Phase 2 Randomized Clinical Trial of Luminate® as Compared to Avastin® in the Treatment of Diabetic Macular Edema

• Sponsor: Allegro Ophthalmics, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02348918
• Collaborator: Trial Runners, LLC (Other), Duke University (Other)
• Enrollment: 218
• Locations: 17
• Arms: 9
• Actual Duration (Months): 32
• Patients Per Site: 12.8
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

A Phase 2 Multi center, Randomized, Controlled, Double-Masked Clinical Trial Designed To Evaluate The Safety And Exploratory Efficacy Of Luminate® (Alg-1001) As Compared To Avastin® In The Treatment Of Diabetic Macular Edema

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: Luminate 1.0mg; Drug: Luminate 2.0mg; Drug: Luminate 3.0mg; Drug: Avastin; Drug: Luminate 0.5mg	Phase 2

Detailed Description

To evaluate the safety and efficacy of Luminate® (ALG-1001) as compared to Avastin® in patients with diabetic macular edema

• Stage 1: 120 eligible subjects with DME will be enrolled and randomized to one of 4 treatment groups at an allocation ratio of 1:1:1:1, i.e., one of three doses (1.0 mg, 2.0 mg and 3.0 mg) of Luminate intravitreal injection or Avastin intravitreal injection. Subjects will be followed monthly for 24 weeks (6 months).

Stage 2 (select sites): 75 eligible subjects with DME will be enrolled and randomized to one of 5 treatment groups at an allocation ratio of 1:1:1:1:1; i.e., one of 2 doses of Luminate intravitreal injection or Avastin intravitreal injection (0.5 mg and 1.0 mg). Subjects will be followed monthly for 20 weeks (5 months).

Study Design

• Study Type: Interventional
• Actual Enrollment: 218 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Randomized, Controlled, Double-Masked, Multicenter Clinical Trial Designed to Evaluate the Safety and Exploratory Efficacy of Luminate® (ALG-1001) as Compared to Avastin® in the Treatment of Diabetic Macular Edema (DME)
• Actual Study Start Date: Oct 13, 2014
• Actual Primary Completion Date: May 16, 2017
• Actual Study Completion Date: Jun 13, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Luminate 1.0mg group Stage 1- Luminate 1.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks.	Drug: Luminate 1.0mg; Other Names: ALG-1001
Active Comparator: Luminate 2.0mg group Stage 1 -Luminate 2.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks.	Drug: Luminate 2.0mg; Other Names: ALG-1001
Active Comparator: Luminate 3.0mg group Stage 1- Luminate 3.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks.	Drug: Luminate 3.0mg; Other Names: ALG-1001
Active Comparator: Avastin® group Stage 1- Avastin 1.25 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Avastin injection at weeks 12, 16, or 20 for a total of at least 3 and up to 6 Avastin injections. Sham injections may be performed at weeks 12, 16, and 20 if prn Avastin is not required.	Drug: Avastin; Other Names: bevacizumab
Active Comparator: Avastin then Luminate 1.0 mg IVT + sham injection Stage 2 - Week 0 (Baseline): Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 1.0 mg IVT + sham injection Weeks 12 and 16: Sham IVT	Drug: Luminate 1.0mg; Other Names: ALG-1001 ; Drug: Avastin; Other Names: bevacizumab
Active Comparator: Avastin then Luminate 0.5 mg IVT + sham injection Stage 2- Week 0 (Baseline); Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + sham injection Weeks 12 and 16: Sham IVT	Drug: Avastin; Other Names: bevacizumab ; Drug: Luminate 0.5mg; Other Names: ALG-1001
Active Comparator: Sham then Luminate 1.0 mg + Avastin 1.25 mg IVT Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Luminate 1.0 mg + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT	Drug: Luminate 1.0mg; Other Names: ALG-1001 ; Drug: Avastin; Other Names: bevacizumab
Active Comparator: Sham then Luminate 0.5 mg IVT + Avastin 1.25 mg IVT Stage 2 : Week 0: Sham IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT	Drug: Avastin; Other Names: bevacizumab ; Drug: Luminate 0.5mg; Other Names: ALG-1001
Active Comparator: Avastin 1.25 mg + Sham IVT Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Avastin 1.25 mg + Sham IVT Weeks 12 and 16: Avastin PRN	Drug: Luminate 0.5mg; Other Names: ALG-1001

Outcome Measures

Primary Outcome Measures

1. Change in BCVA at Week 24 [Value of 24 Weeks minus baseline value]

   Primary efficacy outcome is BCVA changes at Week 24 as compared to baseline

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female, 18 years of age or older.

• Study eye with clinically significant diabetic macular edema (DME) with central subfield thickness ≥ 350µm on spectral domain OCT

• Best corrected visual acuity (BCVA) of 20/50 to 20/320 ETDRS equivalent (65 letters to 23 letters) in the study eye, with BCVA decrement primarily attributable to DME.

• Treatment naïve, i.e., no previous anti-VEGF treatment in the study eye or no anti-VEGF treatment in the 45 days prior to study enrollment.

• In the investigator's opinion, the subject still has significant intraretinal fluid with room for improvement in both macular edema and BCVA.

• Intra-Ocular Pressure (IOP) is under control (i.e., IOP

≤ 25 mm in the study eye) and study eye is not receiving any IOP lowering drops.

• Willing and able to return for all study visits.

• Able to meet the extensive post-op evaluation regimen.

• Understands and signs the informed consent form.

Exclusion Criteria:

• Active proliferative diabetic retinopathy (PDR) in the study eye such as NVE, NVD, vitreous hemorrhage, or neovascular glaucoma.

• Uncontrolled hypertension defined as systolic >180 mmHg or > 160 mmHg on 2 consecutive measurements or diastolic > 100 mmHg on optimal medical regimen

• Screening HgA1c blood test > 10.0

• Focal laser photocoagulation or intravitreal/periocular steroids of any type in the study eye within the last 90 days prior to study enrollment.

• A history of intravitreal anti-VEGF injection of any type in the study eye within the last 45 days prior to study enrollment.

• History of rhegmatogenous retinal detachment, retinal tear(s), or traction retinal detachments in the study eye.

• Epiretinal membrane and/or vitreomacular traction in the study eye as determined by the central reading center.

• Previous pars plana vitrectomy in the study eye

• Any intraocular surgery in the study eye within the last 90 days prior to study enrollment.

• YAG laser treatment in the study eye in last 30 days prior to study enrollment.

• High myopia in the study eye, with a spherical equivalent of >8.00D at screening

• Other ocular pathologies that in the investigator's opinion would interfere with the subject's vision in the study eye.

• Chronic or recurrent uveitis.

• Ongoing ocular infection or inflammation in either eye.

• A history of cataract surgery complications/vitreous loss in the study eye.

• Congenital eye malformations in the study eye.

• A history of penetrating ocular trauma in the study eye.

• Mentally handicapped.

• Pregnant female, as determined for women less than 60 years old by a positive urine pregnancy test during the screening window.

• Nursing female.

• Currently participating in any other clinical research study.

• Contraindication to the study medication.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Associated Retina Consultants	Phoenix	Arizona	United States	85020
2	Retina Vitreous Associates Medical Group	Beverly Hills	California	United States	90211
3	Northern California Retina Vitreous Associates	Mountain View	California	United States	94040
4	West Coast Retina	San Francisco	California	United States	94109
5	Orange County Retina Medical Group	Santa Ana	California	United States	92705
6	New England Retina Associates	New London	Connecticut	United States	06320
7	Florida Eye Clinic	Altamonte Springs	Florida	United States	32701
8	Retina Specialty Institute	Pensacola	Florida	United States	32503
9	Center for Retina and Macular Disease	Winter Haven	Florida	United States	33880
10	Wilmer Eye Institute at John Hopkins University	Baltimore	Maryland	United States	21205
11	TLC Eye Group	Jackson	Michigan	United States	49202
12	Island Retina	Shirley	New York	United States	11967
13	Charlotte EENT Associates	Charlotte	North Carolina	United States	28210
14	Black Hills Regional Eye Institute	Rapid City	South Dakota	United States	57701
15	Austin Retina Associates	Austin	Texas	United States	78705
16	Retina Consultant of Houston	Houston	Texas	United States	77098
17	Spokane Eye Clinical Research	Spokane	Washington	United States	99204

Sponsors and Collaborators

• Allegro Ophthalmics, LLC
• Trial Runners, LLC
• Duke University

Investigators

• Study Director: Vicken Karageozian, Cheif Medical Officer

Study Documents (Full-Text)

• Study Protocol - Mar 7, 2016
• Statistical Analysis Plan - Mar 17, 2017

More Information

Publications

None provided.

• Responsible Party: Allegro Ophthalmics, LLC
• ClinicalTrials.gov Identifier: NCT02348918
• Other Study ID Numbers: DME 202B
• First Posted: Jan 28, 2015
• Last Update Posted: Dec 7, 2018
• Last Verified: Dec 1, 2018

• Additional relevant MeSH terms: Macular Edema; Edema; Bevacizumab

Study Results

Participant Flow

Arm/Group Title	Luminate 1.0mg Group	Luminate 2.0mg Group	Luminate 3.0mg Group	Avastin® Group	Avastin Then Luminate 1.0 mg IVT + Sham Injection	Avastin Then Luminate 0.5 mg IVT + Sham Injection	Sham Then Luminate 1.0 mg + Avastin 1.25 mg IVT	Sham Then Luminate 0.5 mg IVT + Avastin 1.25 mg IVT	Avastin 1.25 mg + Sham IVT
Arm/Group Description	Stage 1- Luminate 1.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 1.0mg	Stage 1 -Luminate 2.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 2.0mg	Stage 1- Luminate 3.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 3.0mg	Stage 1- Avastin 1.25 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Avastin injection at weeks 12, 16, or 20 for a total of at least 3 and up to 6 Avastin injections. Sham injections may be performed at weeks 12, 16, and 20 if prn Avastin is not required. Avastin	Stage 2 - Week 0 (Baseline): Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 1.0 mg IVT + sham injection Weeks 12 and 16: Sham IVT Luminate 1.0mg Avastin	Stage 2- Week 0 (Baseline); Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + sham injection Weeks 12 and 16: Sham IVT Avastin Luminate 0.5mg	Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Luminate 1.0 mg + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT Luminate 1.0mg Avastin	Stage 2 : Week 0: Sham IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT Avastin Luminate 0.5mg	Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Avastin 1.25 mg + Sham IVT Weeks 12 and 16: Avastin PRN Luminate 0.5mg
Period Title: Overall Study
STARTED	39	33	42	24	19	17	13	16	15
COMPLETED	39	33	42	24	19	17	13	16	15
NOT COMPLETED	0	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Luminate 1.0mg Group	Luminate 2.0mg Group	Luminate 3.0mg Group	Avastin® Group	Avastin Then Luminate 1.0 mg IVT + Sham Injection	Avastin Then Luminate 0.5 mg IVT + Sham Injection	Sham Then Luminate 1.0 mg + Avastin 1.25 mg IVT	Sham Then Luminate 0.5 mg IVT + Avastin 1.25 mg IVT	Avastin 1.25 mg + Sham IVT	Total
Arm/Group Description	Stage 1- Luminate 1.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 1.0mg	Stage 1 -Luminate 2.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 2.0mg	Stage 1- Luminate 3.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 3.0mg	Stage 1- Avastin 1.25 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Avastin injection at weeks 12, 16, or 20 for a total of at least 3 and up to 6 Avastin injections. Sham injections may be performed at weeks 12, 16, and 20 if prn Avastin is not required. Avastin	Stage 2 - Week 0 (Baseline): Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 1.0 mg IVT + sham injection Weeks 12 and 16: Sham IVT Luminate 1.0mg Avastin	Stage 2- Week 0 (Baseline); Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + sham injection Weeks 12 and 16: Sham IVT Avastin Luminate 0.5mg	Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Luminate 1.0 mg + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT Luminate 1.0mg Avastin	Stage 2 : Week 0: Sham IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT Avastin Luminate 0.5mg	Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Avastin 1.25 mg + Sham IVT Weeks 12 and 16: Avastin PRN Luminate 0.5mg	Total of all reporting groups
Overall Participants	39	33	42	24	19	17	13	16	15	218
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	21 53.8%	19 57.6%	29 69%	15 62.5%	10 52.6%	10 58.8%	10 76.9%	12 75%	9 60%	135 61.9%
>=65 years	18 46.2%	14 42.4%	13 31%	9 37.5%	9 47.4%	7 41.2%	3 23.1%	4 25%	6 40%	83 38.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.9 (9.05)	61 (9.91)	63.8 (9.45)	60.3 (8.83)	67.1 (10.47)	65.5 (9.41)	60.1 (10.92)	60.5 (8.29)	62.1 (9.35)	62.3 (9.35)
Sex: Female, Male (Count of Participants)
Female	23 59%	13 39.4%	17 40.5%	6 25%	10 52.6%	12 70.6%	7 53.8%	8 50%	10 66.7%	106 48.6%
Male	16 41%	20 60.6%	25 59.5%	18 75%	9 47.4%	5 29.4%	6 46.2%	8 50%	5 33.3%	112 51.4%
Race/Ethnicity, Customized (Count of Participants)
white	33 84.6%	29 87.9%	38 90.5%	17 70.8%	17 89.5%	15 88.2%	7 53.8%	13 81.3%	12 80%	181 83%
Black or African American	4 10.3%	1 3%	3 7.1%	3 12.5%	1 5.3%	1 5.9%	5 38.5%	1 6.3%	2 13.3%	21 9.6%
Asian	1 2.6%	1 3%	0 0%	3 12.5%	0 0%	1 5.9%	1 7.7%	2 12.5%	0 0%	9 4.1%
Other	1 2.6%	2 6.1%	0 0%	1 4.2%	1 5.3%	0 0%	0 0%	0 0%	0 0%	5 2.3%
American Indian or Alaska Native	0 0%	0 0%	1 2.4%	0 0%	0 0%	0 0%	0 0%	0 0%	1 6.7%	2 0.9%
Region of Enrollment (Count of Participants)
United States	39 100%	33 100%	42 100%	24 100%	19 100%	17 100%	13 100%	16 100%	15 100%	218 100%

Outcome Measures

1. Primary Outcome

Title	Change in BCVA at Week 24
Description	Primary efficacy outcome is BCVA changes at Week 24 as compared to baseline
Time Frame	Value of 24 Weeks minus baseline value

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Luminate 1.0mg Group	Luminate 2.0mg Group	Luminate 3.0mg Group	Avastin® Group	Avastin Then Luminate 1.0 mg IVT + Sham Injection	Avastin Then Luminate 0.5 mg IVT + Sham Injection	Sham Then Luminate 1.0 mg + Avastin 1.25 mg IVT	Sham Then Luminate 0.5 mg IVT + Avastin 1.25 mg IVT	Avastin 1.25 mg + Sham IVT
Arm/Group Description	Stage 1- Luminate 1.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 1.0mg	Stage 1 -Luminate 2.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 2.0mg	Stage 1- Luminate 3.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 3.0mg	Stage 1- Avastin 1.25 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Avastin injection at weeks 12, 16, or 20 for a total of at least 3 and up to 6 Avastin injections. Sham injections may be performed at weeks 12, 16, and 20 if prn Avastin is not required. Avastin	Stage 2 - Week 0 (Baseline): Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 1.0 mg IVT + sham injection Weeks 12 and 16: Sham IVT Luminate 1.0mg Avastin	Stage 2- Week 0 (Baseline); Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + sham injection Weeks 12 and 16: Sham IVT Avastin Luminate 0.5mg	Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Luminate 1.0 mg + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT Luminate 1.0mg Avastin	Stage 2 : Week 0: Sham IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT Avastin Luminate 0.5mg	Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Avastin 1.25 mg + Sham IVT Weeks 12 and 16: Avastin PRN Luminate 0.5mg
Measure Participants	39	33	42	24	19	17	13	16	15
Mean (Standard Error) [Letters on ETDRS eye chart]	5.2 (3)	2.7 (3)	-1.5 (3)	7 (3)	7.1 (3)	4.6 (3)	1.4 (3)	3.9 (3)	6.7 (3)

Adverse Events

Time Frame	The adverse events were collected from October 13, 2014 thru May 16th 2017 (2 years 7 months)
Arm/Group Title	Luminate 1.0mg Group		Luminate 2.0mg Group		Luminate 3.0mg Group		Avastin® Group		Avastin Then Luminate 1.0 mg IVT + Sham Injection		Avastin Then Luminate 0.5 mg IVT + Sham Injection		Sham Then Luminate 1.0 mg + Avastin 1.25 mg IVT		Sham Then Luminate 0.5 mg IVT + Avastin 1.25 mg IVT		Avastin 1.25 mg + Sham IVT
Arm/Group Description	Stage 1- Luminate 1.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 1.0mg		Stage 1 -Luminate 2.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week 20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 2.0mg		Stage 1- Luminate 3.0 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Luminate injection at week20 for a total of at least 3 and no more than 4 Luminate injections. Sham injections will be performed at weeks 12 and 16 and may also be performed at week 20 if prn Luminate is not required; sham laser treatment will be administered at baseline and at 16 weeks. Luminate 3.0mg		Stage 1- Avastin 1.25 mg intravitreal injection administered at baseline (Day 0), 4 weeks and 8 weeks with prn Avastin injection at weeks 12, 16, or 20 for a total of at least 3 and up to 6 Avastin injections. Sham injections may be performed at weeks 12, 16, and 20 if prn Avastin is not required. Avastin		Stage 2 - Week 0 (Baseline): Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 1.0 mg IVT + sham injection Weeks 12 and 16: Sham IVT Luminate 1.0mg Avastin		Stage 2- Week 0 (Baseline); Avastin 1.25 mg IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + sham injection Weeks 12 and 16: Sham IVT Avastin Luminate 0.5mg		Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Luminate 1.0 mg + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT Luminate 1.0mg Avastin		Stage 2 : Week 0: Sham IVT Weeks 1, 4 and 8: Luminate 0.5 mg IVT + Avastin 1.25 mg IVT Weeks 12 and 16: Sham IVT Avastin Luminate 0.5mg		Stage 2 : Week 0 (Baseline): Sham IVT Weeks 1, 4 and 8: Avastin 1.25 mg + Sham IVT Weeks 12 and 16: Avastin PRN Luminate 0.5mg
All Cause Mortality
	Luminate 1.0mg Group		Luminate 2.0mg Group		Luminate 3.0mg Group		Avastin® Group		Avastin Then Luminate 1.0 mg IVT + Sham Injection		Avastin Then Luminate 0.5 mg IVT + Sham Injection		Sham Then Luminate 1.0 mg + Avastin 1.25 mg IVT		Sham Then Luminate 0.5 mg IVT + Avastin 1.25 mg IVT		Avastin 1.25 mg + Sham IVT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/39 (2.6%)		0/33 (0%)		1/42 (2.4%)		1/24 (4.2%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		0/15 (0%)
Serious Adverse Events
	Luminate 1.0mg Group		Luminate 2.0mg Group		Luminate 3.0mg Group		Avastin® Group		Avastin Then Luminate 1.0 mg IVT + Sham Injection		Avastin Then Luminate 0.5 mg IVT + Sham Injection		Sham Then Luminate 1.0 mg + Avastin 1.25 mg IVT		Sham Then Luminate 0.5 mg IVT + Avastin 1.25 mg IVT		Avastin 1.25 mg + Sham IVT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/39 (20.5%)		3/33 (9.1%)		6/42 (14.3%)		3/24 (12.5%)		2/19 (10.5%)		1/17 (5.9%)		1/13 (7.7%)		2/16 (12.5%)		3/15 (20%)
Cardiac disorders
Cardiac disorders	2/39 (5.1%)		0/33 (0%)		1/42 (2.4%)		0/24 (0%)		2/19 (10.5%)		0/17 (0%)		0/13 (0%)		1/16 (6.3%)		0/15 (0%)
Eye disorders
eye disorders	3/39 (7.7%)		1/33 (3%)		3/42 (7.1%)		1/24 (4.2%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		0/15 (0%)
General disorders
general disorders	0/39 (0%)		0/33 (0%)		1/42 (2.4%)		1/24 (4.2%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		0/15 (0%)
Infections and infestations
Infections and infestations	2/39 (5.1%)		1/33 (3%)		1/42 (2.4%)		1/24 (4.2%)		0/19 (0%)		1/17 (5.9%)		0/13 (0%)		0/16 (0%)		2/15 (13.3%)
Metabolism and nutrition disorders
Metabolism and nutritional disorders	0/39 (0%)		0/33 (0%)		2/42 (4.8%)		0/24 (0%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		1/15 (6.7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorders	0/39 (0%)		0/33 (0%)		1/42 (2.4%)		0/24 (0%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		0/15 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign malignant and unspecified	0/39 (0%)		1/33 (3%)		0/42 (0%)		0/24 (0%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		2/15 (13.3%)
Nervous system disorders
Nervous system disorder	1/39 (2.6%)		0/33 (0%)		1/42 (2.4%)		1/24 (4.2%)		0/19 (0%)		0/17 (0%)		1/13 (7.7%)		0/16 (0%)		0/15 (0%)
Renal and urinary disorders
Renal and urinary disorders	0/39 (0%)		0/33 (0%)		0/42 (0%)		0/24 (0%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		1/16 (6.3%)		0/15 (0%)
Respiratory, thoracic and mediastinal disorders
Respitatory, thoracic and mediastinal	1/39 (2.6%)		0/33 (0%)		1/42 (2.4%)		1/24 (4.2%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		0/15 (0%)
Surgical and medical procedures
Surgical and medical procedures	0/39 (0%)		0/33 (0%)		1/42 (2.4%)		0/24 (0%)		0/19 (0%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		0/15 (0%)
Vascular disorders
Vascular disorders	0/39 (0%)		0/33 (0%)		0/42 (0%)		0/24 (0%)		1/19 (5.3%)		0/17 (0%)		0/13 (0%)		0/16 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Luminate 1.0mg Group		Luminate 2.0mg Group		Luminate 3.0mg Group		Avastin® Group		Avastin Then Luminate 1.0 mg IVT + Sham Injection		Avastin Then Luminate 0.5 mg IVT + Sham Injection		Sham Then Luminate 1.0 mg + Avastin 1.25 mg IVT		Sham Then Luminate 0.5 mg IVT + Avastin 1.25 mg IVT		Avastin 1.25 mg + Sham IVT
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/39 (71.8%)		20/33 (60.6%)		25/42 (59.5%)		16/24 (66.7%)		10/19 (52.6%)		5/17 (29.4%)		6/13 (46.2%)		7/16 (43.8%)		3/15 (20%)
Blood and lymphatic system disorders
Blood and Lymphatic	2/39 (5.1%)	2	0/33 (0%)	0	0/42 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/17 (0%)	0	0/13 (0%)	0	0/16 (0%)	0	0/15 (0%)	0
Cardiac disorders
Cardiac disorders	3/39 (7.7%)	4	0/33 (0%)	0	0/42 (0%)	0	0/24 (0%)	0	2/19 (10.5%)	2	0/17 (0%)	0	0/13 (0%)	0	0/16 (0%)	0	0/15 (0%)	0
Eye disorders
eye disorders	17/39 (43.6%)	18	9/33 (27.3%)	9	11/42 (26.2%)	20	7/24 (29.2%)	19	6/19 (31.6%)	7	1/17 (5.9%)	1	4/13 (30.8%)	9	5/16 (31.3%)	6	1/15 (6.7%)	1
Gastrointestinal disorders
gastrointestinal disorders	0/39 (0%)	0	3/33 (9.1%)	3	4/42 (9.5%)	4	0/24 (0%)	0	0/19 (0%)	0	0/17 (0%)	0	1/13 (7.7%)	1	0/16 (0%)	0	1/15 (6.7%)	1
Infections and infestations
infections and infestations	6/39 (15.4%)	6	5/33 (15.2%)	5	4/42 (9.5%)	5	3/24 (12.5%)	3	1/19 (5.3%)	1	2/17 (11.8%)	2	2/13 (15.4%)	3	1/16 (6.3%)	1	0/15 (0%)	0
Injury, poisoning and procedural complications
Injury, poisoning and procedural complications	5/39 (12.8%)	5	3/33 (9.1%)	3	0/42 (0%)	0	3/24 (12.5%)	3	0/19 (0%)	0	1/17 (5.9%)	1	0/13 (0%)	0	0/16 (0%)	0	0/15 (0%)	0
Investigations
Investigations	0/39 (0%)	0	0/33 (0%)	0	4/42 (9.5%)	4	0/24 (0%)	0	0/19 (0%)	0	0/17 (0%)	0	0/13 (0%)	0	0/16 (0%)	0	0/15 (0%)	0
Metabolism and nutrition disorders
Metabolism and nutritional disorders	2/39 (5.1%)	2	0/33 (0%)	0	4/42 (9.5%)	5	2/24 (8.3%)	3	0/19 (0%)	0	1/17 (5.9%)	2	0/13 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Musculoskeletal and connective tissue disorders
musculoskeletal and connective tissue	2/39 (5.1%)	3	2/33 (6.1%)	2	0/42 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/17 (0%)	0	0/13 (0%)	0	0/16 (0%)	0	0/15 (0%)	0
Nervous system disorders
Nervous system disorders	0/39 (0%)	0	0/33 (0%)	0	0/42 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/17 (0%)	0	0/13 (0%)	0	0/16 (0%)	0	1/15 (6.7%)	1
Psychiatric disorders
psychiatric disorders	0/39 (0%)	0	0/33 (0%)	0	0/42 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/17 (0%)	0	1/13 (7.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Renal and urinary disorders
Renal and urinary disorders	0/39 (0%)	0	0/33 (0%)	0	0/42 (0%)	0	2/24 (8.3%)	2	0/19 (0%)	0	0/17 (0%)	0	0/13 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0
Skin and subcutaneous tissue disorders
skin and subcutaneous tissue disorders	0/39 (0%)	0	0/33 (0%)	0	2/42 (4.8%)	2	0/24 (0%)	0	0/19 (0%)	0	0/17 (0%)	0	1/13 (7.7%)	1	0/16 (0%)	0	0/15 (0%)	0
Vascular disorders
Vascular disorders	4/39 (10.3%)	4	2/33 (6.1%)	2	0/42 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/17 (0%)	0	0/13 (0%)	0	1/16 (6.3%)	1	0/15 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Investigator will submit to Sponsor a copy of the proposed publication or presentation and the name of the scientific journal or forum to which it will be submitted- at least ninety (90) days prior to the submission.Investigator shall comply with Sponsor's request to delete references to Confidential Information,in any such paper or presentation and agrees to withhold publication or presentation of same for an additional ninety (90) days in order to permit Sponsor to obtain patent protection.