Dose-Ranging Study of the Bimatoprost Ocular Insert

• Sponsor: ForSight Vision5, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02358369
• Collaborator: (none)
• Enrollment: 156
• Locations: 10
• Arms: 3
• Actual Duration (Months): 8.6
• Patients Per Site: 15.6
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The Bimatoprost Ocular Insert is intended to provide sustained delivery of bimatoprost to the ocular surface to lower the intraocular pressure (IOP) in patients with Open-Angle Glaucoma or Ocular Hypertension.

This study evaluated the safety and efficacy of two different doses of the Bimatoprost Ocular Insert, compared to an active control arm with timolol ophthalmic solution (0.5%).

Condition or Disease	Intervention/Treatment	Phase
Primary Open-Angle Glaucoma; Ocular Hypertension	Drug: Bimatoprost; Drug: Timolol 0.5%; Device: Placebo Ocular Insert; Drug: Placebo Eye Drops	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Prospective, Multicenter, Randomized, Double-masked, Controlled Study to Evaluate the Efficacy and Safety and Dose-response of the Bimatoprost Ocular Insert (2.2 mg, 13 mg) With and Without Concomitant Artificial Tears Compared to a Placebo Ocular Insert With and Without Concomitant Timolol (0.5%) Ophthalmic Solution in Patients With Open-angle Glaucoma or Ocular Hypertension
• Actual Study Start Date: Jan 19, 2015
• Actual Primary Completion Date: Aug 31, 2015
• Actual Study Completion Date: Oct 7, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 13 mg Bimatoprost Ocular Insert Washout + Placebo Ocular Insert in each eye for 4 to 6 weeks, followed by 13 mg Bimatoprost Ocular Insert in each eye (OU) for 12 weeks. Note: participants also self-administered placebo ophthalmic eye drops to each eye twice a day (BID) for the first 6 weeks. After 12 weeks, 13 mg Bimatoprost Ocular Insert in each eye for an additional 12 weeks.	Drug: Bimatoprost; Bimatoprost sustained release Ocular Insert; Device: Placebo Ocular Insert; Placebo ocular insert OU.; Drug: Placebo Eye Drops; Placebo eye drops BID OU.
Experimental: 2.2 mg Bimatoprost Ocular Insert Washout + Placebo Ocular Insert in each eye for 4 to 6 weeks, followed by 2.2 mg Bimatoprost Ocular Insert in each eye for 12 weeks. Note: participants also self-administered placebo ophthalmic eye drops in each eye twice a day for the first 6 weeks. After 12 weeks, 13 mg Bimatoprost Ocular Insert in each eye for an additional 12 weeks.	Drug: Bimatoprost; Bimatoprost sustained release Ocular Insert; Device: Placebo Ocular Insert; Placebo ocular insert OU.; Drug: Placebo Eye Drops; Placebo eye drops BID OU.
Active Comparator: Timolol 0.5% Washout + Placebo Ocular Insert in each eye for 4 to 6 weeks, followed by 0.5% timolol ophthalmic solution in each eye for 6 weeks. Note: participants simultaneously wore placebo ocular inserts for 12 weeks. After 12 weeks, 13 mg Bimatoprost Ocular Insert in each eye for an additional 12 weeks.	Drug: Bimatoprost; Bimatoprost sustained release Ocular Insert; Drug: Timolol 0.5%; BID drops OU, 0.5% ophthalmic solution; Device: Placebo Ocular Insert; Placebo ocular insert OU.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Intraocular Pressure (IOP) at Week 8 [Baseline (Day 0) to Week 8]

   IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Week 8. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.

2. Change From Baseline in IOP at Week 12 [Baseline (Day 0) to Week 12]

   IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Week 12. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.

3. Percentage of Participants by Change From Baseline in Best-corrected Visual Acuity (BCVA) Categories at Week 8 [Baseline (Day 0) to Week 8]

   BCVA is measured using an eye chart and is reported as the number of letters read correctly (ranging from 0 to 100 letters). The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved.

4. Percentage of Participants by Change From Baseline in Best-corrected Visual Acuity (BCVA) Categories at Week 12 [Baseline (Day 0) to Week 12]

   BCVA is measured using an eye chart and is reported as the number of letters read correctly (ranging from 0 to 100 letters). The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved.

5. Percentage of Participants With Clinically Significant Change From Baseline in Slit-Lamp Examination Findings at Week 12 [Baseline (Day 0) to Week 12]

   The clinician examined and graded the eyelids, conjunctiva, cornea and anterior chamber of the eye with the aid of a slit-lamp, (conjunctival erythema was assessed as part of the examination). Fluorescein dye was instilled into the ocular cul-de-sac to facilitate this examination.

6. Change From Baseline in Automated Visual Field at Week 12 [Baseline (Day 0) to Week 12]

   Automated Visual Field was examined used the Humphrey Visual Field Analyzer, a test that measures the entire area of peripheral vision that can be seen while the eye is focused on a central point. A positive change from Baseline indicates improvement.

7. Dilated Fundus Exam: Cup-to-Disc-Ratio [Week 12]

   The cup-to-disk-ratio is an eye test to assess the progression of glaucoma. The diameter of the cup is compared to the diameter of the disk and a ratio is determined. The normal cup-disk ratio is 0.3. An increase in the cup-to-disc-ratio is a possible indication of glaucoma.

8. Percentage of Participants by Dilated Fundus Exam Pathology Grade at Week 12 [Week 12]

   Dilated fundus examination pathology findings were noted, described and graded on a scale of None (0), Mild (+1), Moderate (+2) and Severe (+3). The percentage of participants in each grade is reported.

9. Percentage of Participants With Ocular and Non-ocular Adverse Events (AE) by Severity in Period A/B [Baseline (Day 0) to Week 12]

   An AE was defined as any untoward medical occurrence (eg, sign, symptom, disease, syndrome, intercurrent illness) that occurred in a study participant, regardless of the suspected cause during the study. An ocular AE is an AE that occurred in the eye and non-ocular is an AE that occurred not in the eye. Th investigator assessed the worst severity of each AE as: Mild=aware of sign or symptom, but readily tolerated, Moderate=discomfort enough to cause interference with usual activity or Severe=incapacitating with inability to work or do usual activity.

10. Percentage of Participants With Ocular and Non-ocular Adverse Events (AE) by Severity in Period C [Week 12 to Week 24]

    An AE was defined as any untoward medical occurrence (eg, sign, symptom, disease, syndrome, intercurrent illness) that occurred in a study participant, regardless of the suspected cause during the study. An ocular AE is an AE that occurred in the eye and non-ocular is an AE that occurred not in the eye. The investigator assessed the worst severity of each AE as: Mild=aware of sign or symptom, but readily tolerated, Moderate=discomfort enough to cause interference with usual activity or Severe=incapacitating with inability to work or do usual activity.

Secondary Outcome Measures

1. Change From Baseline in IOP at Week 2 [Baseline (Day 0) to Week 2]

   IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Week 2. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.

2. Change From Baseline in IOP at Week 6 [Baseline (Day 0) to Week 6]

   IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Week 6. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.

3. Change From Baseline in IOP in Period C [Baseline (Day 0) to Weeks 14, 18 and 24]

   IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Weeks 14, 18 and 24. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• Written informed consent

• At least 18 years of age

• Diagnosis in both eyes of either primary open-angle glaucoma (POAG) or ocular hypertension

• Best corrected-distance visual acuity score equivalent to 20/80 or better

• Stable visual field

• Central corneal thickness between 490 - 620 micrometers

Inclusion Criteria at the Randomization Visit:

("T" is defined as time and "hr" is defined as hour[s])

• IOP for each eye is ≥ 23 mm Hg at T=0 hr, ≥ 20 mm Hg at T=2 hr and T=8 hr.

• Inter-eye IOP difference of ≤ 5.0 mm Hg at T=0 hr, T=2 hr and T=8 hr.

• IOP for each eye is ≤ 30 mm Hg at T=0 hr, T=2 hr and T=8 hr.

Key Exclusion Criteria:

• Any known contraindication to prostaglandin analog (latanoprost, travoprost, bimatoprost, tafluprost) or timolol

• A cardiac or pulmonary condition that in the opinion of the Investigator would contraindicate the use of beta-blocker drops

• Cup-to-disc ratio of greater than 0.8

• Significant risk of angle closure due to pupil dilation, defined as a Shaffer classification of less than Grade 2 based on gonioscopy

• Ocular, orbital, and/or eyelid surgery of any type within the past six (6) months from screening date

• Laser surgery for glaucoma / ocular hypertension on one (1) or both eyes within the last six (6) months

• Past history of any incisional surgery for glaucoma at any time

• Past history of corneal refractive surgery

• Corneal abnormalities that would interfere with accurate IOP readings with an applanation tonometer

• Current participation in an investigational drug or device study or participation in such a study within 30 days of Screening

• Inability to adequately evaluate the retina

• Participants who will require contact lens use during the study period.

• Participants who currently have punctal occlusion

• Pregnant, lactating or of child-bearing potential and not using a medically acceptable form of birth control

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vold Vision	Fayetteville	Arkansas	United States	72704
2	Sall Medical Research Center	Artesia	California	United States	90701
3	Eye Research Foundation	Newport Beach	California	United States	92663
4	Clayton Eye Center	Morrow	Georgia	United States	30260
5	Mundorf Eye Center	Charlotte	North Carolina	United States	28204
6	Cornerstone Health Care	High Point	North Carolina	United States	27262
7	Apex Eye	Madeira	Ohio	United States	45243
8	University of Eye Specialists	Maryville	Tennessee	United States	37803
9	Total Eye Care	Memphis	Tennessee	United States	38119
10	R&R Eye Research, LLC	San Antonio	Texas	United States	78229

Sponsors and Collaborators

• ForSight Vision5, Inc.

Investigators

• Study Director: Michelle Chen, PhD, Allergan

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: ForSight Vision5, Inc.
• ClinicalTrials.gov Identifier: NCT02358369
• Other Study ID Numbers: FSV5-004
• First Posted: Feb 9, 2015
• Last Update Posted: Jun 4, 2020
• Last Verified: May 1, 2020

• Additional relevant MeSH terms: Glaucoma; Glaucoma, Open-Angle; Ocular Hypertension; Hypertension; Timolol; Bimatoprost; Ophthalmic Solutions

Study Results

Participant Flow

Pre-assignment Detail	156 participants were enrolled and entered the washout placebo and trial-wear period. A total of 121 participants were randomized to one of three treatment groups.

Arm/Group Title	Washout + Placebo Ocular Insert	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period C)
Arm/Group Description	Glaucoma medication washout and placebo ocular insert in each eye for 4 to 6 weeks prior to randomization.	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following Treatment Period A/B, 13 mg Bimatoprost Ocular Insert for 12 weeks in Period C (Week 12 to 24).
Period Title: Pre-Randomization Washout Period
STARTED	156	0	0	0	0
COMPLETED	121	0	0	0	0
NOT COMPLETED	35	0	0	0	0
Period Title: Pre-Randomization Washout Period
STARTED	0	40	40	41	0
COMPLETED	0	38	38	37	0
NOT COMPLETED	0	2	2	4	0
Period Title: Pre-Randomization Washout Period
STARTED	0	0	0	0	113
COMPLETED	0	0	0	0	106
NOT COMPLETED	0	0	0	0	7

Baseline Characteristics

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5%	2.2 mg Bimatoprost Ocular Insert	13 mg Bimatoprost Ocular Insert	Total
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular inserts in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued. In Treatment Period C all participants were fitted with 13 mg Bimatoprost Ocular Inserts for 12 weeks.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued. In Treatment Period C all participants were fitted with 13 mg Bimatoprost Ocular Insert in each eye for 12 weeks.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued. In Treatment Period C all participants were fitted with 13 mg Bimatoprost Ocular Insert in each eye for 12 weeks.	Total of all reporting groups
Overall Participants	40	40	41	121
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.7 (8.70)	64.1 (9.24)	63.0 (10.01)	64.9 (9.47)
Sex: Female, Male (Count of Participants)
Female	27 67.5%	20 50%	35 85.4%	82 67.8%
Male	13 32.5%	20 50%	6 14.6%	39 32.2%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Intraocular Pressure (IOP) at Week 8
Description	IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Week 8. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.
Time Frame	Baseline (Day 0) to Week 8

Outcome Measure Data

Analysis Population Description

Participants from the FAS, all participants who were randomized, treated and returned for at least one post-treatment visit, with data available at Week 8.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	38	35	36
Change from Baseline to Week 8 (T=0 hour)	-4.68 (2.931)	-3.68 (3.105)	-4.56 (3.007)
Change from Baseline to Week 8 (T=2 hour)	-3.62 (2.924)	-3.31 (3.063)	-3.98 (3.522)
Change from Baseline to Week 8 (T=8 hour)	-3.21 (2.812)	-3.23 (2.573)	-3.22 (3.061)

2. Primary Outcome

Title	Change From Baseline in IOP at Week 12
Description	IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Week 12. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.
Time Frame	Baseline (Day 0) to Week 12

Outcome Measure Data

Analysis Population Description

FAS, all participants who were randomized, treated and returned for at least one post-treatment visit, with data available at Week 12. Participants on rescue therapy with missing data during the evaluation period or measurements out of the pre-specified visit window had IOP data imputed using LOCF (last observation carried forward) for the visit.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	38	35	37
Change from Baseline to Week 12 (T=0 hour)	-3.37 (3.147)	-3.64 (3.454)	-4.08 (2.893)
Change from Baseline to Week 12 (T=2 hour)	-2.74 (2.891)	-3.67 (3.182)	-3.40 (3.815)
Change from Baseline to Week 12 (T=8 hour)	-2.34 (2.756)	-3.20 (2.491)	-2.69 (2.523)

3. Primary Outcome

Title	Percentage of Participants by Change From Baseline in Best-corrected Visual Acuity (BCVA) Categories at Week 8
Description	BCVA is measured using an eye chart and is reported as the number of letters read correctly (ranging from 0 to 100 letters). The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved.
Time Frame	Baseline (Day 0) to Week 8

Outcome Measure Data

Analysis Population Description

Participants from the Safety Population, all randomized participants who had an ocular insert placed, with data available for analysis at Week 8.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	38	39	36
Right Eye, 10+ Letter Improvement	2.6 6.5%	0 0%	2.8 6.8%
Right Eye, 5+ Letter Improvement	18.4 46%	7.7 19.3%	5.6 13.7%
Right Eye, No Change	65.8 164.5%	69.2 173%	77.8 189.8%
Right Eye, 5- Letter Worsening	13.2 33%	17.9 44.8%	13.9 33.9%
Right Eye, 10- Letter Worsening	0 0%	5.1 12.8%	0 0%
Left Eye, 10+ Letter Improvement	2.6 6.5%	0 0%	5.6 13.7%
Left Eye, 5+ Letter Improvement	10.5 26.3%	20.5 51.3%	19.4 47.3%
Left Eye, No Change	68.4 171%	66.7 166.8%	66.7 162.7%
Left Eye, 5- Letter Worsening	15.8 39.5%	7.7 19.3%	5.6 13.7%
Left Eye, 10- Letter Worsening	2.6 6.5%	5.1 12.8%	2.8 6.8%

4. Primary Outcome

Title	Percentage of Participants by Change From Baseline in Best-corrected Visual Acuity (BCVA) Categories at Week 12
Description	BCVA is measured using an eye chart and is reported as the number of letters read correctly (ranging from 0 to 100 letters). The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved.
Time Frame	Baseline (Day 0) to Week 12

Outcome Measure Data

Analysis Population Description

Participants from the Safety Population, all randomized participants who had an ocular insert placed, with data available for analysis at Week 12.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	38	38	36
Right Eye, 10+ Letter Improvement	0 0%	0 0%	2.8 6.8%
Right Eye, 5+ Letter Improvement	7.9 19.8%	5.3 13.3%	11.1 27.1%
Right Eye, No Change	73.7 184.3%	57.9 144.8%	61.1 149%
Right Eye, 5- Letter Worsening	13.2 33%	28.9 72.3%	22.2 54.1%
Right Eye, 10- Letter Worsening	5.3 13.3%	7.9 19.8%	2.8 6.8%
Left Eye, 10+ Letter Improvement	0 0%	0 0%	5.6 13.7%
Left Eye, 5+ Letter Improvement	7.9 19.8%	13.2 33%	19.4 47.3%
Left Eye, No Change	71.1 177.8%	68.4 171%	61.1 149%
Left Eye, 5- Letter Worsening	18.4 46%	15.8 39.5%	13.9 33.9%
Left Eye, 10- Letter Worsening	2.6 6.5%	2.6 6.5%	0 0%

5. Primary Outcome

Title	Percentage of Participants With Clinically Significant Change From Baseline in Slit-Lamp Examination Findings at Week 12
Description	The clinician examined and graded the eyelids, conjunctiva, cornea and anterior chamber of the eye with the aid of a slit-lamp, (conjunctival erythema was assessed as part of the examination). Fluorescein dye was instilled into the ocular cul-de-sac to facilitate this examination.
Time Frame	Baseline (Day 0) to Week 12

Outcome Measure Data

Analysis Population Description

Safety population included all participants who had an ocular insert placed.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	40	40	41
Number [percentage of participants]	0 0%	0 0%	0 0%

6. Primary Outcome

Title	Change From Baseline in Automated Visual Field at Week 12
Description	Automated Visual Field was examined used the Humphrey Visual Field Analyzer, a test that measures the entire area of peripheral vision that can be seen while the eye is focused on a central point. A positive change from Baseline indicates improvement.
Time Frame	Baseline (Day 0) to Week 12

Outcome Measure Data

Analysis Population Description

Safety Population included all randomized participants who had an ocular insert placed. The number of participants analyzed is the number of participants with data available at the given time-point.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	40	40	41
Baseline	-2.58 (3.377)	-1.45 (4.041)	-2.70 (2.934)
Change from Baseline to Week 12	-0.18 (2.010)	0.02 (1.819)	0.39 (1.446)

7. Primary Outcome

Title	Dilated Fundus Exam: Cup-to-Disc-Ratio
Description	The cup-to-disk-ratio is an eye test to assess the progression of glaucoma. The diameter of the cup is compared to the diameter of the disk and a ratio is determined. The normal cup-disk ratio is 0.3. An increase in the cup-to-disc-ratio is a possible indication of glaucoma.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Participants from the Safety Population, all randomized participants who had an ocular insert placed, with data available for analysis. The number analyzed is the number of participants with data available at the given time-point.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	38	38	36
Right Eye, Week 12	0.53 (0.172)	0.55 (0.161)	0.47 (0.184)
Left Eye, Week 12	0.54 (0.160)	0.56 (0.157)	0.48 (0.176)

8. Primary Outcome

Title	Percentage of Participants by Dilated Fundus Exam Pathology Grade at Week 12
Description	Dilated fundus examination pathology findings were noted, described and graded on a scale of None (0), Mild (+1), Moderate (+2) and Severe (+3). The percentage of participants in each grade is reported.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Safety Population included all randomized participants who had an ocular insert placed. The number of participants analyzed is the number of participants with data available at the given time-point.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	40	40	41
Right Eye, None	63.2 158%	71.1 177.8%	50.0 122%
Left Eye, None	62.2 155.5%	71.1 177.8%	47.2 115.1%
Right Eye, Mild	34.2 85.5%	26.3 65.8%	44.4 108.3%
Left Eye, Mild	35.1 87.8%	26.3 65.8%	50.0 122%
Right Eye, Moderate	2.6 6.5%	2.6 6.5%	5.6 13.7%
Left Eye, Moderate	2.7 6.8%	2.6 6.5%	2.8 6.8%

9. Primary Outcome

Title	Percentage of Participants With Ocular and Non-ocular Adverse Events (AE) by Severity in Period A/B
Description	An AE was defined as any untoward medical occurrence (eg, sign, symptom, disease, syndrome, intercurrent illness) that occurred in a study participant, regardless of the suspected cause during the study. An ocular AE is an AE that occurred in the eye and non-ocular is an AE that occurred not in the eye. Th investigator assessed the worst severity of each AE as: Mild=aware of sign or symptom, but readily tolerated, Moderate=discomfort enough to cause interference with usual activity or Severe=incapacitating with inability to work or do usual activity.
Time Frame	Baseline (Day 0) to Week 12

Outcome Measure Data

Analysis Population Description

Safety Population included all randomized participants who had an ocular insert placed.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	40	40	41
Ocular, Mild	12.5 31.3%	17.5 43.8%	26.8 65.4%
Ocular, Moderate	2.5 6.3%	5.0 12.5%	4.9 12%
Ocular, Severe	0 0%	0 0%	0 0%
Non-ocular, Mild	5.0 12.5%	5.0 12.5%	9.8 23.9%
Non-Ocular, Moderate	15.0 37.5%	2.5 6.3%	7.3 17.8%
Non-ocular, Severe	0 0%	2.5 6.3%	0 0%

10. Primary Outcome

Title	Percentage of Participants With Ocular and Non-ocular Adverse Events (AE) by Severity in Period C
Description	An AE was defined as any untoward medical occurrence (eg, sign, symptom, disease, syndrome, intercurrent illness) that occurred in a study participant, regardless of the suspected cause during the study. An ocular AE is an AE that occurred in the eye and non-ocular is an AE that occurred not in the eye. The investigator assessed the worst severity of each AE as: Mild=aware of sign or symptom, but readily tolerated, Moderate=discomfort enough to cause interference with usual activity or Severe=incapacitating with inability to work or do usual activity.
Time Frame	Week 12 to Week 24

Outcome Measure Data

Analysis Population Description

Safety Population included all randomized participants who had an ocular insert placed.

Arm/Group Title	13 mg Bimatoprost Ocular Insert (Period C)
Arm/Group Description	Following Treatment Period A/B, 13 mg Bimatoprost Ocular Insert in each eye for 12 weeks in Period C (Week 12 to Week 24).
Measure Participants	113
Ocular, Mild	23.9 59.8%
Ocular, Moderate	5.3 13.3%
Ocular, Severe	0 0%
Non-ocular, Mild	5.3 13.3%
Non-ocular, Moderate	4.4 11%
Non-ocular, Severe	0.9 2.3%

11. Secondary Outcome

Title	Change From Baseline in IOP at Week 2
Description	IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Week 2. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.
Time Frame	Baseline (Day 0) to Week 2

Outcome Measure Data

Analysis Population Description

Participants from the FAS, all participants who were randomized, treated and returned for at least one post-treatment visit, with data available at Week 2.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	39	40	40
Change from Baseline to Week 2 (T=0 hour)	-6.84 (2.264)	-4.56 (3.134)	-5.95 (2.367)
Change from Baseline to Week 2 (T=2 hour)	-5.71 (2.277)	-4.14 (2.637)	-5.34 (2.499)
Change from Baseline to Week 2 (T=8 hour)	-4.81 (2.612)	-3.76 (2.320)	-4.52 (2.594)

12. Secondary Outcome

Title	Change From Baseline in IOP at Week 6
Description	IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Week 6. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.
Time Frame	Baseline (Day 0) to Week 6

Outcome Measure Data

Analysis Population Description

Participants from the FAS, all participants who were randomized, treated and returned for at least one post-treatment visit, with data available at Week 6.

Arm/Group Title	Placebo Ocular Insert + Timolol 0.5% (Period A/B)	2.2 mg Bimatoprost Ocular Insert (Period A/B)	13 mg Bimatoprost Ocular Insert (Period A/B)
Arm/Group Description	Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular insert in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.	Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops to each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued.
Measure Participants	39	36	38
Change from Baseline to Week 6 (T=0 hour)	-6.42 (2.770)	-4.87 (3.212)	-5.30 (2.941)
Change from Baseline to Week 6 (T=2 hour)	-4.97 (2.948)	-4.40 (3.138)	-4.42 (2.830)
Change from Baseline to Week 6 (T=8 hour)	-4.40 (2.529)	-3.73 (2.393)	-3.77 (2.291)

13. Secondary Outcome

Title	Change From Baseline in IOP in Period C
Description	IOP is a measurement of the fluid pressure inside the eye. Diurnal IOP measurements were taken at 8 am (T=0 hour), 10 am (T=2 hour), and 4 pm (T=8 hour) at Weeks 14, 18 and 24. IOP readings from both eyes were averaged to compute a single IOP value for each diurnal timepoint. A negative change from Baseline indicated an improvement.
Time Frame	Baseline (Day 0) to Weeks 14, 18 and 24

Outcome Measure Data

Analysis Population Description

Participants from the FAS, all participants who were randomized, treated and returned for at least one post-treatment visit, with data available at the given timepoint.

Arm/Group Title	13 mg Bimatoprost Ocular Insert (Period C)
Arm/Group Description	Following Treatment Period A/B, 13 mg Bimatoprost Ocular Insert in each eye for 12 weeks in Period C (Week 12 to Week 24).
Measure Participants	113
Change from Baseline to Week 14 (T=0 hour)	-5.72 (2.919)
Change from Baseline to Week 14 (T=2 hour)	-4.64 (3.100)
Change from Baseline to Week 14 (T=8 hour)	-4.13 (2.849)
Change from Baseline to Week 18 (T=0 hour)	-5.62 (3.135)
Change from Baseline to Week 18 (T=2 hour)	-4.33 (3.072)
Change from Baseline to Week 18 (T=8 hour)	-4.17 (2.714)
Change from Baseline to Week 24 (T=0 hour)	-4.85 (2.882)
Change from Baseline to Week 24 (T=2 hour)	-3.99 (2.847)
Change from Baseline to Week 24 (T=8 hour)	-2.99 (3.010)

Adverse Events

Time Frame	Adverse event data were collected for a period of 28 to 30 weeks, from the beginning of the Washout Period (starting on Week -6 to -4) to the end of study (Week 24).
Adverse Event Reporting Description	During the Washout Period (4 to 6 weeks) prior to randomization, adverse event data were collected for all participants in a single arm. During the entire 24 weeks of treatment (consisting of Treatment Periods A, B and C), adverse event data were not collected by the intervention received, but instead, according to the arm participants were randomized to at the start of Treatment Period A (Week 0).
Arm/Group Title	Washout + Placebo Ocular Insert		Placebo Ocular Insert + Timolol 0.5%		2.2 mg Bimatoprost Ocular Insert		13 mg Bimatoprost Ocular Insert
Arm/Group Description	Glaucoma medication washout and placebo ocular insert in each eye for 4 to 6 weeks prior to randomization.		Following the washout period, timolol ophthalmic solution 0.5% twice a day in each eye plus placebo ocular inserts in each eye for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the placebo ocular inserts for 6 weeks but the eye drops were discontinued. In Treatment Period C all participants were fitted with 13 mg Bimatoprost Ocular Inserts for 12 weeks.		Following the washout period, 2.2 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 2.2 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued. In Treatment Period C all participants were fitted with 13 mg Bimatoprost Ocular Insert in each eye for 12 weeks.		Following the washout period, 13 mg Bimatoprost Ocular Insert in each eye plus placebo eye drops in each eye twice a day for 6 weeks in Treatment Period A. In Treatment Period B participants continued to wear the 13 mg Bimatoprost Ocular Inserts for 6 weeks but the eye drops were discontinued. In Treatment Period C all participants were fitted with 13 mg Bimatoprost Ocular Insert in each eye for 12 weeks.
All Cause Mortality
	Washout + Placebo Ocular Insert		Placebo Ocular Insert + Timolol 0.5%		2.2 mg Bimatoprost Ocular Insert		13 mg Bimatoprost Ocular Insert
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Washout + Placebo Ocular Insert		Placebo Ocular Insert + Timolol 0.5%		2.2 mg Bimatoprost Ocular Insert		13 mg Bimatoprost Ocular Insert
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/156 (0%)		3/40 (7.5%)		1/40 (2.5%)		1/41 (2.4%)
Cardiac disorders
Supraventricular tachycardia	0/156 (0%)		1/40 (2.5%)		0/40 (0%)		0/41 (0%)
General disorders
Device dislocation	0/156 (0%)		1/40 (2.5%)		0/40 (0%)		0/41 (0%)
Nervous system disorders
Brain hypoxia	0/156 (0%)		0/40 (0%)		1/40 (2.5%)		0/41 (0%)
Transient ischaemic attack	0/156 (0%)		0/40 (0%)		0/40 (0%)		1/41 (2.4%)
Ischaemic stroke	0/156 (0%)		1/40 (2.5%)		0/40 (0%)		0/41 (0%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/156 (0%)		1/40 (2.5%)		0/40 (0%)		0/41 (0%)
Other (Not Including Serious) Adverse Events
	Washout + Placebo Ocular Insert		Placebo Ocular Insert + Timolol 0.5%		2.2 mg Bimatoprost Ocular Insert		13 mg Bimatoprost Ocular Insert
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/156 (5.8%)		16/40 (40%)		12/40 (30%)		20/41 (48.8%)
Eye disorders
Conjunctival hyperaemia	3/156 (1.9%)		2/40 (5%)		3/40 (7.5%)		3/41 (7.3%)
Eye discharge	5/156 (3.2%)		5/40 (12.5%)		7/40 (17.5%)		7/41 (17.1%)
Eye pruritus	1/156 (0.6%)		3/40 (7.5%)		2/40 (5%)		1/41 (2.4%)
Punctate keratitis	0/156 (0%)		3/40 (7.5%)		1/40 (2.5%)		6/41 (14.6%)
Conjunctival haemorrhage	0/156 (0%)		2/40 (5%)		2/40 (5%)		1/41 (2.4%)
Eye irritation	0/156 (0%)		2/40 (5%)		1/40 (2.5%)		0/41 (0%)
Dry eye	0/156 (0%)		2/40 (5%)		0/40 (0%)		0/41 (0%)
Vision blurred	0/156 (0%)		1/40 (2.5%)		1/40 (2.5%)		4/41 (9.8%)
Infections and infestations
Upper respiratory tract infection	1/156 (0.6%)		2/40 (5%)		1/40 (2.5%)		3/41 (7.3%)
Urinary tract infection	0/156 (0%)		2/40 (5%)		0/40 (0%)		1/41 (2.4%)
Metabolism and nutrition disorders
Diabetes mellitus	0/156 (0%)		1/40 (2.5%)		0/40 (0%)		3/41 (7.3%)
Vascular disorders
Hypertension	1/156 (0.6%)		2/40 (5%)		0/40 (0%)		3/41 (7.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

No presentation or publication of Institution's data relating to the Trial may occur until after the Trial has been completed at all sites. If Investigator desires to present or publish, investigator must submit any and all manuscripts, posters, abstracts, or other intended publications (hereinafter collectively referred to as "manuscripts") to Sponsor at least sixty (60) days prior to the actual submission of such manuscript(s) for publication.