Efficacy & Safety Trial of Intravitreal Injections Combined With PRP for CSME Secondary to Diabetes Mellitus (DAVE)

Diabetic Macular Edema Clinical Trial

— DAVE  

Official title:

A Phase I/II, Randomized, Study for Diabetic Macular Edema Using 0.3mg Ranibizumab Combined With Targeted PRP Monthly for 4 Months,Then PRN vs. 0.3mg Ranibizumab 4 Months Monotherapy, Then as Needed(DME-AntiVEgf) DAVE

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01552408
• Other study ID #: ML27954
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 2012
• Est. completion date: May 18, 2017

Study information

• Verified date: October 2018
• Source: Greater Houston Retina Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a Phase I/II, multicenter, randomized, study of the efficacy and safety of ranibizumab injection monotherapy verses a duel therapy of 0.3mg ranibizumab combined with ultra wide, 200° field angiography guided pan retinal photocoagulation in patients with CSME-CI secondary to diabetes mellitus (Type 1 or 2).

Description:

Approximately 40 eyes will be randomized at 3 investigational centers in the United States. This study consists of a screening period of up to 14 days (Days -14 to -1), and a 36-month treatment period (Day 0 to Month 36). Subjects who provide consent will enter the screening period to determine eligibility. As part of the screening process, the examining investigator will evaluate the macular foveal avascular zone fluorescein images to determine subjects' eligibility. Eligible subjects will be randomized in a 1:1 ratio so that approximately 20 eyes will receive 0.3 mg ranibizumab monotherapy, and approximately 20 eyes will receive 0.3 mg ranibizumab combined with Ultra wide 200° field angiogram guided targeted pan retinal photocoagulation (PRP). Subjects must meet VA and retinal thickness eligibility requirements during the screening period. The subject can have both eyes in the study. If both eyes are eligible, one eye will be randomized, to cohort 1 while the other eye will be randomized to the cohort 2. A subject with both eyes in the trial will have each eye in a separate cohort.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: May 18, 2017
• Est. primary completion date: May 18, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Willingness to provide signed informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.

• Age = 18 years

• Diabetes Mellitus (Type 1 or 2). The following will be considered as sufficient evidence that diabetes is present:

• Current regular use of insulin for the treatment of diabetes

• Current regular use of oral antihyperglycemic agents for the treatment of diabetes

• Documented diabetes according to the American Diabetes Association and/or World Health Organization criteria.

• BCVA score in the study eye of 20/32 to 20/320 approximate snellen equivalent using the ETDRS protocol at an initial testing distance of 4 meters, confirmed by the investigator.

• High Definition OCT (Spectralis) central retinal thickness measurement of = 300 µm

• Decrease in visual acuity is determined to be primarily the result of DME and not to other cause.

• Ability and willingness to return for all scheduled visits and assessments.

• Clear ocular media and adequate pupillary dilatation to permit good quality fundus photography.

Exclusion Criteria:

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

General Exclusion Criteria

• Pregnancy (positive pregnancy test) or lactation

• Sexually active women of childbearing potential* who are unwilling to practice adequate contraception or abstinence during the study. (*Although no birth control method is 100% effective, the following are considered adequate means of contraception: surgical sterilization, use of oral contraceptives, barrier contraception using either a condom or diaphragm with spermicidal gel, intrauterine devices, or contraceptive hormone implants or patches. A subject's primary care physician, obstetrician, or gynecologist should be consulted regarding an appropriate form of birth control)

• 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] Ocular Exclusion Criteria

• Prior Ocular Treatment:

• History of vitrectomy surgery in the study eye

• Any pan-retinal photocoagulation in the study eye

• Prior treatment with intraocular or subconjunctival steroids in the study eye 4 months prior to screen

• Previous treatment with antiangiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc.) within 2 months of Day 0 visit

• Systemic corticosteroids 4 months prior to screen

Concurrent Ocular Conditions:

• Any concurrent ocular condition in the study eye (e.g., cataract or age-related macular degeneration) that, in the opinion of the investigator could: require medical or surgical intervention during the study period to prevent or treat visual loss that might result from that condition; or, if allowed to progress untreated, could likely contribute to a loss of at least 2 Snellen equivalent lines of BCVA over the study period

• Active intraocular inflammation (grade trace or above) in the study eye

• Current vitreous hemorrhage in the study eye

• History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the study eye

• Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye

• Aphakia or absence of the posterior capsule in the study eye

• Intraocular surgery (including cataract surgery) in the study eye within 2 months preceding Day 0

• Uncontrolled glaucoma in the study eye (defined as IOP = 30 mmHg despite treatment with anti-glaucoma medication)

• History of glaucoma-filtering surgery in the study eye

• History of corneal transplant in the study eye

• High Risk PDR: New vessels within one disc diameter of the optic nerve head that are larger than one-third disc area

• Vitreous or preretinal hemorrhage associated with less extensive NVD or with NVE one-half disc area or more in size

• Extensive damage to the fovea vascular zone as determined by the principal investigator or designated site personnel

• Spherical equivalent of the refractive error in the study eye of more that -8.00 diopter of myopia

• Vitreomacular traction (vitreomacular attachment ok) Concurrent Systemic Conditions

• Uncontrolled blood pressure (defined as systolic > 180 mmHg and/or diastolic > 110 mmHg while patient is seated. *If a subject's initial reading exceeds these values, a second reading may be taken 30 or more minutes later. If the subject's blood pressure needs to be controlled by antihypertensive medication, the subject can become eligible if medication is taken continuously for at least 30 days prior to Day 0

• Atrial fibrillation not managed by subject's primary care physician or cardiologist within 3 months of screening visit

• History of stroke within the last 3 months of screening visit

• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or renders the patient at high risk for treatment complications

• Current treatment for active systemic infection

• Active malignancy

• History of allergy to fluorescein, not amenable to treatment

• Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed and graded.

• Previous participation in any studies of investigational drugs within 1 month preceding Day 0 (excluding vitamins and minerals)

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Edema
• Macular Edema

Intervention

Drug:
• 0.3 mg ranibizumab
Cohort 1: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.

Procedure:
• Targeted Pan Retinal Photocoagulation
Cohort 2: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan retinal photocoagulation (PRP) based on ultra wide 200º field angiography. After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Locations

Country	Name	City	State
United States	Retina Consultants of Houston	Houston	Texas
United States	Retina Consultants of Houston	Katy	Texas
United States	Retina Consultants of Houston	The Woodlands	Texas

Sponsors (2)

Lead Sponsor	Collaborator
David M. Brown, M.D.	Genentech, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (18)

Aiello LP, Edwards AR, Beck RW, Bressler NM, Davis MD, Ferris F, Glassman AR, Ip MS, Miller KM; Diabetic Retinopathy Clinical Research Network. Factors associated with improvement and worsening of visual acuity 2 years after focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2010 May;117(5):946-53. doi: 10.1016/j.ophtha.2009.10.002. Epub 2010 Feb 1. — View Citation

Audren F, Tod M, Massin P, Benosman R, Haouchine B, Erginay A, Caulin C, Gaudric A, Bergmann JF. Pharmacokinetic-pharmacodynamic modeling of the effect of triamcinolone acetonide on central macular thickness in patients with diabetic macular edema. Invest Ophthalmol Vis Sci. 2004 Oct;45(10):3435-41. — View Citation

Cruickshanks KJ, Moss SE, Klein R, Klein BE. Physical activity and the risk of progression of retinopathy or the development of proliferative retinopathy. Ophthalmology. 1995 Aug;102(8):1177-82. — View Citation

Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, Glassman AR, Hartnett E, Ip MS, Kim JE, Kollman C. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009 Mar;127(3):245-51. doi: 10.1001/archophthalmol.2008.610. — View Citation

Diabetic Retinopathy Clinical Research Network, Scott IU, Edwards AR, Beck RW, Bressler NM, Chan CK, Elman MJ, Friedman SM, Greven CM, Maturi RK, Pieramici DJ, Shami M, Singerman LJ, Stockdale CR. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology. 2007 Oct;114(10):1860-7. Epub 2007 Aug 15. — View Citation

Four risk factors for severe visual loss in diabetic retinopathy. The third report from the Diabetic Retinopathy Study. The Diabetic Retinopathy Study Research Group. Arch Ophthalmol. 1979 Apr;97(4):654-5. — View Citation

From the NIH: Study identifies four factors in diabetic retinopathy associated with high risk of severe visual loss. JAMA. 1979 Apr 13;241(15):1581. — View Citation

Jonas JB, Strueven V, Kamppeter BA, Harder B, Spandau UH, Schlichtenbrede F. Visual acuity change after intravitreal triamcinolone in various types of exudative age-related macular degeneration. J Ocul Pharmacol Ther. 2006 Oct;22(5):370-6. — View Citation

Klein M. Prevention and treatment of the complications of diabetes mellitus. N Engl J Med. 1995 Sep 21;333(12):802. — View Citation

Klein R, Meuer SM, Moss SE, Klein BE. Retinal microaneurysm counts and 10-year progression of diabetic retinopathy. Arch Ophthalmol. 1995 Nov;113(11):1386-91. — View Citation

Lüddeke HJ. [Continuing education provided by the Diabetes Society. Results of the UKPDS (United Kingdom Diabetes Society) and therapeutic guidelines concerning diabetes type II]. Fortschr Med. 1998 Nov 30;116(33):35-8. German. — View Citation

Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, Baumal C. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002 May;109(5):920-7. — View Citation

Muggeo M. DCCT and us: how far are we from implementation? Acta Diabetol. 1993;30(3):115-7. — View Citation

Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806. — View Citation

Scott IU, Danis RP, Bressler SB, Bressler NM, Browning DJ, Qin H; Diabetic Retinopathy Clinical Research Network. Effect of focal/grid photocoagulation on visual acuity and retinal thickening in eyes with non-center-involved diabetic macular edema. Retina. 2009 May;29(5):613-7. doi: 10.1097/IAE.0b013e3181a2c07a. — View Citation

Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1987 Jul;94(7):761-74. — View Citation

Watkins P. The UKPDS. A model for gathering the evidence for the management of chronic diseases. UK Prospective Diabetes Study Group. J R Coll Physicians Lond. 1998 Nov-Dec;32(6):510-1. — View Citation

Writing Committee for the Diabetic Retinopathy Clinical Research Network, Fong DS, Strauber SF, Aiello LP, Beck RW, Callanan DG, Danis RP, Davis MD, Feman SS, Ferris F, Friedman SM, Garcia CA, Glassman AR, Han DP, Le D, Kollman C, Lauer AK, Recchia FM, Solomon SD. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007 Apr;125(4):469-80. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total Number of Ranibizumab Injections in Each of the Two Cohorts in a 36 Month Period	Assess the number of ranibizumab injections in the ranibizumab and targeted panretinal photocoagulation (PRP) with ranibizumab cohorts through Month 36.	36 Months
Primary	Mean Change Over Time in Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) Through Month 36	Evaluate the mean change over time in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts through Month 36.	36 Months
Primary	Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36.	Incidence and severity of ocular and non-ocular adverse events (AE's) in the monotherapy and combination cohorts through Month 36.	36 Months
Secondary	Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA.	Percentage of patients in the ranibizumab and targeted PRP with ranibizumab cohorts who experience a loss of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA.	Month 12, 24, and 36
Secondary	Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA	Determine percentage of patients who experience a gain of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts.	Month 12, 24, and 36
Secondary	Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's.	Evaluate mean change in central retinal thickness in the ranibizumab and targeted PRP with ranibizumab cohorts over time through Month 12, 24, and 36 as assessed by high resolution OCT's.	Month 12, 24, and 36
Secondary	Patients With Persistent Macular Edema Post-intravitreal Injection.	Percentage of patients with persistent macular edema post-intravitreal injection in the ranibizumab and targeted PRP with ranibizumab cohorts.	Month 36
Secondary	Mean Change in Peripheral Visual Field as Measured by Goldmann Visual Field at Screen and Month and 36.	Mean change in peripheral visual field as measured by Goldmann visual field at screen and Month 36 in the ranibizumab and targeted PRP with ranibizumab cohorts.	36 Months