REACT: Safety and Efficacy of Ranibizumab for Diabetic Macular Edema

• Sponsor: Justis Ehlers (Other)
• Overall Status: Completed
• CT.gov ID: NCT01982435
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 27
• Locations: 2
• Arms: 2
• Actual Duration (Months): 23.1
• Patients Per Site: 13.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The primary objective of the study is to assess the ocular and systemic adverse events of ranibizumab (Lucentis)for DME (diabetic macular edema) following previous treatment with intravitreal bevacizumab (Avastin).

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: Ranibizumab; Drug: Ranibizumab	Phase 1/Phase 2

Detailed Description

This is an open-label, Phase I/II study of intravitreally administered 0.3mg ranibizumab (Lucentis) in subjects with DME (diabetic macular edema) previously treated with intravitreal bevacizumab (Avastin) with a randomized comparative dosing strategy, monthly vs "treat-and-extend." Thirty patients total will be enrolled in the study, 15 in each group. This study will have a 1-year treatment period. The recruitment period will occur over 1 year with total potential study duration of 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Efficacy of Intravitreal Ranibizumab for Diabetic Macular Edema Previously Treated With Intravitreal Bevacizumab: A Randomized Dual Arm Comparative Dosing Trial
• Actual Study Start Date: Jun 24, 2014
• Actual Primary Completion Date: May 26, 2016
• Actual Study Completion Date: May 26, 2016

Arms and Interventions

Arm	Intervention/Treatment
Other: Group I - Monthly Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group.	Drug: Ranibizumab; Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.; Other Names: Lucentis
Other: Group II - Treat-and-Extend Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results.	Drug: Ranibizumab; Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.; Other Names: Lucentis

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Non-severe Ocular Adverse Events [12 months]

   As identified by eye examination (including visual acuity testing), identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.

2. Number of Participants With Severe Ocular Adverse Events [12 months]

   As identified by eye examination (including visual acuity testing), identified by physical examination, subject reporting, and changes in vital signs.

3. Number of Participants With Non-severe Non-ocular Adverse Event [12 months]

   As identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.

4. Number of Participants With Severe Non-ocular Adverse Event [12 months]

   As identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.

Secondary Outcome Measures

1. Mean Change in BCVA [Months 6 and 12]

   Mean change in best-corrected visual acuity as assessed by the number of letters read correctly on the electronic ETDRS eye chart from baseline to months 6 and 12.

2. Mean Change in Central Foveal Thickness [Months 6 and 12]

   Mean absolute change from baseline central foveal thickness at months 6 and 12 as measured by SDOCT (defined as the average thickness within the central 1 mm subfield)

3. Anatomically Dry Eyes by SDOCT [Months 6 and 12]

   Number of participants with an anatomically "dry" study eye by SDOCT at months 6 and 12

4. Gain in Vision Greater Than or Equal to 15 Letters [Months 6 and 12]

   Number of participants that gained greater than or equal to 15 letters of vision in their study eye at months 6 and 12.

5. Loss in Vision Greater Than or Equal to 15 Letters [Months 6 and 12]

   Number of participants that lost greater than or equal to 15 letters of vision in their study eye at months 6 and 12.

6. Participants With BCVA at 20/40 or Better [Months 6 and 12]

   Number of participants with 20/40 or better best-corrected visual acuity in their study eye at months 6 and 12.

7. Number of Participants With Angiographic Leakage [3, 6 and 12 months]

   Number of participants with angiographic leakage in their study eye measured from baseline to months 3, 6 and 12 (i.e. presence of leakage).

8. Number of Participants With Nonperfusion [3, 6 and 12 months]

   Number of participants with peripheral nonperfusion in their study eye from baseline to months 3, 6, and 12 (i.e. presence of ischemia).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects will be eligible if the following criteria are met:

• Ability to provide written informed consent and comply with study assessments for the full duration of the study

• Age > 18 years

• ETDRS best-corrected visual acuity of 20/25 to 20/320 in the study eye

• Willing, committed, and able to return for ALL clinic visits and complete all study related procedures

• At least 6 previous bevacizumab injections for diabetic macular edema in the last 12 months in the study eye.

• At least 2 bevacizumab injections within 10 weeks and the most recent bevacizumab injection within 6 weeks of baseline study visits in the study eye.

• Persistent foveal-involving diabetic macular edema based on presence of intraretinal and/or subretinal fluid by SDOCT in the foveal center at study entry in the study eye.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from this study:

• Pregnancy (positive pregnancy test) or lactation

• Premenopausal women not using adequate contraception. The following are considered effective means of contraception: surgical sterilization or use of oral contraceptives, barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel, an IUD (intrauterine device), or contraceptive hormone implant or patch.

• Intravitreal steroid or periocular steroid treatment within 3 months of study entry in the study eye.

• Focal/grid laser photocoagulation treatment within 3 months of study entry in the study eye.

• Panretinal photocoagulation treatment within 3 months of study entry in the study eye.

• Prior vitrectomy in the study eye

• History of retinal detachment in the study eye

• Prior trabeculectomy or other filtration surgery in the study eye

• Active intraocular inflammation in either eye

• Active ocular or periocular infection in either eye

• Active scleritis or episcleritis in either eye

• History of any other retinal vascular disease (e.g., retinal vein occlusion, retinal artery occlusion) in the study eye.

• Coexistent retinal disease other than diabetic retinopathy (e.g., AMD (age related macular degeneration), inherited retinal disease) in the study eye.

• Intraocular surgery within 3 months of study entry in the study eye.

• History of corneal transplant or corneal dystrophy in the study eye.

• Significant media opacities in study eye which may interfere with visual acuity in the study eye.

• Participation as a subject in any clinical study within 3 months of study entry.

• History of allergy to topical iodine

• Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated

• Participation in another simultaneous medical investigation or trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cole Eye Institute, Cleveland Clinic	Cleveland	Ohio	United States	44195
2	Cole Eye Institute at Hillcrest Hospital	Mayfield Heights	Ohio	United States	44124

Sponsors and Collaborators

• Justis Ehlers
• Genentech, Inc.

Investigators

• Principal Investigator: Justis Ehlers, M.D., The Cleveland Clinic

Study Documents (Full-Text)

• Study Protocol - Feb 27, 2017
• Statistical Analysis Plan - Nov 7, 2013

More Information

Publications

None provided.

• Responsible Party: Justis Ehlers, Staff physician / Sponsor-Investigator, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT01982435
• Other Study ID Numbers: REACT Study
• First Posted: Nov 13, 2013
• Last Update Posted: Nov 3, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Justis Ehlers, Staff physician / Sponsor-Investigator, The Cleveland Clinic: Diabetes; Macular Edema
• Additional relevant MeSH terms: Macular Edema; Edema; Ranibizumab

Study Results

Participant Flow

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Period Title: Overall Study
STARTED	15	12
COMPLETED	14	12
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend	Total
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.	Total of all reporting groups
Overall Participants	15	12	27
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	10 66.7%	7 58.3%	17 63%
>=65 years	5 33.3%	5 41.7%	10 37%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.5 (6.0)	63.8 (6.4)	63.1 (6.1)
Sex: Female, Male (Count of Participants)
Female	10 66.7%	6 50%	16 59.3%
Male	5 33.3%	6 50%	11 40.7%
Region of Enrollment (Count of Participants)
United States	15 100%	12 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Non-severe Ocular Adverse Events
Description	As identified by eye examination (including visual acuity testing), identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Patients who exited the study early were accounted by using a last observation carried forward approach.

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Blurry Vision	9 60%	5 41.7%
Elevated IOP	4 26.7%	3 25%
Flashes	3 20%	3 25%
Vitreous Floaters	3 20%	2 16.7%
Dry eyes	3 20%	2 16.7%
Redness	1 6.7%	2 16.7%
Pruritus	2 13.3%	0 0%
Tearing	1 6.7%	1 8.3%
Non-severe ocular adverse events	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group I - Monthly, Group II - Treat-and-Extend
	Comments	All analyses were performed with a significance level of 0.05 being assumed for all tests.
	Type of Statistical Test	Other
	Comments	Measures were summarized using means, range and standard error of the means (SEM).
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	Two-sided paired t-tests and two-sided unpaired t-tests were respectively conducted to analyze efficacy endpoints between study initiation to end, and between monthly and TAE injection regimens.
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Number of Participants With Severe Ocular Adverse Events
Description	As identified by eye examination (including visual acuity testing), identified by physical examination, subject reporting, and changes in vital signs.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Endophthalmitis	0 0%	0 0%
Retinal Detachment	0 0%	0 0%

3. Primary Outcome

Title	Number of Participants With Non-severe Non-ocular Adverse Event
Description	As identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Blood and lymphatic adverse event	1 6.7%	0 0%
Cardiac adverse event	8 53.3%	4 33.3%
Gastrointestinal adverse event	6 40%	1 8.3%
General adverse event	14 93.3%	12 100%
Infectious advsere event	1 6.7%	0 0%
Metabolic adverse event	3 20%	2 16.7%
Musculoskeletal adverse event	12 80%	8 66.7%
Cyst, polyp and tumor adverse event	3 20%	0 0%
Nervous system adverse event	2 13.3%	0 0%
Psychiatric adverse event	0 0%	1 8.3%
Renal and urinary adverse event	5 33.3%	3 25%
Reproductive adverse event	1 6.7%	0 0%
Respiratory adverse event	1 6.7%	5 41.7%
Skin and subcutaneous adverse event	8 53.3%	2 16.7%
Vascular adverse event	4 26.7%	0 0%

4. Primary Outcome

Title	Number of Participants With Severe Non-ocular Adverse Event
Description	As identified by physical examination, subject reporting, and changes in vital signs. These outcome measures are also included in more detail in the adverse event section of the results.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Hospitalizations	6 40%	3 25%
TIA	1 6.7%	0 0%
Stroke	1 6.7%	0 0%

5. Secondary Outcome

Title	Mean Change in BCVA
Description	Mean change in best-corrected visual acuity as assessed by the number of letters read correctly on the electronic ETDRS eye chart from baseline to months 6 and 12.
Time Frame	Months 6 and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Month 6	.7 (8.1)	.7 (8.1)
Month 12	2.1 (8.3)	7.4 (10.4)

6. Secondary Outcome

Title	Mean Change in Central Foveal Thickness
Description	Mean absolute change from baseline central foveal thickness at months 6 and 12 as measured by SDOCT (defined as the average thickness within the central 1 mm subfield)
Time Frame	Months 6 and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Month 6	-28.8 (173.4)	104.1 (165.6)
Month 12	-80.9 (184.7)	-124 (157.6)

7. Secondary Outcome

Title	Anatomically Dry Eyes by SDOCT
Description	Number of participants with an anatomically "dry" study eye by SDOCT at months 6 and 12
Time Frame	Months 6 and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Month 6	0 0%	0 0%
Month 12	0 0%	1 8.3%

8. Secondary Outcome

Title	Gain in Vision Greater Than or Equal to 15 Letters
Description	Number of participants that gained greater than or equal to 15 letters of vision in their study eye at months 6 and 12.
Time Frame	Months 6 and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Month 6	0 0%	2 16.7%
Month 12	1 6.7%	2 16.7%

9. Secondary Outcome

Title	Loss in Vision Greater Than or Equal to 15 Letters
Description	Number of participants that lost greater than or equal to 15 letters of vision in their study eye at months 6 and 12.
Time Frame	Months 6 and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Month 6	1 6.7%	0 0%
Month 12	1 6.7%	0 0%

10. Secondary Outcome

Title	Participants With BCVA at 20/40 or Better
Description	Number of participants with 20/40 or better best-corrected visual acuity in their study eye at months 6 and 12.
Time Frame	Months 6 and 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
Month 6	1 6.7%	2 16.7%
Month 12	0 0%	2 16.7%

11. Secondary Outcome

Title	Number of Participants With Angiographic Leakage
Description	Number of participants with angiographic leakage in their study eye measured from baseline to months 3, 6 and 12 (i.e. presence of leakage).
Time Frame	3, 6 and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
3 month	15 100%	12 100%
6 month	15 100%	12 100%
12 month	15 100%	12 100%

12. Secondary Outcome

Title	Number of Participants With Nonperfusion
Description	Number of participants with peripheral nonperfusion in their study eye from baseline to months 3, 6, and 12 (i.e. presence of ischemia).
Time Frame	3, 6 and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group I - Monthly	Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.	Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
Measure Participants	15	12
3 months	13 86.7%	9 75%
6 months	13 86.7%	10 83.3%
12 months	12 80%	9 75%

Adverse Events

Arm/Group Title	Group I - Monthly		Group II - Treat-and-Extend
Arm/Group Description	Enrolled subjects will receive multiple open-label intravitreal injections of 0.3 mg ranibizumab administered every 28 days (+/- 7 days from the last treatment) for 12 months in the monthly group. Ranibizumab: Monthly injections of Intravitreal Ranibizumab 0.3 mg for 12 months in patients previously treated with Avastin for Diabetic Macular Edema.		Enrolled subjects will initially receive 3 loading doses of open-label Ranibizumab 0.3 mg given via intravitreal injection every 28 days (+/- 7 days from the last treatment). After the third loading dose, the follow-up interval is determined by the Principal Investigator based on OCT results as stated in the protocol. The follow-up interval is increased by 2 weeks (+/- 7 days) at each visit up to a maximum interval of 12 weeks (+/- 7 days). There is criteria built into the protocol in case a reduction in the follow-up intervals becomes necessary based upon worsening OCT results. Ranibizumab: Three Monthly injections of Intravitreal Ranibizumab 0.3 mg in patients previously treated with Avastin for Diabetic Macular Edema. Then follow-up visits may be extended by 2 weeks for a total of 12 months.
All Cause Mortality
	Group I - Monthly		Group II - Treat-and-Extend
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/12 (0%)
Serious Adverse Events
	Group I - Monthly		Group II - Treat-and-Extend
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/15 (40%)		3/12 (25%)
Cardiac disorders
TRANSIENT ISCHEMIC ATTACK	1/15 (6.7%)	1	0/12 (0%)	0
ACUTE INFARCT STROKE	1/15 (6.7%)	1	0/12 (0%)	0
UNSTABLE ANGINA AND CHEST PAIN	1/15 (6.7%)	1	0/12 (0%)	0
Endocrine disorders
HOSPITALIZATION FOR HYPERKALEMIA	0/15 (0%)	0	1/12 (8.3%)	1
General disorders
VERTIGO	0/15 (0%)	0	1/12 (8.3%)	1
HOSPITALIZED FOR RECURRENT SOB, LEG EDEMA	1/15 (6.7%)	1	0/12 (0%)	0
Infections and infestations
HOSPITALIZATION FOR GANGRENE	1/15 (6.7%)	1	0/12 (0%)	0
HOSPITALIZATION R DIABETIC FOOT ULCER INFECTION	1/15 (6.7%)	1	0/12 (0%)	0
HOSPITALIZATION FOR GANGRENE/AMPUTATION	1/15 (6.7%)	1	0/12 (0%)	0
HOSPITALIZATION FOR OSTEOMYELITIS/AMPUTATION	1/15 (6.7%)	1	0/12 (0%)	0
Renal and urinary disorders
Worsening of Chronic Kidney Disease	1/15 (6.7%)	1	0/12 (0%)	0
HOSPITALIZED FOR PERITONITIS	1/15 (6.7%)	1	0/12 (0%)	0
Reproductive system and breast disorders
LARGE OVARIAN NEOPLASM	1/15 (6.7%)	1	0/12 (0%)	0
HOSPITALIZATION FOR TOTAL HYSTERECTOMY	0/15 (0%)	0	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
HOSPITALIZED FOR ANGINA/SOB	1/15 (6.7%)	1	0/12 (0%)	0
Skin and subcutaneous tissue disorders
POSSIBLE CELLULITIS TO RIGHT LOWER EXTREMITY	1/15 (6.7%)	1	0/12 (0%)	0
HOSPITALIZED FOR DIABETIC RIGHT HEEL ULCER	1/15 (6.7%)	1	0/12 (0%)	0
Social circumstances
HOSPITALIZED FORCONFUSION/SLURRED SPEECH AFTER FALL	1/15 (6.7%)	1	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	Group I - Monthly		Group II - Treat-and-Extend
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/15 (100%)		12/12 (100%)
Blood and lymphatic system disorders
Thalassemia Trait	1/15 (6.7%)	1	0/12 (0%)	0
Cardiac disorders
Hypertension	4/15 (26.7%)	4	2/12 (16.7%)	2
Hypotension	1/15 (6.7%)	1	1/12 (8.3%)	1
Chest pain	2/15 (13.3%)	2	0/12 (0%)	0
Asymptomatic Bradycardia	0/15 (0%)	0	1/12 (8.3%)	1
Elevated Heart Rate	1/15 (6.7%)	2	0/12 (0%)	0
Eye disorders
Decreased Vision	5/15 (33.3%)	5	4/12 (33.3%)	4
Difficulty with reading	5/15 (33.3%)	5	5/12 (41.7%)	5
Foreign Body Sensation	2/15 (13.3%)	2	1/12 (8.3%)	1
Stye	3/15 (20%)	3	1/12 (8.3%)	1
Diplopia	1/15 (6.7%)	1	0/12 (0%)	0
Epiretinal Membrane	0/15 (0%)	0	3/12 (25%)	3
Ocular irritation	6/15 (40%)	6	2/12 (16.7%)	2
Eye Discharge	1/15 (6.7%)	1	1/12 (8.3%)	1
Optic neuropathy	1/15 (6.7%)	1	1/12 (8.3%)	1
Worsening of cataracts	2/15 (13.3%)	2	0/12 (0%)	0
Glare in vision	2/15 (13.3%)	2	0/12 (0%)	0
Posterior Vitreous Detachment	0/15 (0%)	0	1/12 (8.3%)	1
Ptosis	0/15 (0%)	0	1/12 (8.3%)	1
Ocular swelling	0/15 (0%)	0	1/12 (8.3%)	1
Conjunctivitis	2/15 (13.3%)	3	0/12 (0%)	0
Chronic angle closure glaucoma	1/15 (6.7%)	1	0/12 (0%)	0
Subconjunctival Hemorrhage	2/15 (13.3%)	2	1/12 (8.3%)	1
Puncture wound	1/15 (6.7%)	1	0/12 (0%)	0
Difficulty with watching television	1/15 (6.7%)	1	3/12 (25%)	3
Gastrointestinal disorders
Abdominal pain	2/15 (13.3%)	3	0/12 (0%)	0
Vomitting	1/15 (6.7%)	1	0/12 (0%)	0
Diarrhea	2/15 (13.3%)	2	1/12 (8.3%)	1
Ascites	1/15 (6.7%)	1	0/12 (0%)	0
General disorders
Flu-like symptoms	4/15 (26.7%)	4	5/12 (41.7%)	5
Difficulty with driving	2/15 (13.3%)	2	2/12 (16.7%)	2
Hyperglycemic episode	0/15 (0%)	0	1/12 (8.3%)	1
Hypoglycemic episode	2/15 (13.3%)	2	3/12 (25%)	3
Headache	2/15 (13.3%)	2	1/12 (8.3%)	1
Thyroid cancer	1/15 (6.7%)	1	0/12 (0%)	0
Bladder cancer	1/15 (6.7%)	1	0/12 (0%)	0
Fatigue	1/15 (6.7%)	1	2/12 (16.7%)	2
Elevated microalbumin	0/15 (0%)	0	1/12 (8.3%)	1
Fever	1/15 (6.7%)	1	0/12 (0%)	0
Generalized weakness	1/15 (6.7%)	1	0/12 (0%)	0
Anemia	1/15 (6.7%)	1	0/12 (0%)	0
Elevated Creatinine levels	0/15 (0%)	0	1/12 (8.3%)	1
Elevated d-Dimer	1/15 (6.7%)	1	0/12 (0%)	0
Hypomagnesemia	1/15 (6.7%)	1	0/12 (0%)	0
OSA Worsening	1/15 (6.7%)	1	0/12 (0%)	0
Nausea	0/15 (0%)	0	1/12 (8.3%)	1
Hyperlipidemia	1/15 (6.7%)	1	0/12 (0%)	0
Elevated INR	0/15 (0%)	0	1/12 (8.3%)	1
Pruritus after fluorescein dye	0/15 (0%)	0	1/12 (8.3%)	1
Insomnia - worsening	0/15 (0%)	0	1/12 (8.3%)	1
Hyperkalemia	0/15 (0%)	0	1/12 (8.3%)	1
Medicamentosa suspect	1/15 (6.7%)	1	0/12 (0%)	0
Tingling sensation in feet	1/15 (6.7%)	1	0/12 (0%)	0
Elevated FBS	1/15 (6.7%)	1	0/12 (0%)	0
Addison's Disease worsening	1/15 (6.7%)	1	0/12 (0%)	0
Worsening of trigger finger	1/15 (6.7%)	1	0/12 (0%)	0
Elevated TSH levels	1/15 (6.7%)	1	0/12 (0%)	0
SOB episode - allergy to Zanaflex	0/15 (0%)	0	1/12 (8.3%)	1
Infections and infestations
Staph infection of wound on ankle	1/15 (6.7%)	1	0/12 (0%)	0
Metabolism and nutrition disorders
Weight gain	1/15 (6.7%)	1	1/12 (8.3%)	1
Vitamin Deficiency	2/15 (13.3%)	2	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Shoulder pain	4/15 (26.7%)	4	1/12 (8.3%)	1
Neck pain	1/15 (6.7%)	1	0/12 (0%)	0
Pain from fall	1/15 (6.7%)	1	2/12 (16.7%)	2
Back pain	1/15 (6.7%)	1	1/12 (8.3%)	1
Osteopenia	0/15 (0%)	0	1/12 (8.3%)	1
Foot pain	1/15 (6.7%)	1	2/12 (16.7%)	2
Knee Pain	0/15 (0%)	0	1/12 (8.3%)	1
Lower extremity sprain	3/15 (20%)	4	0/12 (0%)	0
Leg pain	1/15 (6.7%)	1	0/12 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign polyps	2/15 (13.3%)	2	0/12 (0%)	0
Thyroid nodule	1/15 (6.7%)	1	0/12 (0%)	0
Nervous system disorders
Dizziness	2/15 (13.3%)	2	0/12 (0%)	0
Psychiatric disorders
Anxiety	0/15 (0%)	0	1/12 (8.3%)	1
Renal and urinary disorders
Worsening of diabetes	3/15 (20%)	4	1/12 (8.3%)	1
Urinary Tract infection	2/15 (13.3%)	3	2/12 (16.7%)	2
Reproductive system and breast disorders
Uterine cancer suspect	1/15 (6.7%)	1	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Upper respiratory infection	0/15 (0%)	0	5/12 (41.7%)	5
Atelectasis	1/15 (6.7%)	1	0/12 (0%)	0
Skin and subcutaneous tissue disorders
Cellulitis	2/15 (13.3%)	2	0/12 (0%)	0
Generalized rash	3/15 (20%)	3	0/12 (0%)	0
Dermatitis	0/15 (0%)	0	1/12 (8.3%)	1
Sun damage	0/15 (0%)	0	1/12 (8.3%)	1
Cold Sore	1/15 (6.7%)	1	0/12 (0%)	0
Bullous eruption on glans	1/15 (6.7%)	1	0/12 (0%)	0
Pruritus on neck	1/15 (6.7%)	1	0/12 (0%)	0
Vascular disorders
Edema	3/15 (20%)	3	0/12 (0%)	0
Atherosclerosis	1/15 (6.7%)	1	0/12 (0%)	0

Limitations/Caveats

The relatively small sample size of eyes and short 1 year duration makes it challenging to extrapolate data to generate clinical management guidelines. The lack of a control group is an important limitation to recognize that also limits conclusions.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.