ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12612000004864

Ethics application status

Approved

Date submitted

10/11/2011

Date registered

3/01/2012

Date last updated

21/01/2020

Date data sharing statement initially provided

14/12/2018

Date results provided

21/01/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

A comparison of the number of Lucentis injections(eye injections) required for patients who receive a combination treatment of laser bypass (chorioretinal venous anastomosis) and Lucentis or sham laser bypass and Lucentis for the treatment of macular oedema (swelling at the back of the eye) that has occurred as a result of a central retinal vein occlusion.

Scientific title

A comparison of the number of Lucentis injections required within the observational period 12-24 months post enrolment in patients treated with a combination therapy of Lucentis and laser induced chorioretinal venous anastomosis (L-CRA) or Lucentis and sham L-CRA for macular oedema that is secondary to central retinal vein occlusion.

Secondary ID [1]

Novartis Study Protocol: CRFB002EAU01T

Universal Trial Number (UTN)

U1111-1123-6707

Trial acronym

L-CVBS

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Macular oedema secondary to central retinal vein occlusion.

Condition category

Condition code

Eye

Diseases / disorders of the eye

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Study participants will either be randomised to receive laser induced chorioretinal venous anastomosis (L-CRA) or sham L-CRA. The Ellex diode laser will be used to create the anastomosis. Two sites will be chosen, with one above and one below the optic disc. Both will be over a tributary of a major quadrantic vein at least 2 disc diamteres away from the optic disc. It is not possible to be absolutely specific about the location as this will depend on the individual anatomical arrangement in each patient's eye. The spot size for the L-CRA treatment is 50 um and 500 um for the sham L-CRA, whilst the power will be up to 4W depending on the degree of cataract for the L-CRA, and <100mW for the sham L-CRA. The duration will be 0.1 sec for both treatment groups. There is only one laser session, that consists of two attempts to establish a functional L-CRA.

Both treatment groups will receive monthly intravitreal injections of Lucentis (Ranibizumab) for 6 months after the laser treatment.The dose for each intravitreal injection is 2.3mg/0.23mL(10mg/mL) solution, and the volume injected is 0.05ml. The intravitreal injection procedure including the application of local anaesthetic and cleaning of the conjunctiva will take about 20 minutes.

After the first six injections, patients will be evaluated monthly, and may receive further Lucentis injections based on protocol retreatment criteria. The retreatment criteria are: 1. There is a >50um increase in central thickness on spectral domain OCT compared to the lowest previous measurement, 2. There are new or persistent cyctic retinal changes or subretinal fluid on spectral domain OCT, and 3. There is a loss of 5 or more ETDRS chart letters from the previous best measurement in conjunction with any increase in central foveal thickness on spectral domain OCT. For the first 2 years of the study, patient visits will be monthly. In the extension study (years 3-4) patients in both treatment groups will be evaluted at 2 or 4 month intervals for Lucentis retreatment using the retreatment criteria outlined above.

Intervention code [1]

Treatment: Other

Intervention code [2]

Treatment: Drugs

Comparator / control treatment

Laser induced chorioretinal venous anastomsis (L-CRA)/ sham L-CRA. The sham L-CRA treatment will be a 500um spot of 0.1 second duration and a 100mW power directed with a 3 mirror contact lens into the far nasal periphery of the retina. With this spot size and power, the laser will have no clinical effect but the patient will still experience a green flash that will be identical to the one experienced in the creation of the therapeutic L-CRA.
All patients receive monthly intravitreal Lucentis (Ranibizumab) injections for six months after L-CRA treatment, and may/may not receive further monthly injections based on protocol retreatment criteria for the next 18 months. In the extension protocol, patients may/may not receive further bimonthly injections based on the protocol retreatment criteria for 24 months.

Control group

Placebo

Outcomes

Primary outcome [1]

To compare and establish whether there is a significant difference in the number of Lucentis injections according to the PRN retreatment protocol in the observational period from 12 to 24 months in patients with visual impairment due to macular oedema secondary to central retinal vein occlusion (CRVO) treated with either Lucentis/laser induced chorioretinal anastomsis (L-CRA) or Lucentis/sham L-CRA.

Timepoint [1]

Timepoint: 12 -24 months after L-CRA treatment.

Secondary outcome [1]

Mean average best corrected visual acuity (BCVA) change from baseline to Months 6, 12 and 24 between the L-CRA and sham L-CRA treatment groups.

Timepoint [1]

Timepoint: 6, 12 and 24 Months after L-CRA treatment.

Secondary outcome [2]

A comparison of the residual central retinal thickness of the macula measured by Spectral-domain OCT at 6, 12 and 24 Months between the L-CRA and sham L-CRA treatment groups.

Timepoint [2]

Timepoint: 6, 12 and 24 Months after the L-CRA treatment.

Secondary outcome [3]

A comparison of the degree of peripheral retinal ischaemia between the L-CRA and sham L-CRA treatment groups as measured by Optus wide angle camera at 12 and 24 Months.

Timepoint [3]

Timepoint: 12 and 24 Months after the L-CRA treatment.

Secondary outcome [4]

Comparison of the stability of both treatment groups in the 2 year extension phase measured by BCVA, OCT and number of injections.

Timepoint [4]

48 Months after the L-CRA treatment.

Secondary outcome [5]

To determine both the nature and sequence of changes to the radial peripapillary capillaries and deep capillary networks as a composite secondary outcome using optical coherence tomography angiography (OCTA)..

Timepoint [5]

18 Months after the L-CRA treatment.

Eligibility

Key inclusion criteria

1. Foveal centre involved macular oedema secondary to CRVO less than 9 months in duration.
2. Mean central retinal thickness greater or equal to 250 microns on OCT. (Patients who have had a previous CRVO that has spontaneously resolved will be enrolled provided there is no evidence of macular damage that would confuse visual acuity improvements.)
3. Adults greater or equal to 18 years.
4. BCVA 20/40 to 20/320 (73 to 24 letters on ETDRS chart).
5. Clear ocular media and adequate pupillary dilation.
6. IOP less than or equal to 25mmHg.

7. Written informed consent.
8. No other significant ocular pathology.
9. Willing, committed and able to return for all clinic visits and complete all study related procedures.

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Any previous treatment for central retinal vein occlusion (including laser, steriods or anti-VEGFs).
2. Brisk afferent pupillary defect.
3. Evidence on examination of any diabetic retinopathy.
4. CVA or MI within 3 months prior to day 0.
5. Women of childbearing potential not using contraception method(s) specified in the study, as well as women who are breastfeeding.
6. Known sensitivity to study drug(s) or class of study drug(s).
7. Use of any other investigational agent in the last 30 days.
8. Any other ocular condition in the study eye that would prevent improvement in visual acuity, e.g., macular ischaemia, underlying macular degeneration, epi-retinal membrane.
9. Neovascularisation of the iris, disc or retina.
10. Aphakia or presence of anterior chamber lens in the study eye.
11. Significant media opacities such as cataract.
12. Previous pars plana vitrectomy.
13. History of retinal detachment or surgery for retinal detachment.
14. Any condition which would preclude a patient's ability to comply with the study requirements or to be available for the duration of the study.
15. Any active infection involving ocular adnexa including infectious conjunctivitis, keratitis, sclertitis, endophthalmitis as well as idiopathic or autoimmune-associated uveitis in either eye.
16. Extra capsular extraction of cataract with phacoemulsification within three months preceding baseline, or a history or post-operative complications within the last 12 months preceding baseline in the study (uveitis, cyclitis etc.).
17. Contra indication to pupil dilation in either eye.
18. Anticoagulation with warfarin.

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Potential patients who are likely to meet the study inclusion/exclusion criteria will be asked if they want to participate in the study. The Investigator will explain the study, and give them a copy of the ethics approved Participant Information and Consent Form to take home to read and/or discuss with their family/GP. Once that patient has had time to decide whether they want to participate, they will sign the consent form with the Investigator prior to any study procedures been performed. The patient will then be screened to ascertain whether they are eligible to participate. If eligible, they will be randomly assigned receive the laser induced chorioretinal anastomosis (L-CRA) treatment or the sham L-CRA treatment by using a series of serially numbered, opaque envelopes containing the assignment to treatment or placebo.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

The treatment assignments are compiled using a list of computer generated pseudo-random numbers in permuted blocks of variable size. Patients are randomised for treatment in one eye only.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

Intervention assignment

Parallel

Other design features

Those blinded in the study include: 1. The study participants, 2. The Visual Acuity Examiners and 3. The study photographers who perform the Optical Coherence Tomography and ophthalmic photography.

Phase

Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

4/01/2012

Actual

2/03/2012

Date of last participant enrolment

Anticipated

31/12/2014

Actual

26/06/2015

Date of last data collection

Anticipated

30/06/2019

Actual

10/05/2019

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Lions Eye Institute Day Surgery Centre - Nedlands

Recruitment postcode(s) [1]

6009 - Nedlands

Funding & Sponsors

Funding source category [1]

Other

Name [1]

Lions Eye Institute

Address [1]

2 Verdun St
Nedlands
6009
Western Australia

Country [1]

Australia

Funding source category [2]

Commercial sector/Industry

Name [2]

Novartis Pharmaceuticals

Address [2]

54 Waterloo Rd
North Ryde
2113
New South Wales

Country [2]

Australia

Primary sponsor type

Other

Name

Lions Eye Institute

Address

2 Verdun St
Nedlands
6009
Western Australia

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sir Charles Gairdner Hospital Human Research Ethics Committee

Ethics committee address [1]

Department of Research
2nd Floor, "A" Block
Sir Charles Gairdner Hospital
Hospital Ave
Nedlands
6009
WA

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

24/10/2011

Approval date [1]

16/12/2011

Ethics approval number [1]

2011-090

Summary

Brief summary

Macular oedema that is secondary to central retinal vein occlusion (CRVO) has conventionally been treated with laser photocoagulation. The outcomes of this treatment show a slight improvement in visual acuity. Recently various therapeutic agents such as Triamcinolone, Pegaptanib, Bevacizumab and Ranibizumab have been injected intravitreally into the eye. Bevacizumab and Ranibizumab in particular have been shown to reduce macular oedema in the short term, however, repeated injections are required. The Central Vein Bypass Study, where a high intensity laser is used to create an anastomosis between the a retinal and a choroidal vein as a means of bypassing the obstruction to venous flow (L-CRA), is the only study to date that has addressed the causal pathology of macula oedema secondary to CRVO, rather than simply addressing the sequelae of the retinal venous obstruction. Patients who received the L-CRA had significantly improved visual acuity compared to the sham L-CRA treatment group. In this study patients will either be treated with the L-CRA or sham L-CRA. Both groups will receive monthly injections of Ranibizumab for 6 months. Patients will be assessed for a further 18 months, and may/may not receive further injections depending on whether the retreatment criteria have been met. The primary aim of the study is to show that L-CRA treated patients will require fewer Ranibizumab injections in the 12-24 month phase of the study compared to sham L-CRA treated patients. The use of Ranibizumab in the short term and the long term treatment effects of the L-CRA may prove to be an effective treatment for macular oedema that is secondary to CRVO. A recent study showed that 56% of patients had persistent macular oedema requiring an average of 5.9 injections in the 4th year. The study protocol has been amended to follow the two treatment groups bimonthly or once every four months for a further 24 months. Patients will be assessed according to the retreatment criteria for further injections. The extension study will provide long-term follow up data.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Ian McAllister

Address

Lions Eye Institute
2 Verdun St
Nedlands
6009
Western Australia

Country

Australia

Phone

+61 8 9381 0870

Fax

IanMcAllister@lei.org.au

Contact person for public queries

Name

Prof Ian McAllister

Address

Lions Eye Institute
2 Verdun St
Nedlands
6009
Western Australia

Country

Australia

Phone

+61 8 9381 0870

Fax

+61 8 9381 0766

IanMcAllister@lei.org.au

Contact person for scientific queries

Name

Prof Ian McAllister

Address

Lions Eye Institute
2 Verdun St
Nedlands
6009
Western Australia

Country

Australia

Phone

+61 8 9381 0870

Fax

+61 8 9381 0766

IanMcAllister@lei.org.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

All participant data is de-identified and not linked to the participant.
Ethics approval did not include the release of individual participant data.

What supporting documents are/will be available?

Doc. No.	Type	Email
765	Study protocol	LynneSmithies@lei.org.au
6502	Informed consent form	LynneSmithies@lei.org.au
6503	Ethical approval	LynneSmithies@lei.org.au

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Technique of laser chorioretinal anastomosis creation in central retinal vein occlusion and success rate with a new photocoagulator system.	2016	https://dx.doi.org/10.1097/IAE.0000000000001025
Embase	Two-Year Efficacy of Ranibizumab Plus Laser-Induced Chorioretinal Anastomosis vs Ranibizumab Monotherapy for Central Retinal Vein Occlusion: A Randomized Clinical Trial.	2018	https://dx.doi.org/10.1001/jamaophthalmol.2018.4973
Embase	Functional benefits of a chorioretinal anastomosis at 2 years in eyes with a central retinal vein occlusion treated with ranibizumab compared with ranibizumab monotherapy.	2021	https://dx.doi.org/10.1136/bmjophth-2021-000728
Embase	Benefits of a Laser Chorioretinal Anastomosis Plus Ranibizumab vs Ranibizumab Alone for Central Retinal Vein Occlusion: 4-Year Results.	2023	https://dx.doi.org/10.1016/j.ajo.2023.03.034

N.B. These documents automatically identified may not have been verified by the study sponsor.

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