Ranibizumab and the Risk of Arterial Thromboembolic Events

Study Overview
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Brief Summary
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The investigators assume that ranibizumab might be dangerous in patients with history of coronary artery disease or cerebrovascular events. The main objective of study is to reveal contraindications for ranibizumab prescription in patients with history of coronary artery disease and cerebrovascular events. Moreover, an association between management with ranibizumab and ATE rate in healthy above 50 years old persons is a concern of great interest as well.

Detailed Description
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Age-related macular degeneration (AMD) is a degenerative condition affecting the macula or central area of the retina in elderly people. Early AMD is marked by the presence of soft drusen and/or retinal pigment abnormality (hyper- and hypopigmentation). Late AMD includes 2 forms, nonneovascular (dry) AMD and neovascular (wet) AMD. Despite new medical and surgical interventions, AMD remains a leading cause of vision loss in elderly people all over the world. Ranibizumab is one of the most effective approaches of AMD management. Ranibizumab - a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A (VEGF A) - has been evaluated for the treatment of AMD. Ranibizumab binds to the receptor binding site of active forms of VEGF-A. VEGF-A cause neovascularization and leakage in models of ocular angiogenesis and vascular occlusion, and is thought to contribute to the progression of neovascular AMD and macular edema following RVO. Prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation. There have been a number of studies that have examined a possible association between ranibizumab and arterial thromboembolic events (ATE). The ATE rate in the three controlled neovascular AMD studies during the first year was 1.9% (17 out of 874; 0.3-0.5 mg LUCENTIS) vs 1.1% (5 out of 441) in control arms (AMD-1, AMD-2). In the second year the ATE rate was 2.6% (1323 patients; Lucentis 879) vs Control 444 (p < 0.05). The ATE rate in the two controlled RVO studies (RVO-1, RVO-2) during the first six months was 0.8% (789 patients; Lucentis 527 vs Sham 262). The investigators assume that ranibizumab can be rather dangerous in patients with history of coronary artery disease or cerebrovascular events. The main objective of study is to reveal contraindications for ranibizumab prescription in patients with history of coronary artery disease and cerebrovascular events. Moreover, an association between management with ranibizumab and ATE rate in healthy above 50 years old persons is a concern of great interest as well.

Official Title
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Ranibizumab for Age-Related Macular Degeneration and the Risk of Arterial Thromboembolic Events (RATE)

Conditions
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Age-related Macular Degeneration, Coronary Artery Disease, Cerebrovascular Disorders

Intervention / Treatment
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* Drug: 0.5 mg of ranibizumab
* Procedure: 0.5 mg of ranibizumab + photodynamic therapy
* Other: Sham injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age - 50 years old and older male and female age-related macular degeneration (AMD) have a lesion in the study eye with a total size of less than 12 optic disc areas for minimally classic or occult lesions but no more than 5400 μm in greatest linear dimension for predominantly classic lesions have best corrected visual acuity of 6/12 to approximately 6/96 (Snellen equivalent), assessed with the use of charts from the Early Treatment Diabetic Retinopathy Study (ETDRS) (70 to 25 ETDRS 1 m equivalent letter scores; patients initially view the charts at a starting distance of 4 m, the number of correctly read letters are given a correction factor with the final letter score being the equivalent of a patient reading it at 1m. A score of 55 letters approximates to 6/24 Snellen acuity) have no permanent structural damage to the central fovea have had no previous treatment for exudative age related macular degeneration healthy subjects (no history of cardio- or cerebrovascular events), or history of coronary artery disease (cardiovascular events - myocardial infarction, unstable angina), or history of cerebrovascular events (brain ischemia, and/or stroke), but not in the preceding six months Exclusion Criteria: history of cardiovascular events (myocardial infarction, unstable angina) or cerebrovascular events in the preceding six months stenting, or any surgery in the preceding six months other acute illnesses in the preceding three months III-IV NYHA functional class of heart failure mental and brain disorders pregnancy family hypercholesterolemia blood disorders malignant tumors participation to any drug investigation during the previous three months

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 0.5 mg of ranibizumab<br> | Drug: 0.5 mg of ranibizumab<br>* Intravitreous ranibizumab (0.5 mg, injections at four week intervals for six months followed by further treatment at three month intervals with total duration of treatment until 24 months).<br>* Other names: Lucentis;|
| Active Comparator: injection + photodynamic therapy<br> | Procedure: 0.5 mg of ranibizumab + photodynamic therapy<br>* Photodynamic treatment with ranibizumab for predominantly classic type neovascular age related macular degeneration.<br>* Other names: Lucentis + laser therapy;|
| Sham Comparator: Sham injection<br> | Other: Sham injection<br>* Sham treatment for occult or minimally classic type neovascular age related macular degeneration.<br>* Other names: Sham comparator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arterial thromboembolic events rate | This is a combined primary outcome that included: all cause mortality nonfatal stroke nonfatal myocardial infarction vascular death | at month 6, 12 and 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum concentration of ranibizumab | Serum concentration of ranibizumab | at month 6, 12 and 24 | 
| Serum VEGF | Measurement of serum VEGF | at month 6, 12 and 24 | 
| Mean change in visual acuity (letters) | mean change in visual acuity (letters) | at month 6, 12 an 24 | 
| Coronary and/or cerebral stenting, and/or CABG rate | Coronary and/or cerebral stenting, and/or CABG rate | at month 6, 12 an 24 | 
| Total cholesterol | Total cholesterol measurement | at month 6, 12 and 24 | 
| Systolic blood pressure | Systolic blood pressure | at month 6, 12 and 24 | 
| NYHA (New York Heart Association) functional class of heart failure | NYHA (New York Heart Association) functional class of heart failure | at month 6, 12 and 24 | 
| Diabetes mellitus morbidity | Diabetes mellitus morbidity | at month 6, 12 and 24 | 
| Serum fibrinogen | Serum fibrinogen measurements | at month 6, 12 and 24 | 
| Serum C-RP | Serum C-RP measurements | at month 6, 12 and 24 | 
| Serum D-dimer | Serum D-dimer measurements | at month 6, 12 and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Age-related macular degeneration, ranibizumab, acute thromboembolic events, coronary artery disease, cerebrovascular disease