Combined Ranibizumab and Iluvien for Diabetic Macular Oedema

Diabetes Clinical Trial

— CASSIE  

Official title:

Combined Anti-VEGF Intravitreal Injections With Sustained Steroid Implantation for the Treatment of Diabetic Macular Oedema

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03784443
• Other study ID #: P78912
• Status: Withdrawn
• Phase: Phase 2/Phase 3
• Start date: September 1, 2019
• Est. completion date: September 1, 2023

Study information

• Verified date: September 2023
• Source: Imperial College London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial investigated whether adding Iluvien sustained release steroid intravitreal eye implant at the beginning of regular anti-VEGF (anti Vascular Endothelial Growth Factor) intravitreal eye injection treatment for diabetic macular oedema would improve disease stability and reduce the need for regular anti-VEGF intravitreal eye injections over first two years. Diabetic macular oedema, accumulation of microscopic fluid at the back of the eye, is a major cause of poor vision in patients with diabetes.

This is a double mask randomized control multisite trial, to be conducted at 10 NHS hospital eye clinics in England.

Description:

This study will recruit 58 participants in a double-masked, multi-centre, sham-controlled clinical trial. Participants will receive Iluvien implantation or sham implantation (masked) with a concomitant intravitreal injection of ranibizumab at baseline with an allocation ratio of 1:1. This is followed by regular monthly clinic review and repeat intravitreal ranibizumab injections to the study eye according to a PRN (pro re nata) treatment protocol.

This trial aims to evaluate whether Iluvien implantation in addition to standard anti-VEGF injection treatment for diabetic macular oedema in pseudophakic eyes will show similar visual acuity outcomes but with an improved reduction in CRT (Central Retinal Thickness) while reducing the average number of intravitreal injections during the first 2 years of treatment, due to the continual micro-dosing of Iluvien therapy.

Participants meeting all the eligibility criteria will be randomized to either Iluvien implant or sham implant procedure with an allocation ratio of 1:1. Participants assigned to either treatment arms will receive intravitreal injection of ranibizumab after Iluvien implantation or sham implantation at the same baseline visit.

To maintain double-masking, participants assigned to the control arm will receive sham implantation. This will be performed with an empty Luer Lock Syringe without a needle attached to it, that will not penetrate the eye nor deliver any drug. Patients assigned to either treatment arm will receive ranibizumab intravitreal injection to the study eye at baseline 30 minutes after the Iluvien or sham implantation. The sham injection should be performed by the unmasked investigator. The unmasked investigator should not be involved in any patient assessment in the study.

Participants will be followed up monthly for 2 years. Participants from both arms will receive compulsory Ranibizumab injection during the first three monthly visit and followed by monthly Ranibizumab as per PRN protocol. The end of study visit should take place at 104 weeks from the baseline visit.

Visual acuity measurement should be performed by trial certified optometrist according to the standard ETDRS (Early Treatment of Diabetic Retinopathy Study) protocol. This is to be conducted in certified examination rooms.

Spectral domain OCT (Optical Coherence Tomography) should be used to assess diabetic macular oedema and optic disc morphology at each visit. The OCT viewer software should be able to provide objective retinal thickness measurement of the central 1mm subfield thickness. Technicians should check for segmentation errors with every OCT scan and make appropriate manual adjustments.

OCT machines and designated technicians at each site will be certified prior to study commencement. Patients must always be assessed using the same OCT model.

7-View Fundus Photography and Fluorescein Angiography (FA) will be performed at the screening visit to confirm the diagnosis of diabetic macular oedema and assess diabetic retinopathy.

Additional FAs may be undertaken during subsequent visits should the investigator believe that there is a clinical need for it. Investigators at each local site are responsible for FA and OCT image interpretation. There will be no centralized image reading centre involved in this study.

IOP (Intraocular Pressure) measurement should be performed with Goldman tonometry either with undilated or dilated pupils.

The primary outcome analysis will be performed to test the differences in the average number of intravitreal injections between the two treatment arms up to month 24. This will be carried out according to an intent to treat principle.

The change of visual acuity from baseline to month 24 will be tested for non-inferiority against the control arm. We will analyze the stability of visual acuity and CRT using AUC (Area Under Curve) Analysis and estimate the average cost of resources utilization for both treatment arms.

Methods of dealing with missing data will follow established techniques, using multiple imputation to impute missing data. If necessary sensitivity analyses will be undertaken to examine the dependence of the results on the method of imputation.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: September 1, 2023
• Est. primary completion date: September 1, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

General

1. Willingness and the ability to provide informed consent.

2. Ability and willingness to undertake all scheduled visits, assessment and treatment.

3. Age 18 years or above.

4. Documented diagnosis of diabetes mellitus (Type I or Type II) as per WHO (World Health Organization) criteria.

5. Current regular use of oral anti-hyperglycaemia or insulin therapy.

6. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per year during the study duration of 24 months.

Ocular

1. Macular thickening due to Diabetic Macular Oedema (DMO) involving the centre of fovea as measured by Spectral Domain OCT with CRT of at least 400 microns.

2. DMO confirmed by clinical examination and fundus fluorescein angiography.

3. BCVA between 73 to 25 letters inclusive (Snellen equivalent to 6/12 to 6/96) as measured using ETDRS protocol at 4 meters.

4. Pseudophakia in the study eye.

5. Adequate ocular media clarity and pupillary dilatation allowing for posterior segment examination and OCT scanning.

Exclusion Criteria:

General

1. Cerebral vascular accident, transient ischaemic attack or myocardial infarction within 3 months prior to day 1 (baseline).

2. Pregnancy or breastfeeding, or intention to become pregnant during the study.

3. Participation in an investigational trial involving treatment with any drug or devices within 3 months prior to day 1 (baseline) and must not be enrolled in another investigational trial during their participation in this trial.

4. Systemic anti-VEGF-base therapies within 3 months prior to day 1 (baseline).

Ocular

1. History of prior intravitreal anti-VEGF therapy or steroid implant in the study eye.

2. History of proliferative diabetic retinopathy.

3. History of rubeosis or current rubeosis.

4. History of neovascularization, tractional retinal detachment, retinal vein occlusion, or significant pre-retinal fibrosis distorting the macular architecture.

5. History of retinal detachment or macular hole stage 3 or above.

6. History of vitreoretinal surgery.

7. Aphakia.

8. History of glaucoma or uncontrolled ocular hypertension.

9. Active or suspected ocular or periocular infection or inflammation, including viral diseases of the cornea, conjunctiva and retina, such as active epithelial herpes simplex keratitis (dendritic keratitis), varicella, mycobacterial infections, and fungal diseases.

10. Panretinal Photocoagulation (PRP) laser treatment within 3 months prior to day 1.

11. Macular laser (focal or grid) within 3 months prior to day 1.

12. YAG (yttrium aluminium garnet) laser capsulotomy laser within 3 months prior to day 1.

13. Any periocular steroid treatment within 6 months prior to day 1.

14. Cataract operation within 3 months prior to day 1.

Related Conditions & MeSH terms

• Diabetes
• Diabetic Macular Edema
• Edema
• Macular Edema

Intervention

Drug:
• Iluvien 0.19 MG Drug Implant
Fluocinolone Acetonide Sustained Release Intravitreal Implant at Baseline Visit
• Ranibizumab Injection [Lucentis]
Monthly PRN intravitreal injections

Procedure:
• Sham Intravitreal Injection
Sham injection without penetrating needle and without drug delivery at baseline visit.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Imperial College London

References & Publications (21)

Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J Med. 2005 Aug 25;353(8):839-41. doi: 10.1056/NEJMe058142. No abstract available. — View Citation

Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med. 2012 Mar 29;366(13):1227-39. doi: 10.1056/NEJMra1005073. No abstract available. — View Citation

Arevalo JF, Lasave AF, Wu L, Acon D, Farah ME, Gallego-Pinazo R, Alezzandrini AA, Fortuna V, Quiroz-Mercado H, Salcedo-Villanueva G, Maia M, Serrano M, Rojas S; Pan-American Collaborative Retina Study Group (PACORES). Intravitreal bevacizumab for diabetic macular oedema: 5-year results of the Pan-American Collaborative Retina Study group. Br J Ophthalmol. 2016 Dec;100(12):1605-1610. doi: 10.1136/bjophthalmol-2015-307950. Epub 2016 Feb 24. — View Citation

Bunce C, Wormald R. Causes of blind certifications in England and Wales: April 1999-March 2000. Eye (Lond). 2008 Jul;22(7):905-11. doi: 10.1038/sj.eye.6702767. Epub 2007 Mar 2. — View Citation

Campochiaro PA, Brown DM, Pearson A, Chen S, Boyer D, Ruiz-Moreno J, Garretson B, Gupta A, Hariprasad SM, Bailey C, Reichel E, Soubrane G, Kapik B, Billman K, Kane FE, Green K; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012 Oct;119(10):2125-32. doi: 10.1016/j.ophtha.2012.04.030. Epub 2012 Jun 21. — View Citation

Cunha-Vaz J, Ashton P, Iezzi R, Campochiaro P, Dugel PU, Holz FG, Weber M, Danis RP, Kuppermann BD, Bailey C, Billman K, Kapik B, Kane F, Green K; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous implants: long-term benefit in patients with chronic diabetic macular edema. Ophthalmology. 2014 Oct;121(10):1892-903. doi: 10.1016/j.ophtha.2014.04.019. Epub 2014 Jun 14. — View Citation

Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology. 2003 Sep;110(9):1690-6. doi: 10.1016/S0161-6420(03)00568-2. — View Citation

Funatsu H, Yamashita H, Sakata K, Noma H, Mimura T, Suzuki M, Eguchi S, Hori S. Vitreous levels of vascular endothelial growth factor and intercellular adhesion molecule 1 are related to diabetic macular edema. Ophthalmology. 2005 May;112(5):806-16. doi: 10.1016/j.ophtha.2004.11.045. — View Citation

Goni FJ, Stalmans I, Denis P, Nordmann JP, Taylor S, Diestelhorst M, Figueiredo AR, Garway-Heath DF. Elevated Intraocular Pressure After Intravitreal Steroid Injection in Diabetic Macular Edema: Monitoring and Management. Ophthalmol Ther. 2016 Jun;5(1):47-61. doi: 10.1007/s40123-016-0052-8. Epub 2016 May 10. — View Citation

Grover D, Li TJ, Chong CC. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD005656. doi: 10.1002/14651858.CD005656.pub2. — View Citation

Hernandez-Bel L, Cervera-Taulet E, Navarro-Palop C, Castro-Navarro V, Chiarri-Toumit C, Montero-Hernandez J. Sequential Dexamethasone and Aflibercept Treatment in Patients with Diabetic Macular Edema: Structural and Functional Outcomes at 52 Weeks. Ophthalmologica. 2019;241(2):98-104. doi: 10.1159/000489345. Epub 2018 Jul 11. — View Citation

Mehta H, Gillies M, Fraser-Bell S. Perspective on the role of Ozurdex (dexamethasone intravitreal implant) in the management of diabetic macular oedema. Ther Adv Chronic Dis. 2015 Sep;6(5):234-45. doi: 10.1177/2040622315590319. — View Citation

Minassian DC, Owens DR, Reidy A. Prevalence of diabetic macular oedema and related health and social care resource use in England. Br J Ophthalmol. 2012 Mar;96(3):345-9. doi: 10.1136/bjo.2011.204040. Epub 2011 May 20. — View Citation

Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology. 1998 Jun;105(6):998-1003. doi: 10.1016/S0161-6420(98)96025-0. — View Citation

Parrish RK 2nd, Campochiaro PA, Pearson PA, Green K, Traverso CE; FAME Study Group. Characterization of Intraocular Pressure Increases and Management Strategies Following Treatment With Fluocinolone Acetonide Intravitreal Implants in the FAME Trials. Ophthalmic Surg Lasers Imaging Retina. 2016 May 1;47(5):426-35. doi: 10.3928/23258160-20160419-05. — View Citation

Prunte C, Fajnkuchen F, Mahmood S, Ricci F, Hatz K, Studnicka J, Bezlyak V, Parikh S, Stubbings WJ, Wenzel A, Figueira J; RETAIN Study Group. Ranibizumab 0.5 mg treat-and-extend regimen for diabetic macular oedema: the RETAIN study. Br J Ophthalmol. 2016 Jun;100(6):787-95. doi: 10.1136/bjophthalmol-2015-307249. Epub 2015 Oct 9. — View Citation

Shimura M, Yasuda K, Minezaki T, Noma H. Reduction in the frequency of intravitreal bevacizumab administrations achieved by posterior subtenon injection of triamcinolone acetonide in patients with diffuse diabetic macular edema. Jpn J Ophthalmol. 2016 Sep;60(5):401-7. doi: 10.1007/s10384-016-0458-9. Epub 2016 Jun 15. — View Citation

Virgili G, Parravano M, Menchini F, Evans JR. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev. 2014 Oct 24;(10):CD007419. doi: 10.1002/14651858.CD007419.pub4. — View Citation

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. — View Citation

Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, Brucker AJ, Ferris FL, Hampton GR, Jhaveri C, Melia M, Beck RW; Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016 Jun;123(6):1351-9. doi: 10.1016/j.ophtha.2016.02.022. Epub 2016 Feb 27. — View Citation

Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, Chen SJ, Dekker JM, Fletcher A, Grauslund J, Haffner S, Hamman RF, Ikram MK, Kayama T, Klein BE, Klein R, Krishnaiah S, Mayurasakorn K, O'Hare JP, Orchard TJ, Porta M, Rema M, Roy MS, Sharma T, Shaw J, Taylor H, Tielsch JM, Varma R, Wang JJ, Wang N, West S, Xu L, Yasuda M, Zhang X, Mitchell P, Wong TY; Meta-Analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012 Mar;35(3):556-64. doi: 10.2337/dc11-1909. Epub 2012 Feb 1. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Lucentis Injections received in the study eye	The total number of Lucentis injections needed over 24 months following the intravitreal injection PRN protocol	24 months
Secondary	Change in visual acuity	Change in ETDRS (Early Treatment of Diabetic Retinopathy Study) best corrected visual acuity from baseline to month 24	Month 24
Secondary	Maintaining at least 20/40 vision	Percentage of patients that achieve or maintain 20/40 vision	Month 24
Secondary	Proportion of participants with vision loss	Proportion of participants losing 5, 10, 15 ETDRS letters or more	Month 24
Secondary	Proportion of participants with visual gain	Proportion of participants gaining at least 5, 10, 15 ETDRS letters or more	Month 24
Secondary	Stability of vision	Stability of visual acuity over 24 months using Area Under Curve Analysis (AUC)	Over 24 months
Secondary	Central retinal thickness	Central retinal thickness (CRT) change as measured by Spectral Domain OCT	Month 24
Secondary	CRT stability	Stability of CRT over 24 months using AUC analysis	Over 24 months
Secondary	Retinal thickness variability	The difference between min and max retinal thickness	Over 24 months
Secondary	Change in Diabetic Retinopathy Severity	Measured using the ETDRS DRSS (Diabetic Retinopathy Severity Score)	Between baseline and month 24
Secondary	Number of focal laser treatments	Number of focal laser treatments	Over 24 months