PERMEATE: Peripheral and Macular Retinal Vascular Perfusion and Leakage in DME and RVO

• Sponsor: Justis Ehlers (Other)
• Overall Status: Completed
• CT.gov ID: NCT02503540
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 31
• Location: 1
• Arm: 1
• Actual Duration (Months): 29.7
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This interventional study will evaluate the retinal vascular dynamics associated with Intravitreal Aflibercept Injection (IAI) therapy in eyes with diabetic macular edema (DME) or macular edema secondary to retinal vein occlusion (RVO). Ultra-widefield fluorescein angiography and optical coherence tomography (OCT) angiography will be performed at multiple timepoints to assess the changes in retinal vascular leakage, ischemia, and vascular abnormalities throughout the study duration and compare these alterations to baseline.

Condition or Disease	Intervention/Treatment	Phase
Retinal Vein Occlusion; Diabetic Macular Edema; Branch Retinal Vein Occlusion; Central Retinal Vein Occlusion	Drug: Aflibercept	Phase 4

Detailed Description

Diabetic macular edema (DME) and macular edema secondary to retinal venous occlusive diseases are the most common cause of vision loss from a retinal vascular disease. Recently, vascular endothelial growth factor (VEGF) inhibitors (bevacizumab, aflibercept, and ranibizumab) have been described as new first-line therapies for these conditions. Aflibercept is the most recently approved VEGF inhibitor for the management of these conditions. Clinical trials have shown that treatment with aflibercept improves visual acuity and reduces macular edema in a large percentage of patients.

This study will examine the changes that occur with intravitreal aflibercept to perfusion and leakage in treatment naive eyes over the course of 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Peripheral and Macular Retinal Vascular Perfusion and Leakage Dynamics in Diabetic Macular Edema and Retinal Venous Occlusions During Intravitreal Aflibercept Injection (IAI) Treatment for Retinal Edema: PERMEATE Study
• Actual Study Start Date: Aug 18, 2015
• Actual Primary Completion Date: Feb 6, 2018
• Actual Study Completion Date: Feb 6, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Aflibercept Monthly aflibercept for 6 months and then every other month for 6 months.	Drug: Aflibercept; Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.; Other Names: Eylea

Outcome Measures

Primary Outcome Measures

1. Change in Panretinal Leakage Index at Month 12 From Baseline [12 months]

   Change in panretinal leakage index (defined as the proportion of retinal area involved in angiographic leakage) at month 12 from baseline as measured by ultra-widefield angiography (UWFA).

Secondary Outcome Measures

1. Mean Change in Total Leakage Index [6 months]

   Mean change in total leakage index from baseline to month 6

2. Change in Panretinal Ischemic Index [12 months]

   Change in panretinal ischemic index from baseline to postoperative month 12

3. Change in Panretinal Ischemic Index From Baseline at 6 Months [6 months]

   Change in panretinal ischemic index (defined as the proportion of retinal area with nonperfusion) from baseline at 6 months

4. Mean Change From Baseline Central Subfield Thickness [6 months]

   OCT central subfield thickness change from baseline to 6 months

5. Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) Score Based on ETDRS [12 months]

   Mean change from baseline in best-corrected visual acuity (BCVA) score from baseline to month 12

6. Number of Participants Who Gained 15 ETDRS Letters or More of Vision [12 months]

7. Number of Patients Who Gained 15 ETDRS Letters or More of Vision [6 months]

8. Number of Patients That Showed Visual Acuity 20/40 or Better [6 months]

9. Number of Patients That Showed Visual Acuity 20/200 or Worse [6 months]

10. Ocular Serious Adverse Events [12 months]

11. Number of Participants Who Lost 15 ETDRS Letters or More of Vision [12 months]

12. Number of Participants Who Lost 15 ETDRS Letters or More of Vision [6 months]

13. Number of Patients That Showed Visual Acuity 20/40 or Better [12 months]

14. Number of Patients That Showed Visual Acuity 20/200 or Worse [12 months]

15. Mean Change From Baseline Central Subfield Thickness [12 months]

16. Systemic Serious Adverse Events [12 Months]

    Incidence of systemic SAEs

Eligibility Criteria

Criteria

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

Inclusion Criteria

A subject must meet the following criteria to be eligible for inclusion in the study:

1. Signed Informed Consent.

2. Men and women ≥ 18 years of age.

3. Foveal-involving retinal edema secondary to DME or RVO based on investigator review of SDOCT.

4. E-ETDRS best-corrected visual acuity of: 20/25 to 20/400 in the study eye or Hand Motion (HM) in the study eye.

5. Willing, committed, and able to return for all clinic visits and complete all study related procedures.

6. Able to read, (or, if unable to read due to visual impairment, be read to verbatim by the person administering the informed consent or a family member) understand and willing to sign the informed consent form.

Exclusion Criteria

A subject who meets any of the following criteria will be excluded from the study:

1. Any prior or concomitant therapy with another investigational agent to treat DME or RVO in the study eye.

2. Prior panretinal photocoagulation in the study eye.

3. Prior intravitreal anti-VEGF therapy in the study eye.

4. Prior focal/grid laser photocoagulation in the study eye.

5. Prior history of intravitreal steroid therapy in the study eye.

6. Any history of allergy to fluorescein sodium or other reason that the patient is unable to undergo fluorescein angiography (e.g., inability to get vascular access, unable to tolerate procedure)

7. Prior systemic anti-VEGF therapy, investigational or FDA-approved, is only allowed up to 3 months prior to first dose, and will not be allowed during the study.

8. Significant vitreous hemorrhage obscuring view to the macula or the retinal periphery as determined by the investigator on clinical exam and ultra-widefield angiography.

9. Presence of other causes of macular edema, including myopic degeneration, ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, choroidal neovascularization, neovascular age-related macular degeneration or multifocal choroiditis in the study eye. Epiretinal membranes are allowed.

10. Presence of macula-threatening traction retinal detachment.

11. Prior vitrectomy in the study eye.

12. History of retinal detachment or treatment or surgery for retinal detachment in the study eye.

13. Any history of macular hole of stage 2 and above in the study eye.

14. Any intraocular or periocular surgery within 3 months of Day 1 on the study eye, except lid surgery, which may not have taken place within 1 month of day 1, as long as it's unlikely to interfere with the injection.

15. Prior trabeculectomy or other filtration surgery in the study eye.

16. Uncontrolled glaucoma at baseline evaluation (defined as intraocular pressure ≥25 mmHg despite treatment with anti-glaucoma medication) in the study eye.

17. Active intraocular inflammation in either eye.

18. Active ocular or periocular infection in either eye.

19. Any ocular or periocular infection within the last 2 weeks prior to Screening in either eye.

20. Any history of uveitis in either eye.

21. Active scleritis or episcleritis in either eye.

22. Presence or history of scleromalacia in either eye.

23. Aphakia in the study eye.

24. Previous therapeutic radiation in the region of the study eye.

25. History of full-thickness penetrating keratoplasty in the study eye. Partial thickness corneal transplants including Descemet stripping automated endothelial keratoplasty and Descemet membrane endothelial keratoplasty are allowed.

26. Significant media opacities, including cataract, in the study eye which might interfere with visual acuity, assessment of safety, or fundus photography.

27. Any concurrent intraocular condition in the study eye (e.g. cataract) that, in the opinion of the investigator, could require either medical or surgical intervention during the 52 week study period.

28. Any concurrent ocular condition in the study eye which, in the opinion of the investigator, could either increase the risk to the subject beyond what is to be expected from standard procedures of intraocular injection, or which otherwise may interfere with the injection procedure or with evaluation of efficacy or safety.

29. Participation as a subject in any clinical study within the 12 weeks prior to Day 1.

30. Any systemic therapy with an investigational agent in the past 3 months prior to Day

32. Any history of allergy to povidone iodine.

33. Pregnant or breast-feeding women

34. Women of childbearing potential* who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device (IUD); bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly)

• Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of child bearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cole Eye Institute, Cleveland Clinic	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• Justis Ehlers
• Regeneron Pharmaceuticals

Investigators

• Principal Investigator: Justis P Ehlers, MD, Cole Eye Institute, Cleveland Clinic, OH 44195

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 20, 2017

More Information

Publications

• Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4-25. Review.
• Ferrara N, Houck KA, Jakeman LB, Winer J, Leung DW. The vascular endothelial growth factor family of polypeptides. J Cell Biochem. 1991 Nov;47(3):211-8. Review.
• Ferrara N. Vascular endothelial growth factor and the regulation of angiogenesis. Recent Prog Horm Res. 2000;55:15-35; discussion 35-6. Review.
• Rakic JM, Lambert V, Devy L, Luttun A, Carmeliet P, Claes C, Nguyen L, Foidart JM, Noël A, Munaut C. Placental growth factor, a member of the VEGF family, contributes to the development of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003 Jul;44(7):3186-93.
• Singer M, Tan CS, Bell D, Sadda SR. Area of peripheral retinal nonperfusion and treatment response in branch and central retinal vein occlusion. Retina. 2014 Sep;34(9):1736-42. doi: 10.1097/IAE.0000000000000148.
• Thickett DR, Armstrong L, Millar AB. Vascular endothelial growth factor (VEGF) in inflammatory and malignant pleural effusions. Thorax. 1999 Aug;54(8):707-10.
• Wessel MM, Nair N, Aaker GD, Ehrlich JR, D'Amico DJ, Kiss S. Peripheral retinal ischaemia, as evaluated by ultra-widefield fluorescein angiography, is associated with diabetic macular oedema. Br J Ophthalmol. 2012 May;96(5):694-8. doi: 10.1136/bjophthalmol-2011-300774. Epub 2012 Mar 15.

• Responsible Party: Justis Ehlers, Assistant Professor of Ophthalmology, The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT02503540
• Other Study ID Numbers: 15-442
• First Posted: Jul 21, 2015
• Last Update Posted: May 12, 2021
• Last Verified: May 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Justis Ehlers, Assistant Professor of Ophthalmology, The Cleveland Clinic: macular edema; rvo; diabetic macular edema
• Additional relevant MeSH terms: Macular Edema; Retinal Vein Occlusion; Edema; Aflibercept

Study Results

Participant Flow

Recruitment Details	Recruitment occurred from within ophthalmology clinics.
Pre-assignment Detail	Single arm study.

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Period Title: Overall Study
STARTED	31
COMPLETED	28
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Overall Participants	31
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.1 (9.7)
Sex: Female, Male (Count of Participants)
Female	11 35.5%
Male	18 58.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 19.4%
White	23 74.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	29 93.5%
Baseline best corrected visual acuity (ETDRS letters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ETDRS letters]	54.3 (23.3)
Baseline central subfield thickness (μm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [μm]	541.2 (242.3)
Panretinal leakage index (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	3.4 (3.8)
Panretinal ischemic index (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	5.5 (8)
Number of patient with visual acuity of 20/200 or worse (Count of Participants)
Count of Participants [Participants]	6 19.4%

Outcome Measures

1. Primary Outcome

Title	Change in Panretinal Leakage Index at Month 12 From Baseline
Description	Change in panretinal leakage index (defined as the proportion of retinal area involved in angiographic leakage) at month 12 from baseline as measured by ultra-widefield angiography (UWFA).
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Monthly aflibercept for 6 months and then every other month for 6 months.

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Mean (Standard Deviation) [percentage of region of interest in UWFA]	-3.14 (0.03)

2. Secondary Outcome

Title	Mean Change in Total Leakage Index
Description	Mean change in total leakage index from baseline to month 6
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Mean (Standard Deviation) [percentage of region of interest in UWFA]	0.47 (2.0)

3. Secondary Outcome

Title	Change in Panretinal Ischemic Index
Description	Change in panretinal ischemic index from baseline to postoperative month 12
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	28
Mean (Standard Deviation) [percentage of region of interest in UWFA]	3.2 (0.12)

4. Secondary Outcome

Title	Change in Panretinal Ischemic Index From Baseline at 6 Months
Description	Change in panretinal ischemic index (defined as the proportion of retinal area with nonperfusion) from baseline at 6 months
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	28
Mean (Standard Deviation) [percentage of region of interest in UWFA]	0.67 (0.03)

5. Secondary Outcome

Title	Mean Change From Baseline Central Subfield Thickness
Description	OCT central subfield thickness change from baseline to 6 months
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Mean (Standard Deviation) [μm]	278.0 (251.3)

6. Secondary Outcome

Title	Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) Score Based on ETDRS
Description	Mean change from baseline in best-corrected visual acuity (BCVA) score from baseline to month 12
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Mean (Standard Deviation) [ETDRS letters]	18.4 (21.4)

7. Secondary Outcome

Title	Number of Participants Who Gained 15 ETDRS Letters or More of Vision
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Count of Participants [Participants]	13 41.9%

8. Secondary Outcome

Title	Number of Patients Who Gained 15 ETDRS Letters or More of Vision
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Count of Participants [Participants]	12 38.7%

9. Secondary Outcome

Title	Number of Patients That Showed Visual Acuity 20/40 or Better
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Count of Participants [Participants]	20 64.5%

10. Secondary Outcome

Title	Number of Patients That Showed Visual Acuity 20/200 or Worse
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Count of Participants [Participants]	2 6.5%

11. Secondary Outcome

Title	Ocular Serious Adverse Events
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All enrolled subjects

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	31
Count of Participants [Participants]	0 0%

12. Secondary Outcome

Title	Number of Participants Who Lost 15 ETDRS Letters or More of Vision
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Count of Participants [Participants]	1 3.2%

13. Secondary Outcome

Title	Number of Participants Who Lost 15 ETDRS Letters or More of Vision
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Count of Participants [Participants]	0 0%

14. Secondary Outcome

Title	Number of Patients That Showed Visual Acuity 20/40 or Better
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Count of Participants [Participants]	19 61.3%

15. Secondary Outcome

Title	Number of Patients That Showed Visual Acuity 20/200 or Worse
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Count of Participants [Participants]	0 0%

16. Secondary Outcome

Title	Mean Change From Baseline Central Subfield Thickness
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	29
Mean (Standard Deviation) [μm]	301.3 (250.3)

17. Secondary Outcome

Title	Systemic Serious Adverse Events
Description	Incidence of systemic SAEs
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

All subjects enrolled

Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
Measure Participants	31
Count of Participants [Participants]	3 9.7%

Adverse Events

Time Frame	1 year
Arm/Group Title	Aflibercept
Arm/Group Description	Monthly aflibercept for 6 months and then every other month for 6 months. Aflibercept: Intravitreal aflibercept will be given q4 wks for 6 treatments and then q 8 weeks through month 12.
All Cause Mortality
	Aflibercept
	Affected / at Risk (%)	# Events
Total	2/31 (6.5%)
Serious Adverse Events
	Aflibercept
	Affected / at Risk (%)	# Events
Total	3/31 (9.7%)
General disorders
Death	2/31 (6.5%)
Nervous system disorders
Stroke	1/31 (3.2%)
Other (Not Including Serious) Adverse Events
	Aflibercept
	Affected / at Risk (%)	# Events
Total	0/31 (0%)

Limitations/Caveats

[Not Specified]

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.