LADDER: Study of the Efficacy and Safety of the Ranibizumab Port Delivery System for Sustained Delivery of Ranibizumab in Patients With Subfoveal Neovascular Age-Related Macular Degeneration

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02510794
• Collaborator: (none)
• Enrollment: 225
• Locations: 50
• Arms: 4
• Actual Duration (Months): 42
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase II multicenter, dose-ranging, randomized, active treatment (monthly ITV injection)-controlled study to evaluate the efficacy, safety, and pharmacokinetics of ranibizumab delivered through the Implant using three ranibizumab formulation arms (10 mg/mL, 40 mg/mL, and 100 mg/mL) compared with the control arm (0.5-mg monthly ITV injections of 10-mg/mL formulation) in participants with subfoveal neovascular age-related macular degeneration (nAMD).

Condition or Disease	Intervention/Treatment	Phase
Macular Degeneration	Drug: Ranibizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 225 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicenter, Randomized, Active Treatment-Controlled Study of the Efficacy and Safety of the Ranibizumab Port Delivery System for Sustained Delivery of Ranibizumab in Patients With Subfoveal Neovascular Age-Related Macular Degeneration
• Actual Study Start Date: Sep 28, 2015
• Actual Primary Completion Date: Apr 10, 2018
• Actual Study Completion Date: Mar 28, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Port Delivery System with Ranibizumab 10mg/mL Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Drug: Ranibizumab; Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.; Other Names: Lucentis®
Experimental: Port Delivery System with Ranibizumab 40mg/mL Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Drug: Ranibizumab; Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.; Other Names: Lucentis®
Experimental: Port Delivery System with Ranibizumab 100mg/mL Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Drug: Ranibizumab; Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.; Other Names: Lucentis®
Active Comparator: Intravitreal Injection with Ranibizumab 0.5mg Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.	Drug: Ranibizumab; Ranibizumab will be administered at dose of 0.5 mg monthly ITV injections of 10-mg/mL formulation or delivered through the implant with three different formulations.; Other Names: Lucentis®

Outcome Measures

Primary Outcome Measures

1. Time Until a Participant First Requires the Implant Refill According to Protocol-Defined Refill Criteria [Baseline up to approximately 38 months]

   Protocol-Defined Refill Criteria At 1 month after initial fill: Decrease of ≥ 10 letters in BCVA at the current visit compared with the baseline BCVA, due to nAMD disease activity OR Increase in CFT of ≥ 100 um at the current visit compared with the baseline CFT, due to nAMD disease activity OR Presence of new macular hemorrhage, due to nAMD disease activity For subsequent assessments: Increase in CFT of ≥ 75 μm on SD-OCT at the current visit compared with the average CFT over the last 2 available measurements, due to nAMD disease activity OR Increase in CFT of ≥ 100 um from the lowest CFT measurement on study, due to nAMD disease activity OR Decrease of ≥ 5 letters in BCVA at the current visit compared with the average BCVA over the last 2 available measurements, due to nAMD disease activity OR Decrease of ≥ 10 letters from best recorded BCVA on study, due to nAMD disease activity OR Presence of new macular hemorrhage, due to nAMD disease activity

Secondary Outcome Measures

1. Change From Baseline in Best Corrected Visual Acuity (BCVA) Averaged At Month 9 and 10 [Baseline, Months 9, 10]

   Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning.

2. Change From Baseline in BCVA Over Time [Baseline up to Month 10]

   Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning.

3. Adjusted Average Change From Baseline in BCVA Over Time (MMRM Analysis) [Baseline up to Month 10]

   Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning. Here, the adjusted mean from MMRM analysis is presented).

4. Change From Baseline in Central Foveal Thickness (CFT) Over Time as Assessed on Spectral Domain-Optical Coherence Tomography (SD-OCT) [Baseline up to Month 9]

   Central foveal thickness (CFT) is defined as the retinal thickness in the center of the fovea

5. Number of Implant Clogging at Month 9 [Month 9]

   Removed implants identified as meeting serum PK criteria for possible clogging were assessed via lab-based investigation (in vitro drug release testing) to determine whether there was any implant clogging.

6. Observed Maximum Serum Concentration (Cmax) of Ranibizumab [Predose (0 hour) on Day 1 up to 38 months]

   The serum pharmacokinetics of ranibizumab were characterized by estimating Cmax between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.

7. Area Under the Concentration-Time Curve From Dosing to Last Observation (AUClast) of Ranibizumab [Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field)]

   AUCLast is defined as area under the concentration-time curve from dosing (implant or refill) to last observation before next refill or exiting the study. The serum pharmacokinetics of ranibizumab were characterized by estimating AUC between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.

8. Time to Maximum Concentration (Tmax) of Ranibizumab [Predose (0 hour) on Day 1 up to 38 months]

   The serum pharmacokinetics of ranibizumab were characterized by estimating Tmax between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.

9. Terminal Half-Life (t1/2) of Ranibizumab [Predose (0 hour) on Day 1 up to 38 months]

   The serum pharmacokinetics of ranibizumab were characterized by estimating t1/2 between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.

10. Observed Steady-State Serum Concentration at the End of a Dosing Interval (Ctrough) of Ranibizumab [Predose (0 hour) on Day 1 up to 38 months]

11. Number of Participants With Ocular and Non-Ocular Adverse Events (AEs) and Serious AEs (SAEs) [Baseline up to approximately Month 38]

12. Percentage of Participants With Positive Serum Antibodies to Ranibizumab [Baseline up to 38 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Newly diagnosed with wet AMD within 9 months of screening visit

• Participant must have received at least 2 prior ITV anti-vascular endothelial growth factor (VEGF) injections. However, the most recent anti-VEGF injection must have been ranibizumab and must have occurred at least 7 days prior to the screening visit

• Demonstrated response to prior ITV anti-VEGF treatment

• Best Corrected Visual Acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts of 20/20-20/200 Snellen equivalent

Exclusion Criteria:

• Treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to the randomization visit in either eye

• Study eye treatment with ITV anti-VEGF agents other than ranibizumab within 1 month prior to the randomization visit

• History of laser photocoagulation, Visudyne®, ITV corticosteroid injection, vitrectomy surgery, submacular surgery, device implantation, or other surgical intervention for AMD in the study eye

• Prior participation in a clinical trial involving anti-angiogenic drugs, other than ranibizumab, in either eye within 2 months of the randomization visit

• Subretinal hemorrhage in the study eye that involves the center of the fovea

• Subfoveal fibrosis, or atrophy in the study eye

• Choroidal neovascularization (CNV) in either eye due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia

• Uncontrolled ocular hypertension or glaucoma in the study eye

• History of glaucoma-filtering surgery, tube shunts, or microinvasive glaucoma surgery in the study eye

• Uncontrolled blood pressure

• Uncontrolled atrial fibrillation within 3 months of informed consent

• History of myocardial infarction or stroke within the last 3 months prior to informed consent

• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of ranibizumab or placement of the Implant, that might affect interpretation of the results of the study or renders the participant at high risk of treatment complications

• Use of oral corticosteroids

• Current treatment for any active systemic infection

• Use of anticoagulants, anti-platelets (other than aspirin), or medications known to exert similar effects

• Active malignancy within 12 months of randomization

• History of allergy to fluorescein

• Previous participation in any non-ocular (systemic) disease studies of investigational drugs within 1 month preceding the informed consent (excluding vitamins and minerals)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Barnet Dulaney Perkins Eye Center	Mesa	Arizona	United States	85206
2	Retinal Research Institute, LLC	Phoenix	Arizona	United States	85014
3	Associated Retina Consultants	Phoenix	Arizona	United States	85020
4	The Retina Partners	Encino	California	United States	91436
5	Jacobs Retina center at the Shiley eye Institute UCSD	La Jolla	California	United States	92037
6	Jules Stein Eye Institute/ UCLA	Los Angeles	California	United States	90095-7000
7	N CA Retina Vitreous Assoc	Mountain View	California	United States	94040
8	Retinal Consultants Med Group	Sacramento	California	United States	95825
9	West Coast Retina Medical Group	San Francisco	California	United States	94109
10	UCSF; Ophthalmology	San Francisco	California	United States	94143
11	Orange County Retina Med Group	Santa Ana	California	United States	92705
12	California Retina Consultants	Santa Barbara	California	United States	93103
13	Retina Consultants of Southern	Colorado Springs	Colorado	United States	80909
14	Colorado Retina Associates, PC	Lakewood	Colorado	United States	80228
15	Florida Eye Microsurgical Inst	Boynton Beach	Florida	United States	33426
16	National Ophthalmic Research Institute	Fort Myers	Florida	United States	33912
17	Retina Specialty Institute	Pensacola	Florida	United States	32503
18	Retina Vitreous Assoc of FL	Saint Petersburg	Florida	United States	33711
19	Retina Associates of Florida, LLC	Tampa	Florida	United States	33609
20	Southeast Retina Center	Augusta	Georgia	United States	30909
21	Illinois Retina Associates	Joliet	Illinois	United States	60435
22	Wolfe Eye Clinic	West Des Moines	Iowa	United States	50266
23	Retina Associates of Kentucky	Lexington	Kentucky	United States	40509
24	Paducah Retinal Center	Paducah	Kentucky	United States	42001
25	Johns Hopkins Med; Wilmer Eye Inst	Baltimore	Maryland	United States	21287
26	Retina Group of Washington	Chevy Chase	Maryland	United States	20815
27	Retina Specialists	Towson	Maryland	United States	21204
28	Vitreo-Retinal Associates, PC	Worcester	Massachusetts	United States	01605
29	Foundation for Vision Research	Grand Rapids	Michigan	United States	49546
30	Vitreoretinal Surgery	Edina	Minnesota	United States	55435
31	Sierra Eye Associates	Reno	Nevada	United States	89502
32	Retina Center of New Jersey	Bloomfield	New Jersey	United States	07003
33	Mid Atlantic Retina - Wills Eye Hospital	Cherry Hill	New Jersey	United States	08034
34	Eye Associates of New Mexico	Albuquerque	New Mexico	United States	87102
35	University of New Mexico; School of Med	Albuquerque	New Mexico	United States	87131
36	Retina Assoc of Western NY	Rochester	New York	United States	14620
37	Char Eye Ear &Throat Assoc	Charlotte	North Carolina	United States	28210
38	Cincinnati Eye Institute	Cincinnati	Ohio	United States	45242
39	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
40	Retina Northwest	Portland	Oregon	United States	97221
41	Oregon HSU; Casey Eye Institute	Portland	Oregon	United States	97239
42	Palmetto Retina Center	Florence	South Carolina	United States	29501
43	Charles Retina Institute	Germantown	Tennessee	United States	38138
44	Tennessee Retina PC.	Nashville	Tennessee	United States	37203
45	Texas Retina Associates	Arlington	Texas	United States	76012
46	Retina Research Center	Austin	Texas	United States	78750
47	Retina Consultants of Texas	Bellaire	Texas	United States	77401
48	Med Center Ophthalmology Assoc	San Antonio	Texas	United States	78240
49	Retina Associates of Utah	Salt Lake City	Utah	United States	84107
50	Wagner Macula & Retina Center	Norfolk	Virginia	United States	23502

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Feb 7, 2018
• Statistical Analysis Plan - Jun 21, 2018

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT02510794
• Other Study ID Numbers: GX28228
• First Posted: Jul 29, 2015
• Last Update Posted: May 6, 2021
• Last Verified: Apr 1, 2021

• Additional relevant MeSH terms: Macular Degeneration; Ranibizumab

Study Results

Participant Flow

Recruitment Details

Participants with subfoveal neovascularization secondary to AMD diagnosed within 9 months and treated with ITV anti-VEGF agents were enrolled in the study. Written informed consent was obtained before initiation of any study-related procedures. A participant's screening occurred no sooner than 7 days following administration of the last ITV ranibizumab treatment to the study eye. The screening visit was followed by the randomization visit.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Period Title: Overall Study
STARTED	59	62	63	41
COMPLETED	51	56	56	36
NOT COMPLETED	8	6	7	5

Baseline Characteristics

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg	Total
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.	Total of all reporting groups
Overall Participants	59	62	63	41	225
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	8 13.6%	7 11.3%	9 14.3%	7 17.1%	31 13.8%
>=65 years	51 86.4%	55 88.7%	54 85.7%	34 82.9%	194 86.2%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	74.6 (8.4)	75.0 (8.5)	73.8 (8.1)	71.9 (8.8)	74.0 (8.4)
Sex: Female, Male (Count of Participants)
Female	37 62.7%	39 62.9%	42 66.7%	28 68.3%	146 64.9%
Male	22 37.3%	23 37.1%	21 33.3%	13 31.7%	79 35.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 5.1%	3 4.8%	3 4.8%	1 2.4%	10 4.4%
Not Hispanic or Latino	56 94.9%	56 90.3%	60 95.2%	39 95.1%	211 93.8%
Unknown or Not Reported	0 0%	3 4.8%	0 0%	1 2.4%	4 1.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	1 1.6%	0 0%	1 0.4%
Asian	0 0%	0 0%	2 3.2%	0 0%	2 0.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 1.7%	0 0%	0 0%	0 0%	1 0.4%
White	58 98.3%	61 98.4%	60 95.2%	41 100%	220 97.8%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 1.6%	0 0%	0 0%	1 0.4%

Outcome Measures

1. Primary Outcome

Title	Time Until a Participant First Requires the Implant Refill According to Protocol-Defined Refill Criteria
Description	Protocol-Defined Refill Criteria At 1 month after initial fill: Decrease of ≥ 10 letters in BCVA at the current visit compared with the baseline BCVA, due to nAMD disease activity OR Increase in CFT of ≥ 100 um at the current visit compared with the baseline CFT, due to nAMD disease activity OR Presence of new macular hemorrhage, due to nAMD disease activity For subsequent assessments: Increase in CFT of ≥ 75 μm on SD-OCT at the current visit compared with the average CFT over the last 2 available measurements, due to nAMD disease activity OR Increase in CFT of ≥ 100 um from the lowest CFT measurement on study, due to nAMD disease activity OR Decrease of ≥ 5 letters in BCVA at the current visit compared with the average BCVA over the last 2 available measurements, due to nAMD disease activity OR Decrease of ≥ 10 letters from best recorded BCVA on study, due to nAMD disease activity OR Presence of new macular hemorrhage, due to nAMD disease activity
Time Frame	Baseline up to approximately 38 months

Outcome Measure Data

Analysis Population Description

Efficacy Population defined as all participants who were randomly assigned to study treatment and received at least one study treatment, excluding 5 participants who were given surgery.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.
Measure Participants	58	62	59
Median (80% Confidence Interval) [Months]	8.7	13.0	15.8

2. Secondary Outcome

Title	Change From Baseline in Best Corrected Visual Acuity (BCVA) Averaged At Month 9 and 10
Description	Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning.
Time Frame	Baseline, Months 9, 10

Outcome Measure Data

Analysis Population Description

Efficacy Population defined as all participants who were randomly assigned to study treatment and received at least one study treatment. Assessments are censored for PDS participants meeting the following situations: At the time of an ITV anti-VEGF injection in study eye prior to Month 10. Prohibited therapy other than oral corticosteroids more than 10 mg/day or any fellow eye treatment. At the time of explant.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	58	62	59	41
Mean (95% Confidence Interval) [Units on scale]	-3.3	-0.3	5.0	3.2

3. Secondary Outcome

Title	Change From Baseline in BCVA Over Time
Description	Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning.
Time Frame	Baseline up to Month 10

Outcome Measure Data

Analysis Population Description

Efficacy Population defined as all participants who were randomly assigned to study treatment and received at least one study treatment. Assessments are censored for PDS participants meeting the following situations: At the time of an ITV anti-VEGF injection in study eye prior to Month 10. Prohibited therapy other than oral corticosteroids more than 10 mg/day or any fellow eye treatment. At the time of explant.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	58	62	59	41
Month 1	-6.6	-4.7	-4.9	2.4
Month 2	-2.4	-1.4	1.6	2.0
Month 3	-0.7	-0.6	2.4	2.7
Month 4	-1.4	-1.1	3.1	1.9
Month 5	-1.3	-0.6	3.8	3.0
Month 6	-0.4	-1.7	3.8	2.7
Month 7	-0.9	-1.8	3.9	3.5
Month 8	-2.4	-1.2	4.0	3.3
Month 9	-3.3	-0.5	5.0	3.9
Month 10	-3.3	-0.2	5.1	2.5

4. Secondary Outcome

Title	Adjusted Average Change From Baseline in BCVA Over Time (MMRM Analysis)
Description	Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. The minimum score possible is 0 and maximum possible is 100. A higher score represents better functioning. Here, the adjusted mean from MMRM analysis is presented).
Time Frame	Baseline up to Month 10

Outcome Measure Data

Analysis Population Description

Efficacy Population defined as all participants who were randomly assigned to study treatment and received at least one study treatment. Assessments are censored for PDS participants meeting the following situations: At the time of an ITV anti-VEGF injection in study eye prior to Month 10. Prohibited therapy other than oral corticosteroids more than 10 mg/day or any fellow eye treatment. At the time of explant.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	45	60	55	37
Mean (Standard Deviation) [Units on scale]	-7.5 (74.0)	-8.5 (59.1)	29.7 (54.7)	21.3 (65.1)

5. Secondary Outcome

Title	Change From Baseline in Central Foveal Thickness (CFT) Over Time as Assessed on Spectral Domain-Optical Coherence Tomography (SD-OCT)
Description	Central foveal thickness (CFT) is defined as the retinal thickness in the center of the fovea
Time Frame	Baseline up to Month 9

Outcome Measure Data

Analysis Population Description

Efficacy Population defined as all participants who received at least one study treatment. Here, "Number of Participants analyzed" indicates Number of Participants Included in MMRM Analysis. Assessments are censored for PDS participants meeting the following situations: At the time of an ITV anti-VEGF injection in study eye prior to Month 10. Prohibited therapy other than oral corticosteroids more than 10 mg/day or any fellow eye treatment. At the time of explant.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	58	62	59	41
Month 1	16.5	7.2	-2.9	2.5
Month 2	19.8	11.9	-1.8	1.5
Month 3	24.9	7.3	6.4	-7.3
Month 4	31.0	4.1	1.9	-1.7
Month 5	30.9	0.4	8.0	4.0
Month 6	31.9	2.1	5.9	-2.0
Month 7	39.9	0.7	-4.3	-9.8
Month 8	42.8	3.1	5.1	-2.4
Month 9	54.8	-0.7	-1.7	-6.3

6. Secondary Outcome

Title	Number of Implant Clogging at Month 9
Description	Removed implants identified as meeting serum PK criteria for possible clogging were assessed via lab-based investigation (in vitro drug release testing) to determine whether there was any implant clogging.
Time Frame	Month 9

Outcome Measure Data

Analysis Population Description

Efficacy Population defined as all participants who were randomly assigned to study treatment and received at least one study treatment.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.
Measure Participants	58	62	59
Number [Participants]	0 0%	0 0%	0 0%

7. Secondary Outcome

Title	Observed Maximum Serum Concentration (Cmax) of Ranibizumab
Description	The serum pharmacokinetics of ranibizumab were characterized by estimating Cmax between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.
Time Frame	Predose (0 hour) on Day 1 up to 38 months

Outcome Measure Data

Analysis Population Description

PK Population with exclusion (randomized participants who had received at least one study drug administration and provided at least one serum and/or aqueous PK sample for determination of ranibizumab concentration excluding participants who had prior intravitreal bevacizumab, received fellow eye ranibizumab treatment, and/or received supplemental intravitreal ranibizumab)

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	16	25	27	0
Interval following implant insertion before first refill	105.52 (258.0)	220.87 (46.4)	1080.69 (272.5)
All Dose Intervals	91.47 (187.2)	297.61 (115.2)	1131.01 (256.6)

8. Secondary Outcome

Title	Area Under the Concentration-Time Curve From Dosing to Last Observation (AUClast) of Ranibizumab
Description	AUCLast is defined as area under the concentration-time curve from dosing (implant or refill) to last observation before next refill or exiting the study. The serum pharmacokinetics of ranibizumab were characterized by estimating AUC between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.
Time Frame	Predose (0 hour) on Day 1 up to approximately 38 months (detailed timeframe is provided in description field)

Outcome Measure Data

Analysis Population Description

PK Population with exclusion (randomized participants who had received at least one study drug administration and provided at least one serum and/or aqueous PK sample for determination of ranibizumab concentration excluding participants who had prior intravitreal bevacizumab, received fellow eye ranibizumab treatment, and/or received supplemental intravitreal ranibizumab)

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	16	25	27	0
Interval following implant insertion before first refill	5.89 (225.1)	28.39 (107.6)	90.83 (64.7)
All Dose Intervals	3.43 (176.8)	22.93 (96.9)	66.12 (71.4)

9. Secondary Outcome

Title	Time to Maximum Concentration (Tmax) of Ranibizumab
Description	The serum pharmacokinetics of ranibizumab were characterized by estimating Tmax between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.
Time Frame	Predose (0 hour) on Day 1 up to 38 months

Outcome Measure Data

Analysis Population Description

PK Population with exclusion (randomized participants who had received at least one study drug administration and provided at least one serum and/or aqueous PK sample for determination of ranibizumab concentration excluding participants who had prior intravitreal bevacizumab, received fellow eye ranibizumab treatment, and/or received supplemental intravitreal ranibizumab)

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	16	25	27	0
Interval following implant insertion before first refill	11.45	12.87	29.01
All Dose Intervals	4.87	6.71	6.97

10. Secondary Outcome

Title	Terminal Half-Life (t1/2) of Ranibizumab
Description	The serum pharmacokinetics of ranibizumab were characterized by estimating t1/2 between dose intervals. Estimates for these parameters were tabulated and summarized by descriptive statistics.
Time Frame	Predose (0 hour) on Day 1 up to 38 months

Outcome Measure Data

Analysis Population Description

PK Population with exclusion (randomized participants who had received at least one study drug administration and provided at least one serum and/or aqueous PK sample for determination of ranibizumab concentration excluding participants who had prior intravitreal bevacizumab, received fellow eye ranibizumab treatment, and/or received supplemental intravitreal ranibizumab)

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	16	25	27	0
Interval following implant insertion before first refill	168.20 (163.3)	88.30 (46.7)	119.07 (128.4)
All Dose Intervals	162.36 (129.3)	118.87 (76.2)	143.87 (171.4)

11. Secondary Outcome

Title	Observed Steady-State Serum Concentration at the End of a Dosing Interval (Ctrough) of Ranibizumab
Time Frame	Predose (0 hour) on Day 1 up to 38 months

Outcome Measure Data

Analysis Population Description

PK Population with exclusion (randomized participants who had received at least one study drug administration and provided at least one serum and/or aqueous PK sample for determination of ranibizumab concentration excluding participants who had prior intravitreal bevacizumab, received fellow eye ranibizumab treatment, and/or received supplemental intravitreal ranibizumab)

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	16	25	27	0
Interval following implant insertion before first refill	14.96 (76.4)	61.64 (95.8)	129.63 (149.2)
All Dose Intervals	11.58 (65.7)	105.07 (77.4)	62.19 (345.2)

12. Secondary Outcome

Title	Number of Participants With Ocular and Non-Ocular Adverse Events (AEs) and Serious AEs (SAEs)
Time Frame	Baseline up to approximately Month 38

Outcome Measure Data

Analysis Population Description

Safety analyses were based on the Safety Population which was composed of participants receiving at least one study treatment.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Ranibizumab PD All Participants	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL either the 10 mg/mL [approximately 0.2 mg dose], 40 mg/mL [approximately 0.8 mg dose], or 100 mg/mL formulation [approximately 2-mg dose] of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10 mg/mL, 40 mg/mL, or 100 mg/mL formulations of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	58	62	59	179	41
Participants with ocular SAEs in study eye	7 11.9%	6 9.7%	4 6.3%	17 41.5%	0 0%
Participants with ocular AEs in study eye	56 94.9%	58 93.5%	52 82.5%	166 404.9%	26 11.6%
Participants with non-ocular SAEs	8 13.6%	16 25.8%	13 20.6%	37 90.2%	4 1.8%
Participants with non-ocular AEs	46 78%	52 83.9%	52 82.5%	150 365.9%	36 16%

13. Secondary Outcome

Title	Percentage of Participants With Positive Serum Antibodies to Ranibizumab
Time Frame	Baseline up to 38 months

Outcome Measure Data

Analysis Population Description

Safety analyses were based on the Safety Population which was composed of participants receiving at least one study treatment. Here, number of analyzed participants represents number of participants from whom samples were collected and analyzed. Baseline evaluable participant is a participant with an ADA assay result from a baseline sample(s). Post-baseline evaluable participant is a participant with an ADA assay result from at least one post-baseline sample.

Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL	Port Delivery System With Ranibizumab 40mg/mL	Port Delivery System With Ranibizumab 100mg/mL	Ranibizumab PD All Participants	Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants had the Implant (prefilled with approximately 20 μL either the 10 mg/mL [approximately 0.2 mg dose], 40 mg/mL [approximately 0.8 mg dose], or 100 mg/mL formulation [approximately 2-mg dose] of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10 mg/mL, 40 mg/mL, or 100 mg/mL formulations of ranibizumab according to their randomization as per protocol-specified refill criteria.	Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
Measure Participants	58	62	59	179	41
Participants with a positive sample at time of entry into the study (Baseline)	10.3 17.5%	5.0 8.1%	5.1 8.1%	6.8 16.6%	0 0%
Participants positive for Treatment Emergent ADA (Post-baseline)	6.9 11.7%	14.5 23.4%	15.3 24.3%	12.3 30%	14.6 6.5%

Adverse Events

Time Frame	Baseline up to approximately Month 38
Adverse Event Reporting Description	Number of events includes all occurrences. Table summary includes adverse events that started or worsened (for existing condition) on or after the date of first study treatment during the study.
Arm/Group Title	Port Delivery System With Ranibizumab 10mg/mL		Port Delivery System With Ranibizumab 40mg/mL		Port Delivery System With Ranibizumab 100mg/mL		Intravitreal Injection With Ranibizumab 0.5mg
Arm/Group Description	Participants had the Implant (prefilled with approximately 20 μL of 10-mg/mL ,approximately 0.2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 10-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.		Participants had the Implant (prefilled with approximately 20 μL of 40-mg/mL, approximately 0.8 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 40-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.		Participants had the Implant (prefilled with approximately 20 μL of 100-mg/mL, approximately 2 mg dose, of ranibizumab) surgically inserted in the study eye at the Day 1 visit following their randomization visit. Starting at the Month 1 visit, participants were evaluated monthly for the need for Implant refill with the 100-mg/mL formulation of ranibizumab according to their randomization as per protocol-specified refill criteria.		Participants received ranibizumab 0.5 mg monthly ITV injections of 10 mg/mL formulation at Day 1 and every month thereafter.
All Cause Mortality
	Port Delivery System With Ranibizumab 10mg/mL		Port Delivery System With Ranibizumab 40mg/mL		Port Delivery System With Ranibizumab 100mg/mL		Intravitreal Injection With Ranibizumab 0.5mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/58 (1.7%)		2/62 (3.2%)		1/59 (1.7%)		1/41 (2.4%)
Serious Adverse Events
	Port Delivery System With Ranibizumab 10mg/mL		Port Delivery System With Ranibizumab 40mg/mL		Port Delivery System With Ranibizumab 100mg/mL		Intravitreal Injection With Ranibizumab 0.5mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/58 (24.1%)		19/62 (30.6%)		17/59 (28.8%)		4/41 (9.8%)
Blood and lymphatic system disorders
APLASTIC ANAEMIA	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
Cardiac disorders
ANGINA UNSTABLE	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
ATRIAL FIBRILLATION	0/58 (0%)	0	2/62 (3.2%)	2	0/59 (0%)	0	0/41 (0%)	0
ATRIAL FLUTTER	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
ATRIOVENTRICULAR BLOCK	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
CARDIAC FAILURE CONGESTIVE	1/58 (1.7%)	1	1/62 (1.6%)	1	0/59 (0%)	0	1/41 (2.4%)	1
CORONARY ARTERY DISEASE	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	1/41 (2.4%)	1
MYOCARDIAL INFARCTION	1/58 (1.7%)	1	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
Eye disorders
CONJUNCTIVAL EROSION	1/58 (1.7%)	2	1/62 (1.6%)	1	1/59 (1.7%)	1	0/41 (0%)	0
HYPOTONY OF EYE	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
RETINAL HAEMORRHAGE	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
RETINAL TEAR	0/58 (0%)	0	1/62 (1.6%)	3	0/59 (0%)	0	0/41 (0%)	0
RETINOPATHY PROLIFERATIVE	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
RHEGMATOGENOUS RETINAL DETACHMENT	2/58 (3.4%)	2	1/62 (1.6%)	2	2/59 (3.4%)	2	0/41 (0%)	0
TRACTIONAL RETINAL DETACHMENT	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
VISION BLURRED	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
VISUAL ACUITY REDUCED	1/58 (1.7%)	1	1/62 (1.6%)	1	1/59 (1.7%)	1	0/41 (0%)	0
VITREOUS HAEMORRHAGE	3/58 (5.2%)	3	2/62 (3.2%)	2	2/59 (3.4%)	2	0/41 (0%)	0
Gastrointestinal disorders
GASTROINTESTINAL HAEMORRHAGE	0/58 (0%)	0	1/62 (1.6%)	1	1/59 (1.7%)	1	0/41 (0%)	0
GASTROOESOPHAGEAL REFLUX DISEASE	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
HIATUS HERNIA	0/58 (0%)	0	2/62 (3.2%)	2	0/59 (0%)	0	0/41 (0%)	0
General disorders
CHEST PAIN	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
Hepatobiliary disorders
CHOLECYSTITIS	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
CHOLECYSTITIS ACUTE	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
Infections and infestations
BACTERAEMIA	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
BRONCHITIS	0/58 (0%)	0	0/62 (0%)	0	2/59 (3.4%)	2	0/41 (0%)	0
CELLULITIS	0/58 (0%)	0	1/62 (1.6%)	2	0/59 (0%)	0	0/41 (0%)	0
DIVERTICULITIS	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
ENDOPHTHALMITIS	1/58 (1.7%)	1	1/62 (1.6%)	1	1/59 (1.7%)	1	0/41 (0%)	0
GASTROENTERITIS	0/58 (0%)	0	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
INFLUENZA	0/58 (0%)	0	2/62 (3.2%)	2	0/59 (0%)	0	0/41 (0%)	0
PNEUMONIA	2/58 (3.4%)	2	4/62 (6.5%)	6	0/59 (0%)	0	1/41 (2.4%)	1
POSTOPERATIVE WOUND INFECTION	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
SEPSIS	0/58 (0%)	0	3/62 (4.8%)	3	0/59 (0%)	0	0/41 (0%)	0
URINARY TRACT INFECTION	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
Injury, poisoning and procedural complications
BRAIN CONTUSION	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
CERVICAL VERTEBRAL FRACTURE	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
CONJUNCTIVAL FILTERING BLEB LEAK	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
CONJUNCTIVAL RETRACTION	0/58 (0%)	0	1/62 (1.6%)	1	1/59 (1.7%)	1	0/41 (0%)	0
FALL	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
FRACTURE DISPLACEMENT	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
HIP FRACTURE	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
HYPHAEMA	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
ILIOTIBIAL BAND SYNDROME	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
OCULAR PROCEDURAL COMPLICATION	0/58 (0%)	0	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
PERIPROSTHETIC FRACTURE	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
SKULL FRACTURED BASE	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
SUBDURAL HAEMATOMA	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
UPPER LIMB FRACTURE	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
WOUND SECRETION	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
Investigations
INTRAOCULAR PRESSURE INCREASED	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
WEIGHT DECREASED	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
Metabolism and nutrition disorders
DEHYDRATION	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
DIABETES MELLITUS	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
Musculoskeletal and connective tissue disorders
INTERVERTEBRAL DISC DISORDER	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ADENOCARCINOMA GASTRIC	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
BREAST CANCER RECURRENT	0/58 (0%)	0	0/62 (0%)	0	0/59 (0%)	0	1/41 (2.4%)	1
LUNG CARCINOMA CELL TYPE UNSPECIFIED STAGE IV	0/58 (0%)	0	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
PANCREATIC CARCINOMA	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
Nervous system disorders
CAROTID ARTERY STENOSIS	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
CEREBROVASCULAR ACCIDENT	0/58 (0%)	0	2/62 (3.2%)	3	1/59 (1.7%)	1	0/41 (0%)	0
DIZZINESS	0/58 (0%)	0	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
HYPERTENSIVE ENCEPHALOPATHY	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
MIGRAINE	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
PRESYNCOPE	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
SUBARACHNOID HAEMORRHAGE	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
TRANSIENT ISCHAEMIC ATTACK	0/58 (0%)	0	2/62 (3.2%)	2	0/59 (0%)	0	0/41 (0%)	0
Product Issues
DEVICE DISLOCATION	0/58 (0%)	0	1/62 (1.6%)	1	1/59 (1.7%)	1	0/41 (0%)	0
DEVICE MALFUNCTION	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
Renal and urinary disorders
ACUTE KIDNEY INJURY	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
HAEMATURIA	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
Reproductive system and breast disorders
PROSTATOMEGALY	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY FAILURE	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE	2/58 (3.4%)	2	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
LUNG CONSOLIDATION	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
PULMONARY EMBOLISM	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
RESPIRATORY DISORDER	0/58 (0%)	0	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
Vascular disorders
AORTIC STENOSIS	0/58 (0%)	0	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
FEMORAL ARTERY ANEURYSM	0/58 (0%)	0	1/62 (1.6%)	1	0/59 (0%)	0	0/41 (0%)	0
HYPERTENSION	0/58 (0%)	0	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
HYPOTENSION	0/58 (0%)	0	2/62 (3.2%)	2	0/59 (0%)	0	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	Port Delivery System With Ranibizumab 10mg/mL		Port Delivery System With Ranibizumab 40mg/mL		Port Delivery System With Ranibizumab 100mg/mL		Intravitreal Injection With Ranibizumab 0.5mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/58 (98.3%)		59/62 (95.2%)		58/59 (98.3%)		35/41 (85.4%)
Eye disorders
ANTERIOR CHAMBER CELL	1/58 (1.7%)	1	2/62 (3.2%)	2	6/59 (10.2%)	6	0/41 (0%)	0
ANTERIOR CHAMBER FLARE	1/58 (1.7%)	1	0/62 (0%)	0	3/59 (5.1%)	3	0/41 (0%)	0
BLEPHARITIS	1/58 (1.7%)	1	1/62 (1.6%)	1	3/59 (5.1%)	8	1/41 (2.4%)	1
CATARACT	3/58 (5.2%)	4	5/62 (8.1%)	8	12/59 (20.3%)	16	5/41 (12.2%)	7
CATARACT CORTICAL	3/58 (5.2%)	3	2/62 (3.2%)	3	0/59 (0%)	0	3/41 (7.3%)	5
CATARACT NUCLEAR	3/58 (5.2%)	3	3/62 (4.8%)	3	2/59 (3.4%)	3	1/41 (2.4%)	2
CHOROIDAL DETACHMENT	3/58 (5.2%)	3	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
CHOROIDAL NEOVASCULARISATION	4/58 (6.9%)	4	1/62 (1.6%)	1	0/59 (0%)	0	1/41 (2.4%)	1
CONJUNCTIVAL BLEB	3/58 (5.2%)	3	3/62 (4.8%)	3	1/59 (1.7%)	1	0/41 (0%)	0
CONJUNCTIVAL HAEMORRHAGE	41/58 (70.7%)	53	44/62 (71%)	54	37/59 (62.7%)	38	8/41 (19.5%)	11
CONJUNCTIVAL HYPERAEMIA	18/58 (31%)	20	13/62 (21%)	14	14/59 (23.7%)	16	0/41 (0%)	0
CONJUNCTIVAL OEDEMA	6/58 (10.3%)	7	6/62 (9.7%)	6	1/59 (1.7%)	1	0/41 (0%)	0
CORNEAL OEDEMA	6/58 (10.3%)	6	3/62 (4.8%)	3	4/59 (6.8%)	4	0/41 (0%)	0
DERMATOCHALASIS	0/58 (0%)	0	0/62 (0%)	0	3/59 (5.1%)	5	1/41 (2.4%)	2
DIPLOPIA	3/58 (5.2%)	4	3/62 (4.8%)	4	1/59 (1.7%)	2	1/41 (2.4%)	2
DRY EYE	7/58 (12.1%)	10	2/62 (3.2%)	3	5/59 (8.5%)	7	1/41 (2.4%)	2
EYE DISCHARGE	2/58 (3.4%)	2	1/62 (1.6%)	2	3/59 (5.1%)	3	0/41 (0%)	0
EYE IRRITATION	9/58 (15.5%)	9	7/62 (11.3%)	9	7/59 (11.9%)	7	2/41 (4.9%)	3
EYE PAIN	12/58 (20.7%)	16	12/62 (19.4%)	15	15/59 (25.4%)	18	5/41 (12.2%)	7
EYELID OEDEMA	1/58 (1.7%)	1	2/62 (3.2%)	2	3/59 (5.1%)	3	1/41 (2.4%)	1
EYELID PTOSIS	3/58 (5.2%)	3	2/62 (3.2%)	2	4/59 (6.8%)	4	1/41 (2.4%)	1
EYELIDS PRURITUS	4/58 (6.9%)	5	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
FOREIGN BODY SENSATION IN EYES	4/58 (6.9%)	6	7/62 (11.3%)	7	7/59 (11.9%)	8	0/41 (0%)	0
IRIDOCYCLITIS	3/58 (5.2%)	3	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
IRITIS	8/58 (13.8%)	9	13/62 (21%)	14	7/59 (11.9%)	7	0/41 (0%)	0
LACRIMATION INCREASED	3/58 (5.2%)	4	2/62 (3.2%)	3	0/59 (0%)	0	0/41 (0%)	0
MACULAR DEGENERATION	3/58 (5.2%)	3	0/62 (0%)	0	0/59 (0%)	0	1/41 (2.4%)	1
NEOVASCULAR AGE-RELATED MACULAR DEGENERATION	8/58 (13.8%)	8	10/62 (16.1%)	10	10/59 (16.9%)	12	3/41 (7.3%)	3
OCULAR HYPERAEMIA	3/58 (5.2%)	3	2/62 (3.2%)	2	0/59 (0%)	0	1/41 (2.4%)	1
PHOTOPHOBIA	1/58 (1.7%)	1	4/62 (6.5%)	4	1/59 (1.7%)	1	0/41 (0%)	0
POSTERIOR CAPSULE OPACIFICATION	4/58 (6.9%)	6	5/62 (8.1%)	7	5/59 (8.5%)	7	5/41 (12.2%)	6
PUNCTATE KERATITIS	5/58 (8.6%)	7	3/62 (4.8%)	4	2/59 (3.4%)	3	1/41 (2.4%)	1
RETINAL HAEMORRHAGE	6/58 (10.3%)	7	6/62 (9.7%)	11	5/59 (8.5%)	5	1/41 (2.4%)	1
VISION BLURRED	8/58 (13.8%)	11	3/62 (4.8%)	8	5/59 (8.5%)	6	3/41 (7.3%)	3
VISUAL ACUITY REDUCED	2/58 (3.4%)	3	3/62 (4.8%)	3	3/59 (5.1%)	5	0/41 (0%)	0
VITREOUS DETACHMENT	7/58 (12.1%)	7	6/62 (9.7%)	8	4/59 (6.8%)	6	7/41 (17.1%)	9
VITREOUS DISORDER	1/58 (1.7%)	1	0/62 (0%)	0	3/59 (5.1%)	3	1/41 (2.4%)	1
VITREOUS FLOATERS	13/58 (22.4%)	13	9/62 (14.5%)	13	12/59 (20.3%)	15	4/41 (9.8%)	5
VITREOUS HAEMORRHAGE	4/58 (6.9%)	4	5/62 (8.1%)	6	4/59 (6.8%)	6	0/41 (0%)	0
Gastrointestinal disorders
CONSTIPATION	3/58 (5.2%)	3	1/62 (1.6%)	1	2/59 (3.4%)	2	0/41 (0%)	0
DIARRHOEA	1/58 (1.7%)	1	2/62 (3.2%)	2	3/59 (5.1%)	3	0/41 (0%)	0
GASTROOESOPHAGEAL REFLUX DISEASE	2/58 (3.4%)	2	2/62 (3.2%)	3	3/59 (5.1%)	3	0/41 (0%)	0
NAUSEA	5/58 (8.6%)	6	4/62 (6.5%)	5	4/59 (6.8%)	4	0/41 (0%)	0
General disorders
CHEST PAIN	1/58 (1.7%)	1	1/62 (1.6%)	1	3/59 (5.1%)	3	0/41 (0%)	0
FATIGUE	0/58 (0%)	0	0/62 (0%)	0	3/59 (5.1%)	3	0/41 (0%)	0
Infections and infestations
BRONCHITIS	3/58 (5.2%)	3	9/62 (14.5%)	9	4/59 (6.8%)	4	5/41 (12.2%)	6
DIVERTICULITIS	0/58 (0%)	0	0/62 (0%)	0	3/59 (5.1%)	3	0/41 (0%)	0
EAR INFECTION	4/58 (6.9%)	5	1/62 (1.6%)	1	1/59 (1.7%)	1	1/41 (2.4%)	1
HORDEOLUM	1/58 (1.7%)	1	0/62 (0%)	0	0/59 (0%)	0	3/41 (7.3%)	3
INFLUENZA	5/58 (8.6%)	5	1/62 (1.6%)	1	4/59 (6.8%)	4	3/41 (7.3%)	3
NASOPHARYNGITIS	12/58 (20.7%)	17	8/62 (12.9%)	15	9/59 (15.3%)	11	6/41 (14.6%)	9
SINUSITIS	2/58 (3.4%)	2	5/62 (8.1%)	7	9/59 (15.3%)	11	7/41 (17.1%)	9
TOOTH INFECTION	2/58 (3.4%)	2	1/62 (1.6%)	1	1/59 (1.7%)	1	3/41 (7.3%)	3
UPPER RESPIRATORY TRACT INFECTION	1/58 (1.7%)	1	6/62 (9.7%)	6	3/59 (5.1%)	3	3/41 (7.3%)	3
URINARY TRACT INFECTION	5/58 (8.6%)	6	10/62 (16.1%)	17	6/59 (10.2%)	9	2/41 (4.9%)	2
Injury, poisoning and procedural complications
CONTUSION	1/58 (1.7%)	1	1/62 (1.6%)	1	5/59 (8.5%)	6	1/41 (2.4%)	1
CORNEAL ABRASION	3/58 (5.2%)	3	0/62 (0%)	0	1/59 (1.7%)	1	0/41 (0%)	0
FALL	5/58 (8.6%)	5	2/62 (3.2%)	2	4/59 (6.8%)	6	0/41 (0%)	0
HYPHAEMA	3/58 (5.2%)	3	1/62 (1.6%)	1	5/59 (8.5%)	5	0/41 (0%)	0
PROCEDURAL PAIN	2/58 (3.4%)	2	4/62 (6.5%)	4	4/59 (6.8%)	5	0/41 (0%)	0
Investigations
BLOOD CHOLESTEROL INCREASED	2/58 (3.4%)	2	1/62 (1.6%)	1	3/59 (5.1%)	3	0/41 (0%)	0
INTRAOCULAR PRESSURE DECREASED	3/58 (5.2%)	3	3/62 (4.8%)	3	0/59 (0%)	0	0/41 (0%)	0
INTRAOCULAR PRESSURE INCREASED	8/58 (13.8%)	14	3/62 (4.8%)	3	6/59 (10.2%)	8	3/41 (7.3%)	6
Musculoskeletal and connective tissue disorders
ARTHRALGIA	1/58 (1.7%)	1	1/62 (1.6%)	1	6/59 (10.2%)	7	0/41 (0%)	0
ARTHRITIS	1/58 (1.7%)	1	1/62 (1.6%)	1	3/59 (5.1%)	4	2/41 (4.9%)	2
BACK PAIN	1/58 (1.7%)	1	2/62 (3.2%)	2	6/59 (10.2%)	6	4/41 (9.8%)	4
OSTEOARTHRITIS	2/58 (3.4%)	2	4/62 (6.5%)	4	2/59 (3.4%)	2	1/41 (2.4%)	1
PAIN IN EXTREMITY	2/58 (3.4%)	2	0/62 (0%)	0	4/59 (6.8%)	4	0/41 (0%)	0
ROTATOR CUFF SYNDROME	0/58 (0%)	0	0/62 (0%)	0	3/59 (5.1%)	3	0/41 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA	4/58 (6.9%)	5	4/62 (6.5%)	6	3/59 (5.1%)	4	2/41 (4.9%)	2
Nervous system disorders
HEADACHE	9/58 (15.5%)	10	8/62 (12.9%)	9	11/59 (18.6%)	11	1/41 (2.4%)	1
Renal and urinary disorders
HYPERTONIC BLADDER	3/58 (5.2%)	3	0/62 (0%)	0	0/59 (0%)	0	0/41 (0%)	0
NEPHROLITHIASIS	0/58 (0%)	0	3/62 (4.8%)	3	3/59 (5.1%)	4	0/41 (0%)	0
Respiratory, thoracic and mediastinal disorders
COUGH	4/58 (6.9%)	5	3/62 (4.8%)	3	2/59 (3.4%)	2	2/41 (4.9%)	2
Skin and subcutaneous tissue disorders
ACTINIC KERATOSIS	0/58 (0%)	0	0/62 (0%)	0	3/59 (5.1%)	4	1/41 (2.4%)	1
Vascular disorders
HYPERTENSION	5/58 (8.6%)	5	2/62 (3.2%)	2	6/59 (10.2%)	6	3/41 (7.3%)	3

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.