Combination OZURDEX® & EyLea® vs. OZURDEX® Monotherapy in IncompLete-Responders wIth Diabetic Macular Edema

NCT03629210 | Withdrawn Phase 2 DMC

• 1 other identifier: COLLIDE2018-05
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

COLLIDE is a multi-center, open-label, 1:1 randomized study looking at the effects of aflibercept (AFL; 2.0mg) plus OZURDEX (DEX; 0.7mg) implant combination therapy versus DEX monotherapy in phakic or pseudophakic eyes with center-involved DME that have demonstrated prior incomplete response to 3-6 anti-VEGF treatment in 3-9 months. The primary outcome will be 24 week central subfield thickness. Secondary outcomes include the change in ETDRS BCVA letters, number of re-injections and re-injection interval, proportion of eyes with 15- and 10- ETDRS letter gained/lost, proportion of eyes with PDR as per Optos color and FA at the study completion (24+/- 2 weeks) and OCT and OCT angiography biomarkers.

Conditions

Diabetic Macular Edema

Outcome Measures

Primary Outcomes (1)

• Central Subfield Thickness

  Foveal central subfield (FCS) thickness is defined as the average thickness in the central 1mm diameter circle of the ETDRS grid.

  At 24 Weeks

Secondary Outcomes (5)

• ETDRS BCVA letters

  From Baseline to 24 Weeks

• Number of re-injections

  At 24 Weeks

• Proportion of eyes with 15- and 10-ETDRS letters gained/lost at study completion

  24 Weeks

• Proportion of study eyes with PDR as per Optos color and FA at the study completion

  24 Weeks

• Ocular Coherence Tomography

  24 Weeks

Study Arms (2)

Combination Treatment

EXPERIMENTAL

Combination treatment: Participants will receive intravitreal Eylea (AFL, 2.0 mg) injection and OZURDEX implant (0.7 mg) injection within 0 to 8 days of each other.

Drug: OZURDEX; Biological: Eylea

Monotherapy

ACTIVE COMPARATOR

Monotherapy treatment: Participants will receive OZURDEX implant (0.7 mg) injection.

Drug: OZURDEX

Interventions

OZURDEX DRUG

OZURDEX® (DEX implant, 0.7 mg) is a micro-ionized and non-preserved dexamethasone within a cylindrically-shaped 0.45 mm diameter x 6.5 mm length biodegradable Poly D, L-lactate-co-glycolic acid pellet allowing for sustained delivery dexamethasone into the vitreous cavity and retina following intravitreal injection. Health Canada has granted approval for use of DEX implant in the treatment of ME following central retinal vein occlusion, non-infectious uveitis affecting the posterior segment and pseudophakic DME in adult patients. (OZURDEX® Canadian Product Monograph, April 14, 2015). DEX implant will be provided as investigational treatment by Allergan Inc., Markham, ON, Canada.

Also known as: DEX, dexamethasone

Combination Treatment; Monotherapy

Eylea BIOLOGICAL

EYLEA® (AFL 2.0 mg intravitreal injections) is an anti-VEGF treatment. AFL (2.0 mg) has received approval from Health Canada for the treatment of DME. Health Canada has also granted approval for AFL (2.0 mg) in the treatment of age-related macular degeneration, and ME secondary to retinal vein occlusion.

Combination Treatment

Eligibility Criteria

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

You may qualify if:

• Type 1 or 2 diabetic adult (≥18 years) patients
• Known glycosylated haemoglobin (HbA1c) levels ≤ 11%
• Screening Snellen Va / Baseline ETDRS BCVA between 20/20 - 20/320
• Lens status: Phakic without significant cataract; \<1+ nuclear sclerosis and \<1+ posterior subcapsular or pseudophakic with intact posterior lens capsule and / or Nd:YAG laser capsulotomy that in the investigator's opinion is not likely to permit dislocation of DEX implant into the anterior chamber
• Center-involved DME \> 250 µm
• Duration of DME ≤ 2 years
• Eyes with intraocular pressure (IOP) ≤ 21 with or without treatment with \< 2 topical IOP-lowering medications
• Eyes with history of previous angle closure that have been successfully treated with either laser or surgical intervention are allowed as long as the visual fields and optic nerves have been stable for \> 1 year prior to study entry
• Demonstrated incomplete response to 3-6 prior intravitreal anti-VEGFs (AVASTIN®, LUCENTIS®, or EYLEA®; administered every 4 ± 2 weeks over 12-36 weeks (or 3-9 months)); incomplete response is defined herein as a treatment effect resulting in:
• \< 25% reduction in central subfield thickness (CST) by SD-OCT during two recent visits OR
• \< 10-letter (2 lines) increase in visual acuity compared to the baseline first anti-VEGF injection
• If both eyes qualify, investigators can enrol the eye that has developed DME most recently.
• Written informed patient consent

You may not qualify if:

• Prior panretinal or macular laser treatments
• Any Intravitreal injection prior to run-in phase
• Previous vitrectomy
• Any ocular condition that in the opinion of the investigator would not permit improvement of visual acuity with resolution of ME (e.g., epiretinal membrane, foveal atrophy, known macular ischemia, pigment abnormalities, dense subfoveal hard exudates and/or poor foveal architecture suggestive of photoreceptor loss)
• Patients with retinal diseases, other than diabetes that can affect ME
• HbA1c levels \> 11%
• Patient has suffered from a stroke in the last 3 months
• Eyes with a history of advanced glaucoma (optic nerve head change consistent with glaucoma damage and / or glaucomatous visual field loss), uncontrolled ocular hypertension (baseline IOP \> 21 mmHg despite use of ≥ 2 topical IOP-lowering medication)
• Eyes with a history of steroid response (i.e., increase of ≥ 5 mmHg IOP following topical steroid treatment)
• Patients with ACIOL (Anterior Chamber Intraocular Lens) or rupture of the posterior lens capsule that in the investigator's opinion is likely to permit dislocation of DEX implant into the anterior chamber
• Female patients who are pregnant or breast feeding: all women of child bearing potential (i.e. women who are not surgically sterile or who have had one or more menstrual cycle in the previous 12 months) must have a negative pregnancy test prior to randomization, and must agree to use appropriate measures to avoid pregnancy during the trial period.
• Patients who are unable to attend scheduled follow-up visits throughout the 24-week study
• Use of systemic steroid, systemic anti-VEGF or pro-VEGF treatment within 4 months prior to enrolment or anticipated use during the study (these drugs are prohibited from use during the study)
• Patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases.
• Patients with known hypersensitivity to any components of anti-VEGF or DEX implant

Sponsors & Collaborators

• Pradeepa Yoganathan: lead
• Unity Health Toronto: collaborator

Related Publications (29)

• Antcliff RJ, Marshall J. The pathogenesis of edema in diabetic maculopathy. Semin Ophthalmol. 1999 Dec;14(4):223-32. doi: 10.3109/08820539909069541.

  PMID: 10758223 BACKGROUND

• Antonetti DA, Wolpert EB, DeMaio L, Harhaj NS, Scaduto RC Jr. Hydrocortisone decreases retinal endothelial cell water and solute flux coincident with increased content and decreased phosphorylation of occludin. J Neurochem. 2002 Feb;80(4):667-77. doi: 10.1046/j.0022-3042.2001.00740.x.

  PMID: 11841574 BACKGROUND

• Boyer DS, Faber D, Gupta S, Patel SS, Tabandeh H, Li XY, Liu CC, Lou J, Whitcup SM; Ozurdex CHAMPLAIN Study Group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. 2011 May;31(5):915-23. doi: 10.1097/IAE.0b013e318206d18c.

  PMID: 21487341 BACKGROUND

• Boyer DS, Yoon YH, Belfort R Jr, Bandello F, Maturi RK, Augustin AJ, Li XY, Cui H, Hashad Y, Whitcup SM; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014 Oct;121(10):1904-14. doi: 10.1016/j.ophtha.2014.04.024. Epub 2014 Jun 4.

  PMID: 24907062 BACKGROUND

• Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, Schlottmann PG, Rundle AC, Zhang J, Rubio RG, Adamis AP, Ehrlich JS, Hopkins JJ; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013 Oct;120(10):2013-22. doi: 10.1016/j.ophtha.2013.02.034. Epub 2013 May 22.

  PMID: 23706949 BACKGROUND

• Chang-Lin JE, Attar M, Acheampong AA, Robinson MR, Whitcup SM, Kuppermann BD, Welty D. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci. 2011 Jan 5;52(1):80-6. doi: 10.1167/iovs.10-5285.

  PMID: 20702826 BACKGROUND

• Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet. 2010 Jul 10;376(9735):124-36. doi: 10.1016/S0140-6736(09)62124-3. Epub 2010 Jun 26.

  PMID: 20580421 BACKGROUND

• Diabetic Retinopathy Clinical Research Network; Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL 3rd, Friedman SM, Glassman AR, Miller KM, Scott IU, Stockdale CR, Sun JK. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 Jun;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031. Epub 2010 Apr 28.

  PMID: 20427088 BACKGROUND

• Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology. 2009 Jan;116(1):73-9. doi: 10.1016/j.ophtha.2008.09.037.

  PMID: 19118698 BACKGROUND

• Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology. 2006 Sep;113(9):1533-8. doi: 10.1016/j.ophtha.2006.02.065. Epub 2006 Jul 7.

  PMID: 16828501 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.

  PMID: 3658348 BACKGROUND

• Haller JA, Bandello F, Belfort R Jr, Blumenkranz MS, Gillies M, Heier J, Loewenstein A, Yoon YH, Jacques ML, Jiao J, Li XY, Whitcup SM; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010 Jun;117(6):1134-1146.e3. doi: 10.1016/j.ophtha.2010.03.032. Epub 2010 Apr 24.

  PMID: 20417567 BACKGROUND

• Hooper P, Boucher MC, Colleaux K, Cruess A, Greve M, Lam WC, Shortt S, Tourville E. Contemporary management of diabetic retinopathy in Canada: from guidelines to algorithm guidance. Ophthalmologica. 2014;231(1):2-15. doi: 10.1159/000354548. Epub 2013 Nov 12.

  PMID: 24246998 BACKGROUND

• Kiddee W, Trope GE, Sheng L, Beltran-Agullo L, Smith M, Strungaru MH, Baath J, Buys YM. Intraocular pressure monitoring post intravitreal steroids: a systematic review. Surv Ophthalmol. 2013 Jul-Aug;58(4):291-310. doi: 10.1016/j.survophthal.2012.08.003.

  PMID: 23768920 BACKGROUND

• Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS, Midena E, Kaiser PK, Terasaki H, Marcus DM, Nguyen QD, Jaffe GJ, Slakter JS, Simader C, Soo Y, Schmelter T, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Zeitz O, Metzig C, Brown DM. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014 Nov;121(11):2247-54. doi: 10.1016/j.ophtha.2014.05.006. Epub 2014 Jul 8.

  PMID: 25012934 BACKGROUND

• Lazic R, Lukic M, Boras I, Draca N, Vlasic M, Gabric N, Tomic Z. Treatment of anti-vascular endothelial growth factor-resistant diabetic macular edema with dexamethasone intravitreal implant. Retina. 2014 Apr;34(4):719-24. doi: 10.1097/IAE.0b013e3182a48958.

  PMID: 23975006 BACKGROUND

• Massin P, Bandello F, Garweg JG, Hansen LL, Harding SP, Larsen M, Mitchell P, Sharp D, Wolf-Schnurrbusch UE, Gekkieva M, Weichselberger A, Wolf S. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010 Nov;33(11):2399-405. doi: 10.2337/dc10-0493.

  PMID: 20980427 BACKGROUND

• Maturi RK, Glassman AR, Liu D, Beck RW, Bhavsar AR, Bressler NM, Jampol LM, Melia M, Punjabi OS, Salehi-Had H, Sun JK; Diabetic Retinopathy Clinical Research Network. Effect of Adding Dexamethasone to Continued Ranibizumab Treatment in Patients With Persistent Diabetic Macular Edema: A DRCR Network Phase 2 Randomized Clinical Trial. JAMA Ophthalmol. 2018 Jan 1;136(1):29-38. doi: 10.1001/jamaophthalmol.2017.4914.

  PMID: 29127949 BACKGROUND

• Medeiros MD, Alkabes M, Navarro R, Garcia-Arumi J, Mateo C, Corcostegui B. Dexamethasone intravitreal implant in vitrectomized versus nonvitrectomized eyes for treatment of patients with persistent diabetic macular edema. J Ocul Pharmacol Ther. 2014 Nov;30(9):709-16. doi: 10.1089/jop.2014.0010. Epub 2014 Sep 26.

  PMID: 25259834 BACKGROUND

• Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, Sutter F, Simader C, Burian G, Gerstner O, Weichselberger A; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):615-25. doi: 10.1016/j.ophtha.2011.01.031.

  PMID: 21459215 BACKGROUND

• Miyamoto K, Khosrof S, Bursell SE, Rohan R, Murata T, Clermont AC, Aiello LP, Ogura Y, Adamis AP. Prevention of leukostasis and vascular leakage in streptozotocin-induced diabetic retinopathy via intercellular adhesion molecule-1 inhibition. Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10836-41. doi: 10.1073/pnas.96.19.10836.

  PMID: 10485912 BACKGROUND

• Nepomuceno AB, Takaki E, Paes de Almeida FP, Peroni R, Cardillo JA, Siqueira RC, Scott IU, Messias A, Jorge R. A prospective randomized trial of intravitreal bevacizumab versus ranibizumab for the management of diabetic macular edema. Am J Ophthalmol. 2013 Sep;156(3):502-510.e2. doi: 10.1016/j.ajo.2013.04.026. Epub 2013 Jun 21.

  PMID: 23795985 BACKGROUND

• Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Apr;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039. Epub 2012 Feb 11.

  PMID: 22330964 BACKGROUND

• Pacella E, Vestri AR, Muscella R, Carbotti MR, Castellucci M, Coi L, Turchetti P, Pacella F. Preliminary results of an intravitreal dexamethasone implant (Ozurdex(R)) in patients with persistent diabetic macular edema. Clin Ophthalmol. 2013;7:1423-8. doi: 10.2147/OPTH.S48364. Epub 2013 Jul 16.

  PMID: 23901252 BACKGROUND

• Maturi RK. (2013). Combined steroids, anti-VEGFs show promise in DME. Ophthalmology Times.

  BACKGROUND

• Maturi RK. (2014). Ozurdex as adjunct to avastin compared to avastin alone in treatment of patients with diabetic macular edema. ClinicalTrials.gov Identifier: NCT01309451 (http://clinicaltrials.gov/ct2/show/record/NCT01309451)

  BACKGROUND

• Tamura H, Miyamoto K, Kiryu J, Miyahara S, Katsuta H, Hirose F, Musashi K, Yoshimura N. Intravitreal injection of corticosteroid attenuates leukostasis and vascular leakage in experimental diabetic retina. Invest Ophthalmol Vis Sci. 2005 Apr;46(4):1440-4. doi: 10.1167/iovs.04-0905.

  PMID: 15790913 BACKGROUND

• Wang K, Wang Y, Gao L, Li X, Li M, Guo J. Dexamethasone inhibits leukocyte accumulation and vascular permeability in retina of streptozotocin-induced diabetic rats via reducing vascular endothelial growth factor and intercellular adhesion molecule-1 expression. Biol Pharm Bull. 2008 Aug;31(8):1541-6. doi: 10.1248/bpb.31.1541.

  PMID: 18670086 BACKGROUND

• Diabetic Retinopathy Clinical Research Network; Wells JA, Glassman AR, Ayala AR, Jampol LM, Aiello LP, Antoszyk AN, Arnold-Bush B, Baker CW, Bressler NM, Browning DJ, Elman MJ, Ferris FL, Friedman SM, Melia M, Pieramici DJ, Sun JK, Beck RW. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015 Mar 26;372(13):1193-203. doi: 10.1056/NEJMoa1414264. Epub 2015 Feb 18.

  PMID: 25692915 BACKGROUND

MeSH Terms

Interventions

Calcium Dobesilate; Dexamethasone; aflibercept

Intervention Hierarchy (Ancestors)

Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Pradeepa Yoganathan, MD, FRCP(C)

  North Toronto Eye Care

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Ophthalmologist

Model Details: Eligible participants will be randomized in a 1:1 manner to one of the following groups: * Combination treatment (Group A): 50 participants will receive an intravitreal AFL (2.0 mg) injection and DEX implant (0.7 mg) injection within 0 to 8 days of each other. * Monotherapy treatment (Group B): 50 participants will receive DEX implant (0.7 mg) injection.

Study Record Dates

• First Submitted: August 9, 2018
• First Posted: August 14, 2018
• Study Start: September 1, 2019
• Primary Completion: February 1, 2021
• Study Completion: May 1, 2021
• Last Updated: November 13, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share