Treatment of severe Diabetic macular oedema with Anti-vascular endothelial growth factor (anti-VEGF) monotherapy versus treatment with anti-VEGF followed by subthreshold Micropulse lasEr when the thickness of the central retina goes below 400 microns: a pragmatic randomised equivalence trial
| ISRCTN | ISRCTN12693443 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12693443 |
| IRAS number | 1010626 |
| Secondary identifying numbers | 24014NL-UC, CPMS 65230 |
- Submission date
- 27/09/2024
- Registration date
- 18/11/2024
- Last edited
- 02/05/2025
- Recruitment status
- Not yet recruiting
- Overall study status
- Ongoing
- Condition category
- Eye Diseases
Plain English Summary
Background and study aims
The macula is the centre of the retina; it gives central sight, colour and fine detail. People with diabetes may develop diabetic macular oedema (DMO). In DMO, fluid leaks from blood vessels and builds up at the macula, causing sight loss. DMO can be mild or severe; this is determined by measuring, in microns (µm), how thick the macula is. One µm is one-thousandth of a millimetre.
People presenting with mild DMO (macula less than 400 µm thick; normally it is around 250 µm but varies with sex and ethnicity) are offered macular laser treatment. Laser works well for these patients. Subthreshold micropulse laser (SML), which does not damage the macula, works as well as standard laser, which produces a burn, and is cost-effective.
However, many people present with severe DMO (macula 400 µm or thicker) where the laser does not work well. The standard treatment is eye injections of anti-VEGFs. VEGF stands for vascular endothelial growth factor. VEGF is high in eyes with DMO and causes blood vessel leakage. Anti-VEGFs block VEGF. They are given monthly to begin with, then every 2-3 months for months or years until DMO clears. In many patients DMO comes back after clearing and anti-VEGFs need to be re-started most often monthly initially again.
To improve the care of people with severe DMO this study will compare the current standard care (anti-VEGFs alone) with a strategy in which patients begin with an anti-VEGF but switch to SML once the macula is less than 400 µm thick.
Who can participate?
Patients aged over 18 years with type 1 or type 2 diabetes and severe DMO
What does the study involve?
Participants are randomly allocated to be treated with either anti-VEGFs alone or anti-VEGFs then SML once the macula is less than 400 µm thick.
What are the possible benefits and risks of participating?
It is considered that the risk associated with the anti-VEGF and SML used within the DAME study is no higher than the risk of standard care. There are a number of expected events associated with the administration of anti-VEGF, SML and intravitreal steroids, Patients will be asked at each visit specifically about each of the following: self-reported central/paracentral scotomas, self-reported reduced colour vision, self-reported metamorphopsia, corneal epithelial erosion, corneal ulcer, endophthalmitis, intraocular inflammation (anterior, posterior or panuveitis), intraocular pressure elevation (over 21 mmHg), intraocular haemorrhage (suprachoroidal/vitreous/pre-retinal haemorrhage), retinal tear, retinal detachment, retinal vasculitis, retinal vascular occlusion (retinal vein or retinal artery occlusion), lens touch (which may occur at the time of an intravitreal injection and may be seen only post-administration in the form of a focal cataract), allergic reaction to any treatments given, including eye drops, angina, myocardial infarction, stroke, transient ischaemic attack (TIA), kidney disease. These events will be collected as safety outcomes and any adverse effects will be monitored by the trial team and DMEC.
Where is the study run from?
Queen’s University Belfast (UK)
When is the study starting and how long is it expected to run for?
September 2024 to September 2028
Who is funding the study?
National Institute for Health and Care Research (UK)
Who is the main contact?
1. Prof. Noemi Lois, n.lois@qub.ac.uk
2. Mary Guiney, mary.guiney@nictu.hscni.net
Contact information
Scientific, Principal Investigator
The Wellcome-Wolfson Institute for Experimental Medicine
Queen’s University Belfast
Belfast
BT9 7BL
United Kingdom
| Phone | +44 (0)7484791071 |
|---|---|
| n.lois@qub.ac.uk |
Public
7 Lennoxvale
Belfast
BT9 5BY
United Kingdom
| Phone | +44 (0)28 961 51447 |
|---|---|
| mary.guiney@nictu.hscni.net |
Study information
| Study design | Pragmatic allocation-concealed single-masked (outcome assessors) multicentre randomized (1:1) equivalence trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Hospital |
| Study type | Safety, Efficacy |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Treatment of severe Diabetic macular oedema with Anti-vascular endothelial growth factor (anti-VEGF) monotherapy versus treatment with anti-VEGF followed by subthreshold Micropulse lasEr when the thickness of the central retina goes below 400 microns: a pragmatic randomised equivalence trial |
| Study acronym | DAME |
| Study hypothesis | Primary objective: To determine if the clinical effectiveness of anti-VEGFs and SML is equivalent to anti-VEGF monotherapy Secondary objectives: 1. To determine the cost-effectiveness of anti-VEGFs and SML compared to anti-VEGF monotherapy via an economic evaluation 2. To evaluate the participant experience and acceptability of anti-VEGFs and SML compared to anti-VEGF monotherapy via a mixed methods evaluation 3. To evaluate the post-trial implementation and scalability of anti-VEGFs and SML via a process evaluation |
| Ethics approval(s) | Approved 15/11/2024, South Central - Oxford B Research Ethics Committee (Health Research Authority, 2 Redman Place, Stratford, E20 1JQ, United Kingdom; +44 (0)207 104 8134, +44 (0)207 104 8019; oxfordb.rec@hra.nhs.uk), ref: 24/SC/0330 |
| Condition | Severe diabetic macular oedema (DMO). |
| Intervention | Comparator Arm: Anti-VEGF Monotherapy (standard care) Anti-VEGFs including ranibizumab and biosimilars, aflibercept, faricimab, and brolucizumab will be used, as per the standard of care at participating sites. The anti-VEGF should be administered in line with the summary of product characteristics (SmPC). Intervention Arm: Subthreshold Micropulse Laser (SML) SML will be applied in line with the DAME Guideline and follow the DAME participant pathway. Eligible participants who provide consent will be randomised 1:1 to receive SML or to continue with anti-VEGF monotherapy. A minimisation algorithm will be used to ensure balanced allocation of participants across trial arms for potentially important factors including centre, duration of DMO (≤1year, >1year), number of doses of anti-VEGFs received up to the time of randomisation (1-6; 7-12), type of anti-VEGF used (ranibizumab, ranibizumab-biosimilar, Brolucizumab, aflibercept, or faricimab) up to the time of randomisation, which will be continued throughout the trial unless lack of efficacy is observed and rescue treatment is needed, presenting BCVA [BCVA ≥ 69 ETDRS letters (Snellen equivalent ≥ 20/40; logMAR ≥ 0.3), 24–68 ETDRS letters (Snellen equivalent ≤20/50-20/320; logMAR 0.4–1.2) and CI-DMO (Yes, No). Minimising randomisation by these variables will ensure both trial arms will be balanced with regard to these potentially important baseline characteristics. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Therapy |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Aflibercept, brolucizumab, ranibizumab, faricimab |
| Primary outcome measure | Change in best corrected visual acuity (BCVA) in the study eye from randomisation (baseline) to 104 weeks (24 months) (equivalence margin +/- 5 ETDRS letters) |
| Secondary outcome measures | All measured at 104 weeks (24 months) from randomisation: 1. Central Retinal Thickness in the study eye. CRT in the central 1 mm of the retina as measured using Spectral-Domain optical Coherence Tomography (SD- OCT) 2. Health-related and vision-related quality of life. National Eye Institute Visual Function Questionnaire (NEI VFQ) 25 and the EuroQoL (EQ 5D 5L) questionnaire 3. Safety based on determined safety outcomes, adverse events, and serious adverse events 4. Number of treatments used (anti-VEGF injections, SML sessions) in the study eye from baseline to week 104 5. Number/proportion of people receiving “rescue” treatment in the study eye from baseline to week 104 6. Number of rescue treatments received in the study eye from baseline to week 104 7. Number/proportion of people discontinuing treatment (with reasons) 8. Number/proportion of people losing (with reasons) ≥5, ≥10 and ≥15 ETDRS letters of best-corrected visual acuity (from baseline to week 104) in the study eye 9. Number/proportion of people gaining ≥5, ≥10 and ≥15 ETDRS letters (from baseline to week 104) in the study eye 10. Number/proportion of people with CRT ≤300μm in the study eye in the central 1 mm if the retina as determined using SD-OCT 11. Number/proportion of people with no DMO, as determined by the ophthalmologists evaluating the patient 12. Health and social care service use and non-healthcare costs as determined using a Health Service Use Questionnaire and Patient Cost Questionnaire 13. Participant experience and acceptability as determined by focus group discussions, the Acceptability Questionnaire ( Theoretical Framework of Acceptability (TFA) ) distributed at week 104, and also by the use of Visual Analogue Score questionnaires that will be distributed 60 minutes prior to treatment, immediately after treatment and 24 hours after treatment at all instances in which treatment is given |
| Overall study start date | 24/09/2024 |
| Overall study end date | 30/09/2028 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 264 |
| Participant inclusion criteria | 1. Adults (>18 years) 2. Diabetes type 1 or type 2 3. Presented with severe centre-involving (CI)-DMO (CRT ≥400 μm) 4. Within the first year of initiating anti-VEGF therapy but who still have DMO and their CRT is below 400 μm (and it remains, at the time of randomisation) following anti-VEGF therapy in either one eye or both eyes |
| Participant exclusion criteria | 1. Causes of macular oedema other than DMO 2. DMO with CRT ≥400 μm 3. Receipt of anti-VEGFs before their presentation with severe DMO (previous macular laser treatment for DMO is allowed) 4. Use of unlicensed anti-VEGFs (e.g. bevacizumab) 5. Inability, for any reason, to attend study visits 6. Active proliferative diabetic retinopathy (PDR) (treated and inactive PDR is allowed) 7. Use of pioglitazone which cannot be stopped for the duration of the trial 8. Cataract surgery or laser pan-retinal photocoagulation (PRP) within the previous 6 weeks 9. Currently enrolled in a CTIMP (Clinical Trial of an Investigational Medical Product) 10. Declined consent for participation |
| Recruitment start date | 01/06/2025 |
| Recruitment end date | 30/04/2026 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Uxbridge
UB8 3NN
United Kingdom
Frimley
Camberley
GU16 7UJ
United Kingdom
De Crespigny Park
Denmark Hill
London
SE5 8AB
United Kingdom
Middlesbrough
TS4 3BW
United Kingdom
369 Fulham Road
London
SW10 9NH
United Kingdom
London
NW10 7NS
United Kingdom
London
EC1V 2PD
United Kingdom
Sunderland
SR2 9HP
United Kingdom
Newport
NP20 2UB
United Kingdom
Bristol
BS1 2LX
United Kingdom
Dunfermline
KY12 0SU
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Gloucester
GL1 3NN
United Kingdom
Prescot Street
Liverpool
L7 8XP
United Kingdom
Hull
HU3 2JZ
United Kingdom
Derby Road
Nottingham
NG7 2UH
United Kingdom
Belfast
BT12 6BA
United Kingdom
Brighton
BN2 5BF
United Kingdom
Newton Road
Torquay
TQ2 7AA
United Kingdom
Redhill
RH1 5RH
United Kingdom
Sponsor information
University/education
Research Office
2nd Floor King Edward Building
The Royal Hospitals
Grosvenor Road
Belfast
BT12 6BA
Northern Ireland
United Kingdom
| Phone | +44 (0)7484791071 |
|---|---|
| ResearchSponsor@belfasttrust.hscni.net | |
| Website | http://www.belfasttrust.hscni.net/ |
"ROR" |
https://ror.org/02tdmfk69 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/03/2029 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Published as a supplement to the results publication |
| Publication and dissemination plan | The results of DAME will be disseminated widely through presentations at national and international ophthalmic/diabetes meetings and at invited speaker’s lectures. The results will be presented at participant group meetings. Diabetes UK Northern Ireland has agreed to contribute to the dissemination efforts to ensure the results are available to participants, their families, and the public. The research team includes lead clinicians and researchers with contacts across the globe. They will use these international contacts to ensure trial results are disseminated widely and incorporated into future guidelines on diabetic retinopathy. DAME will be reported in accordance with the CONSORT guideline. If necessary, the CONSORT and SPIRIT Extension for RCTs Revised in Extenuating Circumstances (CONSERVE) statement will also be applied in the event that extenuating circumstances require major modifications to the trial during its course. The trial protocol, statistical analysis plan and health economic analysis plan will be made publicly available to ensure transparency in our methodology. In accordance with the open-access policies proposed by the NIHR we plan to publish the clinical findings of the trial as well as a separate paper describing the health economic findings of the trial in high-quality, high-impact, peer-reviewed open-access journals. Other manuscripts are planned (e.g. a manuscript presenting data on patient experience and acceptability of the treatments; a manuscript with the results of the SWAT; others). We will actively promote the findings of the study to journal editors and opinion leaders in ophthalmology and diabetes to ensure findings are widely disseminated (e.g. through editorials and conference presentations) and are included in future guidelines. The most significant results will be communicated to the wider public through media releases. An ongoing update of the study will also be provided on the NICTU website. |
| IPD sharing plan | The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 2.0 | 09/09/2024 | 01/10/2024 | No | No |
Additional files
Editorial Notes
02/05/2025: The recruitment start date was changed from 31/03/2025 to 01/06/2025.
07/03/2025: The following changes were made:
1. Study website added.
2. The recruitment start date was changed from 01/01/2025 to 31/03/2025.
16/01/2025: Internal review.
27/12/2024: Ethics approval details added. The overall study end date was changed from 31/03/2028 to 30/09/2028.
27/09/2024: Trial's existence confirmed by NHS HRA.
