| ISRCTN | ISRCTN13623634 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN13623634 |
| EudraCT/CTIS number | 2014-000272-26 |
| Secondary identifying numbers | 17808 |
- Submission date
- 26/11/2014
- Registration date
- 26/11/2014
- Last edited
- 17/06/2021
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Eye Diseases
Plain English summary of protocol
Background and study aims
The retina is a light-sensitive layer at the back of the eye. It has a blood supply that provides oxygen and nutrients. Blood drains from the retina and leaves the eye through the central retinal vein. Blockage of the central retinal vein (CRVO) leads to fluid accumulating in part of the retina called the macula (macular oedema [MO]). This reduces the eye’s ability to distinguish the details and shapes of objects (visual acuity). Until 3 years ago no treatment improved visual acuity in MO due to CRVO. The drugs ranibizumab and aflibercept are effective at improving visual function in patients with MO due to CRVO and cause relatively few side effects. Aflibercept may have a longer duration of action than ranibizumab but there is no data on the comparison for this condition. Bevacizumab, similar to ranibizumab, has been shown to be as good as ranibizumab for another eye disease, wet macular degeneration, and is significantly cheaper. Its use in MO due to CRVO would result in very significant NHS cost savings. However, more data is required to support its routine use for this condition in the NHS. This study will determine whether bevacizumab and aflibercept are as effective as ranibizumab at improving visual function in MO due to CRVO and sufficiently cost effective to merit their use.
Who can participate?
Patients aged over 18 with MO due to CRVO
What does the study involve?
Participants are randomly allocated to be treated with either bevacizumab, aflibercept or ranibizumab injected into the eye, and are followed up for 2 years.
What are the possible benefits and risks of participating?
Not provided at time of registration
Where is the study run from?
The study will take place in approximately 50 Ophthalmology Centres in the UK and will be managed by the King’s Clinical Trials Unit.
When is the study starting and how long is it expected to run for?
December 2014 to November 2018
Who is funding the study?
NIHR CEAT Programme (UK)
Who is the main contact?
Mr Philip Hykin
Contact information
Scientific
Moorfields Eye Hospital
London
EC1V 2PD
United Kingdom
Study information
| Study design | Multicentre Phase III double-masked randomised controlled non-inferiority trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Other |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a patient information sheet |
| Scientific title | A multicentre Phase III double-masked randomised controlled non-inferiority trial comparing the clinical and cost effectiveness of intravitreal therapy with ranibizumab (Lucentis) vs aflibercept (Eylea) vs bevacizumab (Avastin) for macular oedema due to central retinal vein occlusion |
| Study acronym | LEAVO |
| Study objectives | The primary hypothesis is that bevacizumab and aflibercept are as effective as ranibizumab in reducing visual loss from macular oedema due to central retinal vein occlusion. |
| Ethics approval(s) | NRES Committee London - London Bridge, 04/09/2014, ref: 14/LO/1043 |
| Health condition(s) or problem(s) studied | Macula odema due to central retinal vein occlusion |
| Intervention | Intravitreal aflibercept and bevacizumab versus intravitreal ranibizumab |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Aflibercept, bevacizumab, ranibizumab |
| Primary outcome measure | Change in best corrected visual acuity from baseline to 100 weeks in the study eye measured in ETDRS letter score at 4 metres: difference in means between bevacizumab and ranibizumab and between aflibercept and ranibizumab |
| Secondary outcome measures | 1. Clinical effectiveness: multiple additional visual acuity and anatomical outcomes 2. Cost effectiveness outcomes |
| Overall study start date | 01/12/2014 |
| Completion date | 30/11/2018 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 459 |
| Total final enrolment | 463 |
| Key inclusion criteria | 1. Subjects of either sex aged ≥ 18 years 2. Clinical diagnosis of centre-involving macular oedema (MO) due to CRVO 3. CRVO of ≤ 12 months duration 4. Best corrected visual acuity in the study eye ≥ 19 and ≤ 73 ETDRS letters (approximate Snellen VA 3/60 to VA 6/12) 5. Best corrected visual acuity in the non-study eye ≥ 14 ETDRS letters (approximate Snellen VA ≥ 2/60). 6. SD-OCT central subfield thickness (CST) > 320μm (Spectralis) predominantly due to MO secondary to CRVO in the study eye. See appendix 1 for equivalent CST value for alternative SD-OCT machines. 7. Media clarity, pupillary dilatation and subject cooperation sufficient for adequate fundus imaging of the study eye 8. In cases of bilateral CRVO, if both eyes are potentially eligible, unless the patient prefers otherwise the worst seeing eye will be recruited |
| Key exclusion criteria | Current exclusion criteria as of 13/08/2018: The following apply to the study eye only and to the non-study eye only where specifically stated: 1. Macular oedema considered to be due to a cause other than CRVO (e.g. diabetic macular oedema, Irvine-Gass syndrome). 2. An ocular condition is present that, in the opinion of the investigator, might affect macular oedema or alter visual acuity during the course of the study (e.g. vitreomacular traction) 3. Any previously documented diabetic retinopathy or diabetic macular oedema in the study eye at baseline clinical examination of the study eye. 4. Moderate or severe non proliferative diabetic retinopathy (NPDR) or quiescent, treated or active proliferative diabetic retinopathy (PDR) or macular oedema in the non-study eye. Note: Mild NPDR only is permissible in the non-study eye. 5. History of treatment for MO due to CRVO in the past 90 days with intravitreal or peribulbar corticosteroids or in the last 60 days with anti-VEGF drugs or >6 prior anti-VEGF treatments in the previous 12 months. 6. Active iris or angle neovascularisation, neovascular glaucoma, untreated NVD, NVE and vitreous haemorrhage or treatment for these conditions in the last 1 month. 7. Uncontrolled glaucoma [>30mmHg], either untreated or on anti-glaucoma medication at screening. 8. Any active periocular or intraocular infection or inflammation (e.g. conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis). Systemic exclusion criteria: 9. Uncontrolled blood pressure defined as a systolic value > 170mmHg and diastolic value > 110mmHg. 10. Myocardial infarction, stroke, transient ischaemic attack, acute congestive cardiac failure or any acute coronary event < 3 months before randomisation 11. Women of child bearing potential unless using effective methods of contraception throughout the study and for 6 months after their last injection for the trial. Effective contraception is defined as one of the following: 11.1. Barrier method: condoms or occlusive cap with spermicides 11.2. True abstinence: When it is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception 11.3. Have had tubal ligation or bilateral oophorectomy (with or without hysterectomy) 11.4. Male partner sterilisation. The vasectomised male partner should be the only partner for the female participant 11.5. Use of established oral, injected or implanted hormonal methods of contraception and intrauterine device 12. Pregnant or lactating women. 13. Males who do not agree to an effective form of contraception for the duration of the study and for 6 months after their last injection for the trial 14. Hypersensitivity to the active ingredients aflibercept, bevacizumab or ranibizumab or any of the excipients of these drugs 15. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies 16. A condition that, in the opinion of the investigator, would preclude participation in the study. 17. Participation in an investigational trial involving an investigational medicinal product within 90 days of randomisation Previous exclusion criteria: The following apply to the study eye only and to the non-study eye only where specifically stated: 1. Macular oedema considered to be due to a cause other than CRVO (e.g. diabetic macular oedema, Irvine-Gass syndrome). 2. An ocular condition is present that, in the opinion of the investigator, might affect macular oedema or alter visual acuity during the course of the study (e.g. vitreomacular traction) 3. Any previously documented diabetic retinopathy or diabetic macular oedema in the study eye. 4. Moderate or severe non proliferative diabetic retinopathy (NPDR) or quiescent, treated or active proliferative diabetic retinopathy (PDR) or macular oedema in the non-study eye. Note: Mild NPDR only is permissible in the non-study eye. 5. History of treatment for MO due to CRVO in the past 90 days with intravitreal or peribulbar corticosteroids or in the last 60 days with anti-VEGF drugs or >3 prior anti-VEGF treatments in the previous 12 months. 6. Active iris or angle neovascularisation, neovascular glaucoma, untreated NVD, NVE and vitreous haemorrhage or treatment for these conditions in the last 3 months. 7. Uncontrolled glaucoma [>30mmHg], either untreated or on anti-glaucoma medication at screening. 8. Any active periocular or intraocular infection or inflammation (e.g. conjunctivitis, keratitis, scleritis, uveitis, endophthalmitis). Systemic exclusion criteria: 9. Uncontrolled blood pressure defined as a systolic value > 170mmHg and diastolic value > 110mmHg. 10. Myocardial infarction, stroke, transient ischaemic attack, acute congestive cardiac failure or any acute coronary event < 3 months before randomisation 11. Women of child bearing potential unless using effective methods of contraception throughout the study and for 6 months after their last injection for the trial. Effective contraception is defined as one of the following: 11.1. Barrier method: condoms or occlusive cap with spermicides 11.2. True abstinence: When it is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception 11.3. Have had tubal ligation or bilateral oophorectomy (with or without hysterectomy) 11.4. Male partner sterilisation. The vasectomised male partner should be the only partner for the female participant 11.5. Use of established oral, injected or implanted hormonal methods of contraception and intrauterine device 12. Pregnant or lactating women. 13. Males who do not agree to an effective form of contraception for the duration of the study and for 6 months after their last injection for the trial 14. Hypersensitivity to the active ingredients aflibercept, bevacizumab or ranibizumab or any of the excipients of these drugs 15. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies 16. A condition that, in the opinion of the investigator, would preclude participation in the study. 17. Participation in an investigational trial involving an investigational medicinal product within 90 days of randomisation |
| Date of first enrolment | 01/12/2014 |
| Date of final enrolment | 16/12/2016 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
EC1V 2PD
United Kingdom
United Kingdom
Sponsor information
Hospital/treatment centre
City Road
London
EC1V 2PD
England
United Kingdom
| Website | www.moorfields.nhs.uk |
|---|---|
"ROR" |
https://ror.org/03tb37539 |
Funders
Funder type
Government
No information available
Results and Publications
| Intention to publish date | 30/11/2019 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not provided at time of registration |
| Publication and dissemination plan | The primary outcomes and the health economics papers will be published in a high impact journal before 30/11/2019. |
| IPD sharing plan |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | Yes | No | ||
| Results article | results | 29/08/2019 | 01/11/2019 | Yes | No |
| Results article | 01/06/2021 | 17/06/2021 | Yes | No | |
| HRA research summary | 28/06/2023 | No | No |
Editorial Notes
17/06/2021: Publication reference added.
01/11/2019: The following changes were made:
1. Publication reference added.
2. The final enrolment number was added from the reference.
21/08/2018: The ethics approval details, publication and dissemination plan, and publication reference were added.
13/08/2018: The following changes were made to the trial record:
1. The overall trial end date was changed from 01/05/2018 to 30/11/2018.
2. The exclusion criteria were updated.
3. The EudraCT number was added.
4. The recruitment end date was changed from 01/05/2018 to 16/12/2016.
12/02/2016: Plain English summary added.
