Clinical trial NCT01941329: Prospective, Randomized, Multicentre, Open-label, Phase II / III Study to Assess Efficacy and Safety of Ranibizumab 0.5 mg Intravitreal Injections Plus Panretinal Photocoagulation (PRP) Versus PRP in Monotherapy in the Treatment of Subjects With High Risk Proliferative Diabetic Retinopathy.
Official title: Prospective, Randomized, Multicentre, Open-label, Phase II / III Study to Assess Efficacy and Safety of Ranibizumab 0.5 mg Intravitreal Injections Plus Panretinal Photocoagulation (PRP) Versus PRP in Monotherapy in the Treatment of Subjects With High Risk Proliferative Diabetic Retinopathy. (PROTEUS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: High Risk Proliferative Diabetic Retinopathy
Keywords: Diabetes
Proliferative Retinopathy
Ranibizumab
Panretinal Photocoagulation
Lead sponsor: Association for Innovation and Biomedical Research on Light and Image
Sponsor class: OTHER
Collaborators: name: European Vision Institute Clinical Research Network
First posted: 2013-09-13
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a prospective, randomized, multicentre, open label study that intents to compare the efficacy and safety of ranibizumab 0.5 mg Intravitreal (ITV) injections plus Panretinal Photocoagulation versus Panretinal Photocoagulation alone in the regression of the neovascularization area in patients with High Risk Proliferative Diabetic Retinopathy over a 12-month treatment period.

One of the major complications of the diabetes mellitus is Diabetic Retinopathy (DR), one of the leading causes of visual impairment in working age in industrialized countries. Longer diabetes duration and poor glycaemic and blood pressure control are strongly associated with Diabetic Retinopathy. The overall prevalence of any form of Diabetic Retinopathy is 34.4% and 6.96% corresponds to Proliferative Diabetic Retinopathy (PDR). Therefore, approximately 93 million people have Diabetic Retinopathy and 17 million of them have Proliferative Diabetic Retinopathy.

It has been shown that treatment with repeated injections of ranibizumab can improve visual acuity in patients with PDR. Further, , the standard PRP treatment of PDR remains unsatisfactory. The knowledge of the mechanisms of this retinal complication is incomplete and, therefore, efforts should be done to understand and characterize patients' eyes response to combined treatments.

Therefore, the purpose of this study is to compare the standard treatment for PDR (i.e. Panretinal Photocoagulation) with Panretinal Photocoagulation treatment combined with ITV injections of ranibizumab since it is expected that anti-vascular endothelial growth factor (VEGF) treatment with ITV injections will increase the rate of success of Panretinal Photocoagulation in regression of neovascularization with improved final visual acuity.


Eligibility criteria: Inclusion Criteria:

* High-risk proliferative diabetic retinopathy (HR-PDR); Neovascularization in the disc (NVD) ≥ 1/4 disc area (DA) OR Neovascularization elsewhere (NVE) ≥ 1/2 DA; NVE \< 1/2 DA + vitreous and/or pre-retinal haemorrhage and/or rubeosis; NVD \<1/4 DA + vitreous and/or pre-retinal haemorrhage and/or rubeosis;
* BCVA at baseline ≥ 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters score (approximate Snellen equivalent 20/320);
* Type I or Type II diabetic subjects of either gender;
* Age ≥ 18 years;
* Ability to provide written informed consent;
* Ability to return for all clinical trial visits;

Exclusion Criteria:

* Any intraocular surgery within 6 months before trial enrolment, including:

Prior scatter (panretinal) or focal/grid photocoagulation; Eyes who have received yttrium aluminum garnet (YAG) laser, or peripheral retinal cryoablation, or laser retinopexy (for retinal tears only);

* Fibrovascular proliferation with retinal traction;
* Other cause of retinal NV (retinal vein occlusion, radiation retinopathy or others);
* Atrophy/scarring/fibrosis/ hard exudates involving the centre of the macula;
* Significant media opacities or inadequate pupillary dilation, which might interfere with visual acuity, assessment of toxicity or fundus photography;
* Any likelihood that the subject will require cataract surgery within the following 1 year;
* Diabetic macular edema (DME) with central involvement, i.e., central macular thickness (Central Point Thickness) \> 300 µm (Stratus OCT) equivalent values measured by spectral domain (SD)-OCT, adjusted according to the SD-OCT machine used;
* Previous vitrectomy;
* Intraocular pressure \> 21 mmHg;
* Previous anti-VEGF therapy within the last 3 months;
* Known serious allergies or history of hypersensitivity to fluorescein used in angiography, or to components of Lucentis® formulation;
* Acute ocular or periocular infection;
* Previous filtering surgery (e.g., trabeculectomy) or placement of a glaucoma drainage device (e.g., tube-shunt surgery); General Exclusion Criteria
* Systolic BP \> 170 mmHg or diastolic BP \> 100 mmHg;
* HbA1C level \>11% or recent signs of uncontrolled diabetes;
* Any of the following underlying systemic diseases:

History or evidence of severe cardiac disease, e.g. New York Heart Association (NYHA) Functional Class III or IV, clinical or medical history of unstable angina, acute coronary syndrome, myocardial infarction, or revascularization procedure within 6 months prior to baseline, or ventricular tachyarrhythmia requiring treatment; History or evidence of clinically significant peripheral vascular disease such as intermittent claudication or prior amputation; Renal failure requiring dialysis or renal transplant or renal insufficiency with creatinine levels \> 2.0 mg/dl at screening; Stroke (within 12 months of trial entry); Any major surgical procedure within one month before trial enrolment;

* Subject with a condition (such as advanced, severe or unstable disease or its treatment) or is in a situation which may put him/her at significant risk, which may confound the study results or may interfere significantly with the subject's participation in the study;
* Previous radiation to the head in the region of the study eye;
* Use of any other investigational drugs within the last 3 months (for DR or other condition);
* History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases;
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation.

Primary outcomes:
measure: Regression of neovascularization
timeFrame: 12-month treatment
Secondary outcomes:
measure: Changes in Best Corrected Visual Acuity (BCVA)
timeFrame: 12-Month treatment
measure: Time to complete neovascularization regression
timeFrame: 12-Month treatment
measure: Recurrence of neovascularization
timeFrame: 12-Month treatment
measure: Macular retinal thickness
timeFrame: 12-Month treatment
measure: Need of treatment for Diabetic Macular Edema
timeFrame: 12-Month treatment
measure: Need of vitrectomy due to the occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of Diabetic Retinopathy.
timeFrame: 12-Month treatment
measure: Adverse events related to the treatments
timeFrame: 12-Month treatment
Other outcomes:
Locations:
city: Dijon
country: France
facility: Department of Ophthalmology, University Hospital, CHU Dijon
city: Paris
country: France
facility: Department of Ophthalmology, Lariboisière Hospital
city: Paris
country: France
facility: Centre d'Investigation Clinique - Centre National d'Ophtalmologie des Quinze-Vingts
city: Milan
country: Italy
facility: Department of Ophthalmology, University Vita Salute - Scientific Institute of San Raffael
city: Padova
country: Italy
facility: Centre for Clinical Trials, Department of Ophthalmology, University of Padova
city: Rome
country: Italy
facility: G.B.Bietti Eye Foundation - IRCCS
city: Coimbra
country: Portugal
facility: Centre for Clinical Trials - Association for Innovation and Biomedical Research on Light and Image
city: Coimbra
country: Portugal
facility: Espaço Médico de Coimbra
city: Lisboa
country: Portugal
facility: Instituto de Retina de Lisboa
city: Vila Franca de Xira
country: Portugal
facility: Serviço de Oftalmologia,Hospital de Vila Franca de Xira
city: Frimley
country: United Kingdom
facility: Ophthalmology Clinical Trials Unit Frimley Park Hospital Foundation Trust
city: Gloucestershire
country: United Kingdom
facility: Clinical Trial Unit, Dep. Ophth., Gloucestershire Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Laser and Retinal Research Unit, King's Health Partners
Study officials:
affiliation: Association of Innovation and Biomedical Research on Light and Image
name: José Cunha-Vaz, MD, PhD
role: STUDY_CHAIR
References: