moves, withdraws from an investigation, or retires, the responsibility for 
maintaining the records may be transferred to another person (e.g., Sponsor, other 
Investigator) who will accept the responsibility. Notice of this transfer, including written 
acceptance, must be made to and agreed upon by the Sponsor. 
11.5 
Independent Ethics Committee/Competent Ethics Committee (IEC/ CEC) 
This protocol, materials used to recruit subjects, and materials used to document consent 
must be approved by the IEC/ CEC prior to initiation of the study. The name and address of 
each reviewing IEC/ CEC will be documented in the Trial Master File for each participating 
country. Written IEC/ CEC approval must adequately identify the protocol and informed 
consent.  In addition to approving the protocol, the IEC/ CEC must also approve the Subject 
Information and Consent Form, as well as any advertising tools that will be used for the 
study.  
Written approval also must indicate whether approval was granted based on full committee 
review or expedited review.  Copies of all approved materials, all correspondence with the 
IEC/ CEC and written approval from the IEC/ CEC must be made available to the Sponsor, 
prior to the start of subject enrollment into the study. The investigator will report promptly to 
the IEC/ CEC any new information that may adversely affect the safety of the subjects or the 
conduct of the study. The investigator will submit written summaries of the study to the IEC/ 
CEC as required. On completion of the study the IEC/ CEC will be notified that the study has 
ended. 
11.6 
Protocol Deviations 
Per ICH E6 (GCP) R2 Section 4.5.1 the investigator/institution should conduct the trial in 
compliance with the protocol agreed with the sponsor and, if required, by the Regulatory 
Authority(ies) and which was given approval/favorable opinion by IEC/CEC  
Protocol waivers or deviations from the protocol inclusion and exclusion criteria are not 
allowed because they can potentially jeopardize the scientific integrity of the study regulatory 
acceptability or subject safety. Therefore, adherence to the criteria as specified in the protocol 
is essential.  
The site will contact the Sponsor for clarification of inclusion /exclusion criteria as needed 
prior to enrollment of the study subject. The sponsor will document clarification requests and 
responses or their representative. If a subject does not meet all the inclusion and exclusion 
criteria during screening, that subject may not be enrolled into the study. 


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If a protocol deviation is identified by the investigator or through site monitoring activities an 
immediate submission to the IEC/ CEC may be required e.g. 24 or 48 hours.  The Sponsor 
will assess any protocol deviation and decide whether any of these non-compliances should 
be reported to the relevant competent authority as a serious breach of GCP and the protocol. 
If per the relevant competent authorities’ requirements, the protocol deviation is not required 
to be reported immediately but is still required to be notified to the IEC/ CEC, the specific 
protocol deviation will be added to the annual progress report.   
The Sponsor will review, designate, and/or approve all protocol deviations prior to the data 
base lock. 
11.7 
Informed Consent Requirements 
Written informed consent will be obtained from each subject before any subject specific 
procedures are initiated. A copy of the signed and dated consent document will be given to 
each subject. The original signed and dated informed consent document must be maintained 
in the study files at the Investigator’s site. 
The investigator is responsible for ensuring that no subject is subject to any study-related 
examination or activity before that subject has given informed consent. The subject must 
give written consent after the receipt of detailed information. The verbal explanation will 
cover all the elements specified in the written information provided for the subject. 
It should be emphasized that the subject is at liberty to withdraw consent to participate at any 
time, without penalty or loss of benefits to which the subject is otherwise entitled. 
Subjects who refuse to give, or withdraw, written informed consent may not be included or 
continued in this study, but this will not impact on their subsequent care. 
The investigator will inform the subject of the aims, methods, anticipated benefits and 
potential hazards of the study, including any discomfort it may entail. The subject must be 
given every opportunity to clarify any points he/she does not understand and if necessary, ask 
for more information. At the end of the interview, the subject may be given time to reflect if 
this is required, or if the subject requests more time. All Subjects will be required to sign and 
date the informed consent form. 
Signed informed consent must be attained prior to the conductance of any study procedures. 
12. DATA HANDLING AND RECORD KEEPING 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting ICH and according to the requirements of the EU Clinical Trials 
Directive/2001/20/EC guidelines for the handling and analysis of data for clinical trials. 


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12.1 
Data Generation and Analysis 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database. Query reports pertaining 
to data omissions and discrepancies will be forwarded to the clinical Investigator and the 
Sponsor for resolution. The study database will be updated by the clinical investigator or 
their staff, in accordance with the resolved query reports. All changes to the study database 
will be documented. 
12.2 
Archiving of Data 
Archived versions of the database will be saved by the Sponsor consistent with ICH Good 
Clinical Practices Guidelines E6 (R2) section 5.5.11 (see Appendix 4), complying with 
whichever of the requirements is longer. The Sponsor will notify the investigator when 
documents should be returned. 
12.3 
Records Retention 
The Investigator’s site and clinical laboratory will retain all records related to the study in 
compliance with ICH Good Clinical Practices Guidelines E6 (R2) Section 4.9.4 (see 
Appendix 5).   
12.4 
Amendments to the Protocol 
Modifications of the signed protocol are only possible by approved protocol amendments and 
with the agreement of all responsible persons. The procedure for approval of a protocol 
amendment is identical to that for approval of the protocol. The ethics committee must be 
informed of all protocol amendments and should be asked for its opinion as to whether a full 
re-evaluation of the ethical aspects of the study is necessary by the committee. This should 
be fully documented. 
The investigator must not implement any deviation from or change to the protocol, without 
discussion with, and agreement by the sponsor and prior review and documented 
approval/favourable opinion of the amendment from the relevant ethics committee or 
competent authority, except where it is necessary to eliminate an immediate hazard to study 
subjects, or where the change(s) involves only logistical or administrative aspects of the 
study (e.g., change in monitor(s), change of telephone number(s)). 
Protocol amendments will be submitted to the appropriate authority(ies) as required by the 
applicable regulatory requirement(s).  
 


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13. REFERENCES 
13.1 
Published References 
1. 
AGIS Investigators. The Advanced Glaucoma Intervention Study (AGIS): 7. The 
relationship between control of intraocular pressure and visual field deterioration. Am 
J Ophthalmol 2000; 130:429-40. 
2. 
Bacharach J, Dubiner HB, Levy B, et al. Double-masked, randomized, dose-response 
study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. 
Ophthalmology. 2015; 122:302-307. 
3. 
Bailey IL, Lovie JE. New design principles for visual acuity letter charts. Am JOptom 
Physiol Opt 1976;53:740-5. 
4. 
Chan RY, Smith JA, Richardson KT. Arch Ophthalmol. 1981 Arch Ophthalmol. 1981 
Jan; 99(1):104-7. Anterior segment configuration correlated with Shaffer's grading of 
anterior chamber angle. 
5. 
Chen J, Runyan SA, Robinson MR.  Novel ocular antihypertensive compounds in 
clinical trials. Clin Ophthalmol 2011; 5:667-77. 
6. 
Clinical Trials Facilitation Group; Recommendations related to contraception and 
pregnancy testing. 
7. 
Collaborative Normal-Tension Glaucoma Study Group.  The effectiveness of 
intraocular pressure reduction in the treatment of normal-tension glaucoma.  Am J 
Ophthalmol 1998; 126:498-505. 
8. 
European Glaucoma Society, Tip of the Month, November 2011, Ann Hoste, 
Antwerp. 
9. 
FDA Draft Guidance on Brimonidine Tartrate recommended Sep2008: Revised 2014, 
Dec 2014, Mar 2015 
10. 
Ferris FL, Freidlin V, Kassoff A, et al. Relative letter and position difficulty on visual 
acuity charts from the early Treatment Diabetic Retinopathy Study. Am JOphthalmol 
1993; 116:735-40. 
11. 
GANFORT® SmPC. 
12. 
Heijl A, Leske MC, Bengtsson B, et al.  Reduction of intraocular pressure and 
glaucoma progression: results from the Early Manifest Glaucoma Trial.  Arch 
Ophthalmol 2002; 120: 1268-79. 
13. 
Hughes BA, Bacharach J, Craven ER, et al. A three-month, multicenter, double-
masked study of the safety and efficacy of travoprost 0.004%/timolol 0.5% 
ophthalmic solution compared to travoprost 0.004% ophthalmic solution and timolol 
0.5% dosed concomitantly in subjects with open angle glaucoma or ocular 
hypertension. J Glaucoma 2005; 14:392-9. 
14. 
Kass MA, Heuer DK, Higginbotham EJ, et al.  The Ocular Hypertension Treatment 
Study.  Arch Ophthalmol 2002; 120:701-13. 


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15. 
Kass MA, Gordon MO, Gao F, et al.  Delaying Treatment of Ocular Hypertension: 
The Ocular Hypertension Treatment Study. Arch Ophthalmol 2010; 128:276-87. 
16. 
Kiel JW, Kopczynski CC.  Effect of AR-13324 on episcleral venous pressure in 
Dutch Belted rabbits.  J Ocul Pharmacol Ther 2015; 31(3):146-51. 
17. 
Kolker AE, Hetherington J Jr, eds, Becker and Shaffer’s diagnosis and therapy of 
glaucomas 5th ed.  St Louis: CV Mosby, 1976. 
18. 
Kopczynski CC and Epstein DL.  Emerging Trabecular Outflow Drugs.  J Ocul 
Pharmacol Ther 2014; 30:85-7. 
19. 
Lewis RA, Levy B, Ramirez N, et al. for the PG324-CS201 Study Group.  Fixed-dose 
combination of AR-13324 and latanoprost: a double-masked, 28-day, randomised, 
controlled study in patients with open-angle glaucoma or ocular hypertension.  Br J 
Ophthalmol 2015; doi: 10.1136/bjophthalmol-2015-306778. 
20. 
Lichter PR, Musch DC, Gillespie BW, et al.  Interim clinical outcomes in the 
Collaborative Initial Glaucoma Treatment Study comparing initial treatment 
randomized to medications or surgery.  Ophthalmology 2001; 108:1943–53. 
21. 
Mangione, C. M., Lee, P. P., Gutierrez, P. R., Spritzer, K., Berry, S., & Hays, R. D. 
Development of the 25-item National Eye Institute Visual Function Questionnaire 
(VFQ-25) (2001) Archives of Ophthalmology, 119, 1050-1058. 
22. 
Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5% 
timolol fixed-combination therapy vs. monotherapy with timolol or brimonidine in 
patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch 
Ophthalmol 2006; 124:1230-8. 
23. 
Stewart WC, Holmes KT, Johnson MA. Washout periods for brimonidine 0.2% and 
latanoprost 0.05%. Am J Ophthalmol. 2001;798-9. 
24. 
Stone JL, Robin AL, Novack GD, et al. An objective evaluation of eye-drop 
instillation in glaucoma patients. Arch Ophthalmol 2009; 127:732-6. 
25. 
Wang R-F, Williamson JE, Kopczynski C, et al. Effect of 0.04% AR-13324, a ROCK 
and Norepinephrine Transporter Inhibitor, on Aqueous Humour Dynamics in 
Normotensive Monkey Eyes. J Glaucoma, 2015; 24:51-4. 
26. 
Wang SK and Chang RT.  An emerging treatment option for glaucoma: Rho kinase 
inhibitors.  Clin Ophthalmol 2014; 8:883-90. 
27. 
Ware, J.E., Jr., SF-36 Health Survey Update SPINE 2000; 25 (24): 3130-9. 
13.2 
Internal References 
1. 
Aerie Pharmaceuticals, Inc., AR-13324 and PG324 Investigator’s Brochure. 
2. 
AR-13324-CS101 Clinical Study Report: An Open-Label Study Assessing the Ocular 
and Systemic Safety and Systemic Absorption of AR-13324 Ophthalmic Solution 
0.02% in Healthy Volunteers (2014). 


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3. 
AR-13324-CS102 Clinical Study Report: A double masked, randomized, paired 
comparison, controlled study of the aqueous humor dynamics of AR-13324 
Ophthalmic Solution 0.02% in healthy volunteers (2016). 
4. 
AR-13324-CS201 Clinical Study Report: A Phase 2, double-masked, randomized, 
placebo-controlled, dose-response study assessing the safety and ocular hypotensive 
efficacy of three doses of AR-13324 Ophthalmic Solution in patients with elevated 
intraocular pressure (2012). 
5. 
AR-13324-CS202 Clinical Study Report: A phase 2, double-masked, randomized, 
multi-center, active-controlled, dose-response parallel-group study comparing the 
safety and ocular hypotensive efficacy of AR-13324 to latanoprost in patients with 
elevated intraocular pressure (2013). 
6. 
AR-13324-CS301 Clinical Study Report: A double-masked, randomized, multi-
center, active-controlled, parallel, 3-month study assessing the safety and ocular 
hypotensive efficacy of AR-13324 Ophthalmic Solution, 0.02% compared to timolol 
maleate ophthalmic solution, 0.5% in patients with elevated intraocular pressure 
(2015). 
7. 
AR-13324-CS302 Clinical Study Report: A double masked, randomized, multi-
center, active controlled, parallel 12-month study assessing the safety and efficacy of 
AR-13324 Ophthalmic Solution, 0.02% q.d. and b.i.d compared to Timolol Maleate 
Ophthalmic Solution, 0.5% b.i.d in patients with elevated intraocular pressure (2016). 
8. 
AR-13324-CS304 Clinical Study Report: A double masked, randomized, multi-
center, active controlled, parallel 6-month study with a 3-month interim analysis 
assessing the ocular hypotensive efficacy and safety of AR-13324 Ophthalmic 
Solution, 0.02% QD compared to Timolol Maleate Ophthalmic Solution, 0.5% BID 
in patients with elevated intraocular pressure (2017) 
9. 
PG324-CS201 Clinical Study Report: A double-masked, randomized, controlled 
study assessing the safety and ocular hypotensive efficacy of PG324 Ophthalmic 
Solution, 0.01% and PG324 Ophthalmic Solution 0.02%, compared to AR-13324 
Ophthalmic Solution 0.02% and Latanoprost Ophthalmic Solution 0.005% in patients 
with elevated intraocular pressure (2014). 
10. 
PG324-CS301 Clinical Study Report: A prospective, double-masked, randomized, 
multi-center, active-controlled, parallel-group 12-month study assessing the safety 
and ocular hypotensive efficacy of PG324 Ophthalmic Solution compared to AR-
13324 Ophthalmic Solution, 0.02% and Latanoprost Ophthalmic Solution, 0.005% in 
subjects with elevated intraocular pressure (2018) 
11. 
PG324-CS302 Clinical Study Report: A prospective, double-masked, randomized, 
multi-center, active-controlled, parallel-group, 3-month study assessing the safety and 
ocular hypotensive efficacy of PG324 Ophthalmic Solution compared to AR-13324 
Ophthalmic Solution, 0.02% and Latanoprost Ophthalmic Solution, 0.005% in 
subjects with elevated intraocular pressure (2018) 
 


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Appendix 1 
Schedule of Visits and Examinations 
Day (D)/ Week (W)/ 
Month (M) 
Screening 
Qual. #1 
(Day -7 
to -2) 
Qual. #2 D1 
W2 (Day 15±3) 
W6 (Day 43±3) 
M3 (Day 90±3) 
M4 
(Day 120±3), 
M5 
(Day 150±3) 
M6 
(Day180±7) 
Visit 
1 
2 
3.0 
3.1 
3.2 
4.0 
4.1 
4.2 
5.0 
5.1 
5.2 
6.0 
6.1 
6.2 
7.0 + 8.0 
9.0 
Hour (XY = XY:00) 
08 
08 
10 
16 
08 
10 
16 
08 
10 
16 
08 
10 
16 
10 
10 
Informed Consent 
X 
Inclusion/Exclusion 
X 
X 
X 
X 
X 
Washout1 
X 
Demography 
X 
Medical/Ophthalmic History 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
HR/BP 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test10 
X 
X10 
X 
X 
X 
X 
X 
X 
Clinical Labs (Chem/ Hem)2 
X2 
X 
Symptoms/AEs3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual Acuity (ETDRS) 
X 
X 
X 
X 
X 
X 
X 
X 
IOP4 
X 
X4 
X4 
X4 
X4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Gonioscopy5/Pachymetry6 
G/P 
P 
P 
Visual Field7 
X 
X 
X 
Ophthalmoscopy (dilated) 
X 
X 
X 
Cup:disc ratio 
X 
X 
X 
Eye-Drop Instillation 
Evaluation 
X 
VFQ-25 questionnaire 
X 
X 
SF-36 v.2 questionnaire 
X 
X 
Study Medications Dispensed9 
X 
X 
X 
X 
X 
Study Medications Collected8 
X8 
X8 
X8 
X8 
X8 
Study Completed 
X 
Abbreviations: D=Day; W = Week; M = Month; HR/BP = heart rate/blood pressure; Chem/ Hem = Chemistry/Hematology; AE = adverse event; ETDRS = Early 
Treatment of Diabetic Retinopathy Study; IOP = Intraocular pressure; G = Gonioscopy; P = Pachymetry; Self-Admin = Self-Administered 
Early Discontinuation: Visit 9.0 procedures are to be completed plus a dilated ophthalmoscopy examination. 


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Visit Requirements: IOP measurements at all visits are to be made within ±1 hour of the protocol-specified times of 08:00, and ±½ hour of 10:00 and 16:00 hours 
with the exception of the screening visit. 
 
1. 
Subjects must undergo a minimum washout period of current ocular hypotensive medication(s). 
2. 
For subjects who are unable or unwilling to have blood drawn for clinical labs at Visit 1 (screening), the blood sample may be drawn at Visit 2 (Qualification 
Visit #1) or during the washout period at a visit where interim IOP measurements are being performed so long as the results of the clinical labs are 
available for that subject prior to Visit 3 (Qualification Visit #2). 
3. 
Ocular symptoms: Subjects will be queried at each visit “How are you feeling?” and treatment emergent AEs beginning at Visit 4 (Qualification Visit #2) will 
be documented on the AE form. Additional symptoms reported after screening and before randomization will be documented on the medical history form. AEs 
will be recorded for every study visit (i.e., at 0800, 10.00, and 16:00 hours) as needed. 
4. 
Individuals returning at an unscheduled visit within 1 week are required to only re-measure IOP in both eyes.  
5. 
Gonioscopy evaluation up to 3 months prior to randomization is acceptable. 
6. 
Pachymetry Evaluation at screening visit or within one week prior to screening visit, and at Month 3 (or within 1 week of Month 3 study visit). 
7. 
Entry visual field evaluation up to 3 months prior to randomization is acceptable. Visual field collection must meet the requirement for automated threshold 
visual field assessment (e.g., 30-2 or 24-2 Humphrey or Octopus perimetry) and reliability. 
8. 
Collect used kit(s) dispensed during the previous visit. 
9. 
Per Section 5.2 and 5.3, subjects are required to administer IP on all days of the study, including days of study visits. In addition, per section 7.1.5 IP will be 
dispensed within 48 hours of the randomization visit. 
10. For women of childbearing potential, a pregnancy test will be performed every 4 weeks during study participation. This will include a pregnancy test 
during the washout period, if the washout period extends beyond 4 weeks. 
 
Note: At the investigator’s discretion photography of ocular events, such as cornea verticillata, conjunctival hemorrhage, may be taken. 
 


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Appendix 2 
Procedures 
Procedures: Best Corrected Visual Acuity 
Introduction: Best corrected visual acuity (Distance) will be measured at baseline and at each 
follow-up visit. Visual acuity will be measured using Bailey Lovie charts, ETDRS charts, or 
their equivalents.  Accepted charts are those designed according to the following principles 
described by Bailey and Lovie (1976) and the National Academy of Science-National 
Research Council (NAS-NRC) Committee on Vision 1980 (1980): 1) letters of equal 
legibility; 2) combine the letters so that each line is of approximately equal difficulty (as 
described by Ferris 1993); 3) present five letters at each acuity level; 4) space rows by the 
height of the smaller letter 5) space letters by the width of same-sized letters and 6) use a 
logarithmic progression of letter size from logMAR (Minimum Angle of Resolution to base 
10) -0.3 (20/10) to 1.0 (20/200). 
Rationale: Best corrected acuity taken at follow-up visits as a measure of ocular function. 
Best corrected visual acuity will be measured at screening and frequently throughout the 
study. 
Procedure: Distance visual acuity must be assessed using an Early Treatment of Diabetic 
Retinopathy Study (ETDRS) or equivalent chart. Visual acuity testing should precede 
intraocular pressure measurement, the administration of topical anesthetic agents, or any 
examination requiring contact with the anterior segment. 
Distance visual acuity will be measured with best correction. 
The visual acuity chart may be either retro-illuminated (“back-lit”), or reflectance 
illuminated. If the latter, then the illumination must be checked at regular intervals to be 
consistent with ETDRS guidelines. Standard charts for a distance from subject to chart of 3 
meters to 6 meters must be used. Ideally, the subject should be seated. The right eye should 
be tested first.  Sites are directed to refer to the instructions on the commercial ETDRS 
charts. If there is any question, contact the Sponsor’s monitor. 
The subject should attempt to read each letter, line by line, left to right, beginning with line 1 
at the top of the chart (20/200 line).  The subjects should be told that the chart has letters 
only, no numbers.  If the subject reads a number, he or she should be reminded that the chart 
contains no numbers, and the examiner should then request a letter in lieu of the number. 
The subjects should be asked to read slowly, about one letter per second, so as to achieve the 
best identification of each letter.  He/she is not to proceed to the next letter until he/she has 
given a definite response. 
A maximum effort should be made to identify each letter on the chart. When the subject says 
he/she cannot read a letter, he/she should be encouraged to guess.  If the subject identifies 
two letters (e.g. A or B), he/she should be asked to choose one letter and, if necessary, to 
guess. When it becomes evident that no further meaningful readings can be made despite 
encouragement to read or guess, the examiner should stop the testing for that eye.  However, 


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all letters on the last line should be attempted as letter difficulties vary and the last letter 
may be the only one read correctly. The number of letters missed or read incorrectly should 
be noted.  Repeat with left eye. 
In order to provide standardized and well-controlled assessment of visual acuity during the 
study, all visual acuity assessments for a subject must be performed consistently (e.g., the 
same lighting conditions, viewing distance, etc.) during the entire study. 
The number of letters missed is multiplied by 0.02 and added to the baseline value to 
determine the logMAR visual acuity. Baseline is defined as the last line for which the 
subject reads at least one letter. 
logMAR units VA = Baseline value + (n x 0.02). 
If refraction was used at the screening or baseline, then this refraction should be used in the 
phoropter or trial frame for subsequent examinations. A repeated refraction is not required at 
these subsequent examinations. 
A priori, a change of three lines (visual acuity in either eye is considered clinically 
significant. 
For comparison with Snellen, a chart of the Snellen ratio that best corresponds with 
logMAR is provided in Table 2. This is provided for convenience only. Visual Acuity is not 
to be measured by Snellen Acuity charts in this study. 
Table 2 
Comparison of Snellen ration and logMAR units 
Snellen ratio 
logMAR 
20/200 
+1.0 
20/160 
+0.9 
20/125 
+0.8 
20/100 
+0.7 
20/80 
+0.6 
20/62.5 
+0.5 
20/50 
+0.4 
20/40 
+0.3 
20/32 
+0.2 
20/25 
+0.1 
20/20 
+0.0 
20/16 
-0.1 
20/12.5 
-0.2 
20/10 
-0.3 
Procedures: Visual field examination 
Visual fields must be automated threshold visual fields (e.g., 30-2 or 24-2 Humphrey or 
Octopus Perimetry).  
C-24 SITA Standard preferred, SITA fast also allowed. Visual fields must be reliable, 
defined as those with a) fixation losses less than or equal to 33%, b) false positives less than 


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or equal to 33%, and c) false negatives less than or equal to 33%. Both eyes must have 
fixation losses ≤ 33% to qualify for the study. Visual fields fixation losses should not be 
rounded up to the next whole number value. The gaze track and blind spot should be 
turned on for all visual fields assessments in order to calculate the fixation losses. 
For the visual field required at study entry: 
• In order for an individual to enter the study, unreliable entry visual fields (excessive 
fixation losses, false negatives or false positives) must be repeated until they meet above 
criteria. 
• They may have been performed within three months prior to randomization, given 
that they meet the above requirements. 
• Visual fields are to be performed with a non-dilated pupil unless, in the opinion of the 
Investigator, the pupil is so miotic that dilation is required (e.g., < 3mm). If dilation was 
performed at baseline, it should be performed at all subsequent visual field examinations. 
• If the individual is unreliable on two visual fields, the Investigator should consider that 
this individual is not appropriate for study entry. 
Procedures: Biomicroscopy and measurement of Intraocular pressure (IOP) 
The subject will be seated while being examined. 
External examination and biomicroscopy will be performed using a slit lamp. Magnification 
will be consistent with standard clinical practice. 
The clinician will examine and grade the eyelid. Observations will be documented on the 
appropriate CRF.  The clinician will examine the conjunctiva, cornea, anterior chamber, iris, 
pupil and lens of the eye with the aid of a slit lamp, which is a table-mounted binocular 
microscope.  Fluorescein dye will be instilled into the ocular cul-de-sac to facilitate this 
examination.   
Local anesthetic will also be applied in order to facilitate IOP measurements with the 
Goldmann Applanation Tonometer.  Tonometer validation on at least a monthly basis must 
be documented. 
Two consecutive IOP measurements of each eye must be obtained. If the 2 measurements 
differ by more than 2 mmHg, a third measurement must be obtained. IOP will be analyzed as 
the mean of 2 measurements or as the median of 3 measurements (Sherwood 2006). 
Each Goldmann tonometry value is read as an integer. When calculating the mean or median, 
it is possible to have a fractional value. For purposes of qualification, the number should not 
be rounded up to the nearest complete IOP number. For example, a mean or median value of 
20.5mmHg should not be rounded up 21. Any non –integral mean IOP values obtained 
should be documented for the duration of study.  


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IOP should be measured by qualified individuals using a calibrated Goldmann applanation 
tonometer.  
The Sponsor recommends that the same examiner should conduct all biomicroscopy 
examinations at each time point and at each visit for a given subject. 
Biomicroscopic grading will be done as follows: 
LID 
Erythema 
 
None (0) = 
Normal, without any redness, or less than mild 
Mild (+1) = 
A low grade flushed reddish color 
Moderate (+2) = 
Diffused redness encompassing the entire lid margin 
Severe (+3) = 
Deep diffused reddish color of lid margins and superior or inferior eyelid 
Edema 
 
None (0) = 
Normal, no swelling of the lid tissue, or less than mild 
Mild (+1) = 
Slight diffuse swelling above normal 
Moderate (+2) = 
General swelling 
Severe (+3) = 
Extensive swelling of the eyelid(s), with or without eversion of upper and/or 
lower lids. 
CONJUNCTIVA 
Hyperemia 
 
None (0) = 
Normal. Appears white with a small number of conjunctival blood vessels 
easily observed. 
Mild (+1) = 
Prominent, pinkish-red color of both the bulbar and palpebral conjunctiva; 
Moderate (+2) = 
Bright, scarlet red color of the bulbar and palpebral conjunctiva 
Severe (+3) = 
“Beefy Red” with petechiae --- Dark red bulbar and palpebral conjunctiva 
with evidence of subconjunctival hemorrhage 
Edema 
 
None (0) = 
Normal, no swelling of the conjunctiva or less than mild 
Mild (+1) = 
Slight diffuse or regional swelling of the conjunctiva 
Moderate (+2) = 
General swelling of the conjunctiva 
Severe (+3) = 
Extensive swelling of the conjunctiva 
CORNEA 
Edema 
 
None (0) = 
Transparent and clear or less than mild 
Mild (+1) = 
Dull glassy appearance 
Moderate (+2) = 
Dull glassy appearance of epithelium with large number of vacuoles 
Severe (+3) = 
Stromal edema, localized or diffuse, with stromal striae 


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Staining 
 
None (0) = 
No fluorescein staining of epithelium, OR less than mild 
Mild (+1) = 
Slight punctate fluorescein staining 
Moderate (+2) = 
Regionally dense coalescent fluorescein staining 
Severe (+3) = 
Marked fluorescein staining with immediate stromal leakage as a result of 
epithelial loss 
ANTERIOR CHAMBER 
Cells 
 
None (0) = 
No cells seen or less than mild 
Mild (+1) = 
+ cells 
Moderate (+2) = 
++ cells 
Severe (+3) = 
+++ cells 
Hypopyon (+4) = 
++++ cells, Hypopyon Formation (indicate size of hypopyon) 
Flare 
 
None (0) = 
No Tyndall effect or less than mild 
Mild (+1) = 
Tyndall beam in the anterior chamber has a mild intensity 
Moderate (+2) = 
Tyndall beam in the anterior chamber is of strong intensity 
Severe (+3) = 
Tyndall beam is very intense. The aqueous has a white, milky appearance 
LENS PATHOLOGY 
Lens status 
• Phakic 
• Pseudophakic  
• Aphakic 
Lens Opacity (Phakic only) 
None (0) = 
None present or less than mild 
Mild (+1) = 
Subtle 
Moderate (+2) = 
Moderate 
Severe (+3) = 
Dense 
IRIS/PUPIL PATHOLOGY 
Procedures: Ophthalmoscopy 
The Sponsor recommends that the same masked examiner should conduct all 
ophthalmoscopy exams for a given subject. 
 
 


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RETINA, VITREOUS, MACULA, CHOROID, OPTIC NERVE 
 
0= 
Normal 
1= 
Abnormal 
CUP-DISC RATIO (Vertical) 
Score from 0.1 to 1.0 in 0.1 increments 
A priori, a change of 0.2 units in either eye is considered clinically significant. 
Procedures: Pachymetry - Central corneal thickness 
Central corneal thickness will be measured by ultrasound pachymetry in both eyes (mean of 
two readings per eye).  The mean value will be used for enrollment criteria. An additional 
pachymetry reading will be collected at the Month 3 and Month 6 visit.  
For individuals with mean central corneal thickness greater than 620μm, they may return 
either the same day, or within 7 days for another pachymetry measurement. If the mean of 
two readings on that second pachymetry is ≤ 620μm, then the individual may be considered 
for the study. 
Procedures: Gonioscopy 
The purpose of this examination is to confirm that the iridocorneal angle is open, and that the 
subject does not have narrow angle glaucoma, which is an exclusion criteria for study 
participation. Gonioscopy may be taken up to three months prior to randomization. 
Gonioscopy will be performed at the slit lamp, bilaterally, using a goniolens. 
Procedures: Photography 
At the investigator’s discretion images of treatment emergent events may be taken. Such 
events such as corneal verticillata or conjunctival hemorrhage can be imaged using a slit 
lamp mounted camera system using the investigator’s normal practice. Subjects must confirm 
by checking the relevant section on the patient information and consent form that images can 
be taken and shared with the sponsor.  
Images should be stored electronically ideally in an uncompressed JPEG format identifying 
the subject by site and patient number only and date image acquired.  
Procedures: Symptomatology 
Subjects will be queried “How are you feeling?” and any treatment emergent adverse events 
will be documented on the adverse event form. 
Procedures: Heart Rate 
Heart rate will be measured after the subject has been seated quietly for at least five minutes. 
Pulse will be detected at the wrist, and will be counted for 30 seconds, and multiplied by 2. 


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If an electronic measurement device is used, it must be documented. 
Procedures: Blood pressure 
Blood pressure will be measured after heart rate (and thus the subject will already be in a 
resting state).  Blood pressure will be measured using a sphygmomanometer with appropriate 
size cuff and a stethoscope.  If an electronic measurement device is used, it must be 
documented. 
Procedures: Clinical laboratories 
Central laboratories should be used for clinical chemistries as mandated by the protocol. 
A copy of the certification for the reference laboratory conducting any clinical laboratory 
tests required by this protocol will be provided. Laboratory requisition forms must be 
completed and samples must be clearly labelled with the subject number, protocol number, 
site/center number and visit date. Details for the preparation and shipment of samples and 
reference ranges will be provided in the laboratory manual. 
A Chemistry panel and complete blood count (hematology and differential) will be 
performed as follows.  Note that fasting is NOT required and specific values may be out of 
the typical fasting range.  
• Clinical chemistry: 
o Alanine aminotransferase 
o Albumin 
o Alkaline phosphatase 
o Aspartate aminotransferase 
o Calcium 
o Creatinine 
o Glucose, Random 
o Potassium (K)  
o Sodium (Na)  
o Triglycerides  
• Hematology: 
o White blood cells 


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 Differential Including: 
• Absolute and Percent Neutrophil Count 
• Absolute and Percent Lymphocyte Count 
• Absolute and Percent Monocyte Count 
• Absolute and Percent Eosinophil Count 
• Absolute and Percent Basophil Count 
o Platelets: 
 Mean Platelet Volume 
 Platelet count 
o Red blood cells 
 Hemoglobin 
 Hematocrit 
 Mean corpuscular volume 
 Mean corpuscular hemoglobin 
 Mean corpuscular hemoglobin concentration 
 Red Cell Distribution Width 
• Procedures: Urine Pregnancy Test. 
• Urine Pregnancy test for women of childbearing potential will be performed. 
Procedures:  Self-Administered NEI Visual Functioning Questionnaire-25 (VFQ-25) 
The purpose is to evaluate the change in glaucoma quality of life score from baseline to study 
exit. The NEI Visual Functioning Questionnaire-25 (VFQ-25) will be completed using self-
administered format at baseline and final study visit. Responses from the instrument will be 
coded according to developer recommendations. Further detail on the analyses of this data 
will be addressed in the Study Analysis Plan.  
Translations of the NEI Visual Functioning Questionnaire-25 (VFQ-25), if available, will be 
provided for participating centers in non-English-speaking countries. 


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The NEI Visual Functioning Questionnaire-25 (VFQ-25) is a validated VFQ-25 and reliable 
25-item version of the 51-item National Eye Institute Visual Function Questionnaire (NEI-
VFQ). It is especially useful in settings such as clinical trials. (Mangione 2001). 
Procedures: Self-Administered Short Form Health Survey Questionnaire-36 (SF-36 v.2) 
The purpose is to evaluate the change in overall quality of life score from baseline to study 
exit. The survey taps eight health concepts: physical functioning, bodily pain, role limitations 
due to physical health problems, role limitations due to personal or emotional problems, 
emotional well-being, social functioning, energy/fatigue and general health perceptions. The 
Short Form Health Survey Questionnaire-36 (SF-36 v.2) will be completed using a self-
administered format at baseline and final study visit. Responses from the instrument will be 
coded according to developer recommendations. Further detail on the analyses of this data 
will be addressed in the Study Analysis Plan. 
Translations of the SF-36 v.2, if available, will be provided for participating centers in non-
English-speaking countries. 
 
 


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Appendix 3 
Marketed Product Medication Information – GANFORT® 
SUMMARY OF PRODUCT CHARACTERISTICS 
1. 
NAME OF THE MEDICINAL PRODUCT 
GANFORT 0.3 mg/ml + 5 mg/ml eye drops, solution 
2. 
QUALITATIVE AND QUANTITATIVE COMPOSITION 
One ml of solution contains 0.3 mg of bimatoprost and 5 mg of timolol (as 6.8 mg of timolol 
maleate).  
Excipient with known effect 
Each ml of solution contains 0.05 mg of benzalkonium chloride. 
For the full list of excipients, see section 6.1. 
3. 
PHARMACEUTICAL FORM 
Eye drops, solution. 
Colourless to slightly yellow solution. 
4. 
CLINICAL PARTICULARS 
4.1 
Therapeutic indications 
Reduction of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocular 
hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin 
analogues. 
4.2 
Posology and method of administration 
Posology 
Recommended dosage in adults (including older people) 
The recommended dose is one drop of GANFORT in the affected eye(s) once daily, 
administered either in the morning or in the evening. It should be administered at the same 
time each day. 
Existing literature data for GANFORT suggest that evening dosing may be more effective in 
IOP lowering than morning dosing. However, consideration should be given to the likelihood 
of compliance when considering either morning or evening dosing (see section 5.1). 
If one dose is missed, treatment should continue with the next dose as planned. The dose 
should not exceed one drop in the affected eye(s) daily. 
 


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Renal and hepatic impairment 
GANFORT has not been studied in patients with hepatic or renal impairment. Therefore 
caution should be used in treating such patients. 
Paediatric population 
The safety and efficacy of GANFORT in children aged 0 to 18 years has not been 
established. No data are available. 
Method of administration 
If more than one topical ophthalmic medicinal product is to be used, each one should be 
instilled at least 5 minutes apart. 
When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic 
absorption is reduced. This may result in a decrease in systemic side effects and an increase 
in local activity. 
4.3 
Contraindications 
• Hypersensitivity to the active substances or to any of the excipients listed in 
section 6.1. 
• Reactive airway disease including bronchial asthma or a history of bronchial asthma, 
severe chronic obstructive pulmonary disease. 
• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree 
atrioventricular block, not controlled with pace-maker. Overt cardiac failure, 
cardiogenic shock. 
4.4 
Special warnings and precautions for use 
Like other topically applied ophthalmic medicinal products, the active substances (timolol/ 
bimatoprost) in GANFORT may be absorbed systemically. No enhancement of the systemic 
absorption of the individual active substances has been observed. Due to the beta-adrenergic 
component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions 
as seen with systemic beta-blockers may occur. Incidence of systemic ADRs after topical 
ophthalmic administration is lower than for systemic administration. To reduce the systemic 
absorption, see section 4.2. 
Cardiac disorders 
Patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and 
cardiac failure) and hypotension therapy with beta-blockers should be critically assessed and 
therapy with other active substances should be considered. Patients with cardiovascular 
diseases should be watched for signs of deterioration of these diseases and of adverse 
reactions. 
Due to its negative effect on conduction time, beta-blockers should only be given with 
caution to patients with first degree heart block. 


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Vascular disorders 
Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of 
Raynaud’s disease or Raynaud’s syndrome) should be treated with caution. 
Respiratory disorders 
Respiratory reactions, including death due to bronchospasm in patients with asthma have 
been reported following administration of some ophthalmic beta-blockers. 
GANFORT should be used with caution, in patients with mild/moderate chronic obstructive 
pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk. 
Endocrine disorders 
Beta-adrenergic blocking medicinal products should be administered with caution in patients 
subject to spontaneous hypoglycemia or to patients with labile diabetes as beta-blockers may 
mask the signs and symptoms of acute hypoglycemia. 
Beta-blockers may also mask the signs of hyperthyroidism.  
Corneal diseases 
Ophthalmic β-blockers may induce dryness of eyes. Patients with corneal diseases should be 
treated with caution. 
Other beta-blocking agents 
The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be 
potentiated when timolol is given to the patients already receiving a systemic beta-blocking 
agent. The response of these patients should be closely observed. The use of two topical beta-
adrenergic blocking agents is not recommended (see section 4.5). 
Anaphylactic reactions 
While taking beta-blockers, patients with a history of atopy or a history of severe 
anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge 
with such allergens and unresponsive to the usual dose of adrenaline used to treat 
anaphylactic reactions. 
Choroidal detachment 
Choroidal detachment has been reported with administration of aqueous suppressant therapy 
(e.g. timolol, acetazolamide) after filtration procedures. 
Surgical anaesthesia 
β-blocking ophthalmological preparations may block systemic β-agonist effects e.g. of 
adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol. 
Hepatic 
In patients with a history of mild liver disease or abnormal alanine aminotransferase (ALT), 
aspartate aminotransferase (AST) and/or bilirubin at baseline, bimatoprost had no adverse 
reactions on liver function over 24 months. There are no known adverse reactions of ocular 
timolol on liver function. 


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Ocular 
Before treatment is initiated, patients should be informed of the possibility of eyelash growth, 
darkening of the eyelid or periocular skin and increased brown iris pigmentation since these 
have been observed during treatment with bimatoprost and GANFORT. Increased iris 
pigmentation is likely to be permanent, and may lead to differences in appearance between 
the eyes if only one eye is treated. After discontinuation of GANFORT, pigmentation of iris 
may be permanent. After 12 months treatment with GANFORT, the incidence of iris 
pigmentation was 0.2%. After 12 months treatment with bimatoprost eye drops alone, the 
incidence was 1.5% and did not increase following 3 years treatment. The pigmentation 
change is due to increased melanin content in the melanocytes rather than to an increase in 
the number of melanocytes. The long term effects of increased iridial pigmentation are not 
known. Iris colour changes seen with ophthalmic administration of bimatoprost may not be 
noticeable for several months to years. Neither nevi nor freckles of the iris appear to be 
affected by treatment. Periorbital tissue pigmentation has been reported to be reversible in 
some patients. 
Macular oedema, including cystoid macular oedema, has been reported with GANFORT. 
Therefore, GANFORT should be used with caution in aphakic patients, in pseudophakic 
patients with a torn posterior lens capsule, or in patients with known risk factors for macular 
oedema (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and 
diabetic retinopathy). 
GANFORT should be used with caution in patients with active intraocular inflammation (e.g. 
uveitis) because the inflammation may be exacerbated. 
Skin 
There is a potential for hair growth to occur in areas where GANFORT solution comes 
repeatedly in contact with the skin surface. Thus, it is important to apply GANFORT as 
instructed and avoid it running onto the cheek or other skin areas. 
Excipients 
The preservative in GANFORT, benzalkonium chloride, may cause eye irritation. Contact 
lenses must be removed prior to application, with at least a 15-minute wait before reinsertion. 
Benzalkonium chloride is known to discolour soft contact lenses.  Contact with soft contact 
lenses must be avoided. 
Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic 
ulcerative keratopathy. Therefore monitoring is required with frequent or prolonged use of 
GANFORT in dry eye patients or where the cornea is compromised. 
Other conditions 
GANFORT has not been studied in patients with inflammatory ocular conditions, 
neovascular, inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle 
glaucoma. 
In studies of bimatoprost 0.3 mg/ml in patients with glaucoma or ocular hypertension, it has 
been shown that more frequent exposure of the eye to more than 1 dose of bimatoprost daily 


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may decrease the IOP-lowering effect. Patients using GANFORT with other prostaglandin 
analogues should be monitored for changes to their intraocular pressure. 
4.5 
Interaction with other medicinal products and other forms of interaction 
No specific interaction studies have been performed with the bimatoprost / timolol fixed 
combination. 
There is a potential for additive effects resulting in hypotension, and/or marked bradycardia 
when ophthalmic beta-blockers solution is administered concomitantly with oral calcium 
channel blockers, guanethidine, beta-adrenergic blocking agents, parasympathomimetics, 
anti-arrhythmics (including amiodarone) and digitalis glycosides. 
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported 
during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) 
and timolol. 
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline 
(epinephrine) has been reported occasionally. 
4.6 
Fertility, pregnancy and lactation 
Pregnancy 
There are no adequate data from the use of the bimatoprost / timolol fixed combination in 
pregnant women. GANFORT should not be used during pregnancy unless clearly necessary. 
To reduce the systemic absorption, see section 4.2. 
Bimatoprost 
No adequate clinical data in exposed pregnancies are available. Animal studies have shown 
reproductive toxicity at high maternotoxic doses (see section 5.3). 
Timolol 
Epidemiological studies have not revealed malformative effects but shown a risk for intra 
uterine growth retardation when beta-blockers are administered by the oral route. In addition, 
signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and 
hypoglycaemia) have been observed in the neonate when beta-blockers have been 
administered until delivery. If GANFORT is administered until delivery, the neonate should 
be carefully monitored during the first days of life. Animal studies with timolol have shown 
reproductive toxicity at doses significantly higher than would be used in clinical practice (see 
section 5.3). 
Breast-feeding 
Timolol 
Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye 
drops it is not likely that sufficient amounts would be present in breast milk to produce 


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clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see 
section 4.2. 
Bimatoprost 
It is not known if bimatoprost is excreted in human breast milk but it is excreted in the milk 
of the lactating rat. GANFORT should not be used by breast-feeding women. 
Fertility 
There are no data on the effects of GANFORT on human fertility. 
4.7 
Effects on ability to drive and use machines 
GANFORT has negligible influence on the ability to drive and use machines. As with any 
ocular treatment, if transient blurred vision occurs at instillation, the patient should wait until 
the vision clears before driving or using machines. 
4.8 
Undesirable effects 
GANFORT 
Summary of the safety profile 
The adverse reactions reported in clinical studies using GANFORT were limited to those 
earlier reported for either of the single active substances bimatoprost and timolol. No new 
adverse reactions specific for GANFORT have been observed in clinical studies. 
The majority of adverse reactions reported in clinical studies using GANFORT were ocular, 
mild in severity and none were serious. Based on 12-month clinical data, the most commonly 
reported adverse reaction was conjunctival hyperaemia (mostly trace to mild and thought to 
be of a non-inflammatory nature) in approximately 26% of patients and led to discontinuation 
in 1.5% of patients. 
Tabulated list of adverse reactions 
Table 1 presents the adverse reactions that have been reported during clinical studies with all 
GANFORT formulations (multi-dose and single-dose) (within each frequency grouping, 
adverse reactions are presented in order of decreasing seriousness) or in the post-marketing 
period. 
The frequency of possible adverse reactions listed below is defined using the following 
convention: 
Very common 
≥1/10 
Common 
≥1/100 to <1/10 
Uncommon 
≥1/1,000 to <1/100 
Rare 
≥1/10,000 to <1/1,000 
Very rare 
<1/10,000 
Not known 
Frequency cannot be estimated from available data 
 


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Table 1 
System Organ Class 
Frequency 
Adverse reaction 
Immune system disorders 
Not known 
hypersensitivity reactions 
including signs or symptoms of 
allergic dermatitis, angioedema, 
eye allergy 
Psychiatric disorders 
Not known 
Insomnia2, nightmare2 
Nervous system disorders 
Common 
headache 
Not known 
Dysgeusia2, dizziness 
Eye disorders 
Very common 
conjunctival hyperaemia. 
Common 
punctuate keratitis, corneal 
erosion2, burning sensation2, 
conjunctival irritation1, eye 
pruritus, stinging sensation in the 
eye2, foreign body sensation, dry 
eye, erythema of eyelid, eye 
pain, photophobia, eye 
discharge, visual disturbance2, 
eyelid pruritus, visual acuity 
worsened2, blepharitis2, eyelid 
oedema, eye irritation, 
lacrimation increased, growth of 
eyelashes. 
Uncommon 
iritis2, conjunctival oedema2, 
eyelid pain2, abnormal sensation 
in the eye1, asthenopia, 
trichiasis2, iris 
hyperpigmentation2, deepening 
of eyelid sulcus, eyelid 
retraction2, eyelash 
discolouration (darkening)1. 
Not known 
cystoid macular oedema2, eye 
swelling, vision blurred2, ocular 
discomfort 
Cardiac disorders 
Not known 
Bradycardia 
Vascular disorders 
Not known 
Hypertension 
Respiratory, thoracic and 
mediastinal disorders 
Common 
Rhinitis2 
Uncommon 
dyspnoea 
Not known 
bronchospasm (predominantly 
in patients with pre-existing 
bronchospastic disease)2, 
asthma 


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Skin and subcutaneous tissue 
disorders 
Common 
blepharal pigmentation2, 
hirsutism2, skin 
hyperpigmentation (periocular). 
Not known 
Alopecia, skin discolouration 
(periocular) 
General disorders and 
administration site conditions 
Not known 
fatigue 
1adverse reactions only observed with Ganfort single-dose formulation 
2adverse reactions only observed with Ganfort multi-dose formulation 
Like other topically applied ophthalmic drugs, GANFORT (bimatoprost/timolol) is absorbed 
into the systemic circulation. Absorption of timolol may cause similar undesirable effects as 
seen with systemic beta-blocking agents. The incidence of systemic ADRs after topical 
ophthalmic administration is lower than for systemic administration. To reduce the systemic 
absorption, see section 4.2. 
Additional adverse reactions that have been seen with either of the active substances 
(bimatoprost or timolol), and may potentially occur also with GANFORT are listed below in 
Table 2: 
Table 2 
System Organ Class 
Adverse reaction 
Immune system disorders 
systemic allergic reactions including 
anaphylaxis1 
Metabolism and nutrition disorders 
hypoglycaemia1 
Psychiatric disorders 
depression1, memory loss1, hallucination1 
Nervous system disorders 
syncope1, cerebrovascular accident1, increase 
in signs and symptoms of myasthenia gravis1, 
paraesthesia1, cerebral ischaemia1 
Eye disorders 
decreased corneal sensitivity1, diplopia1, 
ptosis1, choroidal detachment following 
filtration surgery (see section 4.4)1, keratitis1, 
blepharospasm2, retinal haemorrhage2, uveitis2, 
Cardiac disorder 
atrioventricular block1, cardiac arrest1, 
arrhythmia1, cardiac failure1, congestive heart 
failure1, chest pain1, palpitations1, oedema1 
Vascular disorders 
hypotension1, Raynaud’s phenomenon1, cold 
hands and feet1 
Respiratory, thoracic and mediastinal 
disorders 
Asthma exacerbation2, COPD exacerbation2, 
cough1 
Gastrointestinal disorders 
nausea1,2, diarrhoea1, dyspepsia1, dry mouth1, 
abdominal pain1, vomiting1 
Skin and subcutaneous tissue disorders 
psoriasiform rash1 or exacerbation of 
psoriasis1, skin rash1 


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Musculoskeletal and connective tissue 
disorders 
myalgia1 
Reproductive system and breast disorders 
sexual dysfunction1, decreased libido1 
General disorders and administration site 
conditions 
asthenia1,2 
Investigations 
liver function tests (LFT) abnormal2 
1 adverse reactions observed with Timolol 
2 adverse reactions observed with Bimatoprost 
Adverse reactions reported in phosphate containing eye drops 
Cases of corneal calcification have been reported very rarely in association with the use of 
phosphate containing eye drops in some patients with significantly damaged corneas. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is 
important. It allows continued monitoring of the benefit/risk balance of the medicinal 
product. Healthcare professionals are asked to report any suspected adverse reactions via the 
national reporting system listed in Appendix V*. 
4.9 
Overdose 
A topical overdose with GANFORT is not likely to occur or to be associated with toxicity.  
Bimatoprost 
If GANFORT is accidentally ingested, the following information may be useful: in two-week 
oral rat and mouse studies, doses of bimatoprost up to 100 mg/kg/day did not produce any 
toxicity. This dose expressed as mg/m2 is at least 70-times higher than the accidental dose of 
one bottle of GANFORT in a 10 kg child. 
Timolol 
Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, 
headache, dizziness, shortness of breath, and cardiac arrest. A study of patients with renal 
failure showed that timolol did not dialyse readily. 
If overdose occurs treatment should be symptomatic and supportive. 
5. 
PHARMACOLOGICAL PROPERTIES 
5.1 
Pharmacodynamic properties 
Pharmacotherapeutic group: Ophthalmological,– beta-blocking agents – ATC code: 
S01ED51.  
 


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Mechanism of action 
GANFORT consists of two active substances: bimatoprost and timolol. These two 
components decrease elevated intraocular pressure (IOP) by complementary mechanisms of 
action and the combined effect results in additional IOP reduction compared to either 
compound administered alone. GANFORT has a rapid onset of action. 
Bimatoprost is a potent ocular hypotensive active substance . It is a synthetic prostamide, 
structurally related to prostaglandin F2α (PGF2α) that does not act through any known 
prostaglandin receptors. 
Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances 
called prostamides. The prostamide receptor, however, has not yet been structurally 
identified. The mechanism of action by which bimatoprost reduces intraocular pressure in 
man is by increasing aqueous humour outflow through the trabecular meshwork and 
enhancing uveoscleral outflow. 
Timolol is a beta1 and beta2 non-selective adrenergic receptor blocking agent that does not 
have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic 
(membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation. 
The precise mechanism of action is not clearly established, but inhibition of the increased 
cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable. 
Clinical effects 
The IOP-lowering effect of GANFORT is non-inferior to that achieved by adjunctive therapy 
of bimatoprost (once daily) and timolol (twice daily). 
Existing literature data for GANFORT suggest that evening dosing may be more effective in 
IOP lowering than morning dosing. However, consideration should be given to the likelihood 
of compliance when considering either morning or evening dosing. 
Paediatric population 
The safety and efficacy of GANFORT in children aged 0 to 18 years has not been 
established. 
5.2 
Pharmacokinetic properties 
GANFORT medicinal product 
Plasma bimatoprost and timolol concentrations were determined in a crossover study 
comparing the monotherapy treatments to GANFORT treatment in healthy subjects. 
Systemic absorption of the individual components was minimal and not affected by co-
administration in a single formulation. 
In two 12-month studies where systemic absorption was measured, no accumulation was 
observed with either of the individual components. 
Bimatoprost 
Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular 
administration, the systemic exposure of bimatoprost is very low with no accumulation over 


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time. After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes 
for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to 
below the lower limit of detection (0.025 ng/ml) within 1.5 hours after dosing. Mean Cmax and 
AUC 0-24hrs values were similar on days 7 and 14 at approximately 0.08 ng/ml and 0.09 
ng•hr/ml respectively, indicating that a steady drug concentration was reached during the first 
week of ocular dosing. 
Bimatoprost is moderately distributed into body tissues and the systemic volume of 
distribution in humans at steady-state was 0.67 1/kg. In human blood, bimatoprost resides 
mainly in the plasma. The plasma protein binding of bimatoprost is approximately 88%. 
Bimatoprost is the major circulating species in the blood once it reaches the systemic 
circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation 
and glucuronidation to form a diverse variety of metabolites. 
Bimatoprost is eliminated primarily by renal excretion, up to 67% of an intravenous dose 
administered to healthy volunteers was excreted in the urine, 25% of the dose was excreted 
via the faeces. The elimination half-life, determined after intravenous administration, was 
approximately 45 minutes; the total blood clearance was 1.5 1/hr/kg. 
Characteristics in older people 
After twice daily dosing, the mean AUC 0-24hrs  value of 0.0634 ng•hr/ml bimatoprost in the 
elderly (subjects 65 years or older) were significantly higher than 0.0218 ng•hr/ml in young 
healthy adults. However, this finding is not clinically relevant as systemic exposure for both 
elderly and young subjects remained very low from ocular dosing. There was no 
accumulation of bimatoprost in the blood over time and the safety profile was similar in 
elderly and young patients. 
Timolol 
After ocular administration of a 0.5% eye drops solution in humans undergoing cataract 
surgery, peak timolol concentration was 898 ng/ml in the aqueous humour at one hour post-
dose. Part of the dose is absorbed systemically where it is extensively metabolised in the 
liver. The half-life of timolol in plasma is about 4 to 6 hours. Timolol is partially metabolised 
by the liver with timolol and its metabolites excreted by the kidney.  Timolol is not 
extensively bound to plasma. 
5.3 
Preclinical safety data 
GANFORT medicinal product 
Repeated dose ocular toxicity studies on GANFORT showed no special hazard for humans. 
The ocular and systemic safety profile of the individual components is well established. 
Bimatoprost 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, genotoxicity, carcinogenic potential. Studies in rodents produced species-
specific abortion at systemic exposure levels 33- to 97-times that achieved in humans after 
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Monkeys administered ocular bimatoprost concentrations of ≥0.03% daily for 1 year had an 
increase in iris pigmentation and reversible dose-related periocular effects characterised by a 
prominent upper and/or lower sulcus and widening of the palpebral fissure. The increased iris 
pigmentation appears to be caused by increased stimulation of melanin production in 
melanocytes and not by an increase in melanocyte number. No functional or microscopic 
changes related to the periocular effects have been observed, and the mechanism of action for 
the periocular changes is unknown. 
Timolol 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to 
reproduction. 
6. 
PHARMACEUTICAL PARTICULARS 
6.1 
List of excipients 
Benzalkonium chloride 
Sodium chloride 
Sodium phosphate dibasic heptahydrate  
Citric acid monohydrate 
Hydrochloric acid or sodium hydroxide (to adjust pH)  
Purified water 
6.2 
Incompatibilities 
Not applicable. 
6.3 
Shelf life 
2 years. 
Chemical and physical in-use stability has been demonstrated for 28 days at 25°C. 
From a microbiological point of view, the in-use storage times and conditions are the 
responsibility of the user and would normally not be longer than 28 days at 25°C. 
6.4 
Special precautions for storage 
This medicinal product does not require any special storage conditions. 
6.5 
Nature and contents of container 
White opaque low-density polyethylene bottles with polystyrene screw cap. Each bottle has a 
fill volume of 3 ml. 
The following pack sizes are available: cartons containing 1 or 3 bottles of 3 ml. Not all pack 
sizes may be marketed. 


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6.6 
Special precautions for disposal 
No special requirements. 
7. 
MARKETING AUTHORISATION HOLDER 
Allergan Pharmaceuticals Ireland  
Castlebar Road 
Westport  
Co. Mayo  
Ireland 
8. 
MARKETING AUTHORISATION NUMBER(S) 
EU/1/06/340/001-002 
9. 
DATE OF FIRST AUTHORISATION/RENEWAL OF THE 
AUTHORISATION 
Date of first authorisation 19 May 2006  
Date of latest renewal 23 June 2011 
10. 
DATE OF REVISION OF THE TEXT 
<{MM/YYYY}> 
<{DD/MM/YYYY}> 
<{DD month YYYY}> 
Detailed information on this medicinal product is available on the website of the European 
Medicines Agency: http://www.ema.europa.eu/. 
GANFORT® Product Information obtained from www.ema.europa.eu, date of last update 
26 February 2020 
Investigators should review the above website for the current version of the Summary of 
Product Characteristics for GANFORT® eye drops. 
 
 


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Appendix 4 
Sponsor’s Obligations 
Aerie Pharmaceuticals Ireland Ltd. is committed to: 
A. Complying with the local health authority regulations for the conduct of clinical research 
studies. 
B. Informing the Investigator of any new information about the investigational product that 
may affect the subject's welfare or may influence the subject's decision to continue 
participation in the study. 
C. In the event of a serious adverse experience, whether related to the use of the study 
medication or device or not, or the death of a subject, the Sponsor is responsible for 
notifying the regulatory authority(ies) immediately (see Section 7.2, Adverse events 
Assessments and Ocular safety). 
D. When the study is terminated the Sponsor should promptly inform the regulatory 
authority(ies) of the termination and the reason(s) for it. The IEC/CEC should also be 
informed promptly and provide the reason(s) for the termination by the Sponsor as 
specified by the applicable regulatory requirement(s). 
E. Providing to the Investigator the most up-to-date editions of the Clinical Investigator's 
Brochure (for the investigational product), the protocol, Serious Adverse Experience 
forms, and a full set of Case Report Forms for each subject entered into the study to 
document the study evaluation parameters. 
F. Providing study medications suitably masked/blinded, coded and packaged for use with 
subjects entered into the study. 
G. Providing statistical and report writing resources to complete appropriate reporting of 
study results. 
H. Ensuring equity considerations among all Investigators in multicenter studies, including 
all matters of publications and meeting presentations, etc. (where applicable). 
I. Prepare an FDA Form No. 3454 (Certification: Financial Interests and Arrangements of 
Clinical Investigators) or 3455 (Disclosure: Financial Interests and Arrangements of 
Clinical Investigators) or Sponsor’s equivalent. 
 
 


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Appendix 5 
Investigator’s Obligations 
An Investigator for the PG324-CS303 study must be a physician duly qualified to practice 
medicine. The Investigator is obligated to: 
A. Questioning (evaluation of) examination regarding, as well as collection and 
documentation of, adverse events and efficacy parameters. In the event of a serious 
adverse experience, whether related to the use of the study medication or device or not, 
or the death of a subject, the Investigator is responsible for notifying the Sponsor Safety 
Officer immediately (see Section 7.2 Adverse Events Assessment and Ocular Safety). 
The Investigator must also notify the Sponsor Representative and the Institutional 
Review Board (IEC/ CEC) to which he/she is responsible. 
B. Under 21 CFR 54 and according to the EU Clinical Trials Directive 2001/20/EC the 
Investigator/Sub investigator is required to provide the sponsor with sufficient accurate 
financial information to allow for complete disclosure or certification and to update this 
information if any relevant changes occur during the study and for one year following its 
completion 
C. Obtain and submit to the Sponsor a copy of his/her IEC/ CEC approval of the protocol 
prior to initiating the study. 
D. Obtain signed informed consent from each subject or his/her legal guardian prior to 
acceptance of the subject into the study. 
E. Read, and agree to adhere to the study protocol prior to the initiation of the study. 
Deviations from the study protocol are not to be implemented without the prior written 
approval of the Sponsor and IEC/ CEC, unless protection of the safety and welfare of 
study subjects requires prompt action. During the study, if the Investigator feels that in 
his/her clinical judgment, it is necessary to promptly terminate one or more subjects 
from the study, or to promptly implement reasonable alternatives to, or deviations from 
the protocol in consideration of the safety of study subjects, the Sponsor is to be notified 
of these terminations, alternatives, and deviations, and the reasons for such changes are 
to be documented in the study records. The Investigator is to also notify his/her IEC/ 
CEC of any such changes. 
F. Accurately record, at the Investigator’s site, all required data on each subject's CRF. 
G. Replace subjects consistent with the directions in Section 4.1 
H. Keep accurate records of the number of study medication or device units received from 
the Sponsor and dispensed or administered to each subject during the study, and return 
any unused study medication or devices to the Sponsor at the completion of the study. 
Before returning the study medications or devices to the Sponsor, a detailed inventory 
should be recorded and placed in the Investigator’s file. 


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I. Assure that Investigational Products will be dispensed or administered only to subjects 
under his/her personal supervision, or under the supervision of authorized sub-
Investigators responsible to him/her. 
J. Allow a representative of the Sponsor and/or representatives of health regulatory 
agencies to inspect all CRFs and corresponding portions of each study subject's original 
office, hospital, and laboratory records at mutually convenient times at regular intervals 
during the study and upon request after the study has been completed. The purpose of 
these on-site monitoring visits is to provide the Sponsor the opportunity to evaluate the 
progress of the study, document compliance with the protocol and with regulatory 
requirements, verify the accuracy and completeness of subject CRFs, resolve any 
apparent discrepancies or inconsistencies in the study records, and account for all 
investigational supplies. 
K. Provide the governing IEC/CEC with a brief (i.e., 1 to 3 pages) Investigator's summary 
within 90 working days of the study completion. 
L. Complete the study within the time limits agreed upon with the Sponsor prior to the 
initiation of the study. 
M. Maintenance of records 
a. Disposition of drug. An investigator is required to maintain adequate records of 
the disposition of the drug, including dates, quantity, and use by subjects. If the 
investigation is terminated, suspended, discontinued, or completed, the 
investigator shall return the unused supplies of the drug to the Sponsor, or 
otherwise provide for disposition of the unused supplies of the drug according to 
Clinical Trial Directive 2001/20/EC 
b. Case histories. An investigator is required to prepare and maintain adequate and 
accurate case histories that record all observations and other data pertinent to the 
investigation on each individual administered the investigational drug or 
employed as a control in the investigation. Case histories include the case report 
forms and supporting data including, for example, signed and dated consent forms 
and medical records including, for example, progress notes of the physician, the 
individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to 
participation in the study. 
c. Record retention. An investigator shall retain records required to be maintained 
under this part for a period of 2 years following the date a marketing application is 
approved for the drug for the indication for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for such indication, 
until 2 years after the investigation is discontinued and the IEC/ CEC and the 
country specific Competent Authority is notified. 


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These documents should be retained for a longer period however if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. 
If for any reason the Investigator withdraws from the responsibility of maintaining the study 
records for the required period of time, custody of the records may be transferred to any other 
person who will accept responsibility for the records. The Sponsor is to be notified in writing 
of any such transfer. 
 


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Appendix 6 
Declaration of Helsinki 
Recommendations Guiding Medical Doctors in Biomedical Research Involving Human 
Subjects.  
I. BASIC PRINCIPLES 
1. Biomedical research involving human subjects must conform to generally accepted 
scientific principles and should be based on adequately performed laboratory and animal 
experimentation and on a thorough knowledge of the scientific literature. 
2. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol which should be transmitted to a 
specially appointed independent committee for consideration, comment and guidance. 
3. Biomedical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a medically qualified 
person and never rest with the subject of the research, even though the subject has given 
his or her consent. 
4. Biomedical research involving human subjects cannot legitimately be carried out unless 
the importance of the objective is in proportion to the inherent risk to the subject. 
5. Every biomedical research project involving human subjects should be preceded by 
careful assessment of predictable risks in comparison with foreseeable benefits to the 
subject or to others. Concern for the interests of the subject must always prevail over the 
interests of science and society. 
6. The right of the research subject to safeguard his or her integrity must always be 
respected. Every precaution should be taken to respect the privacy of the subject and to 
minimize the impact of the study on the subject's physical and mental integrity and on the 
personality of the subject. 
7. Doctors should abstain from engaging in research projects involving human subjects 
unless they are satisfied that the hazards involved are believed to be predictable. Doctors 
should cease any investigation if the hazards are found to outweigh the potential benefits. 
8. In publication of the results of his or her research, the doctor is obliged to preserve the 
accuracy of the results. Reports of experimentation not in accordance with the principles 
laid down in this Declaration should not be accepted for publication. 
9. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, anticipated benefits and potential hazards of the study and the 
discomfort it may entail. He or she should be informed that he or she is at liberty to 
abstain from participation in the study and that he or she is free to withdraw his or her 


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consent to participation at any time. The doctor should then obtain the subject's given 
informed consent, preferably in writing. 
10. When obtaining informed consent for the research project the doctor should be 
particularly cautious if the subject is in a dependent relationship to him or her or may 
consent under duress. In that case, the informed consent should be obtained by a doctor 
who is not engaged in the investigation and who is completely independent of this official 
relationship. 
11. In case of legal incompetence, informed consent should be obtained from the legal 
guardian in accordance with national legislation. Where physical or mental incapacity 
makes it impossible to obtain informed consent, or when the subject is a minor, 
permission from the responsible relative replaces that of the subject in accordance with 
national legislation. 
12. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that the principles enunciated in the present Declaration are 
complied with. 
II. MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (CLINICAL 
RESEARCH) 
1. In the treatment of the sick person, the doctor must be free to use a new diagnostic and 
therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing 
health or alleviating suffering. 
2. The potential benefits, hazards and discomforts of a new method should be weighed 
against the advantages of the best current diagnostic and therapeutic methods. 
3. In any medical study, all subjects - including those of a control group, if any, should be 
assured of the best proven diagnostic and therapeutic methods. 
4. The refusal of the patient to participate in a study must never interfere with the doctor- 
patient relationship. 
5. If the doctor considers it essential not to obtain informed consent, the specific reasons for 
this proposal should be stated in the experimental protocol for transmission to the 
independent committee. 
6. The doctor can combine medical research with professional care, the objective being the 
acquisition of new medical knowledge, only to the extent that medical research is 
justified by its potential diagnostic or therapeutic value for the patient. 
 
 


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III. NON-THERAPEUTIC BIOMEDICAL RESEARCH INVOLVING HUMAN SUBJECT 
(NONCLINICAL BIOMEDICAL RESEARCH) 
1. In the purely scientific application of medical research carried out on a human being, it is 
the duty of the doctor to remain the protector of the life and health of that person on 
whom biomedical research is being carried out. 
2. The subjects should be volunteers - either healthy person or subjects for whom the 
experimental design is not related to the patient’s illness. 
3. The Investigator or the team should discontinue the research if in his/her or their 
judgment it may, if continued, be harmful to the individual. 
4. In research on man, the interest of science and society should never take precedence over 
consideration related to the well-being of the subject. 
 
 


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Appendix 7 
Self-Administered National Eye Institute Visual Functioning 
Questionnaire-25 (VFQ-25)  
PB/SA 
 
National Eye Institute  
Visual Functioning Questionnaire-25 
(VFQ-25) 
 
Version 2000 
 
 
 
(SELF-ADMINISTERED FORMAT) 
 
 
 
January 2000 
 
 
 
 
 
RAND hereby grants permission to use the "National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25) July 1996, in accordance 
with the following conditions which shall be assumed by all to have been agreed to as a consequence of accepting and using this document: 
 
1.  Changes to the NEI VFQ-25 - July 1996 may be made without the written permission of RAND.  However, all such changes shall be 
clearly identified as having been made by the recipient. 
 
2.  The user of this NEI VFQ-25 - July 1996 accepts full responsibility, and agrees to hold RAND harmless, for the accuracy of any translations 
of the NEI VFQ-25 Test Version - July 1996 into another language and for any errors, omissions, misinterpretations, or consequences thereof. 
 
3.  The user of this NEI VFQ-25 - July 1996 accepts full responsibility, and agrees to hold RAND harmless, for any consequences resulting 
from the use of the NEI VFQ-25. 
 
4.  The user of the NEI VFQ-25 - July 1996 will provide a credit line when printing and distributing this document or in publications of results 
or analyses based on this instrument acknowledging that it was developed at RAND under the sponsorship of the National Eye Institute. 
 
5.  No further written permission is needed for use of this NEI VFQ-25 - July 1996.  
 
7/29/96 
 
 
 
 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
ID2285_item16a:2980 


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The following is a survey with statements about problems which involve your 
eyesight or feelings that you have about your eye condition. After each question 
please choose the response that best describes your situation. 
 
Please answer all the questions as if you were wearing your glasses or contact 
lenses (if any). 
 
Please take as much time as you need to answer each question. All your answers are 
confidential. As the purpose of this survey is to improve our knowledge about eyesight 
problems and how they affect your quality of life, your answers must be as accurate as 
possible. Remember, if you wear glasses or contact lenses, please answer all of the 
following questions as if you were wearing them. 
 
INSTRUCTIONS: 
 
1. 
In general, we would like to have people try to complete these forms on their own. If you find 
that you need assistance, please feel free to ask the project staff and they will assist you. 
 
2. 
Please answer every question (unless you are asked to skip questions because they do not apply 
to you). 
 
3. 
Answer the questions by circling the appropriate number. 
 
4. 
If you are unsure of how to answer a question, please give the best answer you can and make a 
comment in the left margin. 
 
5. 
Please complete the questionnaire before leaving the centre and give it to a member of the 
project staff. Do not take it home. 
 
6. 
If you have any questions, please feel free to ask a member of the project staff, and they will be 
glad to help you. 
 
STATEMENT OF CONFIDENTIALITY: 
 
All information that would permit identification of any person who completed this questionnaire will be 
regarded as strictly confidential.  Such information will be used only for the purposes of this study and 
will not be disclosed or released for any other purposes without prior consent, except as required by law. 
 
 
 
 
 
 
 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
ID2285_item16a:2980 


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Visual Functioning Questionnaire-25 
 
 
 
 
 
 
 
 
PART 1 - GENERAL HEALTH AND VISION 
 
 
1. 
In general, would you say your health is: 
 
 
(Circle One) 
 
Excellent .................................   1 
 
Very Good ...............................   2 
 
Good ........................................   3 
 
Fair ..........................................   4 
 
Poor .........................................   5 
 
 
2. 
At the present time, would you say your eyesight in both eyes (with glasses or contact 
lenses, if you wear them) is excellent, good, fair, poor, or very poor, or are you 
completely blind? 
 
 
(Circle One) 
 
Excellent .................................   1 
 
Good ........................................   2 
 
Fair ..........................................   3 
 
Poor .........................................   4 
 
Very Poor ................................   5 
 
Completely Blind ....................   6 
 
 
 
 
 
 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
ID2285_item16a:2980 


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3. 
How often are you concerned about your eyesight? 
 
 
 
 
 
 
 
(Circle One) 
 
None of the time ..................................   1 
 
A little of the time ...............................   2 
 
Some of the time .................................   3 
 
Most of the time ..................................   4 
 
All of the time? ...................................   5 
 
 
4. 
How much pain or discomfort have you had in and around your eyes (for example, 
burning, itching, or aching)? 
 
 
 
 
 
 
 
(Circle One) 
 
None ........................................   1 
 
Mild .........................................   2 
 
Moderate .................................   3 
 
Severe ......................................   4 
 
Very severe? ............................   5 
 
 
PART 2 - DIFFICULTY WITH ACTIVITIES 
 
The next questions are about how much difficulty, if any, you have doing certain activities 
wearing your glasses or contact lenses if you use them for those activities. 
 
5. 
How much difficulty do you have reading ordinary print in newspapers? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
ID2285_item16a:2980 


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6. 
How much difficulty do you have doing work or hobbies that require you to see well 
close up, such as cooking, sewing, fixing things around the house, or using hand tools? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
7. 
Because of your eyesight, how much difficulty do you have finding something on a 
crowded shelf? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
8. 
How much difficulty do you have reading street signs or the names of shops? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
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9. 
Because of your eyesight, how much difficulty do you have going down steps, stairs, or 
curbs in dim light or at night? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
10. Because of your eyesight, how much difficulty do you have noticing objects on the side 
while you are walking straight ahead? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
11. Because of your eyesight, how much difficulty do you have seeing how people react to 
things you say? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
© R 1996 
 
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PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
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12. Because of your eyesight, how much difficulty do you have picking out and matching 
your own clothes? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
13. Because of your eyesight, how much difficulty do you have visiting with people in their 
homes, at parties, or in restaurants? 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
14. Because of your eyesight, how much difficulty do you have going out to see films, 
plays or sports events? 
 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all .............................................................   1 
 
A little difficulty ...............................................................   2 
 
Moderate difficulty ...........................................................   3 
 
Extreme difficulty .............................................................   4 
 
Stopped doing this because of your eyesight ....................   5 
 
Stopped doing this for other reasons or not 
 
     interested in doing this .................................................   6 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
ID2285_item16a:2980 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
Page 151 of 160 
 
15. Are you currently driving, at least once in a while? 
 
 
(Circle One) 
 
Yes ........................   1 Skip To Q 15c 
 
 
15a. 
IF NO: Have you never driven or have you given up driving? 
 
 
(Circle One) 
 
Never drove ...........   1 Skip To Part 3, Q 17 
 
Gave up .................   2     
 
 
15b. 
IF YOU HAVE GIVEN UP DRIVING: Was that mainly because of your 
eyesight, for some other reason, or because of your eyesight and other reasons? 
 
 
 
 
 
  (Circle One) 
 
Mainly eyesight .........................................   1 Skip To Part 3, Q 17 
 
Mainly other reasons .................................   2 Skip To Part 3, Q 17 
 
Eyesight and other reasons ........................   3 Skip To Part 3, Q 17 
 
 
15c. 
IF CURRENTLY DRIVING: How much difficulty do you have driving during 
the daytime in familiar places? Would you say you have: 
 
 
 
 
  (Circle One) 
 
No difficulty at all .....................................   1 
 
A little difficulty .......................................   2 
 
Moderate difficulty ...................................   3 
 
Extreme difficulty .....................................   4 
 
 
 
 
 
 
 
© R 1996 
 
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ID2285_item16a:2980 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
Page 152 of 160 
 
16. How much difficulty do you have driving at night? 
 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all ...........................................   1 
 
A little difficulty .............................................   2 
 
Moderate difficulty .........................................   3 
 
Extreme difficulty ...........................................   4 
 
Have you stopped doing this because 
 
     of your eyesight ..........................................   5 
 
Have you stopped doing this for other  
 
     reasons or not interested in  
 
     doing this ....................................................   6 
 
16a. How much difficulty do you have driving in difficult conditions, such as in bad 
weather, during the rush hour, on the motorway, or in city traffic?   
 
 
 
 
 
 
 
(Circle One) 
 
No difficulty at all ...........................................   1 
 
A little difficulty .............................................   2 
 
Moderate difficulty .........................................   3 
 
Extreme difficulty ...........................................   4 
 
Have you stopped doing this because 
 
     of your eyesight? ........................................   5 
 
Have you stopped doing this for other  
 
     reasons or are you not interested in  
 
     doing this? ..................................................   6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
ID2285_item16a:2980 
 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
Page 153 of 160 
 
PART 3 - RESPONSES TO VISION PROBLEMS 
 
 
 
 
The next questions are about things you may do because of your vision. For each one, please 
circle the number to indicate whether for you the statement is true for you all, most, some, a 
little, or none of the time. 
 
 
 
 
 
(Circle One On Each Line) 
READ CATEGORIES: 
All of the 
time 
Most of 
the time 
Some of 
the time 
A little 
of the 
time 
None of 
the time 
 
 
17. Do you accomplish less than 
you would like to because of 
your eyesight? ...................... 
 
 
 
 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
18. Are you limited in how long 
you can work or do your 
activities because of your 
eyesight? ............................... 
 
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
19. How often does pain or 
discomfort in or around your 
eyes, for example, burning, 
itching, or aching, keep you 
from doing what you'd like to 
be doing? .............................. 
 
 
 
 
 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
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PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
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For each of the following statements, please circle the number to indicate whether for you the 
statement is definitely true, mostly true, mostly false, or definitely false, or you are not sure. 
 
(Circle One On Each Line) 
 
 
Definitely 
True 
Mostly 
True 
Not sure Mostly 
False 
Definitely 
False 
 
20. I stay at home most of the time 
because of my eyesight
 .................................................... 
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
21. I feel frustrated a lot of the time 
because of my eyesight
 .................................................... 
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
22. I have much less control over 
what I do, because of my 
eyesight
 .................................................... 
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
23. Because of my eyesight, I have to 
rely too much on what other 
people tell me
 .................................................... 
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
24. I need a lot of help from others 
because of my eyesight
 .................................................... 
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
25. I am concerned about doing 
things that might embarrass 
myself or others, because of my 
eyesight
 .................................................... 
eyesight
 .................................................... 
 
 
 
 
 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
© R 1996 
 
NEI-VFQ25 (Self Administered) - UK/English – Version of 26 Aug 04 - Mapi. 
ID2285_item16a:2980 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
Page 155 of 160 
 
Appendix 8 
Health Survey Questionnaire Short Form 36 Questions (SF-36) 
 
 
Your Health and Well-Being 
 
 
This survey asks for your views about your health.  This information will 
help keep track of how you feel and how well you are able to do your 
usual activities. Thank you for completing this survey! 
 
For each of the following questions, please tick the one box that best 
describes your answer. 
 
1. In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
2. Compared to one year ago, how would you rate your health in 
general now? 
Much better 
now than one 
year ago 
Somewhat 
better 
now than one 
year ago 
About the 
same as 
one year ago 
Somewhat 
worse 
now than one 
year ago 
Much worse 
now than one 
year ago 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
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3. The following questions are about activities you might do during a 
typical day.  Does your health now limit you in these activities?  If so, 
how much?  
 
 
 
 
 
 
 
 
 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English))
 
Yes, 
limited 
a lot 
Yes, 
limited 
a little 
No, not 
limited 
at all 
 
   
a Vigorous activities, such as running, lifting  
heavy objects, participating in strenuous sports ...................... 
 1 ............. 
 2 ............. 
 3 
b Moderate activities, such as moving a table, pushing  
a vacuum cleaner, bowling, or playing golf ............................. 
 1 ............. 
 2 ............. 
 3 
c Lifting or carrying groceries .................................................... 
 1 ............. 
 2 ............. 
 3 
d Climbing several flights of stairs ............................................. 
 1 ............. 
 2 ............. 
 3 
e Climbing one flight of stairs .................................................... 
 1 ............. 
 2 ............. 
 3 
f Bending, kneeling, or stooping ................................................ 
 1 ............. 
 2 ............. 
 3 
g Walking more than a mile ........................................................ 
 1 ............. 
 2 ............. 
 3 
h Walking several hundred yards ................................................ 
 1 ............. 
 2 ............. 
 3 
i Walking one hundred yards ..................................................... 
 1 ............. 
 2 ............. 
 3 
j Bathing or dressing yourself .................................................... 
 1 ............. 
 2 ............. 
 3 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
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4.  During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of your physical health? 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
     
a Cut down on the amount of  
 time you spent on work or  
 other activities .................................. 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
b Accomplished less than you  
 would like ........................................ 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
c Were limited in the kind of  
 work or other activities .................... 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
d Had difficulty performing the 
 work or other activities (for  
 example, it took extra effort) ........... 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities as a 
result of any emotional problems (such as feeling depressed or 
anxious)? 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
     
a Cut down on the amount of  
 time you spent on work or  
 other activities .................................. 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
b Accomplished less than you  
 would like ........................................ 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
c Did work or other activities 
 less carefully than usual ................... 
 1 ............. 
 2 .............. 
 3 .............. 
 4 ............. 
 5 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
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6. During the past 4 weeks, to what extent has your physical health or 
emotional problems interfered with your normal social activities with 
family, friends, neighbours, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
 
 
7. How much bodily pain have you had during the past 4 weeks? 
None 
Very mild 
Mild 
Moderate 
Severe 
Very severe 
      
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
  
 6 
 
 
 
 
 
8. During the past 4 weeks, how much did pain interfere with your 
normal work (including both work outside the home and housework)? 
Not at all 
A little bit 
Moderately 
Quite a bit 
Extremely 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
 
 
 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
Page 159 of 160 
 
9. These questions are about how you feel and how things have been with 
you during the past 4 weeks.  For each question, please give the one answer 
that comes closest to the way you have been feeling.  How much of the time 
during the past 4 weeks… 
 
10. During the past 4 weeks, how much of the time has your physical 
health or emotional problems interfered with your social activities (like 
visiting with friends, relatives, etc.)? 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
 
 
 
 
 
  
 1 
  
 2 
  
 3 
  
 4 
  
 5 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
the time 
None of 
the time 
     
a Did you feel full of life? ................. 
 1 ............. 
 2 ............. 
 3 ............. 
 4 ............. 
 5 
b Have you been very nervous? ......... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5 
c Have you felt so down in the  
dumps that nothing could  
cheer you up? .................................. 
 1 ............. 
 2 ............. 
 3 ............. 
 4 ............. 
 5 
d Have you felt calm and   
peaceful? ......................................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5 
e Did you have a lot of energy? ......... 
 1 ............. 
 2 ............. 
 3 ............. 
 4 ............. 
 5 
f Have you felt downhearted   
and low? .......................................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5 
g Did you feel worn out? ................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5 
h Have you been happy? .................... 
 1 .............. 
 2 ............. 
 3 .............. 
 4 ............. 
 5 
i Did you feel tired? .......................... 
 1 ............. 
 2 ............. 
 3 ............. 
 4 ............. 
 5 


PG324 Ophthalmic Solution 
Clinical Study Protocol: PG324-CS303, Amendment 6 
Aerie Pharmaceuticals Ireland Ltd. 
 
 
Confidential 
Page 160 of 160 
 
 
11. How TRUE or FALSE is each of the following statements for you? 
Definitely 
true 
Mostly 
true 
Don’t 
know 
Mostly 
false 
Definitely 
false 




a I seem to get ill more 
easily than other people .................. 
 1 ............. 
 2 ............. 
 3 ............... 
 4 .............. 
 5 
b I am as healthy as  
anybody I know .............................. 
 1 ............. 
 2 ............. 
 3 ............... 
 4 .............. 
 5 
c I expect my health to  
get worse ......................................... 
 1 ............. 
 2 ............. 
 3 ............... 
 4 .............. 
 5 
d My health is excellent ..................... 
 1 ............. 
 2 ............. 
 3 ............... 
 4 .............. 
 5 
 
 
 
 
 
 
 
Thank you for completing these questions! 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SF-36v2® Health Survey  1992, 2002, 2009 Medical Outcomes Trust and QualityMetric Incorporated.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, United Kingdom (English)) 

SAP_001.pdf: 
A pr o s p e cti v e, d o u bl e -m a s k e d, r a n d o mi z e d, m ulti c e nt er, 
a cti v e- c o ntr oll e d,  p ar all el -gr o u p, 6 -m o nt h st u d y 
a s s e s si n g t h e s af et y a n d o c ul ar h y p ot e n si v e  effi c a c y of 
P G 3 2 4 ( n et ar s u dil 0. 0 2 %/l at a n o pr o st 0. 0 0 5 %) 1  
O p ht h al mi c  S ol uti o n c o m p ar e d t o G A N F O R T ® 
( bi m at o pr o st 0. 0 3 %/ti m ol ol 0. 5 %) O p ht h al mi c S ol uti o n i n 
s u bj e ct s wit h el e v at e d i ntr a o c ul ar pr e s s ur e  ( M er c ur y 3) 
 
1  “( n et ar s u dil 0. 0 2 %/l at a n o pr o st 0. 0 0 5 %)” c o u ntr y s p e cifi c a d diti o n t o titl e f or H u n g ar y 
 
 
 
N C T 0 3 2 8 4 8 5 3 
 
 
2 6 A u g 2 0 2 0 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 1 of 4 4 
 
S T A TI S TI C A L A N A L Y SI S P L A N 
Versi o n 2. 0 
 
2 6 A u g 2 0 2 0  
 
 
 
A pr os pecti v e, d o u bl e- m as ke d, r a n d o mize d, m ultice nter, a cti v e-c o ntr olle d, 
p ar all el- gr o u p, 6- m o nt h st u d y assessi n g t he s afet y a n d oc ul ar h y p ote nsi v e 
effic ac y of P G 3 2 4 ( net ars u dil 0. 0 2 %/l at a n o pr ost 0. 0 0 5 %) 1 O p ht h al mic 
S ol uti o n c o m p are d t o G A N F O R T ® ( bi m at o pr ost 0. 0 3 %/ti m ol ol 0. 5 %) 
O p ht h al mic S ol uti o n i n s u bjects wit h ele v ate d i ntr a oc ul a r press ure  
( Merc ur y 3) 
1 
 
c o u ntr y s pecific a d diti o n t o title f o r H u n g ar y  
 
P R O T O C O L N U M B E R P G 3 2 4- C S 3 0 3  
 
 
S P O N S O R E D B Y 
 
 
 
 
 
 
 
 
 
 
P R E P A R E D B Y 
 
 
 
 
 
 
 
  
 
T his d o c u me nt c o ntai ns Aerie P har mace uticals Irela n d Lt d. ( Aerie) i nf or mati o n t hat is c o nfi d e ntial, a tra de secret 
a n d/ or pr o prietar y i n nat ure. It is l o a n e d t o y o u f or y o ur c o nfi d e ntial use o n be half of Aerie a n d is n ot t o b e 
p h ot o c o pie d, discl ose d or tra ns mitte d t o a n y ot her p ers o n or p art y w h o is n ot c o vere d b y a C o nfi d e ntial Discl os ure 
A gree me nt wit h Aerie.   


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 2 of 4 4 
D O C U M E N T V E R SI O N C O N T R O L 
 
Versi o n N u m ber 
D ate 
C o m me nts/ C h a n g es 
0. 1 
 
1 5 J u ne 2 0 1 8 
 
Draft 
 
0. 2 
0 5 J u ne 2 0 1 9 
Sec o n d Draft 
0. 3 
2 7 J u ne 2 0 1 9 
T hir d Draft 
1. 0 
2 4 J ul y 2 0 1 9 
Ori gi nal 
2. 0 
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Versi o n 2. 0 
 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 3 of 4 4 
A P P R O V A L S 
A p pr o ve d:  
 
 
 
 
 
 
 
Date: 
 
 
  
 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
Date: 
 
 
 
 
 
  
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 4 of 4 4 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
Date: 
 
 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 5 of 4 4 
T A B L E O F C O N T E N T S 
LI S T O F A B B R E VI A TI O N S ....................................................................................................... 7  
1.  
P U R P O S E O F T H E A N A L Y S E S ......................................................................................... 9  
2.  
P R O T O C O L S U M M A R Y ................................................................................................... 1 0  
2. 1  St u d y O bj ecti ves ............................................................................................................ 1 0  
2. 2  O verall St u d y Desi g n a n d Pla n ...................................................................................... 1 0  
2. 3  St u d y P o p ulati o n ............................................................................................................ 1 2  
2. 4  Treat me nt Re gi me ns ...................................................................................................... 1 3  
2. 5  Treat me nt Gr o u p Assi g n me nts or Ra n d o mi zati o n ......................................................... 1 3  
2. 6  Sa m pl e Si ze Deter mi nati o n ............................................................................................ 1 3  
3.  
G E N E R A L A N A L Y SI S A N D R E P O R TI N G C O N V E N TI O N S ..................................... 1 4  
4.  
A N A L Y SI S P O P U L A TI O N S .............................................................................................. 1 5  
4. 1  Ra n d o mi ze d P o p ul ati o n ................................................................................................. 1 5  
4. 2  I nte nt-t o- Treat P o p ulati o n (I T T) .................................................................................... 1 5 
4. 3  Per- pr ot o c ol P o p ulati o n ( P P) ......................................................................................... 1 5  
4. 4  Safet y P o p ulati o n ........................................................................................................... 1 5  
5.  
S T U D Y S U B J E C T S ............................................................................................................. 1 6  
5. 1  Dis p ositi o n of S u bjects ................................................................................................... 1 6  
5. 2  Pr ot oc ol De viati o ns ........................................................................................................ 1 6  
6.  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S .......................... 1 7  
6. 1  De m o gra p hics a n d B aseli ne C haracteristi cs .................................................................. 1 7  
6. 2  Pri or a n d C o n c o mit a nt Me dicati o ns ............................................................................... 1 7  
6. 3  Me dical a n d Oc ular Hist or y ........................................................................................... 1 8  
7.  
M E A S U R E M E N T S O F T R E A T M E N T C O M P LI A N C E ................................................ 1 9  
8.  
E F FI C A C Y E V A L U A TI O N ............................................................................................... 2 0  
8. 1  O ver vie w of Effi cac y A nal ysis Iss ues ............................................................................ 2 0  
8. 1. 1  
Ha n dli n g of Dr o p o uts or Missi n g Data ............................................................. 2 0  
8. 1. 2  
M ultice nter St u dies ........................................................................................... 2 0  
8. 1. 3  
Assess me nt Ti me Wi n d o ws .............................................................................. 2 0  
8. 2  Efficac y Varia bles a n d Pri mar y H y p ot heses .................................................................. 2 0  
8. 3  A nal ysis Met h o ds ........................................................................................................... 2 1  
8. 3. 1  
Pri mar y Efficac y A nal yses ................................................................................ 2 4  
8. 3. 2  
Sec o n dar y Effi cac y A nal yses ............................................................................ 2 5  
8. 4  E xa mi nati o n of S u b gr o u ps ............................................................................................. 2 6  
9.  
S A F E T Y E V A L U A TI O N .................................................................................................... 2 8  
9. 1  O ver vie w of Safet y A nal ysis Met h o ds ........................................................................... 2 8  
9. 2  E xte nt of E x p os ure ......................................................................................................... 2 8  
9. 3  A d verse E ve nts ............................................................................................................... 2 9  
9. 4  Deat hs, Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt A d verse E ve nts ...................... 3 0  
9. 5  Cli ni cal La b orat or y E val uati o n ...................................................................................... 3 0  
9. 6  Vit al Si g ns, O p ht hal mic E xa m Fi n di n gs, a n d Ot her Safet y O utc o mes .......................... 3 0  
9. 6. 1  
Vit al Si g ns ......................................................................................................... 3 0  
9. 6. 2  
I ntra oc ular Press ure ........................................................................................... 3 0 
9. 6. 3  
Vis ual Ac uit y .................................................................................................... 3 1  


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 6 of 4 4 
9. 6. 4  
Dilate d O p ht hal m osc o p y a n d C u p-t o- Disc Rati o .............................................. 3 1  
9. 6. 5  
Bi o micr osc o p y .................................................................................................. 3 1  
9. 6. 6  
Vis ual Fiel d E xa mi nati o n, Pac h y metr y, a n d G o ni osc o p y ................................. 3 2  
1 0.  VI S U A L F U N C TI O N A N D Q U A LI T Y O F LI F E Q U E S TI O N N AI R E S ....................... 3 3  
1 0. 1  Vis ual F u ncti o n Q uesti o n naire ( N EI, 2 5 q uesti o ns)....................................................... 3 3  
1 0. 2  Healt h S ur ve y Q uesti o n naire, 3 6 Q uesti o ns, V ersi o n 2 ( S h ort F or m) ........................... 3 4  
1 1.  P H A R M A C O KI N E TI C E V A L U A TI O N .......................................................................... 3 6  
1 2.  O T H E R A N A L Y S E S ........................................................................................................... 3 7  
1 3.  I N T E RI M A N A L Y S E S A N D D A T A M O NI T O RI N G ..................................................... 3 8  
1 4.  C H A N G E S T O T H E A N A L Y S E S P L A N N E D I N T H E P R O T O C O L ........................... 3 9  
1 5.  R E F E R E N C E S ..................................................................................................................... 4 0  
1 6.  A P P E N DI C E S ...................................................................................................................... 4 1  
1 7.  A T T A C H M E N T S ................................................................................................................ 4 3  
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 7 of 4 4 
LI S T O F A B B R E VI A TI O N S 
A E 
A d verse E v e nt 
A N C O V A  
A nal ysis of C o varia nce 
A R- 1 3 3 2 4 
Netars u dil Mes ylate ( Dr u g S u bsta nce) / Netars u dil O p ht hal mic S ol uti o n 
( Dr u g Pr o d uct)  
B C V A 
Best C orrecte d Vis ual A c uit y 
B O C F 
Baseli n e O bser vati o n C arrie d F or war d 
B P 
Bl o o d Press ure 
CI 
C o nfi de nce I nter val 
C R F 
Case R e p ort F or m 
C S R 
Cli nical St u d y Re p ort 
E T D R S 
Earl y Treat me nt of Dia b etic Reti n o pat h y St u d y 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nfere nce o n H ar m o nizati o n 
I O P 
I ntr a oc ular Press ure 
I W R 
I nteracti ve We b Res p o nse 
H R 
H eart Rate 
L O C F 
Last O bser vati o n Carrie d F or war d 
l o g M A R  
L o garit h m of t he Mi ni m u m A n gle of R es ol uti o n 
I P 
I n v esti gati o nal Pr o d uct 
L S Mea n  
Le ast S q uares M ea n 
I T T 
I nte nt-t o- Treat 
I W R S 
I nteracti v e We b- base d R es p o nse S yste m 
M C M C 
M o nte Carl o Mar k o v C h ai n 
M C S 
Me ntal C o m p o ne nt S u m mar y 
Me d D R A  
M e dical Dicti o nar y f or R e g ul at or y A cti vities 
m m H g 
Milli m eters of Merc ur y 
M M R M 
Mi x e d M o del Re peate d Meas ures 
O A G 
O pe n- A n gle Gla uc o ma 
N EI 
Nati o nal E ye I nstit ute 
O H T 
Oc ular H y p ert e nsi o n 
O U 
B ot h e yes 
P C S 
P h ysical C o m p o ne nt S u m m ar y 
P G 3 2 4 
Fi x e d- d ose C o m bi nati o n of Netars u dil a n d Lata n o pr ost 
P M 
E ve ni n g 
P P 
Per- Pr ot oc ol 
P T 
Preferre d Ter m 
Q D 
O nce- d ail y 
S A E 
Seri o us A d verse E v e nt 
S A P 
Statistical A nal ysis Pla n 
S A S 
Statistical A nal ysis S oft ware 
S D 
Sta n dar d De viati o n 
 
 
S E 
Sta n dar d Err or 
S F- 3 6 v. 2  
S h ort F or m ( Healt h S ur ve y Q uesti o n naire, 3 6 q u esti o ns, v ersi o n 2) 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 8 of 4 4 
S O C 
S yste m Or ga n Class  
T E A E 
Treat me nt E mer ge nt A d v erse E ve nt 
V F 
Vis u al Fiel ds 
V F Q- 2 5 
Vis u al F u ncti o n Q uesti o n naire ( N EI, 2 5 q uesti o ns) 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
Pa ge 9 of 4 4 
1.  
P U R P O S E O F T H E A N A L Y S E S 
T his statistical a nal ysis pla n ( S A P) is bei n g d e vel o pe d after re vie w of t he A erie P har mace uti cals 
Irela n d Lt d., pr ot o c ol n u m ber P G 3 2 4- C S 3 0 3 ( A me n d me nt 6, date d 2 7 Ma y 2 0 2 0 a n d 
A me n d me nt 7 date d 2 7 Ma y 2 0 2 0 ( C o u ntr y S pecific 
 H u n gar y) ) b ut bef ore a n y a n al yses of t he 
data.  T he S A P c o ntai ns detaile d i nf or mati o n t o ai d i n t he perf or ma n ce of t he statistical a nal ysis 
a n d re p orti n g of t he st u d y data f or use i n t he fi nal cli nical st u d y re p ort ( C S R).  T his S A P is bei n g 
writte n wit h d ue c o nsi d erati o n of t he rec o m me n dati o ns o utli ne d i n t he m ost rece nt I nter nati o nal 
C o nfere nce o n Har m o nizati o n (I C H) E 9 G ui deli n e e ntitle d: Statisti cal Pri nci pl es f or Cli ni cal 
Trials a n d t h e m ost rece nt I C H E 3 G ui d eli ne, e ntitle d: Str uct ure a n d C o nte nt of Cli ni cal St u d y 
Re p orts. 
T his S A P descri bes t he d ata t hat will be a nal yz e d a n d t he s u bject c h aracteristi cs, efficac y, a n d 
safet y assess me nts t h at will be e val uate d.  T his S A P pr o vi des details of t he s p ecific st atistical 
met h o ds t hat will be use d.  If a d diti o nal a nal yses are re q uire d t o s u p ple me nt t he pla n ne d a nal yses 
descri b e d i n t his S A P, t he y m a y be c o m plet e d a n d will be i d e ntifie d i n t he C S R. 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 0 of 4 4 
2.  
P R O T O C O L S U M M A R Y 
2. 1  
St u d y O bjecti ves 
T he pri mar y o bjecti ve of t his st u d y is t o e val u ate: 
 
 T he oc ular h y p ot e nsi v e efficac y of P G 3 2 4 O p ht h al mic S ol uti o n relati v e t o G A N F O R T ® 
o p ht hal mic s ol uti o n at 0 8: 0 0, 1 0: 0 0 a n d 1 6: 0 0 h o urs at Wee k 2, Wee k 6 a n d M o nt h 3  
  
T he sec o n d ar y o bjecti ves of t his st u d y are t o e val u ate:  
 
 T he oc ular a n d s yste mic safet y of P G 3 2 4 O p ht hal mi c S ol uti o n relati ve t o G A N F O R T ® 
o p ht hal mic s ol uti o n d uri n g a 6- m o nt h treat me nt p eri o d  
 C ha n ge i n s elf-a d mi nistere d N EI Vis ual F u ncti o ni n g Q u esti o n naire- 2 5 ( V F Q- 2 5) s c ore 
fr o m baseli ne t o st u d y e xit f or P G 3 2 4 c o m pare d t o G A N F O R T ®  
 C ha n ge i n s elf-a d mi nistere d S h ort F or m Healt h S ur ve y Q uesti o n naire 3 6 ( S F- 3 6 v 2) 
sc ore fr o m baseli ne t o st u d y e xit f or P G 3 2 4 c o m p are d t o G A N F O R T ®  
 
2. 2  
O ver all St u d y Desi g n a n d Pl a n 
T his is a 6- m o nt h, d o u ble- mas ke d, ra n d o miz e d, m ulti ce nter, acti ve-c o ntr olle d, parallel- gr o u p 
st u d y assessi n g t he safet y a n d oc ular h y p ote nsi v e efficac y of P G 3 2 4 O p ht hal mi c S ol uti o n 
c o m pare d t o G A N F O R T ® ( bi mat o pr ost 0. 0 3 %/ti m ol ol 0. 5 %) O p ht hal mi c S ol uti o n i n s u bjects 
wit h ele vate d i ntra o c ul ar press ure (I O P). All i n vesti gati o nal pr o d ucts will b e d ose d Q D ( P M). A 
t otal of a p pr o xi matel y 4 4 0 s u bjects will be e nr olle d i n t his st u d y at a p pr o xi matel y 7 0 cli nical 
sites i n a p pr o xi m atel y 1 1 E ur o p ea n U ni o n c o u ntries, c o m prisi n g a t otal of u p t o 2 2 0 s u bjects per 
treat me nt ar m f or eac h of 2 treat m e nt ar ms. S u bjects w h o are e nr olle d i n t his st u d y will be t h ose 
at least 1 8 years of a ge wit h dia g n ose d o pe n a n gle gla u c o m a ( O A G) or o c ul ar h y perte nsi o n 
( O H T), w h o are c urre ntl y usi n g t o pical I O P-l o w eri n g me dicati o n, eac h of w h o m meets all 
i ncl usi o n criteria a n d n o n e of t he e xcl usi o n criteria.  
T here will be a t otal of 9 visits desi g nate d as V 1 
 V 9. F or visits 3, 4, 5, a n d 6, t he s u bjects will 
be e val uat e d at m ulti ple ti me p oi nts ( 0 8: 0 0, 1 0: 0 0, a n d 1 6: 0 0 h o urs) wit hi n t he visit da y. T hese 
ti m e p oi nts will be desi g nate d as visit x. 0, x. 1, a n d x. 2 res pecti vel y.  At Visit 2 t he s u bjects will 
be e val uat e d at a si n gle ti me p oi nt ( 0 8: 0 0 h o urs), w hile at visits 7, 8, a n d 9, t h e s u bjects will be 
e val uate d at a si n gl e ti me p oi nt ( 1 0: 0 0 h o urs).   At Visit 1 ( Scree ni n g), t he s u bjects will be 
e val uate d at a si n gl e ti me p oi nt wit h n o desi g nate d h o ur.  T he t otal treat m e nt peri o d is 1 8 0 da ys, 
starti n g at Visit 3 ( Da y 1), a n d t here are f oll o w- u p visits at Wee k 2, Wee k 6, a n d M o nt hs 3, 4, 5, 
a n d 6. 
At Scree ni n g ( Visit 1), a n e xa mi nati o n will be c o n d ucte d, i ncl u di n g meas ure me nts of heart rat e 
a n d bl o o d press ure ( vital si g ns), uri ne pre g n a nc y test (f or w o me n of c hil d b eari n g p ote nti al), 
Vis ual F u ncti o n Q uesti o n naire ( N EI, 2 5 q uesti o ns) ( V F Q- 2 5), S h ort F or m ( Healt h S ur ve y 
Q uesti o n naire, 3 6 q uesti o ns, versi o n 2) ( S F- 3 6 v. 2), a n d a n o p ht hal mic e xa mi nati o n t o i n cl u de 
oc ular s y m pt o ms, best c orrect e d vis ual ac uit y ( B C V A), ce ntral c or n eal t hic k ness b y ultras o u n d 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 1 of 4 4 
pac h y m etr y ( m a y b e ta k e n wit hi n 1 w ee k of Visit 1), i ntra oc ular press ure (I O P; bef ore p u pil 
dilati o n), bi o micr osc o p y, a n d dil ate d o p ht h al m osc o p y).  Vis u al fiel ds a n d g o ni osc o p y ma y b e 
ta ke n u p t o t hree m o nt hs pri or t o ra n d o mizati o n ( Visit 3). S u bject s y m pt o ms will be q uerie d, a n d 
bl o o d sa m ples will be ta ke n f or cli nical c he mistr y a n d he mat ol o g y.  All i n di vi d uals w h o are 
q ualifie d f or e nr oll me nt ( per assess me nt of i n cl usi o n/e x cl usi o n criteria) will ha ve t heir c urre nt 
oc ular h y p ote nsi ve t hera p y re vie we d t o d eter mi ne t he a p pr o priat e was h o ut peri o d, pri or t o Visit 
2, as s pecifie d i n Secti o n 5. 7. 1 of t h e pr ot oc ol.    
At Visit 2 ( Q ualificati o n # 1, Da y - 7 t o - 2, 0 8: 0 0 h o urs), p ote ntial st u d y s u bjects will be 
q uesti o ne d wit h res pect t o c ha n ges i n t heir h ealt h (t o be rec or de d as me dical hist or y) a n d 
c o nc o mita nt me di cati o n use.  St u d y i n cl usi o n/e x cl usi o n criteria will be reassesse d t o c o nfir m 
eli gi bilit y. B C V A, vital si g ns, uri ne pre g na nc y test ( w o me n of c hil d beari n g p ote ntial ( w h o ha ve 
a was h o ut peri o d t hat e xte n ds be y o n d 4 wee ks), I O P, a n d bi o micr osc o p y assess me nts will a gai n 
be perf or me d.  T he p ot e nti al s u bject m ust ha ve a p ost- was h o ut I O P > 2 0 m m H g i n at least o ne 
e ye a n d < 3 6 m m H g i n b ot h e yes t o q u alif y f or f urt her partici p ati o n.  T his is t he first of f o ur 
q ualif yi n g I O Ps f or ra n d o mizati o n. 
Q ualifie d s u bjects will ret ur n f or Visit 3 ( Q u alificati o n # 2, Baseli n e, Da y 1) 2 t o 7 da ys after 
Visit 2. At Visit 3. 0 ( 0 8: 0 0 h o urs), testi n g will i n cl u de rec or di n g s y m pt o m at ol o g y, vital si g ns, 
uri ne pre g n a nc y test ( wit hi n 7 da ys pri or t o ra n d o mizati o n), B C V A, I O P, a n d bi o micr osc o p y 
assess me nts.  A n y s y m pt o ms re p orte d at t his visit s h o ul d be e ntere d i n t he a d verse e ve nt ( A E) 
C R F. T he p ote nti al s u bject m ust ha ve a p ost- was h o ut I O P > 2 0 m m H g i n at least o ne e ye a n d < 
3 6 m m H g i n b ot h e yes t o q ualif y f or f urt her partici p ati o n. T his is t he sec o n d of f o ur q ualif yi n g 
I O Ps ass ess me nts f or r a n d o miz ati o n.    
Q ualif yi n g s u bjects will ret ur n f or t w o a d diti o nal visits o n t his da y ( Visit 3. 1 at 1 0: 0 0 h o urs a n d 
Visit 3. 2 at 1 6: 0 0 h o urs) d uri n g w hi c h s y m pt o mat ol o g y, I O P, a n d bi o micr osc o p y assess me nts 
will b e perf or me d.  T he s u bject m ust ha ve a n I O P of > 1 7 m m H g i n at least o ne e ye a n d < 3 6 
m m H g i n b ot h e yes t o c o nti n ue t o be q ualifie d.  T hese are t h e t hir d a n d t h e f o urt h of f o ur 
q ualif yi n g I O Ps ass ess me nts f or ra n d o mizati o n.   
I n s u m m ar y, t he f oll o wi n g I O P criteria m ust be m et at t he q ualif yi n g visits f or t h e s u bject t o 
q ualif y f or t he st u d y: 
Visit, Da y, Ti me 
I O P Re q uire me nt 
( m m H g) 
Visit 1, Scree ni n g  
 
Visit 2, Da y - 7 t o - 2, 8: 0 0 h o urs  
> 2 0 m m H g i n at le ast o ne e ye a n d < 3 6 m m H g i n b ot h e yes 
Visit 3. 0, Da y 1, 8: 0 0 h o urs  
> 2 0 m m H g i n at least o ne e ye a n d < 3 6 m m H g i n b ot h e yes 
Visit 3. 1, Da y 1, 1 0: 0 0 h o urs  
> 1 7 m m H g i n at le ast o ne e ye a n d < 3 6 m m H g i n b ot h e yes 
Visit 3. 2, Da y 1, 1 6: 0 0 h o urs  
> 1 7 m m H g i n at le ast o ne e ye a n d < 3 6 m m H g i n b ot h e yes 
If a s u bject q u alifies i n o nl y o ne e ye, it m ust be t he sa me e ye f or visits 2, 3. 0, 3. 1, a n d 3. 2 a n d 
t his will be t h e st u d y e ye f or t he d urati o n of t h e st u d y. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 2 of 4 4 
F or eac h q ualifi cati o n visit, i n di vi d uals w h o d o n ot m eet t he I O P re q uir e me nt ma y ret ur n f or u p 
t o 2 a d diti o nal u nsc he d ule d q ualificati o n visits wit hi n 1 w ee k of faili n g t he s pecific q ualificati o n 
visit. 
 
ma y n ot ret ur n f or a d diti o nal q ualifi cati o n visits. I n di vi d uals ret ur ni n g at a n u nsc he d ule d visit 
wit hi n 1 wee k are re q uire d t o o nl y re- meas ure I O P i n b ot h e yes. U p o n ret ur n, s uc h i n di vi d uals 
w o ul d nee d t o q ualif y at 0 8: 0 0, 1 0: 0 0 a n d 1 6: 0 0 h o urs t o c o nti n ue t he st u d y.  
 
F or a s u bject w h o q ualifies i n b ot h e yes b ase d o n I O P a n d oc ular hist or y, t he st u d y e ye will be t he 
e ye wit h t he hi g her I O P at 0 8: 0 0 h o urs o n Visit 3. If b ot h e yes ha ve t h e sa me I O P at 0 8: 0 0 h o urs o n 
Visit 3, t he n t he ri g ht e ye will be t he st u d y e ye. I n eac h s u bject, b ot h e yes will be treate d.  
 
At t his p oi nt, eli gi ble s u bjects will be e nr olle d a n d assi g ne d t o a n i n vesti gati o nal pr o d uct t hr o u g h 
a n I W R S s yste m acc or di n g t o a c o m p uter- ge nerate d ra n d o mi zati o n list. T he first kit re m o ve d 
fr o m a n i n vesti gati o nal pr o d uct pac k er assi g ne d t hr o u g h t he I W R S s yst e m t o t he eli gi ble s u bject 
will b e dis p e nse d u n o pe n e d t o t he s u bject, al o n g wit h writt e n st ora ge i nstr ucti o ns. 
 
S u bjects will be i nstr ucte d t o self-a d mi nister t heir mas ke d me dicati o n at h o me bet w ee n 2 0: 0 0-
2 2: 0 0 h o urs ( 8 P M - 1 0 P M) be gi n ni n g wit h t he first d os e o n t he e ve ni n g of t his st u d y visit or n o 
later t h a n wit hi n 4 8 h o urs of ra n d o mizati o n. 
S u bjects will ret ur n f or p ost-treat me nt Visits 4. 0, 4. 1, a n d 4. 2 ( Wee k 2 [ Da y 1 5]; 0 8: 0 0, 1 0: 0 0, 
a n d 1 6: 0 0 h o urs), Visits 5. 0, 5. 1, a n d 5. 2 ( Wee k 6 [ D a y 4 3]; 0 8: 0 0, 1 0: 0 0, a n d 1 6: 0 0 h o urs), 
Visits 6. 0, 6. 1, a n d 6. 2 ( M o nt h 3 [ D a y 9 0]; 0 8: 0 0, 1 0: 0 0, a n d 1 6: 0 0 h o urs), Visits 7 ( M o nt h 4 
[ Da y 1 2 0]; 1 0: 0 0 h o urs), Visits 8 ( M o nt h 5 [ Da y 1 5 0]; 1 0: 0 0 h o urs), a n d Visits 9 ( M o nt h 6 [ Da y 
1 8 0]; 1 0: 0 0 h o urs). S y m pt o mat ol o g y a n d n o n- dil ate d e ye e x a mi nati o ns i ncl u di n g I O P a n d 
bi o micr osc o p y will be c o n d ucte d at all t hese visits.  Vital si g ns, uri ne pre g n a nc y test, a n d B C V A 
will als o be c o n d ucte d at Visits 4. 0, 5. 0, 6. 0, 7, 8 a n d 9. A n y s y m pt o ms re p orte d, or cli nical si g ns 
o bser ve d w hi c h h a ve w orse ne d, eit her fr o m baseli ne or fr o m pre vi o us visits at t h ese p ost- d ose 
visits, will be rec or de d as treat me nt e mer ge nt a d verse e ve nts ( T E A E). 
Ot her tests will be perf or me d i n a d diti o n t o t h ose me nti o ne d i n t he pre vi o us para gra p h: 
1.  At Visit 6. 0 ( M o nt h 3 [ Da y 9 0], 0 8: 0 0 h o urs), vis ual fiel ds a n d pac h y m etr y will be 
meas ure d. A dilat e d o p ht h al m osc o p y will be perf or me d at Visit 6. 2 ( M o nt h 3 [ Da y 9 0], 
1 6: 0 0 h o urs).   
2.  At Visit 9 ( M o nt h 6 [ Da y 1 8 0]), V F Q- 2 5 Q u esti o n naire, S F- 3 6 v. 2 Q uesti o n naire, vis ual 
fiel ds, a dilate d o p ht hal m osc o p y a n d pac h y m etr y will be assesse d.  Bl o o d will be dra w n 
f or cli nical c he mistr y a n d he mat ol o g y la bs as well.  
A st u d y sc h e d ule of e ve nts ta ble is prese nte d i n A p pe n di x 1. 
2. 3  
St u d y P o p ul ati o n 
T he st u d y p o p ulati o n i n cl u des s u bjects a ge d 1 8 years or ol d er wit h a dia g n osis of O A G or O H T.  
2 8 m m H g i n b ot h e yes. I n a d diti o n, s u bjects m ust ha ve a n u n me di cate d ( p ost- was h o ut) I O P  


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 3 of 4 4 
> 2 0 m m H g i n at least o ne e ye a n d < 3 6 m m H g i n b ot h e yes at 2 eli gi bilit y visits ( 0 8: 0 0 h o ur), 2-
7 da ys a part a n d > 1 7 m m H g i n at least o ne e ye a n d < 3 6 m m H g i n b ot h e yes at 1 0: 0 0 a n d 1 6: 0 0 
h o urs at t he sec o n d q u alificati o n visit i n b ot h e yes.   If a s u bject q u alifies i n o nl y o ne e ye, it m ust 
be t he s a me e ye f or all q ualificati o n visits, e x ce pt scree ni n g.  C orrecte d vis ual ac uit y i n eac h e ye 
m ust be + 1. 0 l o g M A R or better b y earl y treat m e nt of dia betic r eti n o pat h y st u d y ( E T D R S). T he 
s u bject m ust als o be willi n g t o gi ve si g ne d i nf or m c o nse nt a n d f oll o w st u d y i nstr ucti o ns.  T he 
s pecific i ncl usi o n a n d e x cl usi o n crit eria ca n be f o u n d i n Secti o ns 4. 2 a n d 4. 3 of t h e st u d y 
pr ot oc ol. 
  
2. 4  
Tre at me nt Re gi me ns 
T here will be 2 tr eat m e nts i n t his st u d y: 
 P G 3 2 4 ( Netars u dil 0. 0 2 % a n d lata n o pr ost 0. 0 0 5 %) O p ht hal mic S ol uti o n  
 G A N F O R T ® ( bi mat o pr ost 0. 0 3 % / ti m ol ol maleate 0. 5 % o p ht hal mic s ol uti o n)  
S u bjects will be i nstr ucte d t o self-a d mi nister t heir mas ke d me dicati o n o nce a da y ( Q D) i n t he 
e ve ni n g bet w ee n 2 0: 0 0  2 2: 0 0 h o urs ( 8 p m - 1 0 p m). All treat m e nts will be d ose d i n b ot h e yes 
( O U). T h e treat me nt p eri o d will be 1 8 0 da ys.   
2. 5  
Tre at me nt Gr o u p Assi g n me nts o r R a n d o mi z ati o n 
A ra n d o miz ati o n c o de f or all ocati n g t he treat m e nts was pre p are d b y a n i n de pe n de nt 
bi ostatisticia n, w h o was n ot i n v ol v e d i n t he d a y-t o- da y c o n d uct of t he st u d y a n d pr o vi de d i n 
c o nfi de nce t o t he u n mas ke d cli nical s u p pl y m a na ger at Aerie a n d t h e I nteracti ve We b Res p o nse 
(I W R) s yste m pers o n nel.  At Visit 3. 2 ( Da y 1), q u alifie d s u bjects will be ra n d o miz e d i n a 1: 1 
rati o t o recei v e P G 3 2 4 or G A N F O R T  (stratifie d b y i n vesti gati ve site a n d b y ma xi m u m baseli n e 
  Treat m e nt assi g n me nts were m as ke d t o t he I n v esti gat or, t he 
S p o ns or tea m m e m bers i n v ol ve d i n t he da y-t o- da y o versi g ht of t he cli nical st u d y a n d e m pl o yees 
of t he C R O a d mi nistrati n g t he st u d y f or t h e S p o ns or, a n d t he st u d y s u bjects.  At t he e n d of t he 
st u d y, t he ra n d o mize d treat m e nt assi g n me nts will be prese nt e d i n a data listi n g. 
2. 6  
S a m ple Size D eter mi n ati o n 
Ass u mi n g n o differe nce bet w ee n P G 3 2 4 O p ht hal mic S ol uti o n Q. D. a n d G A N F O R T
®  Q. D., a 
t w o -taile d al p ha of 0. 0 5 ( 2-si de d 9 5 % CI) at eac h of 9-ti m e p oi nts, a c o m m o n sta n dar d de viati o n 
( S D) of 3. 5 m m H g, a n d a c orrel ati o n bet w ee n ti me p oi nts of 0. 6 0 or less, 2 0 0 i nte nt-t o-treat 
s u bjects per ar m are n ecessar y t o ha ve 8 5 % p o wer t o s h o w cli nical n o n-i nferi orit y (as defi n e d 
a b o ve) of P G 3 2 4 O p ht h al mic S ol uti o n Q. D. t o G A N F O R T ®  Q. D. i n t he m ea n c ha n ge fr o m 
baseli n e I O P.  T o acc o u nt f or t he p ote ntial of a d diti o nal varia bilit y i n t h e pri m ar y efficac y 
o utc o me d ue t o m ulti ple i m p utati o ns of missi n g data, u p t o 2 2 0 s u bjects per ar m will be 
ra n d o mize d.  


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 4 of 4 4 
3.  
G E N E R A L A N A L Y SI S A N D R E P O R TI N G C O N V E N TI O N S 
T his secti o n disc usses ge neral p olici es t o be e m pl o ye d i n t h e a nal ysis a n d re p orti n g of t he data 
fr o m t he st u d y.  De part ures fr o m t hese ge neral p oli cies ma y b e gi ve n i n t h e s pecific d etaile d 
secti o ns of t his S A P.  W he n t his sit uati o n occ urs, t he r ules set f ort h i n t h e s pecific secti o n ta ke 
prece d e nce o ver t h e ge neral p olicies. 
All c o nti n u o us st u d y ass ess m e nts will be s u m mariz e d b y treat m e nt a n d ti me p oi nt (as a p plica bl e) 
usi n g descri pti v e statistics ( n, mea n, me dia n, sta n dar d de viati o n ( S D), mi ni m u m, a n d ma xi m u m).  
All cate g oric al st u d y assess me nts will be s u m m arize d b y treat me nt a n d ti me p oi nt (as a p plica bl e) 
usi n g fre q ue nc y c o u nts a n d perce nt a ges.   
All st u d y data will be liste d b y treat me nt, s u bject, visit, a n d ti m e p oi nt (as a p plica bl e).  
I n Pr ot oc ol v ersi o ns pri or t o Pr ot oc ol A me n d me nt 4, t here were 3 ti me p oi nts ( 8: 0 0, 1 0: 0 0 a n d 
1 6: 0 0) f or Visits 7, 8, a n d 9 ( M o nt h 4, M o nt h 5 a n d M o nt h 6). I O P a n d bi o micr osc o p y 
assess me nts wer e meas ure d at all ti me p oi nts f or s u bject visits pri or t o Pr ot oc ol A me n d me nt 4; 
h o we ver, t h ese assess m e nts will o nl y be p erf or me d at o ne ti me p oi nt ( 1 0: 0 0 h o urs) f or s u bject 
visits after Pr ot oc ol A me n d me nt 4. F or s u m maries a n d a nal yses of Visits 7, 8, a n d 9 ( M o nt h 4, 
M o nt h 5 a n d M o nt h 6), o nl y t he ass ess m e nt at 1 0: 0 0 h o urs will be i ncl u de d if s u bjects ha ve 
m ulti ple ti me p oi nt assess me nts at a visit. T he assess me nts at 0 8: 0 0 a n d 1 6: 0 0 h o urs will be liste d 
i n data listi n gs o nl y.      
H y p ot h esis testi n g, u nless ot her wise i n dicate d, will be perf or me d at a 2-si de d 0. 0 5 si g nifica nce 
le vel. W here a p plica ble, t w o-si de d 9 5 % c o nfi d e nce i nter v als will be re p orte d.  All p- val ues will 
be dis pla ye d t o f o ur deci mal places, wit h p- val u es less t ha n 0. 0 0 0 1 prese nt e d as ' < 0. 0 0 0 1' a n d p-
 Differ e nces b et wee n P G 3 2 4 a n d G A N F O R T 
will b e calc ulate d as P G 3 2 4 
 G A N F O R T. 
F or di ur nall y a dj uste d I O P, baseli ne will refer t o t he ti me-rele v a nt meas ure at Visits 3. 0 t hr o u g h 
3. 2 (e. g. I O P at 0 8: 0 0 h o urs at Visit 3. 0 will be t he baseli ne f or 0 8: 0 0 h o urs at Visits 4. 0, 5. 0, a n d 
6. 0, etc.; I O P at 1 0: 0 0 h o urs at Visit 3. 1 will be t h e baseli ne f or 1 0: 0 0 h o urs at Visits 4. 1, 5. 1, 
a n d 6. 1, etc.).  F or m ea n di ur nal I O P, baseli ne will refer t o t he m ea n di ur nal I O P at Visit 3.  F or 
all ot her varia bles, b aseli ne is defi ne d as t h e l ast m eas ure me nt pri or t o t he first d ose of st u d y 
me dicati o n. C ha n ge fr o m baseli ne will be cal c ulat e d as f oll o w- u p visit 
 baseli ne visit. 
T he u nit of a nal ysis f or efficac y will b e t he st u d y e ye.  
All st u d y data will be liste d b y s u bj ect, treat m e nt, a n d ti me p oi nt (as a p plic a ble).  I n t h e listi n gs, 
i n di vi d ual s u bjects will be i d e ntifie d b y a c o m bi n ati o n of site n u m ber a n d s u bject n u m b er, e. g., 
X X X- Y Y Y, w here X X X is t he site n u m ber a n d Y Y Y is t h e s u bject n u m ber.  
All data a nal ysis will be perf or me d b y 
 after t h e st u d y is 
c o m plete d a n d t h e d ata base has bee n l o c ke d a n d release d f or u n- mas ki n g.  Statistical 
pr o gra m mi n g a n d a n al ys es will be perf or me d usi n g S A S
 Versi o n 9. 4 or hi g her.  O ut p ut will be 
pr o vi de d i n rtf f or mat f or ta bles a n d p df f or mat f or ta bles, listi n gs, a n d fi g ures.   


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 5 of 4 4 
4.  
A N A L Y SI S P O P U L A TI O N S 
4. 1  
R a n d o mize d P o p ul ati o n 
T he ra n d o mi ze d p o p ulati o n will i ncl u de all s u bjects w h o were ra n d o mize d t o treat m e nt.  
Baseli ne v aria bles a n d de m o gra p hi c c haracteristics will be s u m marize d f or t his p o p ulati o n. 
 
4. 2  
I nte nt-t o- Tre at P o p ul ati o n (I T T) 
T he I T T p o p ulati o n will i ncl u de all ra n d o mi ze d s u bjects w h o ha ve recei v e d at least o ne d ose of 
st u d y me di cati o n. T his p o p ulati o n will be t he pri mar y p o p ulati o n f or efficac y a n al ys es a n d will 
be use d t o s u m marize all effic ac y varia bles a n d will s u m mariz e s u bjects as ra n d o mize d.  
4. 3  
Per- pr ot oc ol P o p ul ati o n ( P P) 
T he P P p o p ulati o n is a s u bset of t he I T T p o p ulati o n, w hic h will i ncl u de t h ose s u bjects (a n d t h eir 
visits) w h o d o n ot ha ve maj or pr ot oc ol de viati o ns li kel y t o seri o usl y affect t he pri mar y o utc o me 
of t he st u d y as j u d ge d b y a mas ke d e v al uati o n pri or t o t he u n mas ki n g of t h e st u d y treat m e nt. 
T his p o p ulati o n will be t he sec o n dar y p o p ulati o n f or efficac y a nal yses a n d will be use d t o 
s u m marize a s u bset of efficac y varia bles. If t he P P a n d I T T p o p ulati o ns are e xactl y t he s a me, 
t he n a d diti o nal effic ac y a n al yses o n t h e P P p o p ulati o n will n ot be perf or me d. T he P P p o p ulati o n 
will s u m marize s u bjects as treate d.  
4. 4  
S afet y P o p ul ati o n 
T he safet y p o p ulati o n will i ncl u de all ra n d o mize d s u bjects w h o ha ve recei v e d at least o ne d os e 
of st u d y me dicati o n.  T his p o p ul ati o n will be use d t o s u m marize safet y v aria bl es a n d will 
s u m marize s u bjects as treate d. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 6 of 4 4 
5.  
S T U D Y S U B J E C T S 
5. 1  
Dis p ositi o n of S u bjects 
S u bject ra n d o mizati o n, a nal ysis p o p ulati o ns, st u d y c o m pleti o n, a n d wit h dra wal fr o m t he st u d y 
will b e s u m m ariz e d a n d liste d f or all ra n d o mize d s u bj ects.  T he s u m mar y ta ble will i ncl u de t he 
n u m bers of s u bjects ra n d o mize d a n d i n cl u de d i n t he a nal ysis p o p ulati o ns b y ra n d o mize d 
treat me nt gr o u p f or t he I T T p o p ulati o n a n d b y act ual treat m e nt gr o u p f or t he P P a n d Safet y 
p o p ulati o ns.  It will als o i n cl u de t h e n u m bers of s u bjects w h o c o m plete d a n d disc o nti n ue d fr o m 
t he st u d y.  T he reas o ns f or s u bject disc o nti n uati o n a n d test a ge nt disc o nti n uati o n will be 
s u m marize d f or t he a p pli ca ble s u bjects.  Re as o ns f or s u bject disc o nti n uati o n will i ncl u de a d verse 
e ve nt ( A E), wit h dra w al of c o nse nt, n o n-c o m plia nce l ost t o f oll o w- u p, lac k of effic ac y, 
disall o we d c o n c urre nt m e dicati o n, i n vesti gat or decisi o n, pr ot oc ol vi olati o n, deat h, a n d a n ot her  
cate g or y f or reas o ns ot her t ha n t h ose pre vi o usl y liste d.  
B y-s u bject listi n gs will i n cl u de ra n d o mi zati o n i nf or mati o n, act u al treat m e nt assi g ne d, first a n d 
last d ose dates, e x p os ure, st u d y e ye, a n d a nal ysis p o p ulati o n i n cl usi o n.  F or s u bjects w h o 
pre mat urel y dis c o nti n ue f oll o wi n g ra n d o mizati o n, a n a d diti o nal b y-s u bject listi n g will be 
pr o vi de d t hat s h o ws treat me nt assi g n me nt, ge n d er, a ge, date of last visit, date of last d ose, 
treat me nt d urati o n at ti m e of disc o nti n uati o n, st u d y da y of disc o nti n uati o n, a n d reas o n f or 
disc o nti n uati o n.  St u d y d a y of dis c o nti n uati o n will be calc ulate d as ( dat e of dis c o nti n uati o n  
date of Visit 3 date + 1).  N ote t hat d ate of first d ose is n ot c ollecte d b ut will be ass u me d t o be t h e 
Visit 3 date.  Treat m e nt d urati o n will be calc ulate d as t h e ( D at e of Last D os e 
 Visit 3 Date + 1). 
5. 2  
Pr ot oc ol D e vi ati o ns 
Pr ot oc ol de viati o ns will be e val uat e d f or all s u bjects. Maj or pr ot o c ol vi olati o ns will be j u d ge d b y 
a mas ke d e v al uati o n a n d s u m m ariz e d i n writi n g pri or t o t he u n mas ki n g of t he st u d y treat m e nt, 
f or t h e p ur p ose of selecti n g t he P P p o p ulati o n. All s u bjects ha vi n g a pr ot o c ol de viati o n will be 
i de ntifie d i n a s u bject dat a listi n g. T he n u m b er a n d perce nt a ge of s u bjects wit h a n y d e viati o ns, 
a n y m aj or or mi n or de viati o ns, relate d t o C O VI D- 1 9 will be s u m marize d b y treat me nt gr o u p 
al o n g wit h t he dis p ositi o n data. A se parate d ata listi n g f or C O VI D- 1 9 relat e d pr ot o c ol de viati o ns 
will b e pr o vi de d. 
Fail ure t o meet all Pr ot oc ol I ncl usi o n Criteria or m eeti n g a n y E x cl usi o n Criteri o n will als o be 
c o nsi dere d f or cate g orizati o n as a m aj or Pr ot oc ol De viati o n.  I ncl usi o n a n d E xcl usi o n Criteria 
will b e prese nte d i n a b y-s u bject listi n g. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 7 of 4 4 
6.  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S 
6. 1  
De m o gr a p hics a n d B aseli n e C h ar acteristics 
De m o gra p hic a n d baseli n e c haracteristics will b e s u m m ariz e d b y treat me nt gr o u p a n d liste d f or 
t he ra n d o mi ze d p o p ulati o n.  De m o gra p hic p ara m eters will i ncl u de ge n der, iris c ol or, a ge i n years 
at si g ni n g of i nf or m e d c o nse nt f or m (I C F), race, et h nicit y, pri or h y p ote nsi v e t hera p y, a n d ti me 
o n c urre nt h y p ote nsi ve t h era p y.  Baseli n e c haracteristi cs will i n cl u de st u d y e ye dia g n osis of 
O H T or O A G, le n gt h of ti m e si nce st u d y e ye dia g n osis of O H T or O A G, st u d y e ye I O P at 
scree ni n g, a n d st u d y e ye mea n di ur nal I O P at b aseli ne. A d diti o nall y, m ea ns f or b ot h t he st u d y 
e ye a n d t he fell o w e ye will be s u m m arize d se paratel y f or t h e baseli ne o c ul ar meas ure me nts of 
de viati o n i n vis ual fiel ds, ce ntral c or neal t hic k ness, a n d c u p-t o- disc rati o.   
A ge will be re p orte d i n years a n d calc ulate d i n S A S usi n g t he f or m ula:  
A ge = Fl o or ((I C F D T 
 D O B) / 3 6 5. 2 5) 
I C F D T is t h e date t h e s u bject si g ne d t h e i nf or me d c o nse nt, 
, 
a n d Fl o or ta k es t h e i nte ger part of t h e res ult. 
Tests of differe nces bet w ee n t h e treat me nt gr o u ps will be perf or me d f or b ot h de m o gra p hic a n d 
baseli n e c haracteristics.  Cate g orical res p o nses w
e x act tests.  
C o nti n u o us meas ures will be teste d usi n g a n a nal ysis of varia nce m o del wit h treat me nt as t he 
o nl y e x pla nat or y varia ble. 
6. 2  
Pri o r a n d C o nc o mit a nt Me dic ati o ns 
All me dicati o ns w hic h t he s u bject has ta k e n wit hi n 3 0 da ys pri or t o ra n d o mizati o n a n d d uri n g 
t he st u d y will be rec or de d o n t he C R F. T he na me of t he dr u g, d ose, r o ut e of a d mi nistrati o n, 
d urati o n of treat m e nt, a n d i n dicati o n will be rec or de d f or eac h me dicati o n. F or c o m bi nati o n 
pr o d ucts (e. g., C o ntac ®), t he bra n d n a me is re q uir e d. F or n o n-c o m bi nati o n pr o d ucts, t he ge neric 
na me is desire d.  T h e use of r o uti ne o p ht hal mi c dia g n ostic p har mace utical a ge nts (e. g., 
fl u orescei n a n d l ocal a n est hetic) will be all o w e d, a n d i n di vi d ual d oc u me ntati o n n ot re q uire d. 
A n y c ha n ge i n d osi n g para meters s h o ul d als o be rec or de d o n t h e C R F. 
All pri or a n d c o nc o mita nt me dicati o ns will be c o de d t o preferre d dr u g na mes a n d t hera pe utic 
dr u g class usi n g t h e W H O  Dr u g Dicti o n ary ( V ersi o n: Marc h 2 0 1 7).  Use of c o nc o mita nt 
me dicati o ns will be s u m marize d f or eac h t h era pe utic dr u g class a n d eac h preferre d dr u g n a me b y 
treat me nt gr o u p.  S u bjects will be c o u nte d o nl y o n ce u n der eac h t hera pe uti c dr u g class a n d 
preferre d t er m f or w hi c h t he y h a ve use d at least o ne c o nc o mita nt me dicati o n. All pri or a n d 
c o nc o mita nt me di cati o n data will als o be liste d. 
T he class of pri or h y p ote nsi ve t hera p y, s u m marize d o n t he baseli ne c haracteristic ta ble a n d liste d 
o n t he was h o ut me di cati o n listi n g, will als o be deri ve d fr o m t he c o d e d me dicati o n data. Classes 
i ncl u de t he f oll o wi n g: Pr osta gla n di ns, -a dre n oce pt or a nta g o nists, a dre ner gic a g o nists (i ncl u di n g 
-a g o nists s uc h as bri m o ni di ne a n d a pracl o ni di ne), M uscari nic a g o nists (e. g., pil ocar pi n e), a n d 
Car b o nic a n h y drase i n hi bit ors (t o pical or oral). F or t he s u m mar y ta ble, c ate g ories will be: 
c o m bi nati o n t hera p y, pr osta gla n di ns ( m o n ot h era p y), ot her ( m o n ot hera p y.  A d diti o nall y, t he 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 8 of 4 4 
f oll o wi n g t w o class es will be s u m marize d: pri or pr osta gla n di n t hera p y a n d n o pri or 
pr osta gl a n di n t hera p y.   
6. 3  
Me dic al a n d Oc ul ar Hist or y 
A me dical a n d o c ular hist or y will b e c ollecte d at s cree ni n g, i ncl u di n g dia g n osis, start date, a n d 
st o p date (as a p plica ble) or o n g oi n g. F or oc ul ar hist or y, t he a p plica ble e ye(s) will be n ote d. A n y 
 t h at occ ur after t h e s u bject si g ns t he i nf or me d 
c o nse nt u ntil 3 0 da ys after t h e last d ose of i n vesti gati o nal pr o d uct s h o ul d be re p ort e d as a d verse 
e ve nts.   
Oc ul ar s ur ger y a n d l aser pr oce d ures will als o be c ollecte d at scree ni n g i ncl u di n g t he pr o ce d ure 
descri pti o n, pr oce d ure d ate, a n d affect e d e ye(s). 
All me dical hist or y a n d o c ular s ur ger y/laser pr oce d ures d ata will be prese nt e d i n a b y-s u bject 
listi n g.  Me dical a n d o c ular hist or y will be c o de d t o preferre d t er ms a n d s yst e m or ga n class usi n g 
t he Me d D R A Dicti o nar y ( Versi o n: 2 0. 0).  Me di cal a n d oc ular hist ories will be s u m m arize d f or 
eac h s yste m or ga n class a n d eac h preferre d ter m b y treat me nt gr o u p.  S u bjects will be c o u nte d 
o nl y o nce u n der eac h s yste m or ga n class a n d preferre d ter m f or w hic h t he y ha ve at least o ne 
me dical/ o c ular hist or y.  
St u d y e ye dia g n osis will be d eri ve d fr o m t he c o d e d oc ular hist or y data.  T he preferre d ter ms of 
pa ge of t he C R F.  A nal ys es base d o n st u d y dia g n osis will use t his defi niti o n. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 1 9 of 4 4 
7.  
M E A S U R E M E N T S O F T R E A T M E N T C O M P LI A N C E 
All s u bjects will be i nstr ucte d t o f oll o w o nce a da y d osi n g re gi me n i n t he e ve ni n g b et wee n 2 0: 0 0 
 2 2: 0 0 h o urs ( 8 p m - 1 0 p m). All treat m e nts will be d ose d i n b ot h e yes ( O U). N o f or mal m eas ure 
of treat m e nt c o m plia nce is pl a n ne d. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 0 of 4 4 
8.  
E F FI C A C Y E V A L U A TI O N 
8. 1  
O ver vie w of Effic ac y A n al ysis Iss ues 
8. 1. 1  H a n dli n g of D r o p o uts or Missi n g D at a 
A n y missi n g, u n us e d, or s p uri o us data will be n ote d i n t he fi n al st atistical re p ort.  A nal yses will 
be perf or me d pri m aril y o n t he I T T p o p ulati o n wit h m ulti ple i m p utati o n tec h ni q ues (e. g., M o nte 
Carl o Mar k o v C h ai n) use d t o i m p ut e missi n g d ata a n d sec o n daril y usi n g: o bser ve d dat a o nl y, l ast 
o bser vati o n carri e d f or w ar d ( L O C F) w h ere L O C F will be perf or me d usi n g ti me-rele va nt 
meas ures (i. e. fr o m t he s a me ti m e p oi nt of t he m ost rece nt visit wit h a n o n- missi n g val ue); a n d 
baseli n e o bser vati o n carrie d f or war d ( B O C F) usi n g ti me-rele va nt meas ures t o deter mi n e t he 
r o b ust ness of res ults. 
 
8. 1. 2  M ultice nter St u dies 
T his st u d y will ha ve a p pr o xi matel y 7 0 differe nt sit es e nr olli n g a n d treati n g s u bjects.  D ue t o t he 
l o w sa m ple size fr o m m ost sit es, c o u ntr y will be i ncl u de d i n t he assess me nt. T he h o m o ge n eit y of 
treat me nt effect acr oss i n v esti gati v e sit es will be e x a mi n e d b y a m o del c o nt ai ni n g t he a d diti o nal 
fact ors of i n v esti gati v e c o u ntries a n d its i nteracti o n wit h treat me nt f or t he pri mar y I O P efficac y 
e n d p oi nt.  
8. 1. 3  Assess me nt Ti me Wi n d o ws 
I n ge neral, it is i nte n de d t hat all safet y a n d efficac y dat a ( wit h s o me e xce pti o ns) will be 
s u m marize d at eac h ti m e p oi nt c ollecte d re gar dless of assess m e nt ti me wi n d o ws.  Beca use 
s u bjects ma y h a ve a n earl y ter mi nati o n visit at a n y ti me or ma y ha ve u nsc he d ule d visits, t he 
f oll o wi n g c o n v e nti o ns will be i m pl e me nte d. 
F or all safet y data, t he visit date or start date (e. g., a d verse e ve nts) will be use d t o calc ulate st u d y 
da y, d efi ne d as t he n u m b er of da ys fr o m t he da y of first d ose. T he d a y of first d ose ( Visit 3) is 
c o nsi dere d st u d y da y 1, s o st u d y da y will be c o m p ute d as ( date of d ata  Visit 3 + 1).  H o we ver, 
if t he visit date or start date ha p pe ns bef ore t h e d ate of first d ose, st u d y da y will be c o m p ute d as 
( date of d ata  Visit 3). St u d y da y will be prese nte d i n listi n gs f or me dical hist or y, c o n c o mita nt 
me dicati o ns, a n d a d verse e ve nts.   
I n all b y- visit safet y assess m e nts, e n d of st u d y visits a n d earl y ter mi n ati o n visits will be 
c o m bi ne d i n or der t o prese nt all data a vail a ble f or eac h s u bject; earl y ter mi nati o n visits will n ot 
be wi n d o we d i nt o t he nearest fitti n g st u d y visit.  Eac h s u bject will ha v e o ne e n d of st u d y visit.  
F or efficac y o utc o m es, earl y t er mi nati o n data will n ot be c o m bi ne d wit h e n d of st u d y visit 
i nf or mati o n as t h e ti mi n g of t he o utc o m e meas ure is i nte gral t o t he a nal ysis. I nste a d, t h e efficac y 
o utc o me will be wi n d o w e d i nt o t he nearest st u d y visit, w here eac h f oll o w- u p visit t hr o u g h 
M o nt h 5 has a ± 3 - da y wi n d o w.  T he M o nt h 6 visit has a ± 7- da y wi n d o w. 
8. 2  
Effic ac y V ari a bl es a n d Pri m ar y H y p ot heses 
1.  
T he pri mar y efficac y o utc o me will be t he c o m paris o n of P G 3 2 4 t o G A N F O R T f or: 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 1 of 4 4 
 Mea n I O P wit hi n a treat m e nt gr o u p at 0 8: 0 0, 1 0: 0 0, a n d 1 6: 0 0 h o urs at t he Wee k 2, 
Wee k 6, a n d M o nt h 3 st u d y visits 
 
2.  
Sec o n dar y effic ac y e n d p oi nts will i ncl u de t h e c o m paris o n of P G 3 2 4 t o G A N F O R T f or:  
 Mea n di ur nal I O P wit hi n a treat m e nt gr o u p at eac h p ost-treat m e nt visit 
 Mea n c ha n ge fr o m di ur n all y a dj uste d b aseli n e I O P at eac h p ost-treat me nt ti m e p oi nt 
 Mea n c ha n ge fr o m b aseli ne i n di ur nal I O P at eac h p ost-treat m e nt visit 
 Mea n p erce nt c h a n ge fr o m di ur nall y a dj uste d b aseli ne I O P at eac h p ost-treat me nt 
ti m e p oi nt 
 Mea n p erce nt c h a n ge fr o m baseli ne i n di ur n al I O P at eac h p ost-treat me nt visit  
 Perce nta ges of s u bjects ac hie vi n g pre-s p ecifie d m ea n, m ea n c ha n ge, a n d p erce nt 
mea n c ha n ge di ur nal I O P le vels at eac h p ost-treat me nt ti m e p oi nt: 
o  Di ur nal m ea n I O P of 
2 2, 
 
o  I O P re d ucti o n fr o m b aseli ne of 
4, 
 (I O P re d ucti o n at a 
visit fr o m baseli ne was c alc ulate d as I O P [ baseli ne] - I O P [ visit], usi n g mea n 
[i nte gral or n o n-i nte gral] I O P v al ues) 
o  I O P p erce nt re d ucti o n fr o m baseli ne of 
(I O P perce nt re d u cti o n at a visit fr o m baseli ne was calc ulate d as [I O P 
re d u cti o n fr o m bas eli n e / I O P ( baseli ne)] * 1 0 0 %) 
3.  
T he pri mar y h y p ot hes es are: 
 H 0: T he differe nce bet w ee n st u d y e yes treate d wit h P G 3 2 4 a n d st u d y e yes treate d wit h 
G A N F O R T ( P G 3 2 4 - G A N F O R T), i n mea n I O P at t he f oll o wi n g ti me p oi nts: 0 8: 0 0, 
1 0: 0 0, a n d 1 6: 0 0 h o urs at t he W ee k 2, Wee k 6, a n d M o nt h 3 Visits, is > 1. 5 m m H g f or at 
least o ne ti me p oi nt o ver all visits or is > 1. 0 m m H g f or a m aj orit y of ti me p oi nts o ver all 
visits.  
 
 H 1: T he differe nce bet w ee n st u d y e yes treate d wit h P G 3 2 4 a n d st u d y e yes treate d wit h 
G A N F O R T ( P G 3 2 4 - G A N F O R T), i n mea n I O P at t he f oll o wi n g ti me p oi nts: 0 8: 0 0, 
1 0: 0 0, a n d 1 6: 0 0 h o urs at t he W ee k 2, Wee k 6, a n d M o nt h 3 Visits, is 
 1. 5 m m H g f or all 
visits a n d is  1. 0 m m H g f or a maj orit y of ti me p oi nts o ver all visits.  
 
Cli nical n o n-i nferi orit y will be c o ncl u de d if t h e u p per li mit of t he 9 5 % CIs ar o u n d t he differe nce 
( P G 3 2 4 - 
g at t he maj orit y of ti me 
p oi nts t hr o u g h M o nt h 3.  
8. 3  
A n al ysis Met h o ds 
All c o nti n u o us st u d y ass ess m e nts will be s u m mariz e d b y treat m e nt a n d ti me p oi nt (as a p plica bl e) 
usi n g descri pti v e statistics ( n, mea n, me dia n, S D, mi ni m u m, a n d ma xi m u m).  All cate g orical 
st u d y assess me nts will b e s u m mariz e d b y treat me nt a n d ti me p oi nt (as a p plica ble) usi n g 
fre q ue nc y c o u nts a n d p erce nta ges.  All st atistical t ests will be perf or me d at a 2-si de d 5 % 
si g nifica nce le v el. F or t h e I O P meas ure me nts, 2-si de d tests a n d 2-si de d 9 5 % c o nfi de n ce i nter v als 
will b e re p orte d. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 2 of 4 4 
Mea n di ur nal I O P v al ues will be c o nstr ucte d b y a vera gi n g t he t hree I O P m eas ure m e nts o n eac h 
of Wee k 2, Wee k 6, a n d M o nt h 3.  Mea n di ur nal baseli ne I O P will be c o nstr ucte d as t h e a vera ge 
of t he t hree Da y 1 I O P m eas ure m e nts.  M ea n c ha n ge fr o m mea n b aseli ne di ur nal I O P will be 
creat e d b y ta ki n g t he a v era ge of t h e t hree ti me p oi nts o n eac h of Wee k 2, W ee k 6, a n d M o nt h 
3a n d s u btracti n g t he mea n baseli ne di ur nal I O P m eas ure m e nt. 
F or di ur nall y a dj uste d I O P meas ures, baseli ne will refer t o t he ti me-rel e va nt m eas ure at Visits 
3. 0 t hr o u g h 3. 2 (e. g., I O P at 0 8: 0 0 h o urs at Visit 3. 0 will be t h e baseli ne f or 0 8: 0 0 h o urs at Visits 
4. 0, 5. 0, a n d 6. 0; I O P at 1 0: 0 0 h o urs at Visit 3. 1 will be t h e b aseli ne f or 1 0: 0 0 h o urs at Visits 4. 1, 
5. 1, 6. 1, 7, 8, a n d 9). I O P at 1 6: 0 0 h o urs at Visit 3. 2 will be t h e baseli ne f or 1 6: 0 0 h o urs at Visits 
4. 2, 5. 2, a n d 6. 2).  F or mea n di ur nal I O P, b aseli ne will refer t o t he mea n di ur nal I O P at Visit 3.  
F or all ot her v aria bles, b aseli n e is defi ne d as t he last meas ure me nt pri or t o t he first d ose of st u d y 
me dicati o n. C ha n ge fr o m baseli ne will be cal c ulat e d as f oll o w- u p visit 
 baseli ne visit. 
Perce nt c ha n ge fr o m di ur nall y a dj uste d b aseli ne I O P will be deter mi ne d b y di vi di n g t h e c ha n ge 
fr o m di ur nall y a dj ust e d baseli ne b y t he c orres p o n di n g baseli n e I O P val ue, s u c h t h at a ne gati ve 
c ha n ge fr o m baseli n e will pr o d uce a ne gati ve perce nt c ha n ge fr o m baseli ne. 
All pri mar y a n d sec o n d ar y efficac y varia bles, al o n g wit h t he pla n n e d a nal ysis m et h o ds f or t h ose 
varia bles, are gi v e n i n T a ble 8- 1.  T hese a nal yses will be perf or me d f or t he I T T p o p ulati o n f or 
all effic ac y varia bles a n d P P p o p ulati o n f or s electe d effi cac y v aria bles. T h e I T T p o p ulati o n will 
be use d f or all effic ac y s u b gr o u p a nal yses.  N ot e t h at eac h s u bje ct will ha v e o ne e ye desi g nate d 
as t he st u d y e ye.  O nl y st u d y e yes will be e val u ate d f or all t he efficac y meas ures; h o we ver, b ot h 
e yes will be treate d.  F ell o w e yes will be e val uate d se parat el y f or t he pri m ar y a nal ysis of t he 
pri mar y efficac y meas ure. 
 
 
 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 3 of 4 4 
T a bl e 8- 1   S u m m a r y of Effic ac y V ari a bles a n d A n al ysis Met h o ds 
 
 
T w o 
S a m ple 
T-test a 
A N C O V A b  
M M R M
c 
E x act 
Test d  
A n al ysis 
P o p ul ati o n 
Missi n g D at a 
I m p ut ati o n 
P ri m ar y A n al ysis 
  
 
  
 
 
 
Mea n I O P at eac h ti me p oi nt at 
Wee k 2, Wee k 6, a n d M o nt h 3 
  
X  
  
  
I T T  
M C M C  
 
Sec o n d a r y A n al ys es 
  
 
  
 
 
 
Mea n I O P at eac h ti me p oi nt at 
Wee k 2, Wee k 6, a n d M o nt h 3 
  
X  
  
  
I T T  
L O C F, B O C F, 
O bser ve d d at a 
X  
 
  
  
I T T, P P  
M C M C, L O C F, 
B O C F, 
O bser ve d d at a  
  
X  
  
  
P P  
M C M C, L O C F, 
B O C F, 
O bser ve d d at a 
  
  
X  
  
I T T  
O bser ve d d at a 
Mea n di ur nal I O P at Wee k 2, 
Wee k 6, a n d M o nt h 3  
X  
X   
  
  
I T T, P P  
M C M C, 
L O C F, B O C F, 
O bser ve d d at a 
Mea n c ha n ge fr o m di ur nall y 
a dj uste d b as eli ne I O P at eac h 
p ost-treat me nt ti me p oi nt  
X  
 
  
  
I T T, P P  
M C M C, 
L O C F, B O C F, 
O bser ve d d at a 
Mea n c ha n ge fr o m baseli ne i n 
di ur nal I O P at Wee k 2, Wee k 6, 
a n d M o nt h 3 
X  
 
  
  
I T T, P P  
M C M C, 
L O C F, B O C F, 
O bser ve d d at a 
Mea n p erce nt c ha n ge fr o m 
di ur nall y a dj uste d b aseli ne I O P 
at eac h p ost-treat me nt ti me 
p oi nt  
X  
 
  
  
I T T, P P  
O bser ve d d at a 
P erce nta ges of s u bj ects 
ac hie vi n g pre-s p ecifie d mea n, 
mea n c ha n ge, a n d p erce nt me a n 
c ha n ge di ur nal I O P le vels 
  
 
  
X  
I T T, P P  
O bser ve d data 
a T w o Sa m ple T-test c o m pari n g act u al mea n I O P val u e at eac h ti me p oi nt b et wee n P G 3 2 4 a n d G A N F O R T. 
b A N C O V A m o d el i n cl u di n g treat me nt as t h e mai n effect a n d baseli n e as t h e c o variate. I n di vi d u al m o d els will be fit f or eac h 
visit a n d ti me p oi nt. 
c Mi xe d M o d el Re peate d Meas ures a nal ysis i n cl u di n g treat m e nt as t h e mai n effe ct, a n d b as eli ne I O P, visit, ti me p oi nt, 
treat me nt * visit, treat me nt *ti me p oi nt, visit *ti me p oi nt, a n d treat me nt * visit *ti me p oi nt as m o del ter ms.  Re p eate d meas ures will 
b e use d t o acc o u nt f or t h e c orrelati o n a m o n g meas ures wit hi n a s u bject.  T h e m o d el will i n cl u d e all p ost- d ose visits a n d ti me 
p oi nts. 
d 
 at eac h ti me p oi nt b et wee n P G 3 2 4 a n d G A N F O R T. 
 
 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 4 of 4 4 
8. 3. 1  Pri m ar y Effic ac y A n al yses 
T he pri mar y a nal ysis of t he pri mar y o utc o me will e m pl o y a li near m o del wit h I O P at t he gi ve n 
visit a n d ti me p oi nt as t he res p o nse, baseli ne I O P as a c o variate, a n d treat me nt as a mai n effect fact or 
at eac h ti me p oi nt ( 0 8: 0 0, 1 0: 0 0, a n d 1 6: 0 0 h o urs at t he Wee k 2, Wee k 6, a n d M o nt h 3 Visits), usi n g 
t he i nte nt-t o-treat p o p ulati o n wit h m ulti ple i m p utati o n tec h ni q ues (e. g., M o nt e Carl o Mar k o v 
C hai n) use d t o i m p ute missi n g data. Eac h ti m e p oi nt wit hi n eac h visit will be m o dele d 
se parat el y. T h e least s q u ares me a n differe nces ( P G 3 2 4  G A N F O R T) will be prese nt e d as w ell 
as 2-si de d 9 5 % c o nfi de n ce i nter vals ( CIs) a n d p- val ues. Cli nical n o n-i nferi orit y f or P G 3 2 4  will be 
c o ncl u de d if t he u p per li mit of t h e 9 5 % CIs ar o u n d t he differe nce ( P G 3 2 4  G A N F O R T) is 1. 5 
m m H g at all 9 ti me p oi nts t hr o u g h M o nt h 3 a n d is 
1. 0 m m H g at a maj orit y of ti me p oi nts (at l east 5 
of 9) t hr o u g h M o nt h 3.  
 
T he f oll o wi n g S A S c o d e will be use d f or m ulti ple i m p utati o ns usi n g t h e M o nte- Carl o Mar k o v 
C hai n met h o d, w here a se parat e m o del will be fit f or eac h ti me p oi nt at eac h visit. 
 
pr oc mi data = i n d at a see d = 4 8 6 6 9 o ut = o ut d at a 1 ; 
   mc mc i nitial = e m; 
   var trt 0 1 p n b aseli n e I O P; 
r u n; 
w here 
- 
i n d at a is t h e na me of t he i n p ut dataset 
- 
o ut d at a  is t h e na me of t he o ut p ut dataset 
- 
trt 0 1 p n is t h e na me of t he treat m e nt gr o u p v aria ble i n n u meric f or m at 
- 
b aseli ne  ca pt ures t h e bas eli ne I O P f or t he gi ve n ti me p oi nt 
- 
I O P is t h e na me of t h e I O P meas ure. 
 
Fi ve c o m plete data sets will be ge nerate d fr o m t he a b o ve c o de. Eac h c o m plete data set will be 
use d t o  a nal yz e t his pri mar y effi cac y e n d p oi nt se p aratel y usi n g a n al ysis of v aria nce. T he n, t he 
S A S pr oce d ure MI A N A L Y Z E will be use d t o a n al yze t he res ults fr o m t he 5 c o m plete data s ets 
t o ge n erate a c o m bi ne d i nfere nce. T he f oll o wi n g S A S c o de will be use d: 
 
o ds o ut p ut diffs = o ut d at a 2 ; 
pr oc mi x e d d ata = o ut d at a 1 ; 
  class trt 0 1 p n; 
  m o del I O P =trt 0 1 p n b as eli ne; 
  ls mea ns trt 0 1 p n / cl p diff; 
  b y _I m p utati o n _; 
r u n; 
 
pr oc s ort data = o ut d at a 2; 
 b y trt 0 1 p n _trt 0 1 p n; 
r u n; 
 
o ds o ut p ut Para meter Esti mates = o ut d at a 3 ; 
pr oc mia nal yz e d ata = o ut d at a 2  al p ha = 0. 0 5 ; 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 5 of 4 4 
   b y trt 0 1 p n _trt 0 1 p n; 
    m o deleffe cts esti m ate; 
    st derr st derr; 
r u n; 
w here 
- 
I O P is t h e na me of t h e I O P meas ure 
- 
trt 0 1 p n is t h e na me of t he treat m e nt gr o u p v aria ble i n n u meric f or m at 
- 
o ut d at a 2  is t he na me of t he o ut p ut dataset t hat c o ntai ns t he statistical res ults of t he 
differe n ces b et wee n tr eat me nt gr o u ps 
- 
o ut d at a 3 is t h e na me of t he o ut p ut dataset t hat c o ntai ns s u m mar y a n d i nfere ntial 
statisti cs. 
 
8. 3. 2  Sec o n d ar y Effic ac y A n al yses 
T he sec o n d ar y efficac y a nal yses will i ncl u de re peati n g t he pri mar y efficac y a n al ysis o n all 
s u bjects a n d a d diti o nal a nal yses of t he pri mar y efficac y e n d p oi nt as well as ot her a nal yses of t h e 
sec o n dar y e n d p oi nts, as o utli ne d bel o w.  
T he pri mar y efficac y a nal ysis will be re peate d o n t he I T T p o p ulati o n usi n g o bser ve d dat a o nl y, 
last o bser vati o n carrie d f or war d ( L O C F) w here L O C F will be perf or me d usi n g ti me-rel e va nt 
meas ures; a n d b aseli n e o bser vati o n carrie d f or war d ( B O C F) usi n g ti m e-rel e va nt meas ures t o 
deter mi n e t h e r o b ust ness of res ults. A d diti o nall y, t he a b o ve a nal yses will be re peat e d o n t he P P 
p o p ulati o n t o deter mi ne r o b ust ness of res ults.  
Sec o n dar y a n al yses of t h e pri mar y e n d p oi nt will b e c o m plete d usi n g i n di vi d ual t w o-sa m ple  
t-tests a n d 9 5 % t- distri b uti o n c o nfi de nce i nter vals f or eac h c o m paris o n ( P G 3 2 4 vs G A N F O R T) 
at eac h ti m e p oi nt ( 0 8: 0 0, 1 0: 0 0, a n d 1 6: 0 0 at t he Wee k 2, Wee k 6 a n d M o nt h 3 Visits) usi n g t he 
I T T a n d P P p o p ulati o ns. Si milar a nal yses will be c o m plete d o n t he sec o n d ar y e n d p oi nts: mea n 
I O P me as ure at M o nt h 4, M o nt h 5, a n d M o nt h 6 visits a n d mea n di ur nal I O P a n d c ha n ge fr o m 
baseli n e di ur nal I O P meas ures base d o n t he I T T a n d P P p o p ulati o ns. M o dels a dj usti n g f or 
baseli n e will o nl y be p erf or me d o n t h e mea n I O P res p o nse v aria ble as i nfere nce is i de ntical 
bet wee n t his res p o ns e a n d t he c ha n ge fr o m baseli ne I O P res p o nse varia bl e i n s uc h a m o del base d 
o n t he I T T a n d P P p o p ulati o ns. 
 
A d diti o nall y, f or t he m ea n I O P val ues at eac h ti me p oi nt, mi x e d m o del re peate d meas ures will 
be r u n wit h baseli ne as t he c o vari ate; treat me nt, visit, ti m e p oi nt, treat m e nt b y visit, treat m e nt b y 
ti m e p oi nt, visit b y ti me p oi nt, a n d treat me nt b y visit b y ti me p oi nt as t he fi x e d effect f act ors; a n d 
s u bject as t h e ra n d o m effect, re p eate d meas ure. A n u nstr uct ure d c o v aria n ce str uct ure will be 
use d t o m o del t he wit hi n s u bject, bet w ee n visit a n d ti me p oi nt varia nces. T his all o ws f or 
differe nt v aria nces a n d c o varia nces wit hi n a n d bet wee n ti me p oi nts a n d visits. T he treat me nt b y 
visit, treat m e nt b y ti me p oi nt, visit b y ti me p oi nt, a n d treat me nt b y visit b y ti me p oi nt 
i nteracti o ns all o w f or a differe nt rate of c ha n ge i n I O P i n t he differe nt treat me nt ar ms a m o n g 
visits a n d ti me p oi nts. T his m o del will be r u n i ncl u di n g t he Wee k 2, Wee k 6, a n d M o nt h 3 visits 
base d o n t he I T T p o p ul ati o n. 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 6 of 4 4 
Perce nt c ha n ge fr o m di ur nall y a dj uste d b aseli ne I O P at eac h ti me p oi nt will be a nal yze d usi n g 
t w o-sa m ple t-tests, bet wee n P G 3 2 4 a n d G A N F O R T, at eac h ti m e p oi nt a n d visit, i n cl u di n g t w o-
sa m ple t-tests a n d 9 5 % t- distri b uti o n c o nfi de nce i nter vals o n t h e differe n ce ( P G 3 2 4  
G A N F O R T). T he a n al ysis will be base d o n t h e I T T a n d P P p o p ulati o ns. 
 
A nal ys es of I O P will als o i ncl u de s u m marizi n g t he n u m ber a n d p erce nta ge of st u d y e yes 
 
i ncre
Wee k 6, a n d M o nt h 3. A d diti o nall y, t h e n u m ber a n d perce nta ge of st u d y e yes attai ni n g a mea n 
m m H g i n 1 m m H g i n cre me nts will be s u m marize d at W ee k 2, Wee k 
6, a n d M o nt h 3. 
-si de d p- val u es) will be use d t o test t he pair wise 
differe n ces b et wee n tr eat me nt gr o u ps f or eac h cat e g or y at eac h visit. T hese a nal yses will be 
prese nte d f or b ot h t he I T T a n d P P p o p ulati o ns wit h  o bser ve d d ata o nl y. 
 
8. 4  
E x a mi n ati o n of S u b gr o u ps 
S u b gr o u p a nal ys es base d u p o n pre-st u d y c h aracteristics i ncl u de: 
 A ge: < 6 5 years, 
6 5 years 
 Ge n d er: Male, Fe male 
 Race: Ca ucasia n, Ot h er  
 Iris C ol or: Bl ue/ Gre y/ Gree n, Br o w n/ Blac k, H azel 
 Ma xi m u m b aseli ne I O P val ue: < 2 2 m m H g, < 2 3 m m H g, < 2 4 m m H g, < 2 5 m m H g, < 2 6 
m m H g, < 2 7 m m H g, < 3 0 m m H g, < 3 2 m m H g 
 Pri or h y p ote nsi ve me di cati o n e x perie nce cate g or y 1: C o m bi nati o n T hera p y, 
Pr osta gla n di n ( m o n ot hera p y), Ot her ( m o n ot hera p y),  
 Pri or h y p ote nsi ve me di cati o n e x perie nce cate g or y 2: Pri or Pr osta gla n di n, N o Pri or 
Pr osta gla n di n 
 C o u ntr y 
F or eac h s u b gr o u p, e xce pt t h ose defi n e d b y u n m e dicate d baseli ne I O P, I O P will be c o m pare d at 
eac h p ost- d os e ti me p oi nt bet wee n treat me nt gr o u ps ( usi n g a n A N C O V A m o del wit h treat me nt 
as t he mai n effect, baseli n e I O P a n d s u b gr o u p as c o v ariates, a n d t he i nteracti o n of treat m e nt b y 
s u b gr o u p.  T h e least s q uares mea n differe nces ( P G 3 2 4  G A N F O R T) will be prese nt e d as well 
as 2-si de d 9 5 % c o nfi de n ce i nter vals ( CIs) a n d p- val ues. T hese s u b gr o u p e x a mi n ati o ns are base d 
o n t he I T T p o p ulati o n a n d use o bser ve d d ata o nl y. 
A n a nal ysis of i n vesti gati ve c o u ntr y will als o be i n cl u de d as a s u b gr o u p a nal ysis.  T h e 
h o m o ge n eit y of treat m e nt effect acr oss i n vesti gati ve re gi o ns will b e e x a mi ne d usi n g a si milar 
m o del as t he a b o ve s u b gr o u p a nal yses. R es ults will be prese nte d i n ta b ul ar f or m. T his a nal ysis is 
base d o n t he I T T p o p ul ati o n a n d use o bser v e d dat a o nl y. 
S u b gr o u p a nal ys es base d u p o n c o u ntr y will be c o m plete d f or A ustria, Bel gi u m, Czec h R, Fra nce, 
Ger m a n y, H u n gar y, Ital y, Lat via, P ola n d, S p ai n, a n d U K. T he a n al ysis of t h ese I O P s u b gr o u ps 
will b e c o m plete d usi n g o nl y t he pri mar y e n d p oi nt a nal ysis strat e g y. 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 7 of 4 4 
S u b gr o u p a nal ys es base d u p o n ma xi m u m u n me dicate d bas eli n e I O P i n t he st u d y e ye a d diti o nall y 
will b e c o m plete d f or ma xi m u m baseli ne I O P < 2 2 m m H g, < 2 3 m m H g, < 2 4 m m H g, < 2 5 m m H g, 
> = 2 5 m m H g,  < 2 6 m m H g, < 2 7 m m H g, < 3 0 m m H g, a n d < 3 2 m m H g. T he a nal ysis of t hes e I O P 
s u b gr o u ps will be c o m plete d usi n g o nl y t he pri mar y e n d p oi nt a nal ysis strat e g y. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 8 of 4 4 
9.  
S A F E T Y E V A L U A TI O N 
9. 1  
O ver vie w of S afet y A n al ysis Met h o ds 
T he assess me nt of s afet y a n d t olera bilit y is t he sec o n dar y o bjecti ve of t his st u d y.  All safet y 
a nal ys es will be carrie d o ut usi n g t he Safet y P o p ul ati o n a n d will i n cl u de t he st u d y e ye a n d fell o w 
e ye se paratel y, w h ere a p pli ca ble. All ta b ular s u m maries will be pr o vi de d pri maril y f or all 
s u bjects.  
T he assess me nt of s afet y will be e val uate d b y: 
 A d vers e e ve nts 
 Heart rate a n d bl o o d press ure  
 Bi o mi cr osc o p y of a nteri or se g me nt i ncl u di n g e val uati o n of c or nea, c o nj u ncti va a n d 
a nteri or c h a m ber.  ( Fl u orescei n stai ni n g t o be use d.) 
 Dilate d o p ht hal m osc o p y 
 Best C orrecte d E T D R S Vis u al Ac uit y  
 Vis ual fiel ds 
 Pac h y m etr y 
 I O P 
 Cli nical c he mistr y a n d h e mat ol o g y la b orat or y fi n di n gs 
 Pre g n a nc y testi n g (f or w o me n of c hil d beari n g p ot e nti al) 
 C ha n ge i n S elf- A d mi nist ere d N EI Vis ual F u n cti o ni n g Q uesti o n naire- 2 5 ( V F Q) s c ore fr o m 
baseli n e t o st u d y e xit 
 C ha n ge i n Self- A d mi nistere d S h ort F or m H ealt h S ur ve y Q uesti o n naire 3 6 ( S F- 3 6 V. 2) 
sc ore fr o m baseli ne t o st u d y e xit 
 
All safet y varia bl es will be descri pti v el y s u m mari ze d b y treat me nt gr o u p at eac h assess m e nt ti me 
a n d f or rele va nt c ha n ges fr o m bas eli n e. 
F or c o m plete i n cl usi o n of s u bjects w h o wit h dra w fr o m t he st u d y earl y, t h e E n d of St u d y visit f or 
safet y o utc o mes will be d efi ne d as eit h er Visit 9 or Earl y Disc o nti n uati o n.   
F or t he first i nteri m a nal ysis, t he M o nt h 3 visit f or safet y o utc o mes will be defi ne d as eit h er Visit 
6 or Earl y Disc o nti n uati o n.   
9. 2  
E xte nt of E x p os ure 
S u m mar y statisti cs will be pres e nt e d f or tr eat m e nt e x p os ure.  Treat me nt e x p os ure will be defi ne d 
as t he n u m ber of d a ys t hat t he s u bject was e x p ose d t o st u d y treat m e nt as calc ulate d usi n g t he 
f or m ula:  
Treat m e nt e x p os ure = Date of Last D ose 
 Visit 3 Dat e + 1.  


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 2 9 of 4 4 
9. 3  
A d verse E ve nts 
A n a d v ers e e ve nt is a n y u nt o war d m e dical o cc urre nce ass o ciate d wit h t he use of a dr u g i n 
h u ma ns, w het her or n ot c o nsi dere d dr u g relate d. All A Es occ urri n g d uri n g t h e st u d y (i. e. o nce 
t he s u bject h as recei ve d o ne d ose of st u d y dr u g) will be defi ne d as treat m e nt e mer ge nt a d v erse 
e ve nts ( T E A Es) a n d m ust be d oc u me nte d, re gar dl ess of t h e ass u m pti o n of ca usal relati o ns hi p, o n 
t he res pecti ve A E C R F. All a d verse e ve nts s h o ul d be d oc u me nte d fr o m t h e ti me t he s u bject si g ns 
t he i nf or me d c o nse nt u ntil 3 0 da ys after t h e last d ose of i n vesti gati o nal pr o d uct.   If a s u bject has 
o n g oi n g A Es at t he ti m e of st u d y c o m pl eti o n, t he o n g oi n g A Es m ust be f oll o we d- u p a n d 
pr o vi de d a p pr o priate m e dical care u ntil t he e ve nt has res ol v e d or st a biliz e d. D oc u me ntati o n of 
A Es i ncl u des o nset date, se verit y, acti o n(s) t a ke n, st u d y me dicati o n relati o ns hi p, o utc o me, 
res ol uti o n date, a n d seri o us ness. A E data p ost st u d y c o m pleti o n date ma y b e i ncl u de d i n t he 
C S R. 
Ver b ati m descri pti o ns of A Es will be ma p pe d t o Me d D R A ( versi o n: 2 0. 0) t hesa ur us ter ms a n d 
be prese nt e d i n a data listi n g. Treat m e nt e mer ge nt A Es, t h ose t hat occ ur after t h e first d ose of 
st u d y me di cati o n, will be s u m marize d b y treat me nt gr o u p usi n g fre q ue ncies a n d pr o p orti o ns f or 
eac h s yste m or ga n class ( S O C) a n d preferre d ter m ( P T) wit hi n eac h S O C. A se parat e s u m m ar y 
will b e prese nte d f or A Es t hat are relate d t o t he st u d y dr u g 
 
s will be use d t o test t h e differe n ce 
i n pr o p orti o ns of s u bjects wit h eac h A E b et w ee n treat m e nt gr o u ps, S O C, a n d P T. A n ot her ta ble 
will b e prese nte d s u m marizi n g A Es b y ma xi m u m se verit y. A d diti o nal s u m m aries will be 
prese nte d f or seri o us A Es a n d A Es lea di n g t o st u d y treat m e nt dis c o nti n uati o n.  
A n o verall s u m mar y ta bl e will be de vel o pe d t o re p ort t he n u m ber of e v e nts a n d t he i n ci d e nce of 
s u bjects ha vi n g at least o ne e ve nt i n t he f oll o wi n g cate g ories:  
 T E A Es 
 Oc ul ar T E A Es 
 N o n- Oc ular T E A Es 
 Seri o us T E A Es ( S A Es) 
 Treat m e nt- Relate d T E A Es (re p orte d as p ossi bl y relate d or relate d t o t he st u d y dr u g) 
 Treat m e nt- Relate d S A Es 
 T E A Es b y m a xi m u m se verit y 
 T E A Es lea di n g t o st u d y dr u g disc o nti n uati o n 
 T E A Es res ulti n g i n d eat h 
W hile t he o verall s u m mar y of T E A Es will prese nt b ot h t he n u m ber of T E A Es a n d t he i nci de nce 
of T E A Es, t he ot her s u m maries will o nl y re p ort t he i nci de nce of T E A Es.  W h e n re p orti n g t h e 
n u m ber of T E A Es, if t he sa me T E A E occ urs f or a s u bject o n m ulti ple occasi o ns t he e ve nt will be 
c o u nte d o nce f or eac h o cc urre n ce.  W he n re p orti n g t he i n ci d e nce, a s u bject will o nl y b e c o u nte d 
o nce if t he y e ver e x perie nce a n e ve nt wit hi n t he S O C a n d e ver e x perie nce t h e i n di vi d ual P T.  
S u m maries will be perf or me d usi n g t h e act ual treat m e nt recei v e d.   


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 0 of 4 4 
9. 4  
De at hs, Seri o us A d v ers e E ve nts, a n d Ot her Si g nific a nt A d verse E ve nts 
A n a d v ers e e ve nt is c o nsi dere d 
s eri o us  if, i n t he vie w of eit h er t h e I n vesti gat or or S p o ns or, it 
res ults i n a n y of t he f oll o wi n g o utc o mes: D eat h, a life-t hreate ni n g a d vers e e ve nt, patie nt 
h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, a persiste nt or si g nifica nt i n ca pacit y or 
s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u ncti o ns, or a c o n ge nital 
a n o mal y/ birt h defect. I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, 
or re q uire h os pit alizati o n ma y be c o nsi dere d seri o us w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o p ar diz e t he patie nt a n d ma y r e q uire me di cal or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n.  
 
Seri o us a d verse e ve nts a n d deat hs will be liste d a n d s u m marize d se paratel y f or t he Safet y 
p o p ulati o n. Se parate listi n gs will als o be pr o vi de d f or t he C O VI D- 1 9 rel ate d A Es, a n d C O VI D-
1 9 relate d  S A Es. 
9. 5  
Cli ni c al L a b or at or y E v al u ati o n 
Cli nical la b orat or y res ults, i ncl u di n g cli nical c h e mistr y a n d he mat ol o g y, will be prese nte d i n data 
listi n gs.  A b n or mal res ults, t h ose a b o ve or b el o w t h e n or mal ra n ge, will be fla g ge d wit h " H" 
" L" 
 bas e d o n t h e la b orat or y ra n ges 
pr o vi de d b y t he la b a n d i ncl u de d i n t he listi n gs.  Descri pti ve statistics will be use d t o s u m marize 
c o nti n u o us meas ures a n d will be prese nte d i n ta b ular f or m i ncl u di n g c ha n ge fr o m baseli ne t o t he 
M o nt h 6 visit.  S hifts fr o m baseli ne t o t he M o nt h 6 visit will als o be prese nte d i n ta b ular f or m f or 
cli nical c he mistries a n d h e mat ol o g y p ara m eters b y treat m e nt gr o u p a n d l a b orat or y d o mai n. 
S u m mar y ta bles als o will be prese nt e d f or t he n u m ber of s u bjects wit h a b n or mal val ues wit hi n 
eac h la b orat or y p ara met er at t he e n d of t h e st u d y. Cli nical la b orat or y res ults, i ncl u di n g cli nical 
c he mistr y, h e mat ol o g y, a n d uri ne pre g n a nc y test will als o be liste d b y s u bject. 
9. 6  
Vit al Si g ns, O p ht h al mic E x a m Fi n di n gs, a n d Ot her S afet y O utc o mes 
9. 6. 1  Vit al Si g ns 
Heart rate a n d bl o o d press ure will b e liste d b y treat me nt gr o u p, s u bject, a n d visit i ncl u di n g 
o bser ve d val u es a n d c ha n ges fr o m baseli ne.  M eas ure me nts a n d c ha n ge fr o m baseli ne 
meas ure me nts will be s u m m arize d b y treat me nt gr o u p a n d visit.  Paire d t-tests will be use d t o 
test wit hi n treat m e nt gr o u p c ha n ges fr o m baseli ne i n vital si g n para meters.  T w o-si de d 9 5 % Cis 
a n d p- val ues will be pr o vi de d. 
 
9. 6. 2  I ntr a oc ul a r Press ure 
I ntra oc ular press ure will be prese nte d i n data listi n gs. I ntra oc ular press ure d ata will be 
s u m marize d at eac h visit a n d ti me p oi nt usi n g c o nti n u o us s u m m aries, i ncl u di n g c h a n ge fr o m 
baseli n e, f or b ot h t he st u d y e ye a n d t h e fell o w e ye, t h e n u m b er a n d p erce nta ge of s u bjects w h o 
.  


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 1 of 4 4 
9. 6. 3  Vis u al Ac uit y 
Vis ual ac uit y s c ores will be prese nt e d i n data listi n gs. S u bjects w h o l ost t hree or m ore li nes will 
be prese nt e d i n a n a d diti o nal listi n g. Vis ual ac uit y data will be s u m marize d at eac h visit usi n g 
c o nti n u o us s u m m aries, i ncl u di n g c h a n ge fr o m baseli ne, f or b ot h t he st u d y e ye a n d t he fell o w 
e ye. A d diti o nall y, discrete s u m maries of t he w orst c ha n ge fr o m baseli ne will be prese nte d f or 
b ot h t h e st u d y e ye a n d t h e fell o w e ye wit h t h e f oll o wi n g gr o u pi n gs base d o n t he l o g M A R sc ores: 
0 or less, > 0 t o + 0. 0 9, + 0. 1 0 t o + 0. 1 9, + 0. 2 0 t o 0. 2 9, + 0. 3 0 or m ore.   
9. 6. 4  Dil ate d O p ht h al m osc o p y a n d C u p-t o- Disc R ati o 
Dilate d o p ht hal m osc o p y a n d c u p-t o- disc rati o res ults fr o m Scree ni n g a n d M o nt hs 3 a n d 6 will be 
prese nte d i n dat a listi n gs. A se parate listi n g will be create d f or t h ose s u bjects wit h a criteri o n 
 N ot 
 
Fre q ue nci es a n d perce nta ges of 
n or mal, a b n or mal o p ht h al m osc o p y res ults will be creat e d f or t h e f oll o wi n g fiel ds: Reti na, 
Mac ula, C h or oi d, O ptic Ner ve, a n d Vitre o us H u m or. A b n or mal res ults will f urt her be br o k e n 
d o w n b y cli nical si g nific a nce.  A s hift ta bl e of st u d y e ye a n d fell o w e ye o p ht h al m osc o p y res ults 
will als o be prese nte d b y treat m e nt gr o u p.   
Vertical c u p-t o- disc r ati o at Scree ni n g will be s u m marize d f or t he st u d y e ye a n d f or t he fell o w 
e ye b y treat m e nt gr o u p i n t h e baseli ne c haracteristi cs ta ble. A d diti o nall y, v ertical c u p-t o- disc 
rati o will be s u m mariz e d at f oll o w- u p visits a n d c h a n ge fr o m b aseli ne t o f oll o w- u p visits usi n g 
c o nti n u o us s u m m ar y statisti cs.  A listi n g of s u bjects wit h i ncreases of  0. 2 i n eit her e ye at e n d 
of st u d y will be prese nte d. 
9. 6. 5  Bi o micr os c o p y 
Bi o mi cr osc o p y res ults will be liste d f or b ot h e yes at eac h visit. A se p arate listi n g will be 
prese nte d f or s u bjects wit h a criteri o n c ha n ge, d efi ne d as a + 1 u nit i ncrease fr o m baseli n e.  
S u m maries of bi o micr osc o p y res ults will als o be prese nte d f or st u d y e yes a n d fell o w e yes b y 
treat me nt gr o u p, visit, a n d ti me p oi nt i n ta b ular f or m.   
A s u m mar y t a ble of t he n u m ber a n d perce nt a ge of s u bjects wit h at least a + 1 u nit i ncrease i n 
sc ore fr o m baseli ne will be prese nt e d b y re gi o n, fi n di n g, ti m e p oi nt a n d e ye (st u d y e ye a n d 
fell o w e ye). I n a d diti o n t o eac h ti me p oi nt
 
A d diti o nall y, f or C o nj u n cti val H y p ere mia, t h e pr o p orti o n of s u bjects wit h a o ne se verit y gra de 
i ncreas e fr o m baseli ne will be c o m pare d bet w ee n Da y 1 5 a n d D a y 9 0 at eac h ti me p oi nt wit hi n a 
A n ot h er s u m mar y ta ble will b e pres e nte d wit h t he n u m ber 
a n d perce nta ge of s u bjects w h o ha d a fi n di n g j u d ge d t o be cli nicall y si g nifi ca nt b y re gi o n, 
c o m pare i n ci d e nce b et wee n treat m e nt gr o u ps i n b ot h ta bles.  A d diti o nall y, C o nj u ncti v al 
H y p ere mia will be prese nte d usi n g c o nti n u o us s u m mar y statistics f or eac h visit, f or t he c ha n ge 
fr o m baseli ne t o eac h p ost- baseli ne visit, a n d f or t he c ha n ge fr o m D a y 1 5 t o Da y 9 0 visit ( w hic h 
will use ti me-s pecific differe n ces [e. g. 0 8: 0 0 at D a y 9 0 
 0 8: 0 0 at Da y 1 5]).  Differe nces 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 2 of 4 4 
bet wee n tr eat m e nt gr o u ps will be teste d usi n g t w o-sa m ple t-tests as well as Wilc o x o n ra n k s u m 
tests.   
Ot her s u m maries f or C o nj u ncti val H y p ere mia:  
N u m ber a n d p erce nta ge of s u bjects wit h at least a cli nicall y si g nifica nt i ncrease fr o m baseli ne i n 
c o nj u ncti val h y p ere mia will be prese nte d b y treat me nt gr o u p. Cli nicall y si g nifica nt i ncrease is 
defi ne d as 
1 u nit s c ore c ha n ge fr o m baseli ne i n eit her e ye, wit h baseli ne defi ne d as t he 
ma xi m u m sc ore pri or t o first d ose of st u d y me dicati o n (a n y ti me p oi nt). 
 
Pr o p orti o n of s u bjects wit h s p ora dic or n o n-s p ora dic c o nj u ncti v al h y pere mia will be prese nte d 
f or all s u bjects wit h c o nj u ncti v al h y p ere mia w h o c o m plete d t he st u d y. N o n-s p ora dic is defi ne d 
as a n e ve nt t hat starte d o n/ bef ore Wee k 2 a n d st o p pe d after st u d y e xit or is o n g oi n g at e xit. 
 
Pr o p orti o n of s u bjects wit h treat me nt-e mer ge nt c o nj u ncti val h y pere mia b y n u m ber of 
c o nsec uti ve visits (e. g. 0, 1, 2, etc.) will be prese nt e d b y treat me nt gr o u p. F or e x a m ple, s u bjects 
wit h t h e e ve nt t hat di d n ot c o ver a n y visit are c o u nte d i n 0 visit. S u bjects wit h t he e ve nt t hat 
c o vere d o nl y 1 visit are c o u nte d i n 1. S u bjects wit h t he e ve nt o nset at Visit 3 a n d c o vere d Visits 
4 t o 6 are c o u nte d i n 4.  
 
9. 6. 6  Vis u al Fiel d E x a mi n ati o n, P ac h y metr y, a n d G o ni osc o p y  
Vis ual fiel d e xa mi nati o n res ults will be c ollecte d at Scree ni n g a n d M o nt hs 3 a n d 6 a n d liste d f or 
eac h s u bje ct.  Vis ual fiel d mea n de viati o n ( d B) will be s u m marize d usi n g c o nti n u o us s u m mar y 
statisti cs f or t he Scree ni n g a n d M o nt hs 3 a n d 6 visits as well as c ha n ge fr o m Scree ni n g t o 
M o nt hs 3 a n d 6 b y treat me nt gr o u p f or t h e st u d y e ye a n d fell o w e ye s e paratel y. 
 
Ce ntral c or neal t hic k ness, c oll ecte d at Scree ni n g a n d M o nt hs 3 a n d 6 will be liste d f or eac h 
s u bject. Ce ntral c or n eal t hic k ness will be s u m marize d usi n g c o nti n u o us s u m mar y statisti cs f or 
t he Scree ni n g a n d M o nt hs 3 a n d 6 visits as w ell as c ha n ge fr o m Scree ni n g t o M o nt hs 3 a n d 6 b y 
treat me nt gr o u p f or t he st u d y e ye a n d fell o w e ye s e parat el y. T he st u d y e ye a n d fell o w e ye mea ns 
at scree ni n g will als o be s u m marize d b y treat me nt gr o u p a n d i n cl u de d wit h baseli n e 
c haracteristics.  
  
G o ni osc o p y will be c ollecte d at scree ni n g f or eac h e ye a n d liste d f or eac h s u bject.  P ossi ble 
val ues will be O pe n A n gl e, N arr o w A n gle, a n d Cl ose d A n gle. 
 
 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 3 of 4 4 
1 0.  
VI S U A L F U N C TI O N A N D Q U A LI T Y O F LI F E Q U E S TI O N N AI R E S 
1 0. 1  Vis u al F u ncti o n Q uesti o n n aire ( N EI, 2 5 q uesti o ns) 
T he V F Q- 2 5 c o nsists of a base set of 2 5 visi o n-tar gete d q uesti o ns re prese nti n g 1 1 visi o n-relate d 
c o nstr ucts, pl us a n a d diti o nal si n gle-ite m ge neral healt h rati n g q uesti o n.  
 
T a bl e 1 0. 1 Ste p 1: R ec o di n g of Ite ms  
Q uesti o n N u m b ers  
Ori gi n al Ite m Sc ore ( a)  
Rec o de d V al ue 
1, 3, 4, 1 5c ( b) 
1 
1 0 0 
 
2 
7 5 
 
3 
5 0 
 
4 
2 5 
 
5 
0 
2 
1 
1 0 0 
 
2 
8 0 
 
3 
6 0 
 
4 
4 0 
 
5 
2 0 
 
6 
0 
5, 6, 7, 8, 9, 1 0, 1 1, 1 2, 1 3, 
1 4, 1 6, 1 6 a  
1 
1 0 0 
 
2 
7 5 
 
3 
5 0 
 
4 
2 5 
 
5 
0 
 
6 
* 
1 7, 1 8, 1 9, 2 0, 2 1, 2 2, 2 3, 2 4, 
2 5 
1 
0 
 
2 
2 5 
 
3 
5 0 
 
4 
7 5 
 
5 
1 0 0 
(a)Refer t o pr ot o c ol f or t he ori gi nal ite m sc ore  
( b)Q uesti o n 1 5 c has f o ur-res p o nse le vels, b ut is e x pe n de d t o  fi ve-le vels usi n g q uesti o n 1 5 b.  
    N ote:  If 1 5 b = 1 t he n 1 5c s h o ul d b e rec o de d t o 0. 
  
If 1 5 b = 2, t he n 1 5 c s h o ul d b e rec o d e d t o missi n g. 
  
If 1 5 b = 3, t he n 1 5 c s h o ul d b e rec o d e d t o missi n g. 
- visi o n relat e d pr o ble ms. 
 
 
T a bl e 1 0. 2 Ste p 2: A ver a gi n g Ite ms t o Ge ner ate V F Q- 2 5 S u b- Sc ales 
 
S u b- Scale 
N u m ber of ite ms  
Ite ms t o be a vera ge d (after 
rec o di n g per Ta ble 1 0. 1) 
Ge neral Healt h 
1 
1 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 4 of 4 4 
Ge neral Visi o n 
1 
2 
Oc ul ar Pai n 
2 
4, 1 9 
Near Acti vities 
3 
5, 6, 7 
Dista nce Acti viti es 
3 
8, 9, 1 4 
Visi o n S p ecific: 
     S ocial F u ncti o ni n g  
2 
1 1, 1 3 
     Me ntal Healt h 
4 
3, 2 1, 2 2, 2 5 
     R ole Diffic ulties 
2 
1 7, 1 8 
     De pe n de nc y 
3 
2 0, 2 3, 2 4 
Dri vi n g 
3 
1 5c, 1 6, 1 6a 
C ol or Visi o n 
1 
1 2 
Peri p heral Visi o n 
1 
1 0 
 
If t he res p o n d e nt is missi n g o ne of t h e ite ms wit hi n a s u b-scale
t o t h e a vera ge of t he n o n- missi n g ite ms.  
 
T o calc ulate a n o verall c o m p osit e sc ore f or V F Q- 2 5, si m pl y a vera ge all t he visi o n-tar get s u b-
scale sc ores, e x cl u di n g t h e Ge n eral H ealt h s u b-scale.   
 
A hi g her s u b-scale sc ore or o verall c o m p osite sc ore i n dicates a b etter perce pti o n of healt h.       
 
T he V F Q- 2 5 s u b-scale sc ores a n d o verall c o m p osit e sc ore will be s u m m ari z e d f or t he Scree ni n g, 
M o nt h 6 a n d M o nt h 6/ E arl y Disc o nti n uati o n visits, i ncl u di n g c h a n ge fr o m Scree ni n g t o M o nt h 6 
a n d c ha n ge fr o m Scree ni n g t o M o nt h 6/ Earl y Disc o nti n uati o n usi n g c o nti n u o us s u m m ar y 
statisti cs. Paire d t-tests will be use d t o pri m aril y a nal yze t h e mea n c ha n ge fr o m Scree ni n g t o 
M o nt h 6 a n d M o nt h 6/ E arl y Disc o nti n uati o n wit hi n a treat me nt gr o u p; a d diti o nall y, t he n o n-
para m etri c Wilc o x o n si g ne d-ra n k t est will be use d sec o n daril y t o a n al yze t he c ha n ge fr o m 
Scree ni n g t o M o nt h 6 a n d M o nt h 6/ E arl y Disc o nti n uati o n. T w o-sa m ple t-tests will be use d t o 
pri maril y a nal yze t h e differe nce i n t he mea n s c ores bet wee n treat me nts at Scree ni n g, M o nt h 6, 
M o nt h 6/ E arl y Disc o nti n uati o n a n d c ha n ge fr o m Scree ni n g t o M o nt h 6 a n d M o nt h 6/ E arl y 
Disc o nti n uati o n; a d diti o nall y, t h e n o n- para metric Wilc o x o n ra n k-s u m test will be use d 
sec o n daril y t o a nal yze t h e differe nces i n sc ores b et wee n treat me nts. 
A nal ys es will be perf or me d usi n g t he safet y p o p ul ati o n. 
1 0. 2  
He alt h S u r ve y Q u esti o n n air e, 3 6 Q uesti o ns, V ersi o n 2 ( S h o rt F or m) 
T he S F- 3 6 is a ge neric h ealt h s ur ve y wit h 3 6 ite ms t hat m eas ure f u ncti o nal healt h a n d well- b ei n g 
fr o m t he s u bject's pers p ecti v e.  
T he s ur ve y is gr o u p e d i nt o 8 di me nsi o ns: p h ysi cal f u ncti o ni n g ( P F), r ole- p h ysical ( R P), b o dil y 
pai n ( B P), ge neral healt h ( G H), vit alit y ( V T), s o cial f u ncti o ni n g ( S F), r ol e-e m oti o nal ( R E), a n d 
me ntal healt h ( M H). Fr o m t he ei g ht healt h di me nsi o ns, a p h ysical c o m p o ne nt s u m mar y ( P C S) 
meas ure, w hi c h is t he a g gre gate sc ore of t he P F; R P; B P a n d G H scales, a n d me ntal c o m p o n e nt 
s u m mar y ( M C S) meas ure, w hic h is t h e a g gre gate sc ore of t he V T; S F; R E a n d M H scales, 
meas ures are d eri ve d. A hi g her di m e nsi o n or c o m p o ne nt s u m mar y s c ore i n dicates a b etter 
perce pti o n of h ealt h. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 5 of 4 4 
T he di me nsi o n sc ores, p h ysical c o m p o ne nt s u m mar y s c ore a n d me ntal c o m p o ne nt s u m mar y 
sc ore will be deri ve d usi n g a certifie d s c ori n g s oft ware ( P R O C o R E) pr o vi d e d b y O pt u m, a n 
e xter nal ve n d or. T he ma xi m u m data rec o ver y o pti o n will be use d as t he i m p utati o n met h o d f or 
missi n g data. T he s oft w are a p plies a v al ue t o a scale ite m re n dere d missi n g if at least o ne of t he 
scale are missi n g. P C S a n d M C S are calc ulat e d w he n at least se v e n of t h e ei g ht pr ofile scales 
ha ve vali d data, eit her act u al or esti m ate d. H o we v er, t o calc ulate P C S, t h e P F scale m ust be o ne 
of t he se ve n s cales ha vi n g vali d dat a. Als o, t o calc ulate M C S, t h e M H scale m ust be o ne of t he 
se ve n scales ha vi n g vali d data.  
T he di me nsi o n sc ores a n d p h ysical a n d me ntal healt h c o m p osite s u m mar y sc or es will be 
s u m marize d f or t he Scree ni n g, M o nt h 6, a n d M o nt h 6/ Earl y Disc o nti n uati o n visits, i n cl u di n g 
c ha n ge fr o m Scree ni n g t o M o nt h 6 a n d c ha n ge fr o m Scree ni n g t o M o nt h 6/ E arl y Disc o nti n uati o n 
usi n g c o nti n u o us s u m mar y statisti cs usi n g o bs er v e d data o nl y. Paire d t-tests will be use d t o 
pri maril y a nal yze t h e mea n c ha n ge fr o m Scree ni n g t o M o nt h 6 a n d M o nt h 6/ E arl y 
Disc o nti n uati o n wit hi n a treat m e nt gr o u p; a d diti o nall y, t he n o n- p ara metric Wilc o x o n si g ne d-
ra n k test will be use d t o s ec o n daril y a n al yz e t h e c h a n ge fr o m Scree ni n g t o M o nt h 6 a n d M o nt h 
6/ Earl y Dis c o nti n uati o n. T w o-sa m ple t-tests will be use d t o pri maril y a nal yze t he differe n ce i n 
t he mea n sc ores bet wee n treat m e nts at Scree ni n g, M o nt h 6, M o nt h 6/ E arl y Disc o nti n uati o n a n d 
c ha n ge fr o m Scree ni n g t o M o nt h 6 a n d M o nt h 6/ Earl y Disc o nti n uati o n; a d diti o nall y, t h e n o n-
para m etri c Wilc o x o n ra n k-s u m test will be use d t o sec o n daril y a n al yze t h e differe n ces i n sc ores 
bet wee n tr eat m e nts. 
A nal ys es will be perf or me d usi n g t he safet y p o p ul ati o n. 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 6 of 4 4 
1 1.  
P H A R M A C O KI N E TI C E V A L U A TI O N 
N ot a p plica ble. 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 7 of 4 4 
1 2.  
O T H E R A N A L Y S E S 
A n y a d diti o nal a nal ys es c o n d ucte d will be c o nsi d ere d e x pl orat or y a n d e n u m erate d i n t he C S R. 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 8 of 4 4 
1 3.  
I N T E RI M A N A L Y S E S A N D D A T A M O NI T O RI N G 
W h e n all s u bjects ha ve c o m plete d t hree m o nt hs of treat me nt, t he S p o ns or bi ostatisti cal 
re pres e ntati ve will u n mas k t he st u d y t o a nal yze t h e 3- m o nt h effic ac y a n d safet y data.  N o ot her 
st u d y pers o n n el ot h er t h a n t he bi ostatisti cia n; S A S pr o gra m m ers; a n d 
 
 
 
 will b e u n mas ke d t o t he i n di vi d ual s u bject treat m e nt 
assi g n me nts a n d d e m o gra p hic i nf or mati o n t o perf or m t he 3- m o nt h effic ac y a n d safet y data 
a nal ysis a n d f urt her e x pl orat or y data a nal ysis as n ecessar y. T his is t h e pri mar y efficac y a nal ysis 
of t he st u d y a n d t heref ore n o al p ha a dj ust me nt f or t his i nteri m a nal ysis will be i m ple me nte d. T he 
i nteri m a nal ysis will be c o m plete d at a n o verall 2-si de d al p ha of 5 %, wit h eac h of t he p air wise 
c o m paris o ns of P G- 3 2 4 t o G A N F O R T.  F or t he efficac y i nt eri m a nal yses, a nal yses will be 
li mite d t o data a vaila ble t hr o u g h 3 m o nt hs of treat m e nt.  A d diti o nall y, ke y a d verse e ve nt 
s u m maries will be li mite d t o data a vaila ble t hr o u g h 3 m o nt hs.   
 
 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 3 9 of 4 4 
1 4.  
C H A N G E S T O T H E A N A L Y S E S P L A N N E D I N T H E P R O T O C O L 
N o c ha n ges t o t he a nal ys es t hat are pl a n ne d i n t he pr ot o c ol. 
  
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 4 0 of 4 4 
1 5.  
R E F E R E N C E S 
U S Fe deral Re gist er. ( 1 9 9 8) I nter nati o nal C o nfere nce o n Har m o nizati o n; G ui da nce f or I n d ustr y: 
Statistical Pri nci pl es f or Cli nical Trials. De part me nt of Healt h a n d H u ma n S er vices: F o o d a n d 
Dr u g A d mi nistrati o n.  Fe deral Re gister, V ol. 6 3, N o. 1 7 9, Se pte m ber 1 6, 1 9 9 8, pa ge 4 9 5 8 3. ( E 9) 
 
U S Fe deral Re gist er. ( 1 9 9 6) I nter nati o nal C o nfere nce o n Har m o nizati o n; G ui da nce f or I n d ustr y: 
Str uct ure a n d C o nte nt of Cli nical St u d y Re p orts. De p art m e nt of Healt h a n d H u ma n Ser vices: 
F o o d a n d Dr u g A d mi nistrati o n.  Fe deral Re gister V ol. 6 1, J ul y 1 7, 1 9 9 6, p a ge 3 7 3 2 0. ( E 3) 
 
 
 


Aerie P har mac e uticals Irela n d Lt d.
C O N FI D E N TI A L
Statistical A nal ysis Pla n
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3 
 
2 6 A u g ust 2 0 2 0 
Versi o n 2. 0 
 
P a ge 4 1 of 4 4 
1 6.  
A P P E N DI C E S 
A p pe n di x 1 Sc he d ul e of Visits a n d E x a mi nati o ns  
 
 
D a y ( D)/ Wee k ( W)/ 
M o nt h ( M) 
 
Scree ni n g  
Q u al. # 1 
( D a y - 7 
t o - 2) 
 
Q u al. # 2 D 1 
 
W 2 ( D a y 1 5 ± 3)  
 
W 6 ( D a y 4 3 ± 3)  
 
M 3 ( D a y 9 0 ± 3)  
M 4 
( D a y 1 2 0 ± 3),  
M 5 
( D a y 1 5 0 ± 3) 
 
M 6 
( D a y 1 8 0 ± 7) 
Visit  
1  
2  
3. 0  
3. 1  
3. 2  
4. 0  
4. 1  
4. 2  
5. 0  
5. 1  
5. 2  
6. 0  
6. 1  
6. 2  
7. 0 + 8. 0  
9. 0  
H o ur ( X Y = X Y: 0 0)  
 
0 8  
0 8  
1 0  
1 6  
0 8  
1 0  
1 6  
0 8  
1 0  
1 6  
0 8  
1 0  
1 6  
1 0  
1 0  
I nf or me d C o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ E xcl usi o n 
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
Was h o ut
1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p h y  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dical/ O p ht hal mic Hist or y  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt M e dicati o ns  
X  
X  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
X  
H R/ B P  
X  
X  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
X  
Uri ne Pre g na nc y T est 1 1  
X  
X  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
X  
Cli nical La bs ( C he m/ He m) 2  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
S y m pt o ms/ A Es 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vis ual Ac uit y ( E T D R S)  
X  
X  
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
X  
I O P4  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Bi o micr osc o p y  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
G o ni osc o p y 5/ P ac h y metr y6  
G/ P  
 
 
 
 
 
 
 
 
 
 
P  
 
 
 
P  
Vis ual Fiel d 7 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
O p ht hal m osc o p y ( dil ate d)  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
X  
C u p: disc rati o  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
X  
E ye- Dr o p I nstillati o n 
E val uati o n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
V F Q -2 5 q uesti o n naire  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
S F -3 6 v. 2 q uesti o n naire  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
St u d y M e dicati o ns Dis p e nse d 9   
 
 
 
X  
 
 
X  
 
 
X  
 
 
X  
X  
 
St u d y M e dicati o ns C ollecte d 8  
 
 
 
 
 
X  
 
 
X  
 
 
X  
 
 
X  
X  
St u d y C o m plete d  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 


Aerie P har mac e uticals Irela n d Lt d.
C O N FI D E N TI A L
Statistical A nal ysis Pla n
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3 
 
2 6 A u g ust 2 0 2 0 
Versi o n 2. 0 
 
P a ge 4 2 of 4 4 
 
A b bre viati o ns: D = D a y; W = Wee k; M = M o nt h; H R/ B P = h eart rate/ bl o o d press ure; C he m/ He m = C he mistr y/ He m at ol o g y; A = 
Earl y Treat me nt of 
Dia betic Reti n o pat h y St u d y; I O P = I ntra o c ular press ure; G = G o ni osc o p y; P = Pac h y m etr y; Self- A d mi n = Self- A d mi nistere d 
E arl y Disc o nti n u ati o n : Visit 9. 0 pr oce d ures are t o be c o m pl ete d pl us a dil ate d o p ht hal m osc o p y e x a mi nati o n. 
Visit Re q uire me nts : I O P meas ure me nts at all visits are t o be ma de wit hi n ± 1 h o ur of t he pr ot oc ol- s pecifi e d ti mes of 0 8: 0 0, a n d ± ½ 
h o ur of 1 0: 0 0 a n d 1 6: 0 0 h o urs wit h t he e x ce pti o n of t he scree ni n g visit. 
 
1. 
S u bjects m ust u n d er g o a mi ni m u m was h o ut p eri o d of c urre nt o c ular h y p ote nsi ve me dicati o n(s). 
2. 
F or s u bjects w h o are u n a ble or u n willi n g t o h a ve bl o o d dra w n f or cli nical la bs at Visit 1 (scree ni n g), t h e bl o o d sa m ple ma y b e dra w n at Visit 2 ( Q u alifi cati o n Visit # 1) or 
d uri n g t h e was h o ut p eri o d at a visit w here i nteri m I O P meas ure me nts are b ei n g p erf or me d s o l o n g as t h e res ults of t h e cli nical la bs are a vaila ble f or t h at s u bject pri or t o Visit 
3 ( Q ualificati o n Visit # 2). 
3. 
Oc ular s y m pt o ms: S u bjects will b e q u erie d at eac h visit 
 are y o u 
 a n d treat me nt e mer g e nt A Es be gi n ni n g at Visit 4 ( Q u alificati o n Visit # 2) will b e 
d o c u me nte d o n t h e A E f or m. A d diti o n al s y m pt o ms re p orte d after s cree ni n g a n d b ef ore ra n d o mizati o n will b e d o c u me nte d o n t h e me dic al hist or y f or m. A Es will b e rec or d e d 
f or e ver y st u d y visit (i.e., at 0 8 0 0, 1 0. 0 0, a n d 1 6: 0 0 h o urs) as nee de d. 
4. 
I n di vi d u als ret ur ni n g at a n u nsc h e d ule d visit wit hi n 1 wee k ar e re q uire d t o o nl y re- me as ure I O P i n b ot h e yes. 
5. 
G o ni osc o p y e val uati o n u p t o 3 m o nt hs pri or t o ra n d o mizati o n is acce pta ble. 
6. 
P ac h y metr y E v al u ati o n at scree ni n g visit or wit hi n o n e wee k pri or t o scree ni n g visit, a n d at M o nt h 3 ( or wit hi n 1 wee k of M o nt h 3 st u d y visit). 
7. 
E ntr y vis u al fiel d e v al uati o n u p t o 3 m o nt hs pri or t o ra n d o mizati o n is acce pta ble. Vis ual fiel d c ollecti o n m ust meet t he re q uire me nt f or a ut o mate d t hres h ol d vis u al fiel d 
assess me nt (e. g., 3 0- 2 or 2 4- 2 H u m p hre y or Oct o p us peri metr y) a n d reli a bilit y. 
8. 
C ollect use d kit(s) dis p e nse d d uri n g t he pre vi o us visit. 
9. 
P er Secti o n 5. 2 a n d 5. 3, s u bjects are re q uire d t o a d mi nister I P o n all d a ys of t h e st u d y, i n cl u di n g d a ys of st u d y visits. I n a d diti o n, per secti o n 7. 1. 5 I P will b e dis p e ns e d 
wit hi n 4 8 h o urs of t he ra n d o mizati o n visit. 
10. At t h e i n vesti gat or s discreti o n p h ot o gra p h y of o c ular e ve nts, s uc h as c or n eal verticillata, c o nj u n cti val he m orr h a ge. 
11. F or w o me n of c hil d beari n g p ote ntial, a pre g n a n c y test will b e p erf or me d e ver y 4 wee ks d uri n g st u d y p artici pati o n. T his will i n cl u d e a pre g n a n c y test d uri n g t he was h o ut 
p eri o d, if t h e was h o ut peri o d e xte n ds be y o n d 4 wee ks. 
 
 
 
 
 
 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 4 3 of 4 4 
1 7.  
A T T A C H M E N T S 
 
P G 3 2 4- C S 3 0 3 Listi n g S hells 
 
P G 3 2 4- C S 3 0 3 Ta bl e S h ells 
 
 


Aerie P har mac e uticals Irela n d Lt d. 
C O N FI D E N TI A L  
Statistical A nal ysis Pla n 
Pr ot o c ol N o. P G 3 2 4- C S 3 0 3
2 6 A u g ust 2 0 2 0
Versi o n 2. 0 
 
P a ge 4 4 of 4 4 
1 8.  R E VI SI O N HI S T O R Y 
D oc u m e ntati o n of re visi o n t o t he S A P will c o m me nce after a p pr o val of t he Fi nal versi o n 1. 0. 
Secti o n # 
Descri pti o n of C ha n ge  
Rati o nale 
2. 6 
2 0 0 i nte nt-
t o-treat s u bjects per ar m
 
C ha n ge b ase d o n pr ot o c ol a me n d 6 
4. 2 
T his 
p o p ulati o n will be t h e 
pri mar y p o p ulati o n f or 
effic ac y a nal yses
 
C ha n ge b ase d o n pr ot o c ol a me n d 6 
4. 3 
T his 
p o p ulati o n will be t h e 
sec o n dar y p o p ul ati o n f or 
effic ac y a nal yses a n d will 
be use d t o s u m marize a 
s u bset of efficac y 
varia bles
 
C ha n ge b ase d o n pr ot o c ol a me n d 6 
5. 2  
A d de d C O VI D- 1 9 relat e d 
pr ot oc ol de vi ati o ns t o 
s u bject dis p ositi o n s u m mar y 
ta ble a n d a se p arate listi n g 
C ha n ge b ase d o n F D A G ui da nce f or Statistical 
C o nsi d erati o ns f or Cli nical Trials D uri n g 
C O VI D- 1 9 P u blic Healt h E mer ge nc y 
8. 3, Ta ble 
8- 1, 8. 4 
U p date d t he pre vi o us 
I T T/ P P p o p ulati o n t o be 
P P/I T T p o p ulati o n 
P o p ulati o n s witc he d base d o n pr ot oc ol a me n d 6 
9. 4  
A d de d C O VI D- 1 9 relat e d 
A E a n d S A E listi n gs 
C ha n ge b ase d o n F D A G ui da nce f or Statistical 
C o nsi d erati o ns f or Cli nical Trials D uri n g 
C O VI D- 1 9 P u blic Healt h E mer ge nc y 
9. 6. 5  
M ore descri pti o ns of 
s u m mar y ta bl es f or 
c o nj u ncti val h y p ere mia 
A d de d f or a nal ysis c o m plete ness