Ranibizumab and the Risk of Arterial Thromboembolic Events

Coronary Artery Disease Clinical Trial

— RATE  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01319188
• Other study ID #: RATE01
• Status: Terminated
• Phase: Phase 4
• First received: March 18, 2011
• Last updated: May 17, 2015
• Start date: June 2010
• Est. completion date: April 2015

Study information

• Verified date: May 2015
• Source: Ural Medical University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Russia: Ethics Committee
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 380
• Est. completion date: April 2015
• Est. primary completion date: October 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 50 Years to 90 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Screening

Related Conditions & MeSH terms

• Age-related Macular Degeneration
• Cerebrovascular Disorders
• Coronary Artery Disease
• Coronary Disease
• Macular Degeneration
• Myocardial Ischemia
• Thromboembolism

Intervention

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).

Procedure:
• 0.5 mg of ranibizumab + photodynamic therapy
Photodynamic treatment with ranibizumab for predominantly classic type neovascular age related macular degeneration.

Other:
• Sham injection
Sham treatment for occult or minimally classic type neovascular age related macular degeneration.

Locations

Country	Name	City	State
Netherlands	De Haar Research Foundation	Rotterdam	South Holland
Russian Federation	Ural Institute of Cardiology	Yekaterinburg

Sponsors (3)

Lead Sponsor	Collaborator
Ural Medical University	De Haar Research Foundation, Ural Institute of Cardiology

Countries where clinical trial is conducted

Netherlands,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Serum concentration of ranibizumab	Serum concentration of ranibizumab	at month 6, 12 and 24	No
Secondary	Serum VEGF	Measurement of serum VEGF	at month 6, 12 and 24	No
Secondary	Mean change in visual acuity (letters)	mean change in visual acuity (letters)	at month 6, 12 an 24	No
Secondary	Coronary and/or cerebral stenting, and/or CABG rate	Coronary and/or cerebral stenting, and/or CABG rate	at month 6, 12 an 24	No
Secondary	Total cholesterol	Total cholesterol measurement	at month 6, 12 and 24	No
Secondary	Systolic blood pressure	Systolic blood pressure	at month 6, 12 and 24	No
Secondary	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	No
Secondary	Diabetes mellitus morbidity	Diabetes mellitus morbidity	at month 6, 12 and 24	No
Secondary	Serum fibrinogen	Serum fibrinogen measurements	at month 6, 12 and 24	No
Secondary	Serum C-RP	Serum C-RP measurements	at month 6, 12 and 24	No
Secondary	Serum D-dimer	Serum D-dimer measurements	at month 6, 12 and 24	No

External Links

•   Ural Institute of Cardiology
•   Ural State Medical Academy