Diabetic Macular Edema, Diabetes
Conditions
Keywords
Diabetes, Eye, Macular Oedema, Intravitreal Injection, Ranibizumab, Fluocinolone Acetonide
Brief 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.
Detailed 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.
Interventions
Fluocinolone Acetonide Sustained Release Intravitreal Implant at Baseline Visit
Monthly PRN intravitreal injections
PROCEDURESham Intravitreal Injection
Sham injection without penetrating needle and without drug delivery at baseline visit.
Sponsors
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
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. The Iluvien and the sham injection should be performed by the unmasked investigator. The unmasked investigator should not be involved in any patient assessment in the study.
Intervention model description
Double masking randomized control trial with 2 parallel treatment arms: intervention (Iluvien plus Ranibizumab) vs control (Sham plus Ranibizumab)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Lucentis Injections received in the study eye | 24 months | The total number of Lucentis injections needed over 24 months following the intravitreal injection PRN protocol |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maintaining at least 20/40 vision | Month 24 | Percentage of patients that achieve or maintain 20/40 vision |
| Proportion of participants with vision loss | Month 24 | Proportion of participants losing 5, 10, 15 ETDRS letters or more |
| Proportion of participants with visual gain | Month 24 | Proportion of participants gaining at least 5, 10, 15 ETDRS letters or more |
| Stability of vision | Over 24 months | Stability of visual acuity over 24 months using Area Under Curve Analysis (AUC) |
| Change in visual acuity | Month 24 | Change in ETDRS (Early Treatment of Diabetic Retinopathy Study) best corrected visual acuity from baseline to month 24 |
| CRT stability | Over 24 months | Stability of CRT over 24 months using AUC analysis |
| Retinal thickness variability | Over 24 months | The difference between min and max retinal thickness |
| Change in Diabetic Retinopathy Severity | Between baseline and month 24 | Measured using the ETDRS DRSS (Diabetic Retinopathy Severity Score) |
| Number of focal laser treatments | Over 24 months | Number of focal laser treatments |
| Central retinal thickness | Month 24 | Central retinal thickness (CRT) change as measured by Spectral Domain OCT |
Outcome results
None listed