Comparing the Effectiveness and Costs of Bevacizumab to Ranibizumab in Patients With Diabetic Macular Edema

A Randomized Clinical Trial (The BRDME Study)

A.M.E. Schauwvlieghe; G. Dijkman; J.M. Hooymans; F.D. Verbraak; C.B. Hoyng; M.G.W. Dijkgraaf; R. Van Leeuwen; J.R. Vingerling; A.C. Moll; Reinier O. Schlingemann

Disclosures

BMC Ophthalmol. 2015;15(71)

Summary

In order to determine the best first line anti-VEGF medicine in the treatment of DME we decided to set up a head-to-head comparison with monthly injections during six months. The primary clinical target is the improvement of best corrected visual acuity, while the primary health economic target is cost reduction without a loss in health gain as measured by a change in visual acuity or by quality adjusted life years.

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Abbreviations
DR: Diabetic retinopathy, DME: Diabetic macular edema, RCT: Randomized clinical trial, VEGF: Vascular endothelial growth factor, OCT: Optical tomography, FA: Fluoroangiography, BCVA: Best corrected visual acuity, IOP: Intraocular pressure, TIA: Transient ischemic attack

Acknowledgements
We would like to thank Netherlands Organisation for Health Research and Development, ZonMW for funding the research. We would also like to thank the peer reviewers of ZonMW for their input.
We would also like to thank the Edmond and Marianne Blaauw foundation for their help in submitting the manuscript.

Table 1. Inclusion criteria
1. patients > 18 years of age who have signed an informed consent.
2. Type 1 or Type 2 diabetes mellitus with glycosylated haemoglobin (HbA1c) less than 12.0 % at screening. Treatment for diabetes must have been stable for at least 2 months.
3. Patients with visual impairment due to DME with a central area thickness >325 μm, who are eligible for anti-VEGF treatment according to the investigator. If both eyes are eligible, the one with the worse visual acuity, as assessed at visit 1, is selected by the investigator as the study eyes
4. BCVA equal or more than 24 and less or equal to 78 letters in the study eye at screening using ETDRS-like visually acuity testing charts at a testing distance of 4 m.

Table 2. Exclusion criteria
Women of child-bearing potential, unless they are using two birth control methods.
Pregnant or nursing (lactating) women.
Inability to comply with study procedures.
Active intraocular inflammation (grade + or above) in either eye at enrolment.
Any active infection in either eye at the time of enrolment.
History of uveitis in either eye at any time.
Structural damage within 600 μm of the centre of the macula in the study eye likely to preclude improvement in visual acuity following in the resolution of macular edema, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), epiretinal membrane involving fovea or organized hard exudate plaques.
Uncontrolled glaucoma in the study eye at screening (IOP > 24 mmHg on medication or according to investigator's judgment).
Neovascularization of the iris in the study eye.
Evidence of vitreomacular traction in the study eye.
Active untreated proliferative diabetic retinopathy in the study eye.
Any intraocular surgery in the study eye within 3 months prior to randomization.
History of vitrectomy in study eye regardless of time prior to randomization.
Planned medical or surgical intervention during the 6 months study period.
Panretinal laser photocoagulation in the study eye within 3 months prior to or during the study.
Focal/grid laser photocoagulation in the study eye 3 months prior to study entry.
Treatment with anti-angiogenic drugs in the study eye within 3 months prior to randomization.
Use of other investigational drugs at the time of enrolment, or within 3 month or 5 half-lives from enrolment, whichever is longer.
History of intravitreal corticosteroids in phakic eye within 18 months prior to randomization or in post-cataract surgery study eye within 4 months prior to randomization.
Ocular conditions in the study eye that require chronic concomitant therapy with topical ocular or systemically administered corticosteroids.
History of stroke or transient ischemic attack (TIA) within 6 months prior to enrolment.
Renal failure requiring dialysis or renal transplant or renal insufficiency with creatinine levels > 2.0 mg/dl at screening.
Blood pressure systolic > 165 mm Hg or diastolic > 105 mmHg at screening and randomization.
Hypertension or change in antihypertensive treatment within 1 month preceding randomization.
Current use of or likely need for systemic medications known to be toxic to the lens, retina or optic nerve, including deferoxamine, chloroquine/hydroxychloroquine (Plaquenil), tamoxifen, phenothiazines and ethambutol.
Known hypersensitivity to fluorescein, ranibizumab or bevacizumab or any component thereof or drugs of similar chemical classes.
Any type of advanced, severe or unstable disease or its treatment, that may interfere with primary and/or secondary variable evaluations including any medical condition that could be expected to progress, recur, or change to such an extent that it may bias the assessment of the clinical status of the patient to a significant degree or put the patient at special risk.
Concomitant conditions in the study eye which would, in the opinion of the investigator, prevent the improvement of visual acuity on study treatment.
Ocular disorders in the study eye that may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the 6-month study period, including cataract, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., AMD, ocular histoplasmosis, or pathologic myopia)

Table 3. Study flow chart
Assessment/	Phase	Treatment
procedure	Visit	1	2	3	4	5	6	7	8
	Month	0		1	2	3	4	5	6
Check inclusion/exclusion criteria		X
Informed consent		X
Medical History		X
Vital Signs		X		X	X	X	X	X	X
Check concomitant medications		X	X	X	X	X	X	X	X
Check adverse events			X	X	X	X	X	X	X
EQ-5D or HUI-3 questionnaire			X			X			X
Blood sample		X
Drug administration			X	X	X	X	X	X
BCVA		X	X	X	X	X	X	X	X
Ophthalmic exam		X	X						X
Fluorescein angiography		X							X
Optical coherence tomography		X	X	X	X	X	X	X	X

Authors and Disclosures

A.M.E. Schauwvlieghe¹, G. Dijkman³, J.M. Hooymans⁴, F.D. Verbraak^1,2,11, C.B. Hoyng⁵, M.G.W. Dijkgraaf⁶, R. Van Leeuwen⁷, J.R. Vingerling^8,9, A.C. Moll¹⁰ and Reinier O. Schlingemann^1,2,12,13*

¹Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. ²Ocular Angiogenesis Group, Departments of Ophthalmology and Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. ³Department of Ophthalmology, Leiden University Medical Centre, Leiden, The Netherlands. ⁴Department of Ophthalmology, University Medical Center Groningen, Groningen, The Netherlands. ⁵Department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. ⁶Clinical Research Unit, Academic Medical Center, Amsterdam, The Netherlands. ⁷Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands. ⁸Department of Ophthalmology, Erasmus Medical Center, Rotterdam, The Netherlands. ⁹Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. ¹⁰Department of Ophthalmology, VU University Medical Centre, Amsterdam, The Netherlands. ¹¹Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. ¹²Netherlands Institute for Neurosciences, Amsterdam, The Netherlands. ¹³Medical Retina Unit and Ocular Angiogenesis Group, Department Of Ophthalmology, Academic Medical Center, Room A2-122, Amsterdam, 1100 DD, The Netherlands

*Correspondence
r.schlingemann@amc.uva.nl

Competing interests
FV. Dutch advisory board Novartis and Bayer. Others none.

Authors' contributions
AS wrote the first draft, wrote the protocol, the funding application and obtained the approval from the ethical committee, is responsible for the final data monitoring. GD, J.H and C.H. J.V. R.V. A.M, YH are local principal investigators, they helped with the study design and finalisation of additional funding in agreement with local health insurance companies, they are responsible for the quality of the data in their site and edited and approved this manuscript. MD helped with the study design, in particular power calculation and economic evaluation, was responsible for the second draft and edited the manuscript. FV helped in the study design, especially the imaging, helps in data collection and edited the manuscript. RS is the initiator of this research and has the final responsibility for publication, helps in data collection and the study design and edited the manuscript. All authors read and approved the final manuscript.

Authors' information
AS, MD, phd student supervised by RS, Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, a.m.schauwvlieghe@amc.uva.nl
RS, MD, PhD, professor and head of the Ocular Angiogenesis Group, Departments of Ophthalmology and Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, affiliated with Netherlands Institute for Neurosciences, Amsterdam, The Netherlands r.schlingemann@amc.uva.nl and Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
GD, MD, PhD, Department of Ophthalmology, Leiden University Medical Centre, Leiden, the Netherlands, G.Dijkman@lumc.nl
JH, MD, Phd, professor at the department of Ophthalmology, University Medical Center Groningen, Groningen, the Netherlands, j.m.m.hooymans@ohk.umcg.nl
C.H., MD, Phd, professor at the department of Ophthalmology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, C.Hoyng@ohk.umcn.nl
MD, Phd, Clinical Research Unit, Academic Medical Center, The Netherlands, m.g.dijkgraaf@amc.uva.nl
RV, MD, Phd, professor at the Department of Ophthalmology, University Medical Center Utrecht, Utrecht, The Netherlands, r.vanleeuwen@umcutrecht.nl
JV, MD, PhD at the Department of Ophthalmology, Erasmus Medical Center, Rotterdam, the Netherlands, and at the Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands, j.vingerling@erasmusmc.nl
AM, MD, Phd at the department of Ophthalmology, VU University Medical Centre, Amsterdam, the Netherlands., a.moll@vumc.nl
FD, MD, PhD affiliated with the Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, f.d.verbraak@amc.uva.nl