Clinical trial NCT04910100
Conditions: Open-Angle Glaucoma Ocular Hypertension
Sponsor: Betaliq, Inc.
Start date: 2021-04-15; Completion date: 2022-04-29
Enrollment: 226 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the safety (in the eye and throughout the body) and effectiveness of nebivolol (0.5 and 1 percent) and timolol (0.5 percent) eye drop suspensions. These eye drops will be compared to timolol 0.5 percent eye drop solution in participants with open angle glaucoma (the most common type of glaucoma) or high eye pressure (ocular hypertension).

Detailed description:
The study will enroll 240 participants (60 in each treatment arm) who will be treated for 84 days (12 weeks). Participants will have OAG (open angle glaucoma) or OHT (ocular hypertension) in both eyes (OAG in one eye and OHT in the follow eye is acceptable) that requires therapy and elevated IOP (intraocular pressure) adequately controlled on no more than 2 ocular hypertensive medications. Participants with OHT on no ocular hypotensive medications are acceptable. After being informed about the study and potential risks, participants giving written informed consent will undergo an washout period, if required, from previous glaucoma medications (28 days for prostaglandin analogs, rho-associated protein kinase inhibitors, or beta blockers; 14 days for adrenergic agonists; and 5 days for muscarinic agonists or carbonic anhydrase inhibitors). Eligible participants must have unmedicated IOP measurements at Visit 3/Baseline ≥ 22 and ≤ 34 mm Hg at 8:00 AM and ≥ 18 and ≤ 34 mm Hg at 10:00 AM and 4:00 PM (each qualifying eye must fall within the required IOP range at all 3 time points and must be at least 22 mm Hg at each consecutive measurement at the 8:00 AM time point). Both eyes will be treated twice daily. Study visits will comprise Visit 1/Screening/Day -35 to -1, Visit 2/Washout Safety Check/Day -14 ± 3 (performed for participants undergoing 28-day washout periods at the Investigator's discretion), Visit 3/Qualification/Baseline/Day 1, Visit 4/Day 15 ± 3, Visit 5/Day 42 ± 3, and Visit 6/Day 84 ± 3. At Visits 4, 5, and 6, participants will be evaluated at 8:00 AM, at 2 hours after study medication dosing at the clinical site (approximately 10:00 AM), and at 4:00 PM (each ± 30 minutes). All ophthalmic assessments will be performed bilaterally.

Arms: arm 1: Administered twice daily to both eyes for 84 days (12 weeks) arm 2: Administered twice daily to both eyes for 84 days (12 weeks) arm 3: Administered twice daily to both eyes for 84 days (12 weeks) arm 4: Administered twice daily to both eyes for 84 days (12 weeks)
Interventions: intervention 1: Nebivolol Ophthalmic Suspension 1 Percent intervention 2: Nebivolol Ophthalmic Suspension 0.5 Percent intervention 3: Timolol Ophthalmic Suspension 0.5 Percent intervention 4: Timolol Ophthalmic Solution 0.5 Percent
Intervention descriptions: intervention 1: 1 drop instilled into each eye twice daily intervention 2: 1 drop instilled into each eye twice daily intervention 3: 1 drop instilled into each eye twice daily intervention 4: 1 drop instilled into each eye twice daily

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE 
  
BTQ-1901-1902-201 
A Randomized, Multicenter, Observer-Masked Study to 
Compare the Safety and Efficacy of BTQ-1901-A,  
BTQ-1901-B, and BTQ-1902 to Timolol 0.5% in Subjects 
with Primary Open Angle Glaucoma or Ocular 
Hypertension 
Study Phase: 
Phase 2 
Product Names: 
BTQ-1901 (nebivolol) ophthalmic suspension, 0.5% and 1.0% 
BTQ-1902 (timolol) ophthalmic suspension, 0.5% 
Protocol Number: 
BTQ-1901-1902-201 
Indication: 
Treatment of elevated intraocular pressure (IOP) in patients with 
ocular hypertension or open-angle glaucoma  
IND: 
145479 
Sponsor: 
Betaliq, Inc. 
Sponsor’s Medical 
Consultant 
Kenneth Sall, MD 
Medical Monitor: 
Robert David, MD 
Protocol Version: 
Original Protocol: 01 June 2020 
 
 
 
 
 


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SIGNATURE PAGE 
Sponsor’s Approval 
The protocol has been approved by Betaliq, Inc. 
 
 
 
Barry Butler, MBA 
Chief Executive Officer 
Betaliq, Inc. 
 
 
 
 
 
Date 
Kenneth Sall 
Medical Consultant to Betaliq, Inc. 
 
 
 
 
 
Date 
 


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INVESTIGATOR’S AGREEMENT 
 
I have read the BTQ-1901-1902-201 protocol. The signature below constitutes the approval of 
this protocol and the attachments, and provides the necessary assurances that this trial will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality, and in compliance with International Conference of Harmonisation (ICH) 
Guidelines, and all applicable United States (US) Federal Regulations and local legal and 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information  
Clinical Study Leader 
Cynthia Rivali 
701-690-3366 (C) 
830-626-8002 (Fax) 
Medical Monitor 
Robert David, MD 
949-246-8368 (C) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: 
Betaliq, Inc. 
Names of Investigational Products: 
 s 
Names of Active Ingredients: 
BTQ-1901: Nebivolol 0.5% and 1.0%; BTQ-1902: Timolol 0.5% 
Protocol Number:  
BTQ-1901-1902-201 
Phase:  
2 
Country:  
United States 
Title of Study: A Randomized, Multicenter, Observer-Masked Study to Compare the Safety and 
Efficacy of BTQ-1901-A, BTQ-1901-B, and BTQ-1902 to Timolol 0.5% in Subjects with Primary 
Open Angle Glaucoma or Ocular Hypertension  
Study center(s): Up to 20 sites in the United States 
Studied period (years):  
Estimated date first patient enrolled: September 2020 
Estimated date last patient completed: June 2021 
Phase of development:  
2 
Objectives: To evaluate ocular and systemic safety and the efficacy of BTQ-1901-A,  
BTQ-1901-B, and BTQ-1902 ophthalmic suspensions in comparison to timolol 0.5% ophthalmic 
solution in subjects with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). 
Methodology: This will be a randomized, multicenter, parallel-group, observer-masked study with 
approximately 240 subjects who will be treated for 84 days (12 weeks).  
Adult subjects will have POAG or OHT in both eyes (presence of POAG in one eye and OHT in the 
fellow eye is acceptable) that requires therapy and elevated intraocular pressure (IOP) adequately 
controlled, in the opinion of the Investigator, on no more than 2 ocular hypotensive medications 
(fixed dose combinations count as 2 medications). Subjects with OHT on no ocular hypotensive 
medication are acceptable. If required, subjects will participate in a minimum washout period of 
28 days for prostaglandin analogs, rho-associated protein kinase (ROCK) inhibitors, or beta (β) 
blockers, 14 days for adrenergic agonists, and 5 days for muscarinic agonists or carbonic anhydrase 
inhibitors (CAIs). A mid-washout onsite safety check may be conducted for subjects undergoing a 
28-day washout period, at the Investigator’s discretion. At Visit 3/Qualification/Baseline (Day 1), 
eligible subjects must have unmedicated IOP measurements ≥ 22 and ≤ 34 mm Hg at 8:00 AM and  
≥ 18 and ≤ 34 mm Hg at 10:00 AM and 4:00 PM in the same eye(s) qualifying at the 8:00 AM time 
point. The IOP must be at least 22 mm Hg at each consecutive measurement at the 8 AM time point. 
At Visit 3, IOP will be taken bilaterally at 8:00 AM, 10:00 AM, and 4:00 PM (each ± 30 minutes). 
Even if only one eye meets all inclusion/exclusion criteria, both eyes will be treated.  
Eligible subjects will be randomized in a 1:1:1:1 ratio into 1 of 4 treatment arms and receive 1 drop in 
each eye twice daily (BID), morning and evening, for 84 days: 
• 
BTQ-1901-A (nebivolol 0.5%) ophthalmic suspension (N = 60) 
• 
BTQ-1901-B (nebivolol 1.0%) ophthalmic suspension (N = 60) 
• 
BTQ-1902 (timolol 0.5%) ophthalmic suspension (N = 60) 
• 
Timolol 0.5% ophthalmic solution (N = 60) 


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Methodology (Continued): 
The study will be observer masked. Randomized study medication will be provided in foil pouches 
contained in identical-appearing boxes. The pouches will contain 5 mL multidose bottles for the 
BTQ-1901-A, BTQ-1901-B, and BTQ-1902 treatment arms and 10 mL multidose bottles for the 
timolol 0.5% treatment arm). An unmasked staff member not involved in performing study  
endpoint-related procedures (i.e., IOP measurement) will be responsible for providing dosing 
instructions, dispensing study medication, and conducting study medication accountability and dosing 
compliance assessment. The identity of the study medications will be masked to the Investigator and 
study personnel responsible for study endpoint-related procedures. Moreover, IOP measurements for 
a given subject should be performed by the same Investigator/designee who will be masked to the 
readout of the tonometer, which will be read and entered into the source documentation (whether 
electronic or paper) by a second staff member once the Investigator/designee reaches the correct 
applanation effect in the slit lamp. 
Study visits will be conducted as follows: Visit 1/Screening/Day -35 to -1, Visit 2/Washout Safety 
Check/Day -14 ± 3 (optional, but conducted at the Investigator’s discretion for subjects undergoing 
28-day washout periods), Visit 3/Qualification/Baseline/Day 1, Visit 4/Day 15 ± 3, 
Visit 5/Day 42 ± 3, and Visit 6/Day 84 ± 3. At Visits 4, 5, and 6, subjects will be evaluated for 
efficacy and safety at 8:00 AM, at 2 hours after study medication dosing at the clinical site 
(~10:00 AM), and at 4:00 PM (each ± 30 minutes). All ophthalmic assessments will be performed 
bilaterally. 
Number of Patients (Planned): The sample size is approximately 60 subjects per group, for a total 
of approximately 240 subjects. 
Inclusion Criteria:  
Individuals must meet the following criteria: 
1. Willing and able to understand and sign an informed consent form prior to any study-related 
procedures. 
2. Able to administer or have a caregiver accurately administer an eye drop. 
3. 18 years of age or older, male, or female. 
4. Have POAG or OHT in both eyes that requires therapy for IOP and is adequately controlled, 
in the opinion of the Investigator, on no more than 2 ocular hypotensive medications (fixed 
dose combinations count as 2 medications). Subjects with OHT on no ocular hypotensive 
medication are acceptable. Presence of POAG in one eye and OHT in the fellow eye is 
acceptable.  
5. Able, in the opinion of the Investigator, to safely discontinue use of ocular hypotensive 
medications, if applicable, and undergo the appropriate required washout period for ocular 
hypotensive medications prior to Visit 3/Qualification/Baseline. 
6. At Visit 3/Qualification/Baseline, at least one eye must have unmedicated (post washout) IOP 
≥ 22 and ≤ 34 mm Hg at 8:00 AM, and ≥ 18 and ≤ 34 mm Hg at 10:00 AM and 4:00 PM (in 
the same eye[s] qualifying at the 8:00 AM time point). The IOP must be at least 22 mm Hg at 
each consecutive measurement at the 8:00 AM time point. 
7. No significant visual field (VF) loss, defined as a mean deviation in either eye greater than 
- 12 dB or a central point of fixation < 5 dB in either eye. If the VF performed at or within 
90 days prior to Visit 1 does not meet study required parameters, it may be repeated (test 
should be prior to randomization at Visit 3/Qualification/Baseline). 


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Inclusion Criteria (continued): 
8. Best corrected visual acuity (BCVA) of +0.6 logMAR or better in both eyes at 
Visit 1/Screening and Visit 3/Qualification/Baseline. 
9. Central corneal thickness ≥ 480 and ≤ 600 μm in both eyes. Pachymetry within 90 days prior 
to Screening is acceptable. 
10. Shaffer gonioscopic grade ≥ 3 (in at least 3 quadrants) in both eyes. Gonioscopy within 
90 days prior to randomization is acceptable.  
11. Female subjects must be 1-year postmenopausal, surgically sterilized (total hysterectomy, 
bilateral oophorectomy or bilateral tubal ligation > 90 days prior to Visit 1/Screening), or 
women of childbearing potential with a negative urine pregnancy test at Visit 1/Screening and 
Visit 3/Qualification/Baseline who are not breastfeeding or planning a pregnancy during the 
study. Women of childbearing potential must use an acceptable form of contraception 
throughout the study. Acceptable methods include the use of at least one of the following:  
• 
Intrauterine (IUD) device,  
• 
Hormonal contraceptive (oral, injection, patch, implant, ring); subjects must have 
been on the same hormonal contraceptive for ≥ 90 days prior to Visit 1/Screening 
• 
Double barrier method (spermicide used with either a condom or diaphragm),  
• 
Abstinence 
Exclusion Criteria 
Ocular 
1. Intraocular pressure ˃ 34 mm Hg in either eye at Visit 1/Screening, Visit 2/Washout Safety 
Check, or Visit 3/Qualification/Baseline. 
2. Other forms of glaucoma in either eye, e.g., congenital glaucoma, closed-angle glaucoma, 
uveitic glaucoma, pseudoexfoliation or pigment dispersion syndrome, or history of angle 
closure. Narrow angles treated with peripheral iridotomy are allowed if at least 4 months 
status post iridotomy. 
3. Current or recent (within 30 days prior to Visit 1/Screening) clinically significant ocular 
infection or inflammation, in the opinion of the Investigator, in either eye.  
4. History of conjunctivitis within 90 days prior to Visit 1/Screening, or history of herpes 
simplex or herpes zoster in either eye. 
5. Clinically significant ocular disease, in the opinion of the Investigator, in either eye 
(including, but not limited to corneal edema, uveitis, severe dry eye, proliferative diabetic 
retinopathy or macular degeneration) that might interfere with the study, confound study 
results, or put the subject at increased risk. 
6. Have a cup-to disc (CD) ratio > 0.8 at Visit 1/Screening in either eye. 
7. Intravitreal steroid injections within 6 months prior to Visit 1/Screening. Subconjunctival or 
subtenon steroid injections within 90 days prior to Visit 1/Screening.  
8. Use of topical ocular medications within 30 days prior to Visit 1/Screening other than ocular 
hypotensive medications and medications used as part of an eye examination (see Table 3). 
Artificial tears may be used during this period provided the use is not required for severe dry 
eye disease. 


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Exclusion Criteria 
Ocular (continued): 
9. Clinically significant ocular trauma or incisional ocular surgery (including routine cataract 
surgery) in either eye within 6 months prior to Visit 1/Screening. Glaucoma filtering surgery 
or minimally invasive glaucoma surgery within 12 months prior to Visit 1/Screening. Laser 
surgery for IOP reduction within 6 months prior to Visit 1/Screening. Non-incisional ocular 
surgery or non-glaucomatous laser treatment within 90 days prior to Visit 1/Screening. 
10. Refractive surgery in either eye (i.e., radial keratotomy, photorefractive keratectomy [PRK], 
laser-assisted in situ keratomileusis [LASIK], corneal cross-linking, limbal relaxing incision) 
within 6 months prior to Visit 1/Screening. 
11. Any ocular (e.g., corneal) abnormality preventing accurate assessment of IOP. 
12. Contact lens wear within 1 week prior to Visit 1/Screening or unwillingness to discontinue 
wear of contacts lenses prior to and during the study period. 
13. Aphakia. 
General 
14. Pregnancy or lactation. 
15. Known hypersensitivity or contraindication to β-blockers (i.e., chronic obstructive pulmonary 
disease, bronchial asthma, unstable or abnormally low blood pressure or heart rate, second or 
third degree heart block or congestive heart failure, severe or unstable diabetes mellitus) that 
in the opinion of the Investigator may put the subject at risk from a topical ocular β-blocker. 
16. Have a condition or be in a situation which, in the Investigator’s opinion, may put the subject 
at significant risk, confound study results, or interfere with the subject’s participation in the 
study. 
17. Clinically significant systemic disease (myasthenia gravis, hepatic, renal, endocrine, or 
cardiovascular disorders) that in the opinion of the Investigator might interfere with the study. 
18. Use of systemic β-adrenergic antagonists unless the dosage has been stable for 1 month prior 
to Visit 1/Screening and is expected to remain stable through the study period. 
19. Use of systemic (oral, injectable, inhaled) or topical steroids within 30 days prior to 
Visit 1/Screening. Topical dermatologic or intranasal steroids are acceptable provided the 
usage meets the criteria outlined in the Summary of Prohibited Medications and Procedures 
in Table 3. 
20. Contraindication to the use of timolol, nebivolol, or any of the components of the 
investigational products. 
21. Changes to systemic medication that could have an effect on IOP within 28 days prior to 
Visit 3/Qualification/Baseline. 
22. Participation in any study of an investigational product within 30 days prior to 
Visit 1/Screening. 
23. History of substance abuse within 1 year prior to Visit 1/Screening. 
24. Screening and enrollment of employees or relatives of employees of the clinical site. 
Investigational Product, Dosage and Mode of Administration:  
BTQ-1901-A (nebivolol 0.5%) or BTQ-1901-B (nebivolol 1.0%) or BTQ-1902 (timolol 0.5%) 
ophthalmic suspension, 1 drop in each eye BID 


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Reference Therapy, Dosage and Mode of Administration: 
Timolol 0.5% ophthalmic solution, 1 drop in each eye BID 
Duration of Treatment:  
Twelve (12) weeks (84 days) 
Criteria for Evaluation: 
Efficacy: Efficacy will be assessed in the study eye at each visit by IOP values at each timepoint as 
measured by Goldmann applanation tonometry. 
Safety: Safety will be assessed at each visit by LogMAR VA, slit lamp examination, resting heart rate 
(HR)/blood pressure (BP), and adverse event (AE) collection. Ophthalmoscopy/dilated fundus 
examination and VF testing will occur at Visit 1/Screening and Visit 6/Day 84 (note: VF testing is not 
mandated at Visit 1/Screening if a test meeting the protocol requirements was performed and the 
results were documented within 90 days prior to Visit 1/Screening). 
Safety/Tolerability Assessments: 
Subjective comfort/tolerability data (i.e., rating of drop comfort as assessed by the subject) will be 
collected at Visit 3/Qualification/Baseline (Day 1), and at each post baseline visit. Conjunctival 
hyperemia will be assessed by the Investigator using the McMonnies photographic scale at 
Visit 3/Qualification/Baseline and at each post baseline visit. 
Pharmacokinetics: 
Plasma concentration will be measured in a subset of 40 subjects; blood samples will be collected 
following dosing at Visit 4/Day 15 and Visit 6/Day 84. 
Study Endpoints: 
Primary Efficacy Endpoint: IOP values at each time point (8:00 AM, 2 hours after study medication 
dosing at the clinical site [~10 AM], 4:00 PM) at Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84.  
Secondary Efficacy Endpoints:  
• 
Change from baseline (Visit 3/Qualification/Baseline) in the average of the 3 daily IOP 
measurements at each post baseline visit. 
• 
Time-matched change from baseline (Visit 3/Qualification/Baseline) in IOP measurements at 
all time points at Visit 4/Day 15, Visit 5/Day 42 and Visit 6/Day 84. 
Statistical Methods: 
Primary efficacy analysis will be conducted on the per protocol (PP) population (those subjects in the 
intent to treat [ITT] population who were both randomized and dosed and who had no major protocol 
deviations). Efficacy analyses will also be conducted on the ITT population. Safety analyses will be 
performed using the safety analysis set (all randomized subjects who received at least one dose of the 
allocated study medication). 
The primary efficacy analysis will be the between-group comparison of the mean IOP values in the 
study eye at each time point at each of the Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84 visits 
(ie, a total of 9 between-group comparisons). A hierarchical analysis will be conducted to compare 
each of the investigational products against the comparator, timolol 0.05%, as follows: (1) BTQ-1902, 
(2) BTQ-1901B, and (3) BTQ-1901A. To demonstrate noninferiority, the upper limits of the 2-sided 
95% confidence interval (CI) for the difference between each comparison should be lower than 
1.5 mm Hg at all timepoints. Additionally, the upper limits of the 95% CI should be lower 
than 1.0 mm Hg for the majority of time points measured (ie, 5 of 9). 


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Statistical Methods (continued): 
All other efficacy, safety, tolerability and pharmacokinetic variables will be analysed using 
appropriate statistical techniques and summarized descriptively. Full details will be provided in the 
Statistical Analysis Plan. 
Sample Size Justification:  
The sample size is not based on a formal sample size calculation; this study is planned to provide 
sufficient data to power the Phase 3 study. 


 s 
 
Betaliq, Inc. 
Protocol Synopsis BTQ-1901-1902-201 
 
IND 145504 
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Table 2: 
Schedule of Procedures 
Screen-
ing 
Washout 
Safety 
Checka 
Qualification/ 
Baseline 
Treatment 
Day 
-35 to -1 
-14 ± 3 
1 
15 ± 3 
42 ± 3 
84 ± 3 
Visit 
1 
2 
3 
4 
5 
6 
Hourb 
 
8:00 
AM 
10:00 
AM 
4:00
PM 
8:00
AM 
2 h 
post 
dose 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
Informed consent 
X 
 
Medical/ophthalmic 
history 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
Urine pregnancy testd 
X 
 
X 
X 
HR/BPe 
X 
 
X 
X 
X 
X 
BCVA (logMAR) 
X 
X 
X 
X 
X 
X 
Grading conjunctival 
hyperemiaf 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biomicroscopy 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOPg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual field testh 
X 
 
X 
Gonioscopyi 
X 
 
Pachymetryj 
X 
 
Dilated ophthalmoscopy 
X 
 
X 
Review eligibility 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood collection (PK)k 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 


 s 
 
Betaliq, Inc. 
Protocol Synopsis BTQ-1901-1902-201 
 
IND 145504 
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Table 2: 
Schedule of Procedures 
Screen-
ing 
Washout 
Safety 
Checka 
Qualification/ 
Baseline 
Treatment 
Day 
-35 to 
-1 
-14 ± 3 
1 
15 ± 3 
42 ± 3 
84 ± 3 
Visit 
1 
2 
3 
 
 4 
5 
6 
Hourb 
- 
- 
8:00 
AM 
10:00 
AM 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
Study medication 
dispensed/redispensed 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Drop instillation/ 
instruction/evaluation 
 
X 
Xl 
Xl 
Xl 
Drop comfort ratingm 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
Study medication 
accountabilityn 
 
X 
X 
X 
X 
Compliance assessmento 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
BP = blood pressure; HR = heart rate: IOP = intraocular pressure; IP = investigational product; PK = pharmacokinetics 
NOTE: Subjects using ocular hypotensive medications must have undergone the appropriate required washout period prior to Visit 3/Qualification/Baseline. 
NOTE: If a study subject is discontinued from study medication before Visit 6/Day 84 but after Visit 3/Qualification/Baseline/Day 1, every effort should be 
taken to perform all the procedures listed for Visit 6/Last Day of Treatment (Section 10.4.3). If the subject is willing to remain at the site for the 8-hour visit, it 
should be conducted as specified, but if the subject is not willing to remain for the full duration, the VF test and the dilated ophthalmoscopy should be conducted 
as the last ophthalmic assessments in the early discontinuation visit. 
a Mid-washout safety check for subjects undergoing 28-day washout periods (i.e., prior prostaglandin analogs, rho-associated protein kinase [ROCK] inhibitors, 
or β-blockers) may be performed at the Investigator’s discretion. 
b The window for each time point is ± 30 minutes. For Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84, the 2 h post-dose timepoint will fall around 
10:00 AM, but the timing of the IOP measurement is dependent on the time study medication was administered at the site that day and should be 2 hours 
(± 30 minutes) after the dose was administered. 
c All AEs that occur following consent and until the final study visit (Visit 6/Day 84) should be collected and recorded on the AE eCRF page. 
d Required only for women of childbearing potential. At Visit 3/Qualification/Baseline/Day 1 it must be performed prior to randomization. At Visit 6/Day 84 it 
may be performed anytime. 
e HR and BP will be measured seated after at least 5 minutes rest. Vital signs may be repeated once, after at least an additional 5 minutes rest in the seated 
position, if they are out of range. 


 s 
 
Betaliq, Inc. 
Protocol Synopsis BTQ-1901-1902-201 
 
IND 145504 
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f It is preferred that conjunctival hyperemia be graded as part of the external eye exam performed prior to biomicroscopy. 
g At Visit 3/Qualification/Baseline, IOP will be taken bilaterally at 8:00 AM, 10:00 AM, and 4:00 PM (each ± 30 minutes). At Visits 4, 5, and 6, IOP will be 
taken bilaterally at 8:00 AM, 2 hours after study medication dosing at the clinical site (~10:00 AM), and at 4:00 PM (each ± 30 minutes). Two consecutive IOP 
measurements of each eye will be performed. If the 2 measurements differ by more than 2 mm Hg, a third measurement will be taken. Consult the Study 
Manual for specific details. 
h Visual field measurement may be performed within 90 days prior to Screening if a test meeting the protocol requirements was performed and the results were 
documented. If the VF performed at or within 90 days prior to Visit 1 does not meet study required parameters, it may be repeated (test should be prior to 
randomization at Visit 3/Qualification/Baseline).The procedure may be performed at any time during the visit prior to dilation for ophthalmoscopy. 
i Gonioscopy may be performed within 90 days prior to Screening. The procedure must be performed after IOP measurement and before dilation for 
ophthalmoscopy. 
j Pachymetry may be performed within 90 days prior to Screening. The procedure may be performed at any time during the visit after IOP measurement. 
k Plasma concentration will be measured in a subset of 40 subjects; samples will be collected 2 hours (± 30 minutes) after study medication dosing at the clinical 
site. 
l Dose instillation should occur as close as possible to 15 minutes after IOP measurement, but not before 10 minutes after IOP measurement. Artificial tear use is 
prohibited within 10 minutes of instillation of study medication. 
m Subjects will be asked to rate the tolerability of the drop according to the following 4-point scale: 0 = No discomfort, 1 = Mild discomfort, 2 = Moderate 
discomfort, 3 = Severe discomfort. This rating should take place ≥ 10 minutes after the IOP measurement. 
n Study medication accountability may be performed at any time during the visit. 
o Compliance will be monitored via subject-reported missing doses in the Missed Doses Log. Documentation of compliance may be performed at any time 
during the visit. 


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Table 3: 
Summary of Prohibited Medications and Procedures 
Duration of Restrictions 
Medications/Procedures 
Ocular 
12 months prior to 
Visit 1/Screening and throughout 
the study period 
Glaucoma filtering surgery, minimally invasive glaucoma surgery 
6 months prior to 
Visit 1/Screening and throughout 
the study period 
Refractive surgery in either eye (i.e., radial keratotomy, photorefractive 
keratectomy [PRK], laser-assisted in situ keratomileusis [LASIK], corneal 
cross-linking, limbal relaxing incision). 
Incisional ocular surgery (including routine cataract surgery)  
Laser surgery for IOP reduction 
Intravitreal steroid injections 
4 months prior to 
Visit 1/Screening 
Peripheral iridotomy for narrow angles  
90 days prior to Visit 1/Screening 
and throughout the study period 
Subconjunctival, subtenon steroid injections 
30 days prior to Visit 1/Screening 
and throughout the study period 
Topical ocular medications other than ocular hypotensives and 
medications used as part of an eye examination (including but not limited 
to topical ocular corticosteroids, immunomodulators, NSAIDs, antibiotics, 
immunosuppressants, antihistamines, antivirals, and LFA-1 antagonists).  
Artificial tears are allowed if not required for severe dry eye disease. See 
Study Manual for details.  
At least 28 days prior to Visit 3/ 
Qualification/Baseline and 
throughout the study period 
Prostaglandins/ROCK inhibitors/β-blockers must be washed out for a 
minimum of 28 days prior to Visit 3/Qualification/Baseline. See Study 
Manual for details. 
At least 14 days prior to Visit 3/ 
Qualification/Baseline and 
throughout the study period 
Adrenergic agonists must be washed out for a minimum of 14 days prior to 
Visit 3/Qualification/Baseline. See Study Manual for details. 
7 days prior to Visit 1/Screening 
and throughout the study period 
Contact lens wear 
At least 5 days prior to Visit 3/ 
Qualification/Baseline and 
throughout the study period 
Muscarinic agonists or CAIs must be washed out for a minimum of 5 days 
prior to Visit 3/Qualification/Baseline. At the discretion of the 
Investigator, CAIs may be used during the washout period by any subject 
if the use is discontinued to allow the appropriate required washout for the 
CAI (i.e., 5 days). See Study Manual for details. 
10 minutes prior to IP dosing 
Artificial tears are prohibited within 10 minutes of instillation of IP, but 
otherwise may be used as needed during the study, provided the use is not 
required for severe dry eye disease. 
 
 
 


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Table 3: 
Summary of Prohibited Medications and Procedures (Continued) 
Duration of Restrictions 
Medications/Procedures 
General 
30 days prior to Visit 1/Screening 
and throughout the study period 
Systemic corticosteroids (oral, injectable, inhaled).  
Topical dermatologic steroids are acceptable if used for less than 3 
consecutive days on no more than 3 separate areas of the body within 
30 days of Visit 1/Screening and the dosage is not expected to increase 
during the study. Intranasal steroids are acceptable if used less than or 
equal to 3 times per week within 30 days of Visit 1 and the dosage is not 
expected to increase during the study. See Study Manual for details. 
Any investigational product other than BTQ-1901 and BTQ-1902. 
Within 28 days of 
Visit 3/Qualification/Baseline and 
throughout the study period 
Any change in dosage of systemic medication that could have an effect on 
IOP. See Study Manual for details. 
Throughout the study period 
Systemic β-adrenergic antagonists unless the dose has been stable for 
1 month prior to Visit 1/Screening and is expected to remain stable 
through the study period.  
Abbreviations: BTQ-1901 = nebivolol 0.5% and 1.0% ophthalmic suspensions; BTQ-1902 = timolol 0.5% 
ophthalmic suspension; CAI = carbonic anhydrase inhibitors; IOP = intraocular pressure; IP = investigational 
product; LFA-1 = lymphocyte function-associated antigen 1; NSAID = non-steroidal anti-inflammatory drug; 
ROCK = rho-associated protein kinase 


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2. 
TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................................ 1 
SIGNATURE PAGE ............................................................................................................................ 2 
INVESTIGATOR’S AGREEMENT................................................................................................... 3 
PROCEDURES IN CASE OF EMERGENCY .................................................................................. 4 
1. 
SYNOPSIS ........................................................................................................................ 5 
2. 
TABLE OF CONTENTS ............................................................................................... 16 
3. 
LIST OF ABBREVIATIONS ........................................................................................ 20 
4. 
INTRODUCTION .......................................................................................................... 22 
5. 
STUDY OBJECTIVE .................................................................................................... 24 
5.1. 
Primary Objective ........................................................................................................... 24 
6. 
INVESTIGATIONAL PLAN ........................................................................................ 25 
6.1. 
Overall Study Design and Plan ...................................................................................... 25 
6.2. 
Number of Subjects ........................................................................................................ 26 
6.3. 
Treatment Assignment ................................................................................................... 26 
6.4. 
Criteria for Study Termination....................................................................................... 26 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................... 27 
7.1. 
Inclusion Criteria ............................................................................................................ 27 
7.2. 
Exclusion Criteria ........................................................................................................... 28 
7.3. 
Criteria for Withdrawal from the Study/Criteria for Discontinuation of Study 
Medication....................................................................................................................... 29 
8. 
TREATMENT OF SUBJECTS ..................................................................................... 31 
8.1. 
Description of Study Drugs............................................................................................ 31 
8.2. 
Randomization and Masking ......................................................................................... 31 
8.2.1. 
Unmasking During the Study Period ............................................................................. 31 
8.3. 
Concomitant Medications .............................................................................................. 32 
8.3.1. 
Permitted Medications and Treatments ......................................................................... 32 
8.4. 
Treatment Compliance ................................................................................................... 32 
8.4.1. 
Prohibited Medications................................................................................................... 32 
8.5. 
Study Medication Materials and Management ............................................................. 32 
8.5.1. 
Packaging and Labeling ................................................................................................. 32 
8.5.2. 
Storage and Administration............................................................................................ 33 


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8.5.3. 
Study Medication Accountability .................................................................................. 33 
9. 
STUDY ASSESSMENTS .............................................................................................. 34 
9.1. 
Demographic and Background Characteristics ............................................................. 34 
9.1.1. 
Demographic/Medical History....................................................................................... 34 
9.1.2. 
Concomitant Medications History ................................................................................. 34 
9.1.3. 
Ophthalmic History and Ophthalmic Intervention History .......................................... 34 
9.1.4. 
Urine Pregnancy Test ..................................................................................................... 34 
9.2. 
Efficacy Assessment ....................................................................................................... 34 
9.2.1. 
Intraocular Pressure ........................................................................................................ 34 
9.3. 
Pharmacokinetic Assessments ....................................................................................... 35 
9.4. 
Safety Assessments......................................................................................................... 35 
9.4.1. 
Visual Acuity .................................................................................................................. 35 
9.4.2. 
Biomicroscopy ................................................................................................................ 35 
9.4.3. 
Grading of Conjunctival Hyperemia ............................................................................. 35 
9.4.4. 
Vital Signs ....................................................................................................................... 35 
9.4.5. 
Ophthalmoscopy/Dilated Fundoscopy .......................................................................... 36 
9.4.6. 
Visual Field Testing........................................................................................................ 36 
9.4.7. 
Subjective Grading of Comfort/Tolerability ................................................................. 36 
9.5. 
Adverse and Serious Adverse Events ............................................................................ 36 
9.5.1. 
Definition of Adverse Events......................................................................................... 36 
9.5.1.1. 
Adverse Event (AE)........................................................................................................ 36 
9.5.1.2. 
Serious Adverse Event (SAE) ........................................................................................ 37 
9.5.2. 
Relationship to Study Drug ............................................................................................ 37 
9.5.3. 
Recording Adverse Events ............................................................................................. 38 
9.5.4. 
Reporting Adverse Events.............................................................................................. 38 
10. 
STUDY ACTIVITIES .................................................................................................... 40 
10.1. 
Screening Visit ................................................................................................................ 40 
10.1.1. 
Visit 1/Screening (Day -35 to -1) .................................................................................. 40 
10.2. 
Washout Period ............................................................................................................... 41 
10.2.1. 
Visit 2/Optional Washout Safety Check (Day -14 ± 3)................................................ 41 
10.3. 
Qualification Visit .......................................................................................................... 42 
10.3.1. 
Visit 3/Qualification/Baseline/Day 1 ............................................................................ 42 


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10.4. 
Treatment Visits .............................................................................................................. 43 
10.4.1. 
Visit 4/Day 15 ± 3........................................................................................................... 43 
10.4.2. 
Visit 5/Day 42 ± 3........................................................................................................... 44 
10.4.3. 
Visit 6/Last Day of Treatment (Day 84 ± 3) ................................................................. 45 
10.5. 
Early Discontinuation Assessment Procedures............................................................. 46 
11. 
STATISTICS .................................................................................................................. 47 
11.1. 
General Considerations .................................................................................................. 47 
11.1.1. 
Handling of Missing Data .............................................................................................. 48 
11.2. 
Determination of Sample Size ....................................................................................... 48 
11.3. 
Analysis Populations ...................................................................................................... 48 
11.3.1. 
Populations for Efficacy Analysis ................................................................................. 48 
11.3.1.1. 
Intent-to-Treat (ITT) Population .................................................................................... 48 
11.3.1.2. 
Per-Protocol (PP) Population ......................................................................................... 48 
11.3.2. 
Safety Population ............................................................................................................ 48 
11.4. 
Demographics and Baseline Characteristics ................................................................. 48 
11.5. 
Efficacy Analysis ............................................................................................................ 48 
11.5.1. 
Hypothesis Testing ......................................................................................................... 49 
11.5.2. 
Primary Efficacy Endpoints ........................................................................................... 49 
11.5.3. 
Primary Efficacy Analysis ............................................................................................. 49 
11.5.4. 
Secondary Efficacy Endpoints ....................................................................................... 49 
11.5.5. 
Secondary Efficacy Analysis ......................................................................................... 49 
11.6. 
Safety Analyses............................................................................................................... 49 
11.7. 
Pharmacokinetic Analyses ............................................................................................. 50 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 51 
13. 
ADMINISTRATIVE CONSIDERATIONS ................................................................. 52 
13.1. 
Institutional Review Board (IRB) Approval ................................................................. 52 
13.2. 
Ethical Conduct of the Study ......................................................................................... 52 
13.3. 
Subject Information and Consent .................................................................................. 52 
13.4. 
Subject Confidentiality ................................................................................................... 52 
13.5. 
Study Monitoring ............................................................................................................ 53 
13.6. 
Case Report Forms and Study Records ......................................................................... 54 
13.7. 
Protocol Deviations ........................................................................................................ 54 


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13.8. 
Access to Source Documentation .................................................................................. 54 
13.9. 
Data Generation and Analysis ....................................................................................... 54 
13.9.1. 
Retention of Data ............................................................................................................ 55 
13.10. 
Publication and Disclosure Policy ................................................................................. 55 
14. 
REFERENCES ............................................................................................................... 56 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................... 4 
Table 2: 
Schedule of Procedures .................................................................................................. 11 
Table 3: 
Summary of Prohibited Medications and Procedures .................................................. 14 
 
 


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3. 
LIST OF ABBREVIATIONS 
Abbreviation  
Explanation 
β 
Beta 
AE 
Adverse event 
ANCOVA  
Analysis of covariance  
ANOVA  
Analysis of variance 
BCVA 
Best-corrected visual acuity 
BID 
Twice daily 
BP 
Blood pressure 
BTQ-1901 
Nebivolol 
BTQ-1902 
Timolol 
CAI 
Carbonic anhydrase inhibitor 
CI 
Confidence interval 
CRO 
Clinical research organization 
CS 
Clinically significant 
eCRF 
Electronic case report form 
eDC 
Electronic data capture 
F6H8 
Perfluorohexyloctane 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR  
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IOP 
Intraocular pressure 
ITT  
Intent-to-treat population  
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LASIK 
laser-assisted in situ keratomileusis 
LOCF 
Last observation carried forward 
LogMAR 
Logarithm of the minimum angle of resolution 
MMRM 
Mixed models for repeated measures 
NCS 
Non-clinically significant 


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Abbreviation  
Explanation 
OHT 
Ocular hypertension 
OU 
Both eyes 
PK 
Pharmacokinetics 
POAG 
Primary open angle glaucoma 
PP 
Per protocol population 
PRK 
photorefractive keratectomy 
ROCK 
Rho-associated protein kinase 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOP 
Standard operating procedure 
US 
United States  
VA  
Visual acuity  
VF 
Visual field 
 


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4. 
INTRODUCTION 
BTQ-1901 (nebivolol) and BTQ-1902 (timolol) ophthalmic suspensions are being developed by 
Betaliq, Inc. (the Sponsor) for the treatment of elevated intraocular pressure (IOP) in patients 
with ocular hypertension (OHT) or primary open-angle glaucoma (POAG). Glaucoma is a 
leading cause of blindness worldwide. The global prevalence is estimated to be 64 million people 
in 2013 and it is expected to increase to nearly 112 million in 2040 (Tham et al, 2014).  
Intraocular pressure is balanced between the secretion of aqueous humor by the ciliary body and 
drainage of aqueous humor through 2 independent pathways—the trabecular meshwork and 
uveoscleral outflow pathways. In POAG, the most common form of glaucoma, there is increased 
resistance to aqueous outflow through the trabecular meshwork. The same mechanism applies to 
OHT, in which IOP is elevated without visual field (VF) deficits or clinically apparent damage to 
the optic nerve. Mechanical stress from continued elevated IOP may result in progressive 
damage to the optic nerve, which can result in visual disability leading to blindness.  
Elevated IOP in eyes with POAG is typically treated with topical ophthalmic medications. Many 
patients with OHT are untreated, but topical hypotensive medication has been found effective in 
delaying or preventing the onset of POAG; in the Ocular Hypertension Treatment Study, the 
incidence of OAG after 60 months of follow-up was 9.5% in the observation group vs 4.4% in 
the treated group (Kass et al, 2002). The most frequently used medications are prostaglandin 
analogues, which increase uveoscleral outflow of aqueous humor, and beta(β)-adrenergic 
blockers, which reduce aqueous humor production. While β-blockers are well tolerated locally, 
they may have important systemic adverse events (AEs), such as bronchospasm, decreased heart 
rate, and congestive heart failure, all of which may limit their use. 
The Sponsor is developing two β-blockers, BTQ-1901 and BTQ-1902, in a unique vehicle 
composed of one excipient, the inert and anhydrous semifluorinated alkane, 
perfluorohexyloctane (F6H8). F6H8 is a clear, colorless, chemically inert liquid without 
pharmacologic activity. Both BTQ-1901 and BTQ-1902 are free of other excipients like oils, 
surfactants, buffers, and preservatives, and are administered in a multidose bottle rather than a 
unit dose vial. Due to the low surface tension of F6H8, the resulting eye drops are relatively small, 
with a volume of approximately 11 μL/drop.  
The active ingredient of BTQ-1901 is nebivolol, a β1 selective β-blocker. The chief advantage of 
β1 selectivity is the absence of β2-adrenergic inhibition which minimizes the risk of respiratory 
side effects. Nebivolol also stimulates nitric oxide release via stimulation of the β3 receptor 
which produces a vasodilatory effect (Kuroedov et al, 2004) that may improve blood flow to the 
optic nerve. While extensively used as a systemic blood pressure medication (Bystolic® was 
approved by the United States [US] Food and Drug Administration [FDA] in 2007 [Bystolic 
package insert, 2019]), nebivolol has not been evaluated for ocular use as an ocular hypotensive 
therapy.  
The active ingredient of BTQ-1902 is timolol. Timolol was the first topical ocular β-blocker 
approved by the FDA (1978), and it is still an integral part of the standard of care for glaucoma. 
Utilizing F6H8 as the vehicle for the BTQ-1901 and BTQ-1902 ophthalmic suspensions allows 
development of these products as non-preserved suspensions in a multi-dose bottle, thus 
minimizing tolerability and ocular irritation issues that may arise when eye drops contain 
preservatives or phosphates. This quality may potentially result in fewer ocular AEs. 


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Importantly, it is postulated that the resulting drug products might have less systemic absorption 
and fewer negative systemic AEs because of the smaller drop size. 
Nonclinical pharmacology, pharmacokinetics, and toxicology studies were conducted in support 
of the development of timolol (topical ocular route) and nebivolol (systemic route). Based on the 
results of the 28-day and 6-month repeat dose toxicology studies in albino rabbits, the 
pharmacological and toxicological data for BTQ-1901-A, BTQ-1901-B, and BTQ-1902 are 
considered adequate to support their safe clinical use for this initial Phase 2 clinical trial. There 
were no significant macroscopic or microscopic findings observed in rabbits dosed with 
nebivolol 1.0% ophthalmic suspension (BTQ-1901-B) 4 times daily for 28 days or twice daily 
(BID) for 6 months, or with timolol 0.5% ophthalmic suspension (BTQ-1902) BID for 6 months. 
Moreover, systemic accumulation of nebivolol 1.0% and timolol 0.5% was very low after the 
6-month treatment period (around the lower limits of quantification [LLOQ]). Therefore, ocular 
instillation of BTQ-1901 or BTQ-1902 twice daily to subjects with a maximum clinical 
concentration of 1.0% nebivolol or 0.5% timolol for up to 12 weeks is considered safe for the 
initial Phase 2 clinical study.  
BTQ-1901 and BTQ-1902 ophthalmic suspensions are topical treatments for POAG or OHT that 
have not been previously evaluated in clinical trials. The planned first in human (FIH) study is a 
randomized, multicenter, observer-masked study to compare the safety and efficacy of 
BTQ-1901-A, BTQ-1901-B, and BTQ-1902 to timolol 0.5% ophthalmic solution in subjects with 
POAG or OHT in both eyes over a 12-week (84-day) treatment period. For additional 
information regarding BTQ-1901 and BTQ-1902 ophthalmic suspensions, please refer to the 
Investigator’s Brochure. 


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5. 
STUDY OBJECTIVE 
5.1. 
Primary Objective 
To evaluate ocular and systemic safety and the efficacy of BTQ-1901-A, BTQ-1901-B, and 
BTQ-1902 ophthalmic suspensions in comparison to timolol 0.5% ophthalmic solution in 
subjects with POAG or OHT. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design and Plan 
This will be a randomized, multicenter, parallel-group, observer-masked study to evaluate ocular 
and systemic safety and the efficacy of BTQ-1901-A (nebivolol 0.5%), BTQ-1901-B (nebivolol 
1.0%) and BTQ-1902 (timolol 0.5%) ophthalmic suspensions in comparison to timolol 0.5% 
ophthalmic solution. The study will enroll approximately 240 subjects with POAG or OHT who 
will be treated for 84 days (12 weeks). 
Adult subjects will have POAG or OHT in both eyes (presence of POAG in one eye and OHT in 
the fellow eye is acceptable) that requires therapy and elevated IOP adequately controlled, in the 
opinion of the Investigator, on no more than 2 ocular hypotensive medications (fixed dose 
combinations count as 2 medications). Subjects with OHT on no ocular hypotensive medications 
are acceptable. If required, subjects will participate in a minimum washout period of 28 days for 
prostaglandin analogs, rho-associated protein kinase (ROCK) inhibitors, or beta (β) blockers; 
14 days for adrenergic agonists; and 5 days for muscarinic agonists or carbonic anhydrase 
inhibitors (CAIs). A mid-washout onsite safety check may be conducted, at the Investigator’s 
discretion, for subjects undergoing a 28-day washout period.  
Eligible subjects must have unmedicated IOP measurements at Visit 3/Qualification/Baseline 
≥ 22 and ≤ 34 mm Hg at 8:00 AM and ≥ 18 and ≤ 34 mm Hg at 10:00 AM and 4:00 PM (each 
qualifying eye must fall within the required IOP range at all 3 time points and must be at least 
22 mm Hg at each consecutive measurement at the 8:00 AM time point).  
At least one eye must qualify for the study, but even if only one eye meets all inclusion/exclusion 
criteria, both eyes will be treated. If both eyes qualify, the qualifying eye with the higher IOP at 
8:00 AM at Visit 3/Qualification/Baseline will be designated as the study eye. Should the 
8:00 AM IOP be the same in both eyes, then the right eye will be designated as the study eye.  
A total of 240 eligible subjects will be randomized in a 1:1:1:1 ratio into 1 of 4 treatment arms: 
BTQ-1901-A: nebivolol 0.5% ophthalmic suspension; BTQ-1901-B: nebivolol 1.0% ophthalmic 
suspension; BTQ-1902: timolol 0.5% ophthalmic suspension; and timolol 0.5% ophthalmic 
solution and receive 1 drop in each eye BID, morning and evening, for 84 days. 
Randomized study medication will be provided in foil pouches contained in identical-appearing 
boxes to conceal the differences in presentation (5 mL multidose bottles for the BTQ-1901-A, 
BTQ-1901-B, and BTQ-1902 treatment arms versus 10 mL multidose bottles for the timolol 
0.5% treatment arm). The identity of the study medications will be masked to the Investigator 
and study personnel responsible for endpoint-related study procedures. Moreover, Goldmann 
IOP measurements should be performed by the same Investigator/designee throughout the study 
who will be masked to the readout of the tonometer, which will be read and entered into the 
source documentation (whether electronic or paper) by a second staff member once the 
Investigator/designee reaches the correct applanation effect in the slit lamp.  
Study visits will be conducted as follows: Visit 1/Screening/Day -35 to -1, Visit 2/Washout 
Safety Check/Day -14 ± 3 (conducted for subjects undergoing 28-day washout periods at the 
Investigator’s discretion), Visit 3/Qualification/Baseline/Day 1, Visit 4/Day 15 ± 3, 
Visit 5/Day 42 ± 3, and Visit 6/Day 84 ± 3. At Visits 4, 5, and 6, subjects will be evaluated for 


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efficacy and safety at 8:00 AM, at 2 hours after study medication dosing at the clinical site 
(~10:00 AM), and at 4:00 PM (each ± 30 minutes). All ophthalmic assessments will be 
performed bilaterally.  
The Schedule of Procedures (Table 2) provides a tabular summary of all scheduled visits and 
procedures to be performed during the clinical study. 
6.2. 
Number of Subjects 
A total of 240 subjects are planned: 60 subjects in each treatment arm. 
6.3. 
Treatment Assignment 
The treatment regimens will be as follows: 
• BTQ-1901-A: nebivolol 0.5% ophthalmic suspension administered BID to both eyes 
for 84 days (12 weeks) 
• BTQ-1901-B: nebivolol 1.0% ophthalmic suspension administered BID to both eyes 
for 84 days (12 weeks) 
• BTQ-1902: timolol 0.5% ophthalmic suspension administered BID to both eyes for 
84 days (12 weeks) 
• Timolol 0.5% ophthalmic solution administered BID to both eyes for 84 days 
(12 weeks) 
6.4. 
Criteria for Study Termination 
The study may be terminated at any time by the Sponsor, following appropriate notification. 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Inclusion Criteria 
1. Willing and able to understand and sign an informed consent form prior to any study 
related procedures. 
2. Able to administer or have a caregiver accurately administer an eye drop. 
3. 18 years of age or older, male, or female. 
4. Have POAG or OHT in both eyes that requires therapy for IOP and is adequately 
controlled, in the opinion of the Investigator, on no more than 2 ocular hypotensive 
medications (fixed dose combinations count as 2 medications). Subjects with OHT on no 
ocular hypotensive medication are acceptable. Presence of POAG in one eye and OHT in 
the fellow eye is acceptable.  
5. Able, in the opinion of the Investigator, to safely discontinue use of ocular hypotensive 
medications, if applicable, and undergo the appropriate required washout period for 
ocular hypotensive medications prior to Visit 3/Qualification/Baseline. 
6. At Visit 3/Qualification/Baseline, at least one eye must have unmedicated (post washout) 
IOP ≥ 22 and ≤ 34 mm Hg at 8:00 AM and ≥ 18 and ≤ 34 mm Hg at 10:00 AM and 
4:00 PM in the same eye(s) qualifying at the Visit 3 8:00 AM time point. The IOP must 
be at least 22 mm Hg at each consecutive measurement at the 8:00 AM time point. 
7. No significant VF loss, defined as a mean deviation in either eye greater than - 12 dB or a 
central point of fixation < 5 dB in either eye. If the VF performed at or within 90 days 
prior to Visit 1 does not meet study required parameters, it may be repeated (test should 
be prior to randomization at Visit 3/Qualification/Baseline). 
8. Best corrected visual acuity (BCVA) of +0.6 logMAR or better in both eyes at 
Visit 1/Screening and Visit 3/Qualification/Baseline. 
9. Central corneal thickness ≥ 480 and ≤ 600 μm in both eyes. Pachymetry within 90 days 
prior to Screening is acceptable. 
10. Shaffer gonioscopic grade ≥ 3 (in at least 3 quadrants) in both eyes. Gonioscopy within 
90 days prior to randomization is acceptable. 
11. Female subjects must be 1-year postmenopausal, surgically sterilized (total hysterectomy, 
bilateral oophorectomy or bilateral tubal ligation > 90 days prior to Visit 1/Screening), or 
women of childbearing potential with a negative urine pregnancy test at Visit 1/Screening 
and Visit 3/Qualification/Baseline who are not breastfeeding or planning a pregnancy 
during the study. Women of childbearing potential must use an acceptable form of 
contraception throughout the study. Acceptable methods include the use of at least one of 
the following:  
• Intrauterine (IUD) device  
• Hormonal contraceptive (oral, injection, patch, implant, ring); subjects must have 
been on the same hormonal contraceptive for ≥ 90 days prior to Visit 1/Screening 


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• Double barrier method (spermicide used with either a condom or diaphragm)  
• Abstinence 
7.2. 
Exclusion Criteria 
Ocular 
1. Intraocular pressure ˃ 34 mm Hg in either eye at Visit 1/Screening, Visit 2/Washout 
Safety Check, or Visit 3/Qualification/Baseline. 
2. Other forms of glaucoma in either eye, e.g., congenital glaucoma, closed-angle glaucoma, 
uveitic glaucoma, pseudoexfoliation or pigment dispersion syndrome, or history of angle 
closure. Narrow angles treated with peripheral iridotomy are allowed if at least 4 months 
status post iridotomy. 
3. Current or recent (within 30 days prior to Visit 1/Screening) clinically significant ocular 
infection or inflammation, in the opinion of the Investigator, in either eye.  
4. History of conjunctivitis within 90 days prior to Visit 1/Screening, or history of herpes 
simplex or herpes zoster in either eye. 
5. Clinically significant ocular disease, in the opinion of the Investigator, in either eye 
(including, but not limited to corneal edema, uveitis, severe dry eye, proliferative diabetic 
retinopathy or macular degeneration) that might interfere with the study, confound study 
results, or put the subject at increased risk. 
6. Have a cup-to disc (CD) ratio > 0.8 at Visit 1/Screening in either eye. 
7. Intravitreal steroid injections within 6 months prior to Visit 1/Screening. Subconjunctival 
or subtenon steroid injections within 90 days prior to Visit 1/Screening. 
8. Use of topical ocular medications within 30 days prior to Visit 1/Screening other than 
ocular hypotensive medications and medications used as part of an eye examination (see 
Table 3). Artificial tears may be used during this period provided the use is not required 
for severe dry eye disease. 
9. Clinically significant ocular trauma or incisional ocular surgery (including routine 
cataract surgery) in either eye within 6 months prior to Visit 1/Screening. Glaucoma 
filtering surgery, or minimally invasive glaucoma surgery within 12 months prior to 
Visit 1/Screening. Laser surgery for IOP reduction within 6 months prior to 
Visit 1/Screening. Non-incisional ocular surgery or non-glaucomatous laser treatment 
within 90 days prior to Visit 1/Screening. 
10. Refractive surgery in either eye (i.e., radial keratotomy, photorefractive keratectomy 
[PRK], laser-assisted in situ keratomileusis [LASIK], corneal cross-linking, limbal 
relaxing incision) within 6 months prior to Visit 1/Screening.  
11. Any ocular (e.g., corneal) abnormality preventing accurate assessment of IOP. 
12. Contact lens wear within 1 week prior to Visit 1/Screening or unwillingness to 
discontinue wear of contacts lenses prior to and during the study period.  
13. Aphakia. 


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General 
14. Pregnancy or lactation. 
15. Known hypersensitivity or contraindication to β-blockers (i.e., chronic obstructive 
pulmonary disease, bronchial asthma, unstable or abnormally low blood pressure or heart 
rate, second or third degree heart block or congestive heart failure, severe or unstable 
diabetes mellitus) that in the opinion of the Investigator may put the subject at risk from a 
topical ocular β-blocker. 
16. Have a condition or be in a situation which, in the Investigator’s opinion, may put the 
subject at significant risk, confound study results, or interfere with the subject’s 
participation in the study. 
17. Clinically significant systemic disease (myasthenia gravis, hepatic, renal, endocrine, or 
cardiovascular disorders) that in the opinion of the Investigator might interfere with the 
study. 
18. Use of systemic β-adrenergic antagonists unless the dosage has been stable for 1 month 
prior to Visit 1/Screening and is expected to remain stable through the study period. 
19. Use of systemic (oral, injectable, inhaled) or topical steroids within 30 days prior to 
Visit 1/Screening; topical dermatologic or intranasal steroids are acceptable provided the 
usage meets the criteria outlined in the Summary of Prohibited Medications and 
Procedures in Table 3. 
20. Contraindication to the use of timolol, nebivolol, or any of the components of the 
investigational products. 
21. Changes to systemic medication that could have an effect on IOP within 28 days prior to 
Visit 3/Qualification/Baseline.  
22. Participation in any study of an investigational product within 30 days prior to 
Visit 1/Screening. 
23. History of substance abuse within 1 year prior to Visit 1/Screening. 
24. Screening and enrollment of employees or relatives of employees of the clinical site. 
7.3. 
Criteria for Withdrawal from the Study/Criteria for Discontinuation 
of Study Medication  
The following are the criteria for considering withdrawal from the study: 
• Withdrawal of subject consent. The subject may request for any reason at any time to 
be withdrawn from the study. 
• Subject lost to follow-up. 
• The Sponsor terminates the study (see Section 6.4). 
If a subject withdraws from the study, the principal reason for withdrawal will be recorded in the 
electronic case report form (eCRF). Subjects who are withdrawn will not be replaced.  


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If a study subject fails to attend a study visit at any point during the study period, every effort 
should be made to keep the subject in the study and conduct all study visits as scheduled; all 
attempts to contact the subject must be documented. If the subject relocates during the study 
period, the clinical research organization (CRO), should be contacted to determine if there is a 
possibility that the subject could continue at another clinical site. 
The following are criteria for considering discontinuation from study medication: 
• Pregnancy: If a subject becomes pregnant during the study, the subject will be 
withdrawn from study medication and followed through the conclusion of the 
pregnancy (Section 9.5.3). 
• Adverse event: A clinically significant or serious AE (SAE) that in the Investigator’s 
or Medical Monitor’s judgment, suggests that continued administration of study 
medication is not in the subject’s best interests for safety reasons. Additionally, if an 
AE requires treatment, the Investigator in consultation with the Medical Monitor may 
determine that study medication should not be concurrently administered with a 
required concomitant medication. 
• Intraocular pressure in either eye >34 mm Hg during the treatment period. 
• Subject request: Subject requests to be withdrawn from study medication. 
When possible, a decision to discontinue a subject from study medication should first be 
discussed with the Medical Monitor. If a subject is discontinued from study medication, every 
effort should be made to encourage the subject to continue to attend study visits to be followed 
for safety, rather than withdrawing the subject from the study or, failing that, to perform all early 
discontinuation assessment procedures at the visit the subject is withdrawn (Section 10.5).  
In case a subject must be withdrawn from the trial, the sponsor will be informed immediately. If 
there is a medical reason for withdrawal, the subject will remain under the supervision of the 
investigator until satisfactory health has returned or the subject´s health has reached a stable 
condition. 


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drugs 
BTQ-1901-A (nebivolol 0.5%), BTQ-1901-B (nebivolol 1.0%), and BTQ-1902 (timolol 0.5%) 
are formulated for topical ocular delivery as sterile, preservative-free ophthalmic suspensions 
and contain the active ingredient (as specified) in a vehicle composed of one excipient, the inert 
and anhydrous semifluorinated alkane, perfluorohexyloctane (F6H8). These study drugs are 
packaged in identical 5 mL multidose bottles to maintain masking of treatment identity.  
The active comparator, timolol, is a sterile, preserved ophthalmic solution that contains timolol 
0.5% and is packaged in 10 mL multidose bottles (Timolol maleate ophthalmic solution 
prescribing information, 2016). 
8.2. 
Randomization and Masking 
Study medication will be randomized in a 1:1:1:1 ratio into 1 of 4 treatment arms (BTQ-1901-A, 
N = 60; BTQ-1901-B, N = 60; BTQ-1902, N = 60; timolol 0.5%, N = 60). A randomized block 
design will be used, and the randomization will be created by a biostatistician independent of the 
trial. Randomization will not be stratified by any factors. 
If subjects meet eligibility criteria (see Section 7) at Visit 1/Screening as well as at 
Visit 3/Qualification/Baseline, sites will access the Interactive Web Response System (IWRS) to 
randomize subjects to study treatment and assign the study medication kit to be dispensed. The 
drug kit and randomization numbers will be recorded in the subject’s eCRF. Study medication 
from the IWRS-assigned kit will be dispensed to the subject after initial dosing at the study site 
on Day 1 (Visit 3/Qualification/Baseline).  
The study will be observer masked. The study medication will be provided in foil pouches 
contained in identical-appearing boxes. The pouches will contain 5 mL bottles for the 
BTQ-1901-A, BTQ-1901-B, or BTQ-1902 treatment arms and 10 mL bottles for the timolol 
0.5% treatment arm (see Section 8.1). An unmasked staff member not involved in performing 
study endpoint-related procedures (i.e., IOP measurement) will be responsible for providing 
dosing instructions, dispensing study medication, and conducting study medication 
accountability and dosing compliance assessment. The identity of the study medications will be 
masked to the Investigator and study personnel responsible for study endpoint-related 
procedures. Moreover, IOP measurements should be performed by the same 
Investigator/designee who will be masked to the readout of the tonometer, which will be read 
and entered into the source documentation (whether electronic or paper) by a second staff 
member once the Investigator/designee reaches the correct applanation effect in the slit lamp. 
8.2.1. 
Unmasking During the Study Period 
Should it be necessary to unmask a subject’s treatment assignment in case of emergency, the 
Investigator may obtain the treatment code for a given randomized subject from the IWRS. The 
treatment code is to be obtained only if a medical emergency exists and knowledge of the 
medication being taken will influence the medical management of the subject.  


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The following procedure should be followed: 
1. The Investigator should attempt to contact the Medical Monitor via phone before 
unmasking a subject unless it is not possible to do so without risk to the subject. 
2. The Investigator should document the AE and justification for unmasking in the eCRF.  
3. If the subject is to be discontinued from study medication, then ALL procedures 
described in the Early Discontinuation Visit (Section 10.5) should be completed. 
4. The Investigator should contact the CRO at safety@trialrunners.com within 24 hours 
with the subject number and details of the AE or SAE and any action taken. 
8.3. 
Concomitant Medications 
8.3.1. 
Permitted Medications and Treatments 
Therapy considered necessary for the subject’s welfare that will not interfere with the evaluation 
of the study medication may be given at the discretion of the Investigator. If there is any question 
as to whether the medication may interfere, the Investigator should contact the Medical Monitor 
or Sponsor. Whenever possible, medications should be administered in dosages that remain 
constant throughout the study duration. Note: Artificial tear use is permitted prior to and during 
the study period as needed provided the use is not required for severe dry eye disease. Artificial 
tears should not be instilled within 10 minutes of administration of study medication. 
8.4. 
Treatment Compliance 
Treatment compliance will be monitored by subject-reported missed doses assessed at each 
treatment visit (Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84) via response to the Missed 
Doses Log. Subjects will be asked to log if they have missed any doses since the previous visit, 
and if so, the date of missed dose, which dose was missed (AM and/or PM), which eye was not 
dosed (right, left, both), and the reason for the missed dose. These data will be analyzed to 
determine an estimate of compliance over the duration of the study. 
8.4.1. 
Prohibited Medications 
The Medical Monitor should be notified before prohibited medication or therapy is administered 
unless the safety of the subject requires immediate action. The decision to administer a 
prohibited medication or therapy should be done with the safety of the subject as the primary 
consideration. The Medical Monitor MUST be contacted to determine whether the subject 
should continue with study medication. 
Prohibited medications and therapies are summarized in Table 3 and specific details are found in 
the Study Manual. 
8.5. 
Study Medication Materials and Management 
8.5.1. 
Packaging and Labeling 
Study medication will be packaged and labeled at a central packaging facility. Study sites will 
utilize the IWRS to assign kits to subjects. Each kit has 3 boxes (subkits). Contents of the boxes 


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(subkits) will differ depending upon treatment allocation (either 5 mL multidose bottles or 10 mL 
multidose bottles).   
• Box 1, dispensed at Visit 3/Qualification/Baseline, includes either 1 bottle (5 mL) of 
BTQ-1901-A, BTQ-1901-B, BTQ-1902 OR 1 bottle of timolol 0.5% (10 mL)  
• Box 2, dispensed at Visit 4/Day 15, includes either 2 bottles (5 mL each) of 
BTQ-1901-A, BTQ-1901-B, BTQ-1902 OR 2 bottles of timolol 0.5% (10 mL)  
• Box 3, dispensed at Visit 5/Day 42, includes either 3 bottles (5 mL each) of 
BTQ-1901-A, BTQ-1901-B, BTQ-1902 OR 3 bottles of timolol 0.5% (10 mL)  
8.5.2. 
Storage and Administration 
Study medication must be stored at room temperature, 15°C - 25°C, or 59°F - 77°F, under 
temperature monitored conditions. Subjects should be instructed not to store or place the study 
medication where it can be exposed to extreme temperatures (e.g., refrigeration or leaving it in a 
hot car) or light.  
An unmasked staff member not involved in performing study endpoint-related procedures will 
instruct the subject on proper instillation technique and dispense the first study medication kit at 
Visit 3/Qualification/Baseline. At each study visit during the treatment period (Visit 4/Day 15 , 
Visit 5/Day 42, and Visit 6/Day 84) the subject (or caregiver, if the subject is not able to 
self-administer the medication) will administer the morning dose of study medication at the 
study site, instilling 1 drop in each eye. Before administering the eye drops, the hands should be 
washed. The steps described in detail in the Subject Dosing and Storage Instructions will be 
followed.  
Each day of dosing, the subject will administer one drop to each eye BID (morning and evening).  
8.5.3. 
Study Medication Accountability 
An unmasked staff member not involved in performing endpoint procedures will maintain full 
accountability records for the study medication and will be responsible for recording the receipt, 
dispensing, and return of all supplies of the study medication using the inventories supplied by 
the Sponsor. At each visit subsequent to Visit 3/Qualification/Baseline (i.e., Visit 4/Day 15, 
Visit 5/Day 42, and Visit 6/Day 84) all bottles that were dispensed at the previous visit (empty, 
used, or unused) should be returned to the site in the kit. At Visits 4 and 5, study medication 
accountability procedures will be conducted, and new study medication kits will be dispensed for 
the next study period. At Visit 6 all study medication materials will be returned to the study site, 
and final study medication accountability will be conducted. Visit 6 will be the last day of study 
treatment; no further study medication will be dispensed at this visit. The monitor will review 
dispensing and study medication accountability records at the completion of the study and note 
any discrepancies. All investigational study medication must be stored in a secure facility with 
limited access. 


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9. 
STUDY ASSESSMENTS 
Prior to entry into the study or initiation of any study-related procedures, the subject must read, 
sign, and date the current Institutional Review Board (IRB)-approved version of the informed 
consent form (ICF). A full discussion of informed consent is presented in Section 13.3. 
Ophthalmic procedures should be performed in the order specified in Table 2. 
9.1. 
Demographic and Background Characteristics 
9.1.1. 
Demographic/Medical History 
A complete medical history will be obtained from each subject. Demographic information 
including date of birth, gender, race, ethnicity, iris color, and date of informed consent will be 
recorded. 
9.1.2. 
Concomitant Medications History 
All concomitant medications (prescription and over-the-counter [OTC]) taken at 
Visit 1/Screening and for 90 days prior to Visit 1 and throughout the course of the study will be 
recorded in the Concomitant Medications page of the eCRF. Information regarding the dates of 
first and last dose, site of dosing (e.g., right eye, left eye, both eyes [OU], systemic), and the 
reason the concomitant medication is being taken must be recorded in the eCRF. When a 
concomitant medication has been taken at a stable dose for longer than 6 months, an estimation 
of the year of the start date is adequate. Standard procedural medications will not be captured in 
the eCRF but are recorded on a standard procedural medication log provided by the CRO. 
9.1.3. 
Ophthalmic History and Ophthalmic Intervention History 
Clinically significant ophthalmic history and ophthalmic intervention history will be documented 
and will include any clinically significant previously diagnosed ophthalmic abnormalities and 
ocular surgeries, including laser procedures. 
9.1.4. 
Urine Pregnancy Test 
A urine pregnancy test will be performed for females of childbearing potential at 
Visit 1/Screening, Visit 3/Qualification/Baseline, and Visit 6 or Early Discontinuation Visit. 
9.2. 
Efficacy Assessment 
The efficacy of BTQ-1901-A (nebivolol 0.5%), BTQ-1901-B (nebivolol 1.0%) or BTQ-1902 
(timolol 0.5%) ophthalmic suspensions will be compared to the active comparator (timolol 0.5% 
ophthalmic solution) as measured by mean IOP values in the study eye at each time point at each 
of the Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84 visits (ie, a total of 9 between-group 
comparisons).  
9.2.1. 
Intraocular Pressure 
Intraocular pressure will be measured utilizing a calibrated Goldmann tonometer and using the 
standard of care. NOTE: For  3 through 6, IOP measurements must be made within 30 minutes 
of the protocol-specified time points (8:00 AM, 10:00 AM, and 4:00 PM for Visit 3 and 8:00 


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AM, 2 hours after study medication dosing at the clinical site [~10:00 AM], and 4:00 PM for 
Visits 4, 5, and 6). For any given subject, IOP should be measured with a calibrated tonometer 
and by the same Investigator/designee, if possible, throughout the study who will be masked to 
the readout of the tonometer, which will be read and entered into the source documentation 
(whether electronic or paper) by a second staff member once the Investigator/designee reaches 
the correct applanation effect in the slit lamp. Two consecutive IOP measurements of each eye 
will be performed. If the 2 measurements differ by more than 2 mm Hg, a third measurement 
will be taken. Consult the Study Manual for specific details. 
9.3. 
Pharmacokinetic Assessments 
Plasma concentration will be measured in a subset of 40 subjects; blood samples will be 
collected 2 hours (± 30 minutes) after study medication dosing at the clinical site at Visit 4/Day 
15 and Visit 6/Day 84. Consult the Study Manual for specific details. 
9.4. 
Safety Assessments 
Safety will be assessed at each visit by LogMAR VA, biomicroscopy, resting heart rate 
(HR)/blood pressure (BP), and AE collection. Ophthalmoscopy/dilated fundus examination and 
VF testing will be performed at Visit 1/Screening and Visit 6/Day 84. Safety/tolerability 
assessments at each visit will include grading of conjunctival hyperemia by the Investigator and 
subjective assessment of comfort/tolerability data by the subject. Ophthalmic assessments should 
be performed in the order in which they appear in the Schedule of Procedures (Table 2).  
9.4.1. 
Visual Acuity 
Best corrected visual acuity measurement will be performed in each eye at all study visits with 
the logMAR eye chart. Consult the Study Manual for specific details. 
9.4.2. 
Biomicroscopy 
A slit-lamp examination will be conducted at each study visit to assess the anterior ocular 
structures. Abnormalities will be documented as abnormal, non-clinically significant (NCS) or 
abnormal, clinically significant (CS). Consult the Study Manual for specific details. 
9.4.3. 
Grading of Conjunctival Hyperemia 
Conjunctival hyperemia will be graded using the McMonnies photographic scale (McMonnies 
and Chapman, 1987a; McMonnies and Chapman, 1987b). Please note that this scale was 
designed for contact lens wearers but validated for non-contact lens wearers (McMonnies and 
Ho, 1991). Consult the Study Manual for specific details. 
9.4.4. 
Vital Signs 
Blood pressure and HR will be measured after at least 5 minutes rest in the sitting position. Vital 
signs may be repeated once, after at least an additional 5 minutes rest in the seated position, if 
they are out of range. Consult the Study Manual for specific details. 


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9.4.5. 
Ophthalmoscopy/Dilated Fundoscopy 
Ophthalmoscopy/dilated fundoscopy will be conducted, and the structures will be graded as 
normal or abnormal, NCS, or abnormal, CS. Consult the Study Manual for specific details.  
9.4.6. 
Visual Field Testing 
Automated perimetry will be performed at Visit 1/Screening and Visit 6/Day 84. The site should 
perform the automated perimetry assessments following the investigator’s standard practices. If 
the VF performed at or within 90 days prior to Visit 1 does not meet study required parameters, 
it may be repeated (test should be prior to randomization at Visit 3/Qualification/Baseline/ 
Day 1).  
The preferred equipment for the VF is the Humphrey Perimeter using the full threshold 24-2 test 
with the SITA Standard or SITA Fast strategy. The same strategy used for the initial test should 
be used for any subsequent VF test. Visual field results should be reliable. Subjects with a 
functionally significant VF loss, defined as mean deviation greater than -12 dB or a central 
fixation point less than 5 dB in either eye, are excluded from the study. Other equipment may be 
used after approval by the Sponsor. Consult the Study Manual for specific details. 
9.4.7. 
Subjective Grading of Comfort/Tolerability 
Subjective comfort/tolerability data (i.e., rating of drop comfort as assessed by the subject) will 
be collected at each post baseline visit (≥ 10 minutes after the IOP measurement). Consult the 
Study Manual for specific details. 
9.5. 
Adverse and Serious Adverse Events 
9.5.1. 
Definition of Adverse Events 
9.5.1.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
study medication (pharmaceutical/biological product) that does not necessarily have a causal 
relationship to this medication. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease temporally associated with the 
use of the study medication, whether or not related to the study medication. Study medication 
includes the investigational drug under evaluation and the comparator product or vehicle placebo 
that is given during any phase of the study. 
Adverse events are collected from the time the subject signs the ICF through the final study visit. 
Medical conditions/diseases present before starting the investigational treatment are only 
considered AEs if they worsen any time after the subject signs the ICF. Abnormal test results 
constitute AEs only if they induce clinical signs or symptoms or require therapy. 
The occurrence of AEs should be sought by open-ended questioning of the subject at each visit 
during the study. At each clinic visit, study personnel should ask the following question: "Have 
you had any problems since your last visit?” AEs also may be detected when they are 
volunteered by the subject during or between visits or through study assessments. 


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9.5.1.2. 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
Note: The term "life-threatening" refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
• Results in persistent or significant disability/incapacity (excluding 
progression/outcome of the disease under study), 
• Is a congenital anomaly/birth defect, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Is medically significant, i.e., defined as an event that jeopardizes the health of the 
subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Treatment on an outpatient emergency basis that does not result in hospital admission, or a 
hospitalization that is elective or is a preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the start of the study, is not 
considered an SAE. 
All SAEs that are ongoing at the time of completion or discontinuation from the study will be 
followed until stabilization or resolution of the event. 
9.5.2. 
Relationship to Study Drug 
The relationship of AEs to the study medication should be assessed by the Investigator using the 
definitions below. 
Not related: The temporal relationship of the event to the study medication makes a causal 
relationship unlikely, or other drugs, therapeutic interventions or underlying conditions provide a 
sufficient explanation for the observed event. 
Related: The temporal relationship of the event to the study medication makes a causal 
relationship possible or other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event. 
If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the study medication and the occurrence of the AE, then the AE should be 
considered “related.” 
If the relationship between the AE/SAE and the investigational product is determined by the 
Sponsor to be “related,” the event will be considered related to the investigational product for the 
purposes of expedited regulatory reporting. 


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9.5.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation, regardless of severity or potential 
association with the study medication or study procedures, will be recorded in the eCRF. 
Changes from baseline assessments that are part of the disease being studied will not necessarily 
be recorded as AEs unless the Investigator deems them as such. Clinically significant changes in 
BP and HR should be reported as AEs. All AEs that occur following consent and until the final 
study visit (Visit 6/Day 84) should be collected and recorded on the AE eCRF page. Serious 
adverse events will be followed until the event is resolved or stabilized. 
The AE term should be reported in standard medical terminology when possible. For each AE, 
the Investigator will evaluate and report the following: 
• Onset (date) 
• Resolution (date) 
• Severity grade (mild, moderate, severe) 
• Relationship to study medication (not related, related) 
• Action taken regarding study medication (none, study medication temporarily 
interrupted, study medication permanently discontinued)  
• Action taken regarding the event (concomitant medication taken; 
hospitalization/prolonged hospitalization; other) 
• Serious (yes/no) 
The severity grade should be determined by the Investigator using the definitions below. 
• Mild: Discomfort noticed but no disruption of normal daily activity  
• Moderate: Discomfort sufficient to cause interference with normal daily activity  
• Severe: Incapacitating, with inability to perform normal activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
(as defined directly above) whereas seriousness is defined by the criteria under Section 9.5.1.2. 
An AE of severe intensity may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the pregnancy form. Pregnancy is 
not regarded as an AE unless there is a suspicion that an investigational product may have 
interfered with the effectiveness of a contraceptive medication. The subject will be withdrawn 
from study medication and followed through conclusion of pregnancy. The outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality) must be followed up and documented. 
9.5.4. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded following consent and until the final study 
visit, Visit 6/Day 84, following the end of treatment exposure. Any SAEs suspected to be related 
to the investigational product should be reported.  


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Any SAE that occurs must be reported to Trial Runners, the CRO, within 24 hours of its 
occurrence or within 24 hours of learning of its occurrence. Recurrent episodes, complications, 
or progression of the initial SAE must be reported to Trial Runners as follow-up to the original 
episode within 24 hours of the Investigator receiving the information. Information about all 
SAEs will be collected and recorded on the SAE form. All pertinent medical records and 
information collected during the treatment and follow-up of the subject should be maintained at 
the site with a copy emailed to safety@trialrunners.com. The Investigator must assess the SAE 
relationship and complete and sign the SAE form. Trial Runners/the Sponsor may request 
additional information. Follow-up information (e.g., discharge summary) will be retained in the 
subject’s chart and a copy will be emailed to safety@trialrunners.com. 
In addition, all SAEs should be recorded on the Adverse Event eCRF page with the serious 
question marked “Yes”. 
It is the Investigator’s responsibility to notify the approving IRB of any SAEs on a timely basis 
as instructed by the Sponsor following the Sponsor’s determination of causality. 
All subjects who experience an SAE should be followed clinically and undergo the appropriate 
diagnostic evaluations until stabilization or resolution of the event. 
The Sponsor will report all SAEs to the US Food and Drug Administration (FDA) on the 
appropriate schedule depending if the event is drug related or not drug related, expected or 
unexpected (based on the available information in the Investigator’s Brochure). 
Any death occurring during the study and follow up period should be reported as an SAE. For 
any death occurring through the end of the study, regardless of the degree of relationship to study 
medication, the SAE resulting in the death must be reported to Trial Runners. A death occurring 
after completion of the study does not require completion of the SAE form. 


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10. 
STUDY ACTIVITIES 
Table 2 provides a tabular summary of all scheduled visits and procedures to be performed 
during the clinical study. Ophthalmic procedures should be performed in the order in which they 
are shown in the Schedule of Procedures. Please note that per Section 10.1.1, procedures 
performed at Visit 1/Screening may be split and conducted at a separate visit (preferably within 
1 week after Visit 1) to be scheduled before Visit 3/Qualification/Baseline/Day 1. 
10.1. 
Screening Visit  
Screening eligibility assessments are obtained during the Screening Visit conducted on or 
between Day -35 to -1 (Visit 1), which is dependent on the required washout period for prior 
ocular hypotensive medications. 
10.1.1. 
Visit 1/Screening (Day -35 to -1)  
At Visit 1/Screening, (Day -35 to -1), subjects will provide informed consent before any 
study-related procedures are conducted. Subjects will then participate in screening procedures to 
establish eligibility for the study.  
If necessary, Visit 1 may be split and a separate visit (preferably within 1 week after Visit 1) may 
be scheduled to allow all required screening procedures to be performed before 
Visit 3/Qualification/Baseline. For example, if dilated ophthalmoscopy is not performed because 
the subject prefers not to be dilated at this visit, the subject may return on another day. Also, if 
the VF performed at or within 90 days prior to Visit 1 does not meet study required parameters, 
it may be repeated (test should be prior to randomization at Visit 3/Qualification/Baseline). 
At the end of the visit/split visit, inclusion/exclusion criteria will be reviewed. Eligible subjects 
will begin the washout period that is required for the ocular hypotensive medication the subject 
was receiving or, if medication naïve, be scheduled for Visit 3/Qualification/Baseline.  


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Screening procedures include the following: 
• Informed consent/assent 
• Demographics 
• Medical and ophthalmic histories 
• Prior and concomitant medications/therapies 
• Urine pregnancy test (females of childbearing potential only) 
• BP/HR 
• BCVA (logMAR) 
• Biomicroscopy 
• IOP 
• Visual field test (may be performed at any time during the Screening visit prior to 
dilation for ophthalmoscopy, or within 90 days prior to Screening) 
• Gonioscopy (may be performed during the Screening visit at any time after IOP and 
before dilation for ophthalmoscopy, or within 90 days prior to Screening) 
• Pachymetry (may be performed during the Screening visit at any time after IOP, or 
within 90 days prior to Screening) 
• Dilated ophthalmoscopy 
• Review eligibility criteria 
• Provide instructions regarding the washout period  
10.2. 
Washout Period 
A washout period will occur for all subjects using ocular hypotensive medications at Screening. 
If required, subjects will participate in a minimum washout period of 28 days for prostaglandin 
analogs, ROCK inhibitors, or β-blockers, 14 days for adrenergic agonists, and 5 days for 
muscarinic agonists or CAIs. 
10.2.1. 
Visit 2/Optional Washout Safety Check (Day -14 ± 3)  
A mid-washout onsite safety check may be conducted for subjects undergoing a 28-day washout 
period, at the Investigator’s discretion. 
Procedures performed at Visit 2 include the following: 
• AE assessment 
• Concomitant medication review 


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• BCVA 
• IOP 
10.3. 
Qualification Visit 
One qualification visit will be conducted, Visit 3/Qualification/Baseline/Day 1.  
At Visit 3, subjects must have unmedicated IOP measurements in at least one eye ≥ 22 and 
≤ 34 mm Hg at 8:00 AM and ≥ 18 and ≤ 34 mm Hg at 10:00 AM and 4:00 PM (each timepoint is 
± 30 minutes). The IOP must be at least 22 mm Hg at each consecutive measurement at the 
8:00 AM time point. 
10.3.1. 
Visit 3/Qualification/Baseline/Day 1 
This visit will be scheduled so that IOP can be taken at 8:00 AM, 10:00 AM, and 4:00 PM 
(± 30 minutes). If the subject has not discontinued using their prior ocular hypotensive 
medications for the required washout period duration (28 days for prostaglandin analogs, ROCK 
inhibitors or β-blockers, 14 days for adrenergic agonists, and 5 days for muscarinic agonists or 
CAIs), the visit will need to be rescheduled. 
Procedures performed at Visit 3 include the following: 
8 AM (± 30 minutes): 
• AE assessment 
• Concomitant medication review 
• Urine pregnancy test (females of childbearing potential only); must be performed 
prior to randomization 
• BCVA 
• Grading conjunctival hyperemia (grading of conjunctival hyperemia must be 
performed prior to randomization) 
• Biomicroscopy/ 
• IOP 
10 AM (± 30 minutes): 
• AE assessment 
• HR/BP 
• Biomicroscopy 
• IOP 
4 PM (± 30 minutes): 
• AE assessment 
• Biomicroscopy 


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• IOP 
• Review eligibility criteria 
• Randomize eligible subjects 
• Dispense study medication 
• Provide instruction and supervise guided practice of drop instillation by 
subject/caretaker (no evening dose should be administered at home after this visit) 
• Conduct drop comfort rating following instillation of study medication (≥ 10 minutes 
after the IOP measurement) 
• Study medication accountability (i.e., document that Kit 1 was dispensed) 
10.4. 
Treatment Visits 
These treatment visits (Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84), will be scheduled so 
that IOP can be taken at 8:00 AM, at 2 hours after the dosing of study medication at the clinical 
site (~10:00 AM), and at 4:00 PM (each ± 30 minutes).  
Subjects should be reminded before each visit not to dose in the morning before coming to the 
site and to bring their box containing all study medication materials (opened and unopened 
bottles/vials and pouches) to the study site for drug accountability/treatment compliance 
assessment. When the subject arrives, confirm that the previous day’s evening dose of study 
medication was administered, and the morning dose of study medication has not been 
administered. Subjects who did not dose the evening before or who dosed prior to the morning 
visit MUST be rescheduled, even if the next appointment is out of window. 
10.4.1. 
Visit 4/Day 15 ± 3  
Procedures performed at Visit 4 include the following: 
8 AM (± 30 minutes): 
• AE assessment 
• Concomitant medication review 
• BCVA 
• Grading conjunctival hyperemia 
• Biomicroscopy 
• IOP 
• Drop instillation (should occur as close as possible to 15 minutes after IOP 
measurement, but not before 10 minutes after IOP measurement) 
• Conduct drop comfort rating following instillation of study medication (≥ 10 minutes 
after the IOP measurement) 


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2 hours ± 30 minutes after drop instillation: 
• AE assessment 
• HR/BP 
• Biomicroscopy 
• IOP 
• Blood collection for pharmacokinetics (PK) assessment (subset of subjects only) 
• Compliance assessment (may be performed at any time during the visit) 
4 PM (± 30 minutes): 
• AE assessment 
• Biomicroscopy 
• IOP 
• Study medication dispensing 
• Study medication accountability (may be performed at any time during the visit) 
10.4.2. 
Visit 5/Day 42 ± 3 
8 AM (± 30 minutes): 
• AE assessment 
• Concomitant medication review 
• BCVA 
• Grading conjunctival hyperemia 
• Biomicroscopy 
• IOP 
• Drop instillation (should occur as close as possible to 15 minutes after IOP 
measurement but not before 10 minutes after IOP measurement) 
• Conduct drop comfort rating following instillation of study medication (≥ 10 minutes 
after the IOP measurement) 
2 hours ± 30 minutes after drop instillation: 
• AE assessment 
• HR/BP 
• Biomicroscopy 
• IOP 
• Compliance assessment (may be performed at any time during the visit) 


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4 PM (± 30 minutes): 
• AE assessment 
• Biomicroscopy 
• IOP 
• Study medication dispensing  
• Study medication accountability (may be performed at any time during the visit) 
10.4.3. 
Visit 6/Last Day of Treatment (Day 84 ± 3) 
At Visit 6, subjects will undergo final efficacy and safety assessments and rate the ocular 
tolerability of study medication. 
Visit 6 procedures include the following: 
8 AM (± 30 minutes): 
• AE assessment 
• Concomitant medication review 
• Urine pregnancy test (females of childbearing potential only) 
• BCVA 
• Grading conjunctival hyperemia 
• Biomicroscopy 
• IOP 
• Drop instillation (should occur as close as possible to 15 minutes after IOP 
measurement, but not before 10 minutes after IOP measurement) 
• Conduct drop comfort rating following instillation of study medication (≥ 10 minutes 
after the IOP measurement) 
• Visual field test (may be performed at any point in the visit prior to dilation for 
ophthalmoscopy) 
2 hours ± 30 minutes after drop instillation: 
• AE assessment 
• HR/BP 
• Biomicroscopy 
• IOP 
• Blood collection for PK assessment (subset of subjects only) 
• Compliance assessment (may be performed at any time during the visit) 


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4 PM (± 30 minutes): 
• AE assessment 
• Biomicroscopy 
• IOP 
• Dilated ophthalmoscopy  
• Study medication accountability (may be performed at any time during the visit) 
10.5. 
Early Discontinuation Assessment Procedures 
If a study subject is discontinued from study medication before Visit 6/Day 84 but after 
Visit 3/Qualification/Baseline/Day 1, every effort should be taken to perform all the procedures 
listed for Visit 6 (Section 10.4.3).  
If the subject is willing to remain at the site for the 8-hour visit, it should be conducted as 
specified, but if the subject is not willing to remain for the full duration, the VF test and the 
dilated ophthalmoscopy should be conducted as the last ophthalmic assessments in the early 
discontinuation visit. 


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11. 
STATISTICS 
11.1. 
General Considerations 
This is a Phase 2 study to evaluate ocular and systemic safety and the efficacy of BTQ-1901-A, 
BTQ-1901-B, and BTQ-1902 ophthalmic suspensions in comparison to timolol 0.5% ophthalmic 
solution in subjects with POAG or OHT. 
Subjects will be randomized in a 1:1:1:1 ratio into 1 of 4 treatment arms and receive 1 drop in 
each eye BID, morning, and evening, for 84 days: 
• BTQ-1901-A (nebivolol 0.5% ophthalmic suspension) (N = 60) 
• BTQ-1901-B (nebivolol 1.0% ophthalmic suspension) (N = 60) 
• BTQ-1902 (timolol 0.5% ophthalmic suspension) (N = 60) 
• Timolol 0.5% ophthalmic solution (N = 60) 
A biostatistician will perform statistical analyses as agreed with the Sponsor according to the 
Statistical Analysis Plan (SAP).  
Primary efficacy analysis will be conducted on the per protocol (PP) population. Efficacy 
analyses will also be conducted on the intent to treat (ITT) population. Safety analyses will be 
performed using the safety analysis population. Definitions for all of the analysis populations can 
be found in Section 11.3. 
At least one eye must qualify for the study. Even if only one eye meets all inclusion/exclusion 
criteria, both eyes will be treated. If both eyes qualify, the qualifying eye with the higher IOP at 
8:00 AM at Visit 3/Qualification/Baseline will be designated as the study eye. Should the 
8:00 AM IOP be the same in both eyes, then the right eye will be designated as the study eye. 
At each IOP measurement time point, 2 consecutive IOP measurements of each eye will be 
performed. If the 2 measurements differ by more than 2 mm Hg, a third measurement will be 
taken. Mean IOP is calculated as the mean of 2 measurements or as the median of 
3 measurements. 
A detailed SAP will be finalized prior to database lock. The analysis of continuous and ordinal 
variables will use the applicable parametric methods (t-test, analysis of variance [ANOVA], and 
analysis of covariance [ANCOVA], and mixed models for repeated measures [MMRM]). 
Descriptive statistics will be used to summarize continuous outcomes (number of subjects [N], 
mean, standard deviation or standard error of the mean, median, maximum, and minimum) and 
categorical variables (frequency and percentage) at each assessment time point (the time points 
at which data are collected are specified in the Schedule of Procedures—see Table 2). 
The primary efficacy analysis will be the between-group comparison of the mean IOP values in 
the study eye at each time point at each of the Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84 
visits (ie, a total of 9 between-group comparisons). 
Final analyses of efficacy will be conducted when all subjects complete Visit 6. 


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11.1.1. 
Handling of Missing Data 
All efficacy analyses will be based on observed cases (without imputation). Multiple imputation 
methods and single imputation methods (e.g., last observation carried forward [LOCF]) will be 
utilized for sensitivity analyses for select variables. Full details will be provided in the SAP. 
11.2. 
Determination of Sample Size 
The sample size is not based on a formal sample size calculation; this study is planned to provide 
sufficient data to power the Phase 3 study. 
11.3. 
Analysis Populations 
Three populations will be used for analysis, as described below. 
11.3.1. 
Populations for Efficacy Analysis 
11.3.1.1. Intent-to-Treat (ITT) Population 
The ITT population is defined as all randomized subjects. Supplemental efficacy analyses will be 
conducted on the ITT population. 
11.3.1.2. Per-Protocol (PP) Population 
The PP population consists of those subjects in the ITT population who were randomized and 
dosed and had no major protocol deviations. The primary efficacy analysis will be conducted on 
the PP population. 
11.3.2. 
Safety Population  
The safety population is defined as all randomized subjects who received at least one dose of the 
allocated study medication. All safety analyses will be performed using the safety population. 
11.4. 
Demographics and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized for all analysis 
populations. Summary tables will be supported with individual subject data listings. 
11.5. 
Efficacy Analysis 
Efficacy analyses will be performed on the PP population for the primary efficacy endpoint using 
observed data only. Analysis of the efficacy endpoints will also be conducted with the ITT 
population. 
Efficacy data will be presented in tables of descriptive statistics and frequency distribution. All 
summary tables will be supported with individual subject data listings. 
The efficacy measures (IOP) taken at Visit 3/Day 1 at 8:00 AM, 10:00 AM, and 4:00 PM will 
serve as baseline.  


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11.5.1. 
Hypothesis Testing 
The primary efficacy analysis will be the between-group comparison of the mean IOP values in 
the study eye at each time point at each of the Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84 
visits (ie, a total of 9 between-group comparisons). A hierarchical analysis will be conducted to 
compare each of the investigational products against the comparator, timolol 0.5%, as follows: 
(1) BTQ-1902, (2) BTQ-1901B, and (3) BTQ-1901A.  
To demonstrate noninferiority, the upper limits of the 2-sided 95% confidence interval (CI) for 
the difference between each comparison should be lower than 1.5 mm Hg at all timepoints. 
Additionally, the upper limits of the 95% CI should be lower than 1.0 mm Hg for the majority of 
time points measured (ie, 5 of 9).  
All other comparisons are considered exploratory. 
11.5.2. 
Primary Efficacy Endpoints 
The primary efficacy endpoint will be IOP values at each time point (8:00 AM, 2 hours after 
dosing of study medication [~10:00 AM], 4:00 PM) at Visit 4/Day 15, Visit 5/Day 42, and 
Visit 6/Day 84. 
11.5.3. 
Primary Efficacy Analysis 
A summary of the efficacy endpoints will be prepared at each time point.  
The between-treatment comparison will employ an MMRM with treatment, visit/time, 
treatment-by-visit/time interaction, and baseline values as fixed effects. Linear contrasts will be 
used to calculate the confidence intervals at all visit/times.  
Sensitivity analyses include repeating the primary analysis with the ITT population, imputing 
missing data using multiple imputation techniques and repeating the primary analysis; utilizing 
LOCF imputed data and ANCOVA models at each visit/time point; and using Wilcoxon rank 
sum tests to compare treatments at each time point. Full details will be provided in the SAP. 
11.5.4. 
Secondary Efficacy Endpoints 
Secondary endpoints will include the following: 
• Change from baseline (Visit 3/Qualification/Baseline) in the average of the 3 daily 
IOP measurements at each post baseline visit. 
• Time-matched change from baseline (Visit 3/Qualification/Baseline) in IOP 
measurements at all time points at Visit 4/Day 15, Visit 5/Day 42 and Visit 6/Day 84. 
11.5.5. 
Secondary Efficacy Analysis 
Similar analysis methods to those used for the primary efficacy endpoints will be utilized for the 
secondary efficacy endpoints. Full details will be provided in the SAP. 
11.6. 
Safety Analyses 
The safety of BTQ-1901 and BTQ-1902 will be compared to timolol 0.5% with analysis of 
safety variables including bilateral ophthalmic examinations (LogMAR BCVA, slit lamp 


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examination, resting HR/BP, ophthalmoscopy/dilated fundus examination, VF testing), and AEs. 
The ocular tolerability of study medication will be rated by the subject. Safety data will be 
presented in tables of descriptive statistics and frequency distribution. All summary tables will be 
supported with individual subject data listings. 
11.7. 
Pharmacokinetic Analyses 
Pharmacokinetic variables will be analyzed using appropriate statistical techniques and 
summarized descriptively. Full details will be provided in the SAP.  


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and/or their contracted agents utilize standard operating procedures (SOPs) 
designed to ensure that research procedures and documentation are consistently 
conducted/prepared to the highest quality standards. These SOPs require compliance with FDA 
regulations and the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
guidance. 
The study will be monitored by clinical research associates (CRAs)/monitors provided by Trial 
Runners, the CRO, to verify that the rights and well-being of human subjects are being protected, 
the reported data are accurate, complete, and verifiable, and that the conduct of the study is in 
compliance with the currently approved protocol, with ICH GCP, and with the applicable 
regulatory requirements. 
To ensure compliance with GCP and all applicable regulatory requirements, the Sponsor or its 
agent may conduct a quality assurance audit at any time during or after completion of a study. 
The Investigator will be given adequate notice if he/she is selected for an audit. The audit will 
include but is not limited to a review of all informed consent/assent forms, medical records, and 
regulatory documentation; an assessment of study conduct and protocol compliance; and a 
review of the study materials receipt, storage, and administration. At the conclusion of an audit, 
the auditor will conduct a brief meeting with the Investigator to review the findings of the audit. 


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13. 
ADMINISTRATIVE CONSIDERATIONS 
13.1. 
Institutional Review Board (IRB) Approval 
The IRB must review, approve, and provide continuing review of the clinical study protocol, 
protocol amendments, the informed consent documents, subject recruitment advertisements, and 
any other written information to be provided to the subjects. Initial IRB approval is an 
affirmative decision that the clinical study has been reviewed and may be conducted at the study 
site within the constraints set forth by the IRB, the institution, GCP, and applicable regulatory 
requirements. A copy of the IRB approval letter for the protocol, the informed consent, the 
intended advertising, and any written material to be provided to the subject must be submitted to 
the Sponsor or designee prior to release of investigational supplies to the study site. Progress 
reports and notifications of serious adverse reactions will be provided to the IRB according to 
local regulations and guidelines. The IRB must be notified of completion or termination of the 
study. The study site must maintain an accurate and complete record of all reports, documents, 
and other submissions made to the IRB concerning this protocol. 
13.2. 
Ethical Conduct of the Study 
The study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and in compliance with ICH guidelines, and all applicable US federal 
regulations and local legal and regulatory requirements. 
13.3. 
Subject Information and Consent 
A sample ICF containing the required elements of informed consent will be provided by the 
Sponsor or designee. Any changes made to this sample must be approved by Betaliq or designee 
prior to submission to the IRB. After approval by the Sponsor or designee, the ICF must be 
submitted to and approved by the IRB. The informed consent must be written in a language in 
which the subject is fluent. Regulations require that foreign language informed consent forms be 
submitted to the IRB for approval. The foreign language translation is required to contain a 
statement of certification of the translation. The Investigator must forward a copy of the consent 
forms, the certified foreign language translation, and an IRB approval letter to the Sponsor or 
designee. 
It is the responsibility of the Investigator to inform each subject of the purpose of this clinical 
trial, including possible risks and benefits, and to document the informed consent process. Prior 
to undergoing any study-related procedures, the subject must read, sign, and date the current 
IRB-approved version of the informed consent form. The original informed consent form is to be 
retained by the study site, and a copy of the signed consent form is to be given to the subject. 
13.4. 
Subject Confidentiality 
Data generated for the study should be stored in a limited-access file area and be accessible only 
to representatives of the study site, the Sponsor, Trial Runners, the IRB, and FDA/relevant 
regulatory agencies. Medical information resulting from a subject’s participation in this study 
may be given to the subject’s personal physician or to the appropriate medical personnel 
responsible for the subject’s welfare. No information that can be related to a specific individual 


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subject will be released or used in any fashion without the signed written consent of that subject. 
All reports and communications relating to study subjects will identify subjects only by initials 
and subject identification number. Complete subject identification will be kept by the 
Investigator for purposes of long-term follow-up, if needed. This information will be treated with 
strict adherence to professional standards of confidentiality. 
13.5. 
Study Monitoring 
The study will be monitored by Trial Runners on behalf of the Sponsor in accordance with 
current GCP to assure compliance with the study protocol and the quality of the data collected. 
Monitoring visits will occur as required and could include a study initiation visit, monitoring 
visit(s), and a study close-out visit. Training will be provided for key investigative personnel in 
all aspects of study conduct. The Investigator will be responsible for making sure that site 
personnel are provided adequate training on conducting delegated tasks.  
Before a site can enter a subject into the study, a representative of the Sponsor will: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities regarding 
protocol adherence and the responsibilities of the Sponsor and or its representatives 
This study will utilize electronic data capture (eDC) to optimize the eCRF source verification 
process with limited separate source documentation. Monitors will review e-source data and 
overall study data/consistency remotely and query discrepancies based upon eCRF entries (eCRF 
initial entry is the source). During this monitoring, data are reviewed as entered by the site, and 
the monitors will flag any abnormalities, trends, or safety signals for Medical Monitor review 
and monitor follow-up onsite, if necessary. Refer to the Study Manual for details regarding the 
direct data entry of study assessments and requirements for maintaining additional source 
documentation via paper/medical record. 
During visits to the study site, the monitor may review the source documents including but not 
limited to signed informed consent forms, inclusion/exclusion checklist, medical/ocular history, 
concomitant medications, study material accountability and storage, the reporting procedures for 
AEs, SAEs, and protocol deviations. The CRA will review the study documents to ensure all 
documentation is current and only qualified and trained staff are appropriately delegated study 
related tasks. The CRA will also review the site-specific processes and research-related SOPs to 
ensure appropriate Investigator oversight is being maintained and documented as required by 
GCP/ICH. 
All data generated during this study and the medical records/documents from which they 
originated are subject to inspection by the Sponsor or designee, the FDA, and other regulatory 
agencies. The Investigator must notify the Sponsor or designee promptly of any inspections 
scheduled by regulatory authorities. 
Upon completion of the study, the clinical monitor will conduct a final visit (closeout) to the site. 
The objectives of this visit are to ascertain that all regulatory records and reports are complete, 
verify that the investigational product (IP) and other supplies have been accounted for 
(returned/destroyed), and ensure that the Investigators are aware of their responsibilities once the 
study ends.  


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The Investigator is responsible for permitting the Sponsor or designee direct access to any study 
documents for monitoring and auditing purposes, for providing adequate space for monitoring, 
and for addressing any questions or issues that might be raised by the monitor or auditor on a 
timely basis. 
13.6. 
Case Report Forms and Study Records 
Data relating to study procedures may be entered by site personnel directly onto eCRFs available 
in the study’s eDC system. When the eCRF is the first place study data are recorded, it will be 
the source document; exceptions are detailed in the Study Manual. Paper source documents will 
be retained at the study site when appropriate. 
13.7. 
Protocol Deviations 
The Investigator should not deviate from the requirements of this protocol except in the event of 
a medical emergency.  
A major protocol deviation is defined as nonadherence to the protocol that involves 
inclusion/exclusion criteria, affects subject safety, or has the potential to affect the integrity of 
the data, for example, enrollment of a subject who does not meet key eligibility criteria, or 
failing to collect data necessary to interpret primary endpoints. All protocol deviations will be 
reported to the Sponsor by entering the event in the appropriate eCRF page. Protocol deviations 
should be reported to the IRB in accordance with IRB-specific guidelines. If there is any 
question as to whether the deviation is reportable, the Sponsor or designee and the IRB should be 
contacted. If subjects are enrolled in error they may be removed after review by the Medical 
Monitor, but removal is not required. Major and minor protocol deviations will be defined before 
unmasking. 
All changes to the protocol will be made by the Sponsor or designee as an approved amendment 
to the protocol, submitted to the FDA, and approved by the IRB prior to implementation. 
13.8. 
Access to Source Documentation 
A trial-related monitoring audit, review by the IRB, and/or regulatory inspection may be 
conducted at any time during or after completion of a study (Section 12). The Investigator will 
be given adequate notice if he/she is selected for an audit and must provide direct access to study 
documentation. The audit may include, but is not limited to, a review of all informed consent 
forms; a review of medical records; a review of regulatory documentation; an assessment of 
study conduct and protocol compliance; and a review of the study materials receipt, storage, and 
administration. 
13.9. 
Data Generation and Analysis 
Management of data and the production of the clinical study report will be the responsibility of 
the Sponsor or its designee. 
During the trial, data queries will be generated for data items that are potentially erroneous and 
require appropriate clarification or correction. Such clarifications and corrections will be 


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discussed with and approved by site personnel and appropriately documented. Prior to database 
lock, data listings will be generated, and anomalous values investigated. 
13.9.1. 
Retention of Data 
Investigators should retain study-related records at the site until informed by the Sponsor. The 
Investigator will not move study documents or discard any records without notifying the 
Sponsor. If the Principal Investigator moves from the current clinical site, the Sponsor should be 
notified of the name of the person who will assume responsibility for maintenance of the records 
at the clinical site or the new address at which the records will be stored. The Investigator will 
notify the Sponsor as soon as possible in the event of accidental loss or destruction of any study 
documentation. If it becomes necessary for the Sponsor or designee, or the FDA or relevant 
regulatory authorities to review any documentation relating to the study, the Investigator must 
permit access to such records. 
13.10. 
Publication and Disclosure Policy 
All information concerning BTQ-1901, BTQ-1902 and the operations of the Sponsor, such as 
patent applications, formulas, manufacturing processes, basic scientific data or formulation 
information not previously published, are considered CONFIDENTIAL and shall remain the sole 
property of the Sponsor. The Investigator agrees to use this information only in accomplishing 
this study and will not use it for other purposes without the written consent of the Sponsor. 
The publication policy is addressed in a separate agreement. 


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14. 
REFERENCES 
BYSTOLIC (nebivolol) [package insert]. Madison, NJ; Allergan; Revised January 2019. 
Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, Parrish RK 2nd, 
Wilson MR, Gordon MO. The Ocular Hypertension Treatment Study: a randomized trial 
determines that topical ocular hypotensive medication delays or prevents the onset of primary 
open-angle glaucoma. Arch Ophthalmol. 2002 Jun;120(6):701-13; discussion 829-30. 
Kuroedov A, Cosentino F, Lüscher TF. Pharmacological mechanisms of clinically favorable 
properties of a selective beta1-adrenoceptor antagonist, nebivolol. Cardiovasc Drug Rev. 2004 
Fall;22(3):155-68. 
McMonnies CW, Chapman-Davies A. Assessment of conjunctival hyperemia in contact lens 
wearers. Part I. Am J Optom Physiol Opt. 1987;64:246-50. (McMonnies and Chapman Davies, 
1987a) 
McMonnies CW, Chapman-Davies A. Assessment of conjunctival hyperemia in contact lens 
wearers. Part II. Am J Optom Physiol Opt. 1987;64:251-5. (McMonnies and Chapman Davies, 
1987b) 
McMonnies CW, Ho A. Conjunctival hyperaemia in non-contact lens wearers. Acta Ophthalmol 
(Copenh). 1991;69:799-801. 
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma 
and projections of glaucoma burden through 2040: a systematic review and meta-analysis. 
Ophthalmology. 2014 Nov;121(11):2081-90. 
Timolol maleate ophthalmic solution [prescribing information]. 2016 Apr [Cited 2020 Apr 20] 
Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/018086s076lbl.pdf 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
CONFIDENTIAL 
 
 
 
 
Betaliq, Inc. 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: 
A Randomized, Multicenter, Observer-Masked Study to 
Compare the Safety and Efficacy of BTQ-1901-A, BTQ-1901-B, 
and BTQ-1902 to Timolol 0.5% in Subjects with Primary Open 
Angle Glaucoma or Ocular Hypertension 
Protocol Number: 
BTQ-1901-1902-201 
Phase: 
Phase 2 
Sponsor: 
Betaliq, Inc. 
3030 North Rocky Point Drive West, Suite 150 
Tampa, FL 33607 
Author: 
Summit Analytical, LLC 
8354 Northfield Blvd. 
Bldg. G Suite 3700 
Denver, CO 80238 
SAP Date: 
12APR2022 
Status: 
FINAL 1.0 
 
 
 


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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ............................................................................................................................... 2 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS................................................................... 5 
3. 
INTRODUCTION ......................................................................................................................................... 7 
3.1. 
Preface .............................................................................................................................................. 7 
3.2. 
Purpose of Analyses .......................................................................................................................... 7 
3.3. 
Summary of Statistical Analysis Changes to the Protocol ................................................................ 7 
4. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................. 8 
4.1. 
Study Objectives ............................................................................................................................... 8 
4.1.1. 
Primary Objective ........................................................................................................... 8 
4.2. 
Study Endpoints ................................................................................................................................ 8 
4.2.1. 
Efficacy Endpoints .......................................................................................................... 8 
4.2.1.1. 
Primary Efficacy Endpoint ..................................................................... 8 
4.2.1.2. 
Secondary Efficacy Endpoints ................................................................ 8 
4.2.2. 
Safety Endpoints ............................................................................................................. 8 
4.2.3. 
Pharmacokinetic Endpoints ............................................................................................. 9 
5. 
STUDY METHODS .................................................................................................................................... 10 
5.1. 
General Study Design and Plan....................................................................................................... 10 
5.2. 
Inclusion – Exclusion Criteria and General Study Population ........................................................ 14 
5.3. 
Randomization and Masking........................................................................................................... 14 
5.4. 
Analysis Variables .......................................................................................................................... 14 
6. 
SAMPLE SIZE ............................................................................................................................................ 14 
7. 
GENERAL CONSIDERATIONS ............................................................................................................... 15 
7.1. 
Analysis Populations ....................................................................................................................... 15 
7.1.1. 
Intent-to-Treat Population (ITT) ................................................................................... 15 
7.1.2. 
Per-Protocol Population (PP) ........................................................................................ 15 
7.1.3. 
Safety Population (SAF) ............................................................................................... 15 
7.1.4. 
Pharmacokinetic Population (PK) ................................................................................. 15 
7.2. 
Covariates and Subgroups ............................................................................................................... 15 
7.2.1. 
Planned Covariates ........................................................................................................ 15 
7.2.2. 
Planned Subgroups ........................................................................................................ 15 
7.3. 
Management of Analysis Data ........................................................................................................ 15 
7.3.1. 
Data Handling ............................................................................................................... 15 
7.3.2. 
Missing Data ................................................................................................................. 16 
7.3.2.1. 
Handling of Missing Date Values ............................................................ 16 
7.3.2.2. 
Baseline .................................................................................................... 17 
7.3.2.3. 
Missing Baseline Data ............................................................................. 17 
7.3.2.4. 
Imputation Methods ................................................................................. 17 
7.3.3. 
Handling of Early Termination Visit Information ......................................................... 18 
7.3.4. 
Pooling of Investigational Sites ..................................................................................... 18 
7.3.5. 
Coding Conventions for Events and Medications ......................................................... 18 
7.3.6. 
Analysis Software ......................................................................................................... 18 
7.3.7. 
Study Data ..................................................................................................................... 18 
7.4. 
Planned Study Analyses .................................................................................................................. 19 
7.4.1. 
Statistical Summaries: Descriptive and Inferential ....................................................... 19 
7.4.2. 
Interim Analyses ........................................................................................................... 19 


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7.4.3. 
Final Analysis and Publication of Study Results .......................................................... 19 
7.5. 
Multiple Testing Procedures ........................................................................................................... 19 
8. 
SUMMARY OF STUDY DATA ................................................................................................................ 20 
8.1. 
Subject Disposition ......................................................................................................................... 20 
8.2. 
Protocol Deviations ......................................................................................................................... 20 
8.3. 
Demographics and Baseline Characteristics ................................................................................... 20 
8.4. 
Concurrent Illness and Medical Conditions .................................................................................... 21 
8.5. 
Prior and Concomitant Medications ................................................................................................ 21 
8.6. 
Treatment Compliance .................................................................................................................... 21 
9. 
EFFICACY ANALYSES ............................................................................................................................ 22 
9.1. 
Primary Efficacy Analysis ............................................................................................................ 22 
9.2. 
Secondary Efficacy Analysis .......................................................................................................... 23 
9.3. 
Sensitivity Analysis......................................................................................................................... 24 
10. SAFETY ANALYSES................................................................................................................................. 25 
10.1. 
Adverse Events ............................................................................................................................... 25 
10.2. 
Deaths, Serious Adverse Events and Other Significant Adverse Events ........................................ 26 
10.2.1. 
Deaths............................................................................................................................ 26 
10.2.2. 
Serious Adverse Events ................................................................................................. 26 
10.2.3. 
Adverse Events Leading to Discontinuation of Study Drug ......................................... 26 
10.3. 
Bilateral Ophthalmic Examinations ................................................................................................ 26 
10.4. 
Vital Signs ....................................................................................................................................... 27 
10.5. 
Other Safety Measures .................................................................................................................... 27 
11. PHARMACOKINETIC (PK) ANALYSES ............................................................................................. 27 
12. REFERENCES ........................................................................................................................................... 27 
 
 


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LIST OF TABLES 
 
Table 1 
Schedule of Procedures ................................................................................................. 11 
 
 
 
 
 


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2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Only abbreviations and terms relevant to the SAP are repeated herein. The reader is referred 
to the protocol for the complete and comprehensive list of abbreviations and definitions of 
terms for the study. 
Abbreviation/Term 
Definition 
AE 
Adverse event 
AIC 
Akaike Information Criteria 
ANCOVA  
Analysis of covariance  
ANOVA  
Analysis of variance 
BCVA 
Best-corrected visual acuity 
BID 
Twice daily 
BP 
Blood pressure 
CI 
Confidence interval 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
HR  
Heart rate 
IOP 
Intraocular pressure 
ITT 
Intent-to-treat population 
IWRS 
Interactive Web Response System 
LOCF 
Last observation carried forward 
LogMAR 
Logarithm of the minimum angle of resolution 
LS mean 
Least squares means 
MMRM 
Mixed model for repeated measures 
MedDRA 
Medical Dictionary for Regulatory Activities 
OD 
Right eye 
OHT 
Ocular hypertension 
OS 
Left eye 
POAG 
Primary open angle glaucoma 
PK 
Pharmacokinetic 
PT 
Preferred term 
ROCK 
Rho-associated protein kinase 
PP 
Per-protocol population 
SAE 
Serious adverse event 
SAF 
Safety population 


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Abbreviation/Term 
Definition 
SAP 
Statistical Analysis Plan 
SE or se 
Standard error 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
VF 
Visual field 
WHO-DD 
World Health Organization Drug Dictionary 


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3. 
INTRODUCTION 
3.1. 
Preface 
This document presents a statistical analysis plan (SAP) for Betaliq, Inc. Protocol BTQ-1901-
1902-201 (A Randomized, Multicenter, Observer-Masked Study to Compare the Safety and 
Efficacy of BTQ-1901-A, BTQ-1901-B, and BTQ-1902 to Timolol 0.5% in Subjects with 
Primary Open Angle Glaucoma or Ocular Hypertension). 
Reference materials for this statistical plan include the protocol BTQ-1901-1902-201 (Version 
1.0 Dated: 01JUN2020) and Case Report Forms (Final Version 4.0, dated 20JUL2021). 
The SAP described hereafter is an a priori plan. The SAP will be finalized and approved prior 
to unmasking of any study data. Statistical programming may occur as study data accumulate 
in order to have analysis programs ready at the time the study finishes. In such an event, 
arbitrary treatment group assignments must be randomly linked to subjects, effectively 
rendering any output of programs meaningless. 
For the reasons stated here the conduct of the study in the field is considered to be independent 
of any study outcome that might materialize upon enactment of the currently proposed 
statistical plan.  
3.2. 
Purpose of Analyses 
The purposes of the planned analyses described in this SAP are to compare the safety and 
efficacy of BTQ-1901-A, BTQ-1901-B, and BTQ-1902 to Timolol 0.5% in subjects with 
primary open angle glaucoma (POAG) or ocular hypertension (OHT). Results from the 
analyses completed will be included in the final clinical study report for BTQ-1901-1902-201, 
and may also be utilized for regulatory submissions, manuscripts, or other clinical development 
activities. 
Post-hoc exploratory analyses not identified in this SAP may be performed to further examine 
the study data. These analyses will be clearly identified, where appropriate, in the final clinical 
study report. Additional analyses not prospectively identified in this SAP may also be 
completed for publications, or regulatory or funding inquiries. These analyses, if performed, 
may not be reported in the clinical study report, but will be fully documented in the document 
containing the additional analyses. 
3.3. 
Summary of Statistical Analysis Changes to the Protocol 
The analyses described in this analysis plan are consistent with the analyses described in the 
study protocol. 


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints defined in the protocol include safety and efficacy endpoints. 
Objectives and pre-specified endpoints are as follows: 
4.1. 
Study Objectives 
4.1.1. 
Primary Objective 
The primary objective of the study is to evaluate ocular and systemic safety and the efficacy 
of BTQ-1901-A, BTQ-1901-B, and BTQ-1902 ophthalmic suspensions in comparison to 
timolol 0.5% ophthalmic solution in subjects with POAG or OHT. 
4.2. 
Study Endpoints 
4.2.1. 
Efficacy Endpoints 
4.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be intraocular pressure (IOP) values at each time point 
(8:00 AM, 2 hours after dosing of study medication [~10:00 AM], 4:00 PM) at Visit 4/Day 15, 
Visit 5/Day 42, and Visit 6/Day 84. 
4.2.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will include the following: 
• Change from baseline (Visit 3/Qualification/Baseline) in the average of the 3 daily IOP 
measurements at each post baseline visit. 
• Time-matched change from baseline (Visit 3/Qualification/Baseline) in IOP 
measurements at all time points at Visit 4/Day 15, Visit 5/Day 42 and Visit 6/Day 84. 
4.2.2. 
Safety Endpoints 
Safety and tolerability endpoints will include the following: 
• Bilateral ophthalmic examination results (LogMAR best-corrected visual acuity 
[BCVA], slit lamp examination, ophthalmoscopy/dilated fundus examination, visual 
field [VF] testing, rating of drop comfort as assessed by the subject, grading of 
conjunctival hyperemia by the Investigator); 
• Resting heart rate and blood pressure (HR/BP); 


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• Incidence, severity of adverse events (AEs), serious AEs (SAEs), their relationship to 
the study drug of AEs, SAEs, and AEs leading to discontinuation of the study drug. 
4.2.3. 
Pharmacokinetic Endpoints 
Pharmacokinetic endpoint will include plasma drug concentration measured in a subset of 40 
subjects with blood samples collected following dosing at Visit 4/Day 15 and Visit 6/Day 84. 


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5. 
STUDY METHODS 
5.1. 
General Study Design and Plan 
As background for the statistical methods presented below, this section provides an overview 
of the study design and plan of study execution. The protocol is the definitive reference for all 
matters discussed in what follows. 
This will be a randomized, multicenter, parallel-group, observer-masked study to evaluate 
ocular and systemic safety and the efficacy of BTQ-1901-A (nebivolol 0.5%), BTQ-1901-B 
(nebivolol 1.0%) and BTQ-1902 (timolol 0.5%) ophthalmic suspensions in comparison to 
timolol 0.5% ophthalmic solution. The study will enroll approximately 240 subjects with 
POAG or OHT who will be treated for 84 days (12 weeks). 
Adult subjects will have POAG or OHT in both eyes (presence of POAG in one eye and OHT 
in the fellow eye is acceptable). If required, subjects will participate in a minimum washout 
period of 28 days for prostaglandin analogs, rho-associated protein kinase (ROCK) inhibitors, 
or beta (β) blockers; 14 days for adrenergic agonists; and 5 days for muscarinic agonists or 
carbonic anhydrase inhibitors (CAIs). 
At least one eye must qualify for the study, but even if only one eye meets all 
inclusion/exclusion criteria, both eyes will be treated. If both eyes qualify, the qualifying eye 
with the higher IOP at 8:00 AM at Visit 3/Qualification/Baseline will be designated as the 
study eye. Should the 8:00 AM IOP be the same in both eyes, then the right eye will be 
designated as the study eye.  
A total of 240 eligible subjects will be randomized in a 1:1:1:1 ratio into 1 of 4 treatment arms: 
BTQ-1901-A: nebivolol 0.5% ophthalmic suspension; BTQ-1901-B: nebivolol 1.0% 
ophthalmic suspension; BTQ-1902: timolol 0.5% ophthalmic suspension; and timolol 0.5% 
ophthalmic solution and receive 1 drop in each eye BID, morning and evening, for 84 days. 
The identity of the study medications will be masked to the Investigator and study personnel 
responsible for endpoint-related study procedures. 
The schedule for assessments and timing of events is presented in Table 1. 
 
 
 


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Table 1 
Schedule of Procedures 
Screen-
ing 
Washout 
Safety 
Checka 
Qualification/ 
Baseline 
Treatment 
Day 
-35 to -1 
-14 ± 3 
1 
15 ± 3 
42 ± 3 
84 ± 3 
Visit 
1 
2 
3 
4 
5 
6 
Hourb 
 
8:00 
AM 
10:00 
AM 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
Informed consent 
X 
 
Medical/ophthalmic 
history 
X 
 
Demographics 
X 
 
Adverse eventsc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Urine pregnancy testd 
X 
 
X 
X 
HR/BPe 
X 
 
X 
X 
X 
X 
BCVA (logMAR) 
X 
X 
X 
X 
X 
X 
Grading conjunctival 
hyperemiaf 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Biomicroscopy 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOPg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual field testh 
X 
 
X 
Gonioscopyi 
X 
 
Pachymetryj 
X 
 
Dilated ophthalmoscopy 
X 
 
X 
Review eligibility 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood collection (PK)k 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 


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Screen-
ing 
Washout 
Safety 
Checka 
Qualification/ 
Baseline 
Treatment 
Day 
-35 to -1 
-14 ± 3 
1 
15 ± 3 
42 ± 3 
84 ± 3 
Visit 
1 
2 
3 
 
 4 
5 
6 
Hourb 
- 
- 
8:00 
AM 
10:00 
AM 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
8:00 
AM 
2 h 
post 
dose 
4:00 
PM 
Study medication 
dispensed/redispensed 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Drop instillation/ 
instruction/evaluation 
 
X 
Xl 
Xl 
Xl 
Drop comfort ratingm 
 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
Study medication 
accountabilityn 
 
X 
X 
X 
X 
Compliance assessmento 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
BP = blood pressure; HR = heart rate: IOP = intraocular pressure; IP = investigational product; PK = pharmacokinetics 
NOTE: Subjects using ocular hypotensive medications must have undergone the appropriate required washout period prior to Visit 3/Qualification/Baseline. 
NOTE: If a study subject is discontinued from study medication before Visit 6/Day 84 but after Visit 3/Qualification/Baseline/Day 1, every effort should be 
taken to perform all the procedures listed for Visit 6/Last Day of Treatment (Section 10.4.3). If the subject is willing to remain at the site for the 8-hour visit, 
it should be conducted as specified, but if the subject is not willing to remain for the full duration, the VF test and the dilated ophthalmoscopy should be 
conducted as the last ophthalmic assessments in the early discontinuation visit. 
a Mid-washout safety check for subjects undergoing 28-day washout periods (i.e., prior prostaglandin analogs, rho-associated protein kinase [ROCK] 
inhibitors, or β-blockers) may be performed at the Investigator’s discretion. 
b The window for each time point is ± 30 minutes. For Visit 4/Day 15, Visit 5/Day 42, and Visit 6/Day 84, the 2 h post-dose timepoint will fall around 
10:00 AM, but the timing of the IOP measurement is dependent on the time study medication was administered at the site that day and should be 2 hours 
(± 30 minutes) after the dose was administered. 
c All AEs that occur following consent and until the final study visit (Visit 6/Day 84) should be collected and recorded on the AE eCRF page. 
d Required only for women of childbearing potential. At Visit 3/Qualification/Baseline/Day 1 it must be performed prior to randomization. At Visit 6/Day 84 
it may be performed anytime. 
e HR and BP will be measured seated after at least 5 minutes rest. Vital signs may be repeated once, after at least an additional 5 minutes rest in the seated 
position, if they are out of range. 
f It is preferred that conjunctival hyperemia be graded as part of the external eye exam performed prior to biomicroscopy. 


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g At Visit 3/Qualification/Baseline, IOP will be taken bilaterally at 8:00 AM, 10:00 AM, and 4:00 PM (each ± 30 minutes). At Visits 4, 5, and 6, IOP will be 
taken bilaterally at 8:00 AM, 2 hours after study medication dosing at the clinical site (~10:00 AM), and at 4:00 PM (each ± 30 minutes). Two consecutive 
IOP measurements of each eye will be performed. If the 2 measurements differ by more than 2 mm Hg, a third measurement will be taken. Consult the Study 
Manual for specific details. 
h Visual field measurement may be performed within 90 days prior to Screening if a test meeting the protocol requirements was performed and the results 
were documented. If the VF performed at or within 90 days prior to Visit 1 does not meet study required parameters, it may be repeated (test should be prior 
to randomization at Visit 3/Qualification/Baseline). The procedure may be performed at any time during the visit prior to dilation for ophthalmoscopy. 
i Gonioscopy may be performed within 90 days prior to Screening. The procedure must be performed after IOP measurement and before dilation for 
ophthalmoscopy. 
j Pachymetry may be performed within 90 days prior to Screening. The procedure may be performed at any time during the visit after IOP measurement. 
k Plasma concentration will be measured in a subset of 40 subjects; samples will be collected 2 hours (± 30 minutes) after study medication dosing at the 
clinical site. 
l Dose instillation should occur as close as possible to 15 minutes after IOP measurement, but not before 10 minutes after IOP measurement. Artificial tear 
use is prohibited within 10 minutes of instillation of study medication. 
m Subjects will be asked to rate the tolerability of the drop according to the following 4-point scale: 0 = No discomfort, 1 = Mild discomfort, 2 = Moderate 
discomfort, 3 = Severe discomfort. This rating should take place ≥ 10 minutes after the IOP measurement. 
n Study medication accountability may be performed at any time during the visit. 
o Compliance will be monitored via subject-reported missing doses in the Missed Doses Log. Documentation of compliance may be performed at any time 
during the visit. 
 
 


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5.2. 
Inclusion – Exclusion Criteria and General Study Population 
The general study population will include a total of 240 subjects with POAG or OHT. The 
inclusion and exclusion criteria defined in the protocol apply to all subjects and are not repeated 
herein the SAP. Reference is made to the final protocol for the specific inclusion and exclusion 
criteria for study subjects. 
5.3. 
Randomization and Masking 
A total of 240 eligible subjects will be randomized in a 1:1:1:1 ratio into 1 of 4 treatment arms 
and receive 1 drop in each eye BID, morning, and evening, for 84 days: 
• BTQ-1901-A (nebivolol 0.5% ophthalmic suspension) (N = 60) 
• BTQ-1901-B (nebivolol 1.0% ophthalmic suspension) (N = 60) 
• BTQ-1902 (timolol 0.5% ophthalmic suspension) (N = 60) 
• Timolol 0.5% ophthalmic solution (N = 60) [active comparator] 
A randomized block design will be used, and the randomization will be created by a 
biostatistician independent of the trial. Randomization will not be stratified by any factors. 
If 
subjects 
meet 
eligibility 
criteria 
at 
Visit 
1/Screening 
as 
well 
as 
at 
Visit 3/Qualification/Baseline, sites will access the Interactive Web Response System (IWRS) 
to randomize subjects to study treatment and assign the study medication kit to be dispensed. 
The drug kit and randomization numbers will be recorded in the subject’s eCRF. Study 
medication from the IWRS-assigned kit will be dispensed to the subject after initial dosing at 
the study site on Day 1 (Visit 3/Qualification/Baseline). The study will be observer masked. 
Rules for unmasking a subject for safety reasons are fully described in the protocol and not 
repeated herein this SAP. 
5.4. 
Analysis Variables 
Variables to be analyzed include demographics and baseline characteristics, efficacy variables 
(IOP values at each timepoint and change from baseline), safety/tolerability variables (adverse 
events, bilateral ophthalmic examinations, vital signs, rating of drop comfort, and conjunctival 
hyperemia grading) and PK concentrations. 
6. 
SAMPLE SIZE 
The sample size is not based on a formal sample size calculation; this study is planned to 
provide sufficient data to power the Phase 3 study. 


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7. 
GENERAL CONSIDERATIONS 
7.1. 
Analysis Populations 
There will be 4 (four) analysis populations defined for this study.  
7.1.1. 
Intent-to-Treat Population (ITT) 
The ITT population is defined as all randomized subjects. Supplemental efficacy analyses will 
be conducted on the ITT population. 
7.1.2. 
Per-Protocol Population (PP) 
The PP population consists of those subjects in the ITT population who were randomized and 
dosed and had no major protocol deviations. The primary efficacy analysis will be conducted 
on the PP population. Subjects who are members of the PP population will be analyzed as 
randomized. 
7.1.3. 
Safety Population (SAF) 
The safety population is defined as all randomized subjects who received at least one dose of 
the allocated study medication. All safety analyses will be performed using the safety 
population. Subjects who are members of the safety population will be analyzed as treated. 
7.1.4. 
Pharmacokinetic Population (PK) 
The PK population will consist of the subjects who were randomized, dosed, and have at least 
one PK value. It is planned that plasma concentration will be measured in a subset of 40 
subjects. Subjects who are members of the PK population will be analyzed as treated. 
7.2. 
Covariates and Subgroups 
7.2.1. 
Planned Covariates 
Planned covariates include baseline IOP for the efficacy analyses. 
7.2.2. 
Planned Subgroups 
There are no planned subgroup analyses. 
7.3. 
Management of Analysis Data 
7.3.1. 
Data Handling 
At least one eye must qualify for the study. Even if only one eye meets all inclusion/exclusion 
criteria, both eyes will be treated. If both eyes qualify, the qualifying eye with the higher IOP 


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at 8:00 AM at Visit 3/Qualification/Baseline will be designated as the study eye. Should the 
8:00 AM IOP be the same in both eyes, then the right eye will be designated as the study eye. 
At each IOP measurement time point, 2 consecutive IOP measurements of each eye will be 
performed. If the 2 measurements differ by more than 2 mm Hg, a third measurement will be 
taken. Mean IOP is calculated as the mean of 2 measurements or as the median of 
3 measurements. 
7.3.2. 
Missing Data 
All data recorded on the electronic case report form (eCRF) will be included in data listings 
that will accompany the clinical study report. All efficacy analyses will be based on observed 
cases (without imputation). Multiple imputation methods and single imputation methods (e.g., 
last observation carried forward [LOCF]) will be utilized for sensitivity analyses for select 
variables. 
7.3.2.1. 
Handling of Missing Date Values 
Partial or Missing Dates 
The following conventions will be used to impute missing portions of dates for AEs and 
concomitant medications, if warranted. Note that the imputed values outlined here may not 
always provide the most conservative date. In those circumstances, the imputed value may be 
replaced by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will be 
assigned a missing value.  
2) 
If the month is unknown, then: 
i) If the year matches the first dose date year, then impute the 
month and day of the first dose date. 
ii) Otherwise, assign ‘January.’  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month and year, 
then impute the day of the first dose date. 
ii) Otherwise, assign the first day of the month. 
B. 
Stop Dates 
1) 
If the year is unknown, then the date will not be imputed and will be 
assigned a missing value. 
2) 
If the month is unknown, then assign ‘December.’ 
3) 
If the day is unknown, then assign the last day of the month. 
 


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7.3.2.2. 
Baseline 
Except for specific analyses noted later (e.g., IOP), baseline values will be the last 
observation measured prior to dosing.  If a repeat value is measured prior to dosing this value 
can be used for baseline. 
7.3.2.3. 
Missing Baseline Data 
Every effort will be made to ensure that accurate baseline information on the subjects is 
collected. In the event that a subject is missing baseline information the subject will be included 
in the safety population for assessment of safety and excluded from the primary analyses. All 
baseline data will be observed cases, without imputation. 
7.3.2.4. 
Imputation Methods 
Multiple imputation methods and single imputation methods (e.g., LOCF) will be utilized for 
sensitivity analyses that include repeating the primary analysis with the ITT population. 
7.3.2.4.1. 
Last Observation Carried Forward (LOCF) 
Subjects with missing post-baseline efficacy data will be imputed using the LOCF method for 
the sensitivity analysis for all primary and secondary efficacy endpoints. For LOCF 
imputation, missing post-baseline efficacy data will be carried forward from the last non-
missing post-baseline value for that endpoint. Baseline efficacy data will not be carried forward 
to any missing post-baseline value.  
7.3.2.4.2. 
Multiple Imputation 
An alternative method of handling missing efficacy data in sensitivity analyses will be the 
method of multiple imputation. The pattern of missing observations in each treatment group 
will not influence the missing value estimation in the other because the imputation will be 
conducted independently for each treatment group.  Missing data will be assumed to be missing 
at random (MAR). 
For the imputation step, missing values will be separated into non-monotone missing values 
(i.e., intermittent missing values between completed assessments) and monotone missing 
values (i.e., missing values after the subject dropped out). SAS PROC MI procedure will 
sequentially estimate an imputation model for the IOP values at each post-baseline timepoint 
where IOP values are collected, separated between the treatment groups. 
For the imputation of intermediate missing values, the missing IOP values in each data set will 
be filled in using the Markov-Chain Monte Carlo (MCMC) method with multiple chains and 
monotone imputing. A total number of imputations will be 100. The seed used for these 
imputations will be 2021. 


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Once the intermediate missing data are imputed, the monotone missing data will be imputed 
for all subjects with monotone regression. The dataset is the output dataset of the partial 
imputation. Since this dataset already has 100 imputed values at each visit, only one imputation 
will be performed. 
Analysis timepoint results will be combined for overall inference to account for the uncertainty 
associated with the imputed values. This will be done using SAS PROC MIANALIZE. 
7.3.3. 
Handling of Early Termination Visit Information 
In the event that a subject is terminated early from this study the early termination visit data 
for safety variables will be analyzed at the closest scheduled visit. If the closest visit has valid 
data, the early termination data will be assigned to the next available visit.  
7.3.4. 
Pooling of Investigational Sites 
The data from all study centers will be pooled together for all planned analyses. 
7.3.5. 
Coding Conventions for Events and Medications 
All adverse events, and medical history will be mapped to the Medical Dictionary for 
Regulatory Activities (MedDRA Version 24.1) system for reporting (preferred term and body 
system). 
Prior and Concomitant medications will be coded using WHO-DD (Drug Dictionary) (Version 
date September 2021 B2/B3). 
7.3.6. 
Analysis Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher) for 
Windows. If the use of other software is warranted, the final clinical study report will detail 
what software was used and for what purposes. 
7.3.7. 
Study Data 
Study data identified in the schedule for time and events (Table 1) are collected, and source 
verified, on the electronic data capture (EDC) tool: Laboratory data are not collected in the 
EDC tool and are provided from external laboratories.  
All study data will be formulated into regulatory compliant data sets to provide transparency, 
traceability, and integrity of trial analysis results from the collection source. 


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7.4. 
Planned Study Analyses 
7.4.1. 
Statistical Summaries: Descriptive and Inferential 
All statistical tests will be two-sided and a difference resulting in a p-value of less than or equal 
to 0.05 will be considered statistically significant. All p-values will be rounded to and 
displayed in four decimals.  If a p-value less than 0.0001 occurs it will be shown in tables as 
<0.0001. 
Descriptive summaries of variables will be provided where appropriate. For continuous 
variables, the number of non-missing values (n) mean, standard deviation, median, minimum, 
and maximum will be tabulated by treatment. For categorical variables, the counts and 
percentage of each value will be tabulated by treatment. Expansion of descriptive table 
categories within each treatment may occur if such elaborations are thought to be useful. 
All study related data collected will be presented in listings. Study related data not subject to 
analysis according to this plan will not appear in any tables or graphs but will be included in 
the data listings. 
7.4.2. 
Interim Analyses 
No formal interim analysis is planned for this study. 
7.4.3. 
Final Analysis and Publication of Study Results 
The final analysis will be completed after all subjects have completed Visit 6 or prematurely 
discontinued the study. 
7.5. 
Multiple Testing Procedures 
The primary efficacy analysis will be the between-group comparison of the mean IOP values 
in the study eye at each time point at each of the Visit 4/Day 15, Visit 5/Day 42, and Visit 
6/Day 84 visits (i.e., a total of 9 between-group comparisons). A hierarchical analysis will be 
conducted to compare each of the investigational products against the comparator, timolol 
0.5%, as follows: (1) BTQ-1902, (2) BTQ-1901B, and (3) BTQ-1901A.  
To demonstrate noninferiority, the upper limits of the 2-sided 95% confidence interval (CI) for 
the difference between each comparison should be lower than 1.5 mm Hg at all timepoints. 
Additionally, the upper limits of the 95% CI should be lower than 1.0 mm Hg for the majority 
of time points measured (i.e., 5 of 9).  
All other comparisons are considered exploratory. 
 
 


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8. 
SUMMARY OF STUDY DATA 
8.1. 
Subject Disposition 
A summary of the analysis sets includes the number and percentage of subjects for the 
following categories: subjects screened, subjects screen failed, subjects randomized, subjects 
in ITT Population, subjects in Safety Population, subjects in the PP Population, and subjects 
in the PK Population. All percentages will be based on the number of subjects randomized. 
End of trial information will also be summarized in this table, including the number of subjects 
completing the study/treatment and the number of subjects that prematurely discontinued the 
study/treatment with reasons for withdrawal. All percentages will be based on the number of 
subjects randomized. 
A by-subject data listing of study completion information including the reason for premature 
study withdrawal and also treatment completion status, if applicable, will be presented. 
8.2. 
Protocol Deviations 
Major protocol deviations, as determined by a Sponsor masked review of the data prior to 
database lock and unmasking of the study, may result in the removal of a subject’s data from 
the PP Population. The Sponsor or designee will be responsible for producing the final 
deviation file; this file will include a description of the protocol deviation and clearly identify 
whether or not this deviation warrants exclusion from the PP Population. This file will be 
finalized prior to database lock. 
All protocol deviations will be presented in a data listing, with a flag to indicate if a deviation 
was considered major and resulted in the exclusion of the subject from the PP Population. A 
summary table will be generated based on the classification of protocol deviations. 
8.3. 
Demographics and Baseline Characteristics 
Subject demographic data and baseline characteristics will be tabulated and summarized 
descriptively by treatment group and overall. The demographic data and baseline 
characteristics will be summarized for all analysis populations (ITT, SAF, PP, and PK). 
Individual subject demographics and baseline characteristics will be provided in listings. 
The demographics consist of age (year), sex, race, ethnicity, and iris color. The baseline 
characteristics consist of baseline diagnosis of Primary Open-Angle Glaucoma and Ocular 
Hypertension by eye (right eye [OD] and left eye [OS]), designated study eye (OD, OS), 
baseline systolic/diastolic BP (mm Hg), baseline HR (beats/min), baseline Visual Field testing 
results (mean deviation), baseline LogMAR BCVA, and pachymetry.  
Age, baseline systolic/diastolic blood pressure, baseline heart rate will be summarized using 
descriptive statistics. The number and percentage of subjects by sex, race, ethnicity, and iris 


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color will also be reported. Percentages will be based on the total number of subjects in the 
study population presentation. 
All demographic and baseline information will be listed by subject. 
8.4. 
Concurrent Illness and Medical Conditions 
The number and percent of subjects with medical/ophthalmic histories will be summarized for 
all subjects by the type of history and eye (ophthalmic history: study eye, ophthalmic history: 
non-study eye, non-ocular medical history) and treatment group. Individual subject listings 
will also be provided for concurrent illness and medical history. 
Medical history will be coded using the MedDRA Version 24.1. The number and percentage 
of subjects with any medical history will be summarized overall and for each system organ 
class (SOC) and preferred term (PT). Percentages will be calculated based on number of 
subjects in the Safety Population.  
Subject medical history data including gonioscopy will be presented in a listing. 
8.5. 
Prior and Concomitant Medications 
The number and percentages of all ocular concomitant medications will be summarized by 
study/non-study eye and treatment group, Anatomical Therapeutic Chemical (ATC) level 2, 
and PT. The total number of concomitant medications and the number and percentages of 
subjects with at least 1 concomitant medication will be summarized by treatment group. All 
summaries will be performed using the Safety Population. 
A concomitant medication is defined as any medication taken on or after the day of first 
exposure to study drug up until 7 days after last dose of study drug. 
Prior medications are defined as any medications started and stopped prior to the day of first 
exposure to any study drug. 
Non-ocular medications will be summarized similarly. 
8.6. 
Treatment Compliance 
Continuous descriptive summaries will be presented for the Safety Population by treatment 
level and will include number of doses, number of doses missed, and study dosing compliance 
(%). Compliance is calculated for each subject using the following formula: 
((Date of last dose – Date of first dose + 1) x2 doses – Missed doses) / ((Date of last visit [Visit 
6 or ET] – Date of Visit 3 + 1) x 2 doses) x100% 


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9. 
EFFICACY ANALYSES 
Unless otherwise noted, all efficacy analyses will be completed using PP and ITT Populations. 
All efficacy analyses will be completed using the planned dose that the subject was randomized 
to.  
Efficacy data will be presented in tables of descriptive statistics and frequency distribution. All 
summary tables will be supported with individual subject data listings. 
In general, and unless otherwise noted, data summaries will be presented by treatment. 
9.1. 
Primary Efficacy Analysis 
The primary efficacy analysis will be the between-group comparison of the mean IOP values 
in the study eye at each time point at each of the Visit 4/Day 15, Visit 5/Day 42, and Visit 
6/Day 84 visits (i.e., a total of 9 between-group comparisons). 
A summary of the efficacy endpoints will be prepared at each time point. 
The between-treatment comparison will employ a mixed model for repeated measures 
(MMRM) with treatment, visit/time, treatment-by-visit/time interaction, and average baseline 
value as fixed effects, and actual IOP value in the study eye as the outcome variable of the 
model. Visit/time will include the following 9 timepoints: Visit 4/Day 15 (8:00 AM, 10:00 
AM, 4:00 PM), Visit 5/Day 42 (8:00 AM, 10:00 AM, 4:00 PM), and Visit 6/Day 84 (8:00 AM, 
10:00 AM, 4:00 PM). Average baseline value is the average result of IOP assessments 
performed at Visit 3/Day 1 (8:00 AM, 10:00 AM, and 4:00 PM). 
An unstructured correlation matrix will be used thus allowing adjustment for correlations 
between time points within patients. A Kenward-Roger approximation will be used for the 
denominator degrees of freedom. If the model with the unstructured correlation matrix fails to 
converge then the following correlation structures will be fitted: variance components, 
compound symmetry, first order autoregressive and Toeplitz. The value of the Akaike 
Information Criteria (AIC) should be considered to choose the most appropriate model (the 
model with the smallest AIC is preferred). In case of inadequate results, further modification 
of the model may be required. 
Example SAS code is provided below. 
proc mixed data=eff method=reml; 
 
class trt visittime subjid; 
 
model actual=trt visittime trt*visittime avgbase/ddfm=kr; 
 
repeated visittime/type=UN subject=subjid; 
 
lsmeans trt*visittime/cl pdiff; 
 
run; 
 


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Where actual is the actual IOP value measured at each visit/time point, trt is treatment (BTQ-
1901-A, BTQ-1901-B, BTQ-1902, or Timolol 0.5% ophthalmic solution), visittime is the 
combination of visit/timepoint (9 total values), and avgbase is the average baseline value. 
Treatment comparisons will be performed for the treatment difference in least squares means 
(LS mean) compared with the Timolol 0.5% treatment group. LS mean (standard error [SE]) 
by treatment group, visit and time, the LS mean difference between treatment groups, along 
with 2-sided 95% CI of the treatment differences and the p-value for the treatment comparison 
will be displayed. To demonstrate noninferiority, the upper limits of 95% CI for the difference 
between each comparison should be lower than 1.5 mm Hg at all timepoints. Additionally, the 
upper limits of the 95% CI should be lower than 1.0 mm Hg for the majority of time points 
measured (i.e., 5 of 9). 
Linear contrasts will be used to calculate the confidence intervals at all visit/times. 
9.2. 
Secondary Efficacy Analysis 
Similar analysis methods to those used for the primary efficacy endpoints will be utilized for 
the secondary efficacy endpoints. 
Secondary efficacy endpoint #1: MMRM will be used for between-treatment comparison of 
change from baseline IOP in the average of the 3 daily IOP measurements at each post baseline 
visit. Treatment, visit, treatment by-visit interaction, and average baseline value will be 
considered as fixed effects, and change from average baseline IOP value in the study eye will 
be considered as the outcome variable of the model. Visits to be analyzed will include Visit 
4/Day 15, Visit 5/Day 42, and Visit 6/Day 84. Average baseline value is the average result of 
IOP assessments performed at Visit 3/Day 1 (8:00 AM, 10:00 AM, and 4:00 PM). Change 
from baseline IOP value is a difference between average result of IOP assessments performed 
at post-baseline visit and baseline value (defined above). 
Example SAS code is provided below. 
proc mixed data=eff method=reml; 
 
class trt visit subjid; 
 
model change=trt visit trt*visit avgbase/ddfm=kr; 
 
repeated visit/type=UN subject=subjid; 
 
lsmeans trt*visit/cl pdiff; 
 
run; 
 
Where change is the IOP change from average baseline value using the average of the 3 daily 
IOP measurements at each visit, trt is treatment (BTQ-1901-A, BTQ-1901-B, BTQ-1902, or 
Timolol 0.5% ophthalmic solution), visit is the visit (Visit 4/Day 15, Visit 5/Day 42, or Visit 
6/Day 84), and avgbase is the average baseline value. 
Treatment comparisons will be performed for the treatment difference in LS mean. LS mean 
(SE) by treatment group, visit and time (applicable for time-matched IOP change from 


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baseline), the LS mean difference between treatment groups, along with 2-sided 95% CI of the 
treatment differences and the p-value for the treatment comparison and within-treatment 
difference will be displayed. 
Secondary efficacy endpoint #2: For the analysis of time-matched change from baseline in 
study eye IOP measurements at all time points MMRM will include treatment, visit/time, 
treatment-by-visit/time interaction, and average baseline value as fixed effects. Visit/time will 
include the following 9 timepoints: Visit 4/Day 15 (8:00 AM, 10:00 AM, 4:00 PM), Visit 
5/Day 42 (8:00 AM, 10:00 AM, 4:00 PM), and Visit 6/Day 84 (8:00 AM, 10:00 AM, 4:00 
PM). The average baseline value is the average result of IOP assessments performed at Visit 
3/Day 1 (8:00 AM, 10:00 AM, and 4:00 PM). Time-matched change from baseline is a 
difference between actual IOP and baseline IOP taken at the same time of Visit 3/Day 1 (e.g. 
Visit 4/Day 15 8:00 AM change from baseline will be based on Visit 3/Day 1 8:00 AM result).  
Example SAS code is provided below. 
proc mixed data=eff method=reml; 
 
class trt visittime subjid; 
 
model timematchchg=trt visittime trt*visittime avgbase/ddfm=kr; 
 
repeated visittime/type=UN subject=subjid; 
 
lsmeans trt*visittime/cl pdiff; 
 
run; 
 
Where timematchchg is the time-matched change from baseline value measured at each 
visit/time point, trt is treatment (BTQ-1901-A, BTQ-1901-B, BTQ-1902, or Timolol 0.5% 
ophthalmic solution), visittime is the combination of visit/timepoint (9 total values), and avgbase 
is the average baseline value. 
Treatment comparisons will be performed for the treatment difference in LS mean. LS mean 
(SE) by treatment group, visit and time (applicable for time-matched IOP change from 
baseline), the LS mean difference between treatment groups, along with 2-sided 95% CI of the 
treatment differences and the p-value for the treatment comparison and within-treatment 
difference will be displayed. 
9.3. 
Sensitivity Analysis 
Sensitivity analyses will be based on ITT population and will be performed for primary and 
secondary efficacy endpoints. This will include the same statistical methodology as in the 
primary and secondary analyses, however when using imputed data preliminary imputation 
steps will have to be completed prior to applying the methods from the primary and secondary 
analyses. 
The following analyses will be performed: 
• repeating the primary and secondary analyses; 


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• utilizing LOCF imputed data (see Section 7.3.2.3.1) and analysis of covariance 
(ANCOVA) model at each visit/time point; 
• imputing missing data using multiple imputation techniques (see Section 7.3.2.3.2) and 
repeating the primary and secondary analyses; 
• using Wilcoxon rank sum tests to compare treatments at each time point. 
10. 
SAFETY ANALYSES 
All Safety analyses will be conducted using the Safety population. Categories for data 
presentation and analysis will consist of each treatment group (BTQ-1901-A, BTQ-1901-B, 
BTQ-1902, timolol 0.5%) and overall treatments summary. All safety analyses will be 
completed using the actual treatment a subject received.  
10.1. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 23.1.  
Treatment-emergent adverse events (TEAEs) are defined as any AE or worsening of an 
existing condition after initiation of the investigational product and through the subject’s last 
study visit (study completion or early termination). Serious adverse events (SAE) will be 
recorded from the date of informed consent, throughout the clinical trial. All SAEs that are 
ongoing at the time of completion or discontinuation from the study will be followed until 
stabilization or resolution of the event. 
If the onset of an AE is on Day 1, then the time of first dose will be compared to the time of 
onset to determine if the AE is treatment-emergent. 
The number and percent of subjects with any TEAEs will be summarized by system organ 
class and preferred term by dose level (and overall). At each level of tabulation (e.g. at the 
preferred term level) subjects will be counted only once if they had more than one such event 
reported during the AE collection period. 
The following summary tables and subject level listings will be presented for TEAE data:  
• 
Overall summary of TEAEs  
• 
Summary table of TEAE descending incidence by PT 
• 
Summary table of TEAEs by SOC and PT  
• 
Summary table of serious TEAEs by SOC and PT  
• 
Summary table of TEAEs by highest relationship level to study drug by SOC and PT  
• 
Summary table of serious TEAEs by highest relationship level to study drug by SOC 
and PT  


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• 
Summary table of TEAEs by maximum intensity by SOC and PT 
• 
Summary table of TEAEs leading to study discontinuation by SOC and PT 
• 
Summary table of TEAEs leading to study drug discontinuation or interruption by 
SOC and PT 
 
Ocular (by study and non-study eye) and non-ocular AE/TEAE will be summarized and listed 
separately. 
10.2. 
Deaths, Serious Adverse Events and Other Significant Adverse Events 
10.2.1. 
Deaths 
All deaths, regardless of causality, will be provided in a table listing and written clinical 
narratives will also be provided. 
10.2.2. 
Serious Adverse Events 
A table listing of SAEs and a table listing of related SAEs will be provided.   
Furthermore, the number and percent of subjects with SAEs will be displayed by SOC and PT, 
and relationship to study medication, for each treatment group.  Within each PT, subjects will 
be counted only once if they had more than one SAE event reported during the treatment 
period.  
10.2.3. 
Adverse Events Leading to Discontinuation of Study Drug 
A table listing of all AEs leading to study discontinuation, or discontinuation/ interruption of 
study drug will be presented. 
Furthermore, the number and percent of subjects with AE’s leading to study discontinuation, 
or discontinuation/interruption of study drug will be displayed by SOC and PT for each 
treatment group. Within each PT, subjects will be counted only once if they had more than one 
AE leading to study discontinuation, or discontinuation/interruption of study drug reported 
during the treatment period.  
10.3. 
Bilateral Ophthalmic Examinations 
Bilateral ophthalmic examinations (LogMAR BCVA, slit lamp biomicroscopy, dilated 
ophthalmoscopy, VF testing) including grading of conjunctival hyperemia by the Investigator 
and assessment of comfort/tolerability by the subject (drop comfort rating) will be summarized 
descriptively for each treatment group by time point. Assessments done on both eyes will be 
summarized separately by study and non-study eye. 
Continuous results will be summarized descriptively for the observed value as well as for the 
change from baseline value. Categorical results will be summarized by counts and percentage. 


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Unscheduled visit results will not be summarized but will be included in patient data listings. 
10.4. 
Vital Signs 
Descriptive statistics of observed values will be presented for vital sign data by scheduled study 
visit, including systolic blood pressure (mm Hg), diastolic blood pressure (mm Hg), heart rate 
(beats/min) by treatment group for subjects in the Safety Population. Changes from baseline 
to each scheduled post-baseline visit will be presented.  
All vital sign data by subject will be presented in a listing. Unscheduled visit results will not 
be summarized but will be included in patient data listings.  
10.5. 
Other Safety Measures 
All collected measures and assessments will be listed. No other safety analyses have been 
prospectively defined. If, however, after study results are reviewed, they will be fully described 
and documented in the final clinical study report. The SAP does not need to be amended to 
complete any other safety measures identified as post-hoc. 
11. 
PHARMACOKINETIC (PK) ANALYSES  
All PK analyses will be conducted using the PK population and actual treatment a subject 
received. Plasma concentration will be measured in this population, blood samples will be 
collected 2 hours (± 30 minutes) after study medication dosing at the clinical site at Visit 4/Day 
15 and Visit 6/Day 84. 
Descriptive summary statistics of concentration data by visit/time and treatment will include 
n, mean, standard deviation, coefficient of variation (%CV), median, minimum, maximum, 
and geometric mean. 
For each analyte, the plasma concentration at each timepoint will be analyzed using analysis 
of variance (ANOVA), considering treatment as fixed effect. For each treatment, LS means 
will be calculated. Mean differences between the test treatments and the comparator (timolol 
0.5%) and the corresponding 90% CI will be calculated.  
All available concentration-time data will be listed by treatment. 
12. 
REFERENCES 
ICH E9 Expert Working Group. Statistical Principles for Clinical Trials: ICH Harmonized 
Tripartite Guideline, September 1998