The University of Southampton
University of Southampton Institutional Repository

A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)

A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)
A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)

BACKGROUND:
Bevacizumab (Avastin(®), Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis(®), Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs.

OBJECTIVE:
To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD.

DESIGN:
Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed.

SETTING:
Twenty-three ophthalmology departments in NHS hospitals.

PARTICIPANTS:
Patients ??50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ??25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter >?6000?µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required.

INTERVENTIONS:
Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5?mg or bevacizumab 1.25?mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated.

MAIN OUTCOME MEASURES:
The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes.

RESULTS:
Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p?=?0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p?=?0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p?=?0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p?=?0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p?=?0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses.

CONCLUSIONS:
Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment.
1366-5278
19(78)
NIHR Journals Library
Chakravarthy, Usha
2c06cdaf-94c0-409a-8eff-2f624c120a5e
Harding, Simon P
f7a586c8-02fb-4274-992d-eb2cabf1286d
Rogers, Chris A
d29926e1-acbe-48e5-a085-23552f635812
Downes, Susan
abd30872-96ba-4388-aee9-3538dc9a530c
Lotery, Andrew J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Dakin, Helen A.
807a9720-bfa0-46c6-a315-e1295982ff9c
Culliford, Lucy
2ebe9e38-51e1-4390-985a-3519410f3856
Scott, Lauren J.
6716aa49-970c-4bf8-a4e4-fab7cf7dc62e
Nash, Rachel L.
c24c4e7a-af01-4661-87ab-63d557df3938
Taylor, Jodi
875cc40a-d428-4a7d-9ee0-710051549a88
Muldrew, Alyson
d381ff36-a66b-43a1-9cf7-54c9a5e74c42
Sahni, Jayashree
2d88c629-bf2b-46bc-bcff-3c6208f018c0
Wordsworth, Susan
251bb0bc-6eca-4942-9a47-87b2726f8a11
Raftery, James
27c2661d-6c4f-448a-bf36-9a89ec72bd6b
Peto, Tunde
e5511bbd-2ef8-4465-a2b3-46c8cc3ce63e
Reeves, Barnaby C
d9e20947-f0e7-4c1f-99a5-419388df45fb
Chakravarthy, Usha
2c06cdaf-94c0-409a-8eff-2f624c120a5e
Harding, Simon P
f7a586c8-02fb-4274-992d-eb2cabf1286d
Rogers, Chris A
d29926e1-acbe-48e5-a085-23552f635812
Downes, Susan
abd30872-96ba-4388-aee9-3538dc9a530c
Lotery, Andrew J.
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Dakin, Helen A.
807a9720-bfa0-46c6-a315-e1295982ff9c
Culliford, Lucy
2ebe9e38-51e1-4390-985a-3519410f3856
Scott, Lauren J.
6716aa49-970c-4bf8-a4e4-fab7cf7dc62e
Nash, Rachel L.
c24c4e7a-af01-4661-87ab-63d557df3938
Taylor, Jodi
875cc40a-d428-4a7d-9ee0-710051549a88
Muldrew, Alyson
d381ff36-a66b-43a1-9cf7-54c9a5e74c42
Sahni, Jayashree
2d88c629-bf2b-46bc-bcff-3c6208f018c0
Wordsworth, Susan
251bb0bc-6eca-4942-9a47-87b2726f8a11
Raftery, James
27c2661d-6c4f-448a-bf36-9a89ec72bd6b
Peto, Tunde
e5511bbd-2ef8-4465-a2b3-46c8cc3ce63e
Reeves, Barnaby C
d9e20947-f0e7-4c1f-99a5-419388df45fb

Chakravarthy, Usha, Harding, Simon P, Rogers, Chris A, Downes, Susan, Lotery, Andrew J., Dakin, Helen A., Culliford, Lucy, Scott, Lauren J., Nash, Rachel L., Taylor, Jodi, Muldrew, Alyson, Sahni, Jayashree, Wordsworth, Susan, Raftery, James, Peto, Tunde and Reeves, Barnaby C (2015) A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN) (Health Technology Assessment, , (doi:10.3310/hta19780), 19(78), 19) Southampton, GB. NIHR Journals Library 297pp.

Record type: Monograph (Project Report)

Abstract


BACKGROUND:
Bevacizumab (Avastin(®), Roche), which is used in cancer therapy, is the 'parent' molecule from which ranibizumab (Lucentis(®), Novartis) was derived for the treatment of neovascular age-related macular degeneration (nAMD). There were reports in the literature on the effectiveness of bevacizumab in treating nAMD, but no trials. The cost per dose of bevacizumab is about 5-10% that of ranibizumab. This trial was a head-to-head comparison of these two drugs.

OBJECTIVE:
To compare the clinical effectiveness and cost-effectiveness of ranibizumab and bevacizumab, and two treatment regimens, for nAMD.

DESIGN:
Multicentre, factorial randomised controlled trial with within-trial cost-utility and cost-minimisation analyses from the perspective of the UK NHS. Participants, health professionals and researchers were masked to allocation of drug but not regimen. Computer-generated random allocations to combinations of ranibizumab or bevacizumab, and continuous or discontinuous regimen, were stratified by centre, blocked and concealed.

SETTING:
Twenty-three ophthalmology departments in NHS hospitals.

PARTICIPANTS:
Patients ??50 years old with active nAMD in the study eye with best corrected distance visual acuity (BCVA) ??25 letters measured on a Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Previous treatment for nAMD, long-standing disease, lesion diameter >?6000?µm, thick blood at the fovea and any other confounding ocular disease were exclusion criteria. One eye per participant was studied; the fellow eye was treated according to usual care, if required.

INTERVENTIONS:
Ranibizumab and bevacizumab were procured commercially. Doses were ranibizumab 0.5?mg or bevacizumab 1.25?mg. The repackaged bevacizumab was quality assured. All participants were treated at visits 0, 1 and 2. Participants randomised to the continuous regimen were treated monthly thereafter. Participants randomised to the discontinuous regimen were not retreated after visit 2 unless pre-specified criteria for active disease were met. If retreatment was needed, monthly injections over 3 months were mandated.

MAIN OUTCOME MEASURES:
The primary outcome was BCVA. The non-inferiority margin was 3.5 letters. Secondary outcomes were contrast sensitivity; near visual acuity; reading index; neovascular lesion morphology; generic and disease-specific patient-reported outcomes, including macular disease-specific quality of life; survival free from treatment failure; resource use; quality-adjusted life-years (QALYs); and development of new geographic atrophy (GA) (outcome added during the trial). Results are reported for the study eye, except for patient-reported outcomes.

RESULTS:
Between 27 March 2008 and 15 October 2010, 610 participants were allocated and treated (314 ranibizumab, 296 bevacizumab; at 3 months, 305 continuous, 300 discontinuous). After 2 years, bevacizumab was neither non-inferior nor inferior to ranibizumab [-1.37 letters, 95% confidence interval (CI) -3.75 to +1.01 letters] and discontinuous treatment was neither non-inferior nor inferior to continuous treatment (-1.63 letters, 95% CI -4.01 to +0.75 letters). Lesion thickness at the fovea was similar by drug [geometric mean ratio (GMR) 0.96, 95% CI 0.90 to 1.03; p?=?0.24] but 9% less with continuous treatment (GMR 0.91, 95% CI 0.85 to 0.97; p?=?0.004). Odds of developing new GA during the trial were similar by drug [odds ratio (OR) 0.87, 95% CI 0.61 to 1.25; p?=?0.46] but significantly higher with continuous treatment (OR 1.47, 95% CI 1.03 to 2.11; p?=?0.033). Safety outcomes did not differ by drug but mortality was lower with continuous treatment (OR 0.47, 95% CI 0.22 to 1.03; p?=?0.05). Continuous ranibizumab cost £3.5M per QALY compared with continuous bevacizumab; continuous bevacizumab cost £30,220 per QALY compared with discontinuous bevacizumab. These results were robust in sensitivity analyses.

CONCLUSIONS:
Ranibizumab and bevacizumab have similar efficacy. Discontinuing treatment and restarting when required results in slightly worse efficacy. Safety was worse with discontinuous treatment, although new GA developed more often with continuous treatment. Ranibizumab is not cost-effective, although it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab at £20,000 per QALY threshold. Future studies should focus on the ocular safety of the two drugs, further optimisation of treatment regimens and criteria for stopping treatment.

Text
FullReport-hta19780 - Version of Record
Download (8MB)

More information

Published date: 8 October 2015
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 383591
URI: https://eprints.soton.ac.uk/id/eprint/383591
ISSN: 1366-5278
PURE UUID: 0c29841b-03a3-44ca-a0cc-b705c4b94379
ORCID for Andrew J. Lotery: ORCID iD orcid.org/0000-0001-5541-4305

Catalogue record

Date deposited: 05 Nov 2015 17:00
Last modified: 31 Jan 2019 01:36

Export record

Altmetrics

Contributors

Author: Usha Chakravarthy
Author: Simon P Harding
Author: Chris A Rogers
Author: Susan Downes
Author: Helen A. Dakin
Author: Lucy Culliford
Author: Lauren J. Scott
Author: Rachel L. Nash
Author: Jodi Taylor
Author: Alyson Muldrew
Author: Jayashree Sahni
Author: Susan Wordsworth
Author: James Raftery
Author: Tunde Peto
Author: Barnaby C Reeves

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×