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Ranibizumab and the Risk of Arterial Thromboembolic Events (RATE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01319188
Recruitment Status : Terminated (The study was terminated under the political pressure of the Federal Security Service of the Russian Federation (FSB) and the Russian Society of Cardiology)
First Posted : March 21, 2011
Last Update Posted : May 19, 2015
Sponsor:
Collaborators:
Ural Institute of Cardiology
De Haar Research Foundation
Information provided by (Responsible Party):
Alexander Kharlamov, Ural Medical University

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.

Condition or disease Intervention/treatment Phase
Age-related Macular Degeneration Coronary Artery Disease Cerebrovascular Disorders Drug: 0.5 mg of ranibizumab Procedure: 0.5 mg of ranibizumab + photodynamic therapy Other: Sham injection Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 380 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Screening
Official Title: Ranibizumab for Age-Related Macular Degeneration and the Risk of Arterial Thromboembolic Events (RATE)
Study Start Date : June 2010
Actual Primary Completion Date : October 2012
Actual Study Completion Date : April 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Ranibizumab

Arm Intervention/treatment
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 Name: 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 Name: Lucentis + laser therapy

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




Primary Outcome Measures :
  1. Arterial thromboembolic events rate [ Time Frame: at month 6, 12 and 24 ]

    This is a combined primary outcome that included:

    • all cause mortality
    • nonfatal stroke
    • nonfatal myocardial infarction
    • vascular death


Secondary Outcome Measures :
  1. Serum concentration of ranibizumab [ Time Frame: at month 6, 12 and 24 ]
    Serum concentration of ranibizumab

  2. Serum VEGF [ Time Frame: at month 6, 12 and 24 ]
    Measurement of serum VEGF

  3. Mean change in visual acuity (letters) [ Time Frame: at month 6, 12 an 24 ]
    mean change in visual acuity (letters)

  4. Coronary and/or cerebral stenting, and/or CABG rate [ Time Frame: at month 6, 12 an 24 ]
    Coronary and/or cerebral stenting, and/or CABG rate

  5. Total cholesterol [ Time Frame: at month 6, 12 and 24 ]
    Total cholesterol measurement

  6. Systolic blood pressure [ Time Frame: at month 6, 12 and 24 ]
    Systolic blood pressure

  7. NYHA (New York Heart Association) functional class of heart failure [ Time Frame: at month 6, 12 and 24 ]
    NYHA (New York Heart Association) functional class of heart failure

  8. Diabetes mellitus morbidity [ Time Frame: at month 6, 12 and 24 ]
    Diabetes mellitus morbidity

  9. Serum fibrinogen [ Time Frame: at month 6, 12 and 24 ]
    Serum fibrinogen measurements

  10. Serum C-RP [ Time Frame: at month 6, 12 and 24 ]
    Serum C-RP measurements

  11. Serum D-dimer [ Time Frame: at month 6, 12 and 24 ]
    Serum D-dimer measurements



Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01319188


Locations
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Netherlands
De Haar Research Foundation
Rotterdam, South Holland, Netherlands, 3071PR
Russian Federation
Ural Institute of Cardiology
Yekaterinburg, Russian Federation, 620144
Sponsors and Collaborators
Ural Medical University
Ural Institute of Cardiology
De Haar Research Foundation
Investigators
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Study Chair: Jan Gabinsky, M.D., Ph.D. Ural Institute of Cardiology
Study Director: Alexander Kharlamov, M.D., Ph.D. Ural Medical University
Principal Investigator: Olga Kovtun, M.D., Ph.D. Ural Medical University
Additional Information:
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Responsible Party: Alexander Kharlamov, Scientific Assistant of C.E.O., Ural Institute of Cardiology, Ural Medical University
ClinicalTrials.gov Identifier: NCT01319188    
Other Study ID Numbers: RATE01
First Posted: March 21, 2011    Key Record Dates
Last Update Posted: May 19, 2015
Last Verified: May 2015
Keywords provided by Alexander Kharlamov, Ural Medical University:
Age-related macular degeneration
ranibizumab
acute thromboembolic events
coronary artery disease
cerebrovascular disease
Additional relevant MeSH terms:
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Cerebrovascular Disorders
Macular Degeneration
Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Thromboembolism
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Retinal Degeneration
Retinal Diseases
Eye Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Embolism and Thrombosis
Ranibizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents