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

NCT01552408 | Completed Phase 1 Results

• 1 other identifier: ML27954
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 3

Brief 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).

Conditions

Diabetic Macular Edema

Keywords

Non Proliferative Diabetic Retinopathy; Diabetic Retinopathy; Macular Edema; Background Diabetic Retinopathy; Pre Proliferative Diabetic Retinopathy

Outcome Measures

Primary Outcomes (3)

• 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

• 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

• 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 Outcomes (5)

• Patients 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

• Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA

  Month 12, 24, and 36

• Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's.

  Month 12, 24, and 36

• Patients With Persistent Macular Edema Post-intravitreal Injection.

  Month 36

• Mean Change in Peripheral Visual Field as Measured by Goldmann Visual Field at Screen and Month and 36.

  36 Months

Study Arms (2)

0.3 mg Ranibizumab

ACTIVE COMPARATOR

Cohort 1: Subjects will receive 4 IVT of 0.3 mg ranibizumab every 28 days (+/- 7 days), then will be seen monthly (+/- 7 days) \& will receive IVT of 0.3 mg ranibizumab on a pro re nata (PRN) schedule per retreatment criteria.

Drug: 0.3 mg ranibizumab

Targeted PRP with 0.3 mg Ranibizumab

EXPERIMENTAL

Cohort 2: Subjects will receive 4 it of 0.3 mg ranibizumab every 28 days (+/- 7 days), then will then be seen monthly (+/- 7 days) \& receive IVT 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 Day 7 they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide field angiography. Ultra wide field angiography will be performed every 3 months to indicate areas of peripheral ischemia, which will be selectively be treated with PRP at Month 6, Month 18, and Month 25, preserving areas of more perfused retina.

Drug: 0.3 mg ranibizumab; Procedure: Targeted Pan Retinal Photocoagulation

Interventions

0.3 mg ranibizumab DRUG

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.

Also known as: Lucentis

0.3 mg Ranibizumab; Targeted PRP with 0.3 mg Ranibizumab

Targeted Pan Retinal Photocoagulation PROCEDURE

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.

Also known as: PRP, Laser Photocoagulation, Pan Retinal Photocoagulation

Targeted PRP with 0.3 mg Ranibizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• David M. Brown, M.D.: lead
• Genentech, Inc.: collaborator

Study Sites (3)

Retina Consultants of Houston

Houston, Texas, 77030, United States

Location

Retina Consultants of Houston

Katy, Texas, 77494, United States

Location

Retina Consultants of Houston

The Woodlands, Texas, 77384, United States

Location

Related Publications (18)

• 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. doi: 10.1001/archopht.1995.01100110046024.

  PMID: 7487599 BACKGROUND

• Klein M. Prevention and treatment of the complications of diabetes mellitus. N Engl J Med. 1995 Sep 21;333(12):802. doi: 10.1056/NEJM199509213331215. No abstract available.

  PMID: 7643896 BACKGROUND

• 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. doi: 10.1016/s0161-6420(95)30893-7.

  PMID: 9097744 BACKGROUND

• 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. doi: 10.1016/j.ophtha.2007.05.062. Epub 2007 Aug 15.

  PMID: 17698196 BACKGROUND

• 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. doi: 10.1001/archopht.125.4.469.

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• 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. No abstract available.

  PMID: 581885 BACKGROUND

• 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. doi: 10.1001/archopht.1979.01020010310003.

  PMID: 426679 BACKGROUND

• 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.

  PMID: 2866759 BACKGROUND

• 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. doi: 10.1016/s0161-6420(87)33527-4.

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• Muggeo M. DCCT and us: how far are we from implementation? Acta Diabetol. 1993;30(3):115-7. doi: 10.1007/BF00572852. No abstract available.

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• Luddeke 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. No abstract available. German.

  PMID: 9889462 BACKGROUND

• 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. No abstract available.

  PMID: 9881303 BACKGROUND

• 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.

  PMID: 19273785 BACKGROUND

• 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.

  PMID: 19373126 BACKGROUND

• 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. doi: 10.1089/jop.2006.22.370.

  PMID: 17076632 BACKGROUND

• 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. doi: 10.1016/s0161-6420(02)00975-2.

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• 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. doi: 10.1167/iovs.03-1110.

  PMID: 15452046 BACKGROUND

• 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.

  PMID: 20122739 BACKGROUND

MeSH Terms

Conditions

Diabetic Retinopathy; Macular Edema

Interventions

Ranibizumab

Condition Hierarchy (Ancestors)

Retinal Diseases; Eye Diseases; Diabetic Angiopathies; Vascular Diseases; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Endocrine System Diseases; Macular Degeneration; Retinal Degeneration

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The key limitation is the small population size analyzed through 3 years; subject attrition due to elderly population.

Results Point of Contact

• Title: David M. Brown, MD
• Organization: Retina Consultants of Houston

dmbmd@houstonretina.com

713-524-3434

Study Officials

• David M Brown, MD

  Director Greater Houston Research

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Director Greater Houston Retina Research

Study Record Dates

• First Submitted: February 28, 2012
• First Posted: March 13, 2012
• Study Start: March 1, 2012
• Primary Completion: May 18, 2017
• Study Completion: May 18, 2017
• Last Updated: October 5, 2018
• Results First Posted: September 14, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)