Clinical trial NCT01319188: Ranibizumab and the Risk of Arterial Thromboembolic Events
Official title: Ranibizumab for Age-Related Macular Degeneration and the Risk of Arterial Thromboembolic Events (RATE)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Age-related Macular Degeneration
Coronary Artery Disease
Cerebrovascular Disorders
Keywords: Age-related macular degeneration
ranibizumab
acute thromboembolic events
coronary artery disease
cerebrovascular disease
Lead sponsor: Ural State Medical University
Sponsor class: OTHER
Collaborators: name: Ural Institute of Cardiology
name: De Haar Research Foundation
First posted: 2011-03-21
Enrollment: 380
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Arterial thromboembolic events rate
timeFrame: at month 6, 12 and 24
Secondary outcomes:
measure: Serum concentration of ranibizumab
timeFrame: at month 6, 12 and 24
measure: Serum VEGF
timeFrame: at month 6, 12 and 24
measure: Mean change in visual acuity (letters)
timeFrame: at month 6, 12 an 24
measure: Coronary and/or cerebral stenting, and/or CABG rate
timeFrame: at month 6, 12 an 24
measure: Total cholesterol
timeFrame: at month 6, 12 and 24
measure: Systolic blood pressure
timeFrame: at month 6, 12 and 24
measure: NYHA (New York Heart Association) functional class of heart failure
timeFrame: at month 6, 12 and 24
measure: Diabetes mellitus morbidity
timeFrame: at month 6, 12 and 24
measure: Serum fibrinogen
timeFrame: at month 6, 12 and 24
measure: Serum C-RP
timeFrame: at month 6, 12 and 24
measure: Serum D-dimer
timeFrame: at month 6, 12 and 24
Other outcomes:
Locations:
city: Rotterdam
country: Netherlands
facility: De Haar Research Foundation
state: South Holland
city: Yekaterinburg
country: Russian Federation
facility: Ural Institute of Cardiology
Study officials:
affiliation: Ural Institute of Cardiology
name: Jan Gabinsky, M.D., Ph.D.
role: STUDY_CHAIR
affiliation: Ural State Medical University
name: Alexander Kharlamov, M.D., Ph.D.
role: STUDY_DIRECTOR
affiliation: Ural State Medical University
name: Olga Kovtun, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: