Ranibizumab and the Risk of Arterial Thromboembolic Events (RATE)

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

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.

Study Overview

• Status: Terminated
• Conditions: Coronary Artery Disease; Cerebrovascular Disorders; Age-related Macular Degeneration
• Intervention / Treatment: Drug: 0.5 mg of ranibizumab; Procedure: 0.5 mg of ranibizumab + photodynamic therapy; Other: Sham injection

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.

• Study Type: Interventional
• Enrollment (Actual): 380
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3071PR
      • De Haar Research Foundation
• Russian Federation
  • Yekaterinburg, Russian Federation, 620144
    • Ural Institute of Cardiology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham injection	Other: Sham injection; Sham treatment for occult or minimally classic type neovascular age related macular degeneration.; Other Names: Sham comparator
Active Comparator: 0.5 mg of ranibizumab	Drug: 0.5 mg of ranibizumab; 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).; Other Names: Lucentis
Active Comparator: injection + photodynamic therapy	Procedure: 0.5 mg of ranibizumab + photodynamic therapy; Photodynamic treatment with ranibizumab for predominantly classic type neovascular age related macular degeneration.; Other Names: Lucentis + laser therapy

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Ural State Medical University
• Collaborators: Ural Institute of Cardiology; De Haar Research Foundation
• Investigators: Study Chair: Jan Gabinsky, M.D., Ph.D., Ural Institute of Cardiology; Study Director: Alexander Kharlamov, M.D., Ph.D., Ural State Medical University; Principal Investigator: Olga Kovtun, M.D., Ph.D., Ural State Medical University

Publications and helpful links

Helpful Links

• Ural Institute of Cardiology
• Ural State Medical Academy

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: March 18, 2011
• First Submitted That Met QC Criteria: March 18, 2011
• First Posted (Estimate): March 21, 2011

Study Record Updates

• Last Update Posted (Estimate): May 19, 2015
• Last Update Submitted That Met QC Criteria: May 17, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: coronary artery disease; Age-related macular degeneration; ranibizumab; cerebrovascular disease; acute thromboembolic events
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Eye Diseases; Retinal Degeneration; Retinal Diseases; Embolism and Thrombosis; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Macular Degeneration; Thromboembolism; Cerebrovascular Disorders; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: RATE01