Corneal Neovascularization
Conditions
Keywords
corneal neovascularization, pazopanib, votrient, rosacea
Brief summary
The purpose of this study is to determine the safety and efficacy of a drug \[Pazopanib (Votrient)\] as a treatment for corneal neovascularization. The cornea is the clear, central portion of the eye and neovascularization means blood vessel growth. The cornea is typically avascular, or without blood vessels. Corneal neovascularization in the cornea and can put vision at risk. Numerous diseases of the cornea such as inflammation, ischemia (restriction of blood supply), infection, degeneration (or deterioration), trauma, or corneal stem cell deficiency can lead to corneal neovascularization. This major ocular complication can lead to corneal scarring, edema (swelling), lipid deposits, and inflammation that may significantly alter your vision. In addition, it worsens the outcome of potential future treatments, such as a corneal transplant. A corneal transplant is a treatment that many patients with severe corneal disease may ultimately need.
Detailed description
Normally avascular, under many pathologic conditions, vessels may invade the cornea from the limbal vascular plexus. Infection, inflammation, ischemia, degeneration, or trauma, and the loss of the limbal stem cell barrier can cause corneal neovascularization. Growth of new vessels may result in corneal scarring, edema, lipid deposition, and inflammation that may alter visual acuity and is a leading cause of monocular visual impairment and blindness. Additionally, it results in the loss of immune response across the cornea, thereby worsening the prognosis of a subsequent penetrating keratoplasty (PK). Growth of new blood and lymphatic vessels from preexisting vessels are mediated by members of the vascular endothelial growth factor (VEGF) family. In previous studies, inhibition of new blood or lymphatic vessels has been achieved by neutralization of vascular endothelial growth factor A (VEGF-A). It has also been shown that platelet-derived growth factor-B (PDGF-B) plays a role in corneal and choroidal neovascularization by regulating mural cell recruitment. Inhibition of PDGF-B and VEGF-A signaling pathways has shown to more effectively promote vessel regression than solely inhibiting VEGF-A. Pazopanib is a drug designed to block these pathways, stop new growth, and regress old vessel growth.
Interventions
DRUGPazopanib (5mg/ml)
Topical pazopanib, 4 times per day for 3 weeks
Sponsors
Reza Dana, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to provide written informed consent * Ability to comply with study assessments and study requirements (for example, able to open the eye drop foil-wrap packaging and eye drop vials, willing to adhere to the daily dosing schedule) for the full duration of study * Age \> 18 years * Patients with superficial or deep corneal neovascularization that extends farther than 1 mm from the limbus * Patients are in stable overall health * Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin ≤ 1.5x upper limit of normal (ULN) or isolated bilirubin \>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35% * Single QTcF \< 450 msec; or QTcF \< 480 msec in subjects with Bundle Branch Block * A female is eligible to enter and participate in this study if she is of Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
Exclusion criteria
* Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) * History of any clotting disorder, including predisposition to hypercoagulation or any previous thromboembolic event * Major surgery within 1 month of screening * Has received treatment with anti-VEGF agents (topical, intraocular or systemic) within 60 days of study entry. This includes both approved and investigational treatments. * Has received investigational therapy within 60 days prior to study entry * Concurrent enrollment in another clinical investigational medicinal product or device study * Concurrent use of anti-VEGF agents * Corneal or ocular surface infection within 30 days prior to study entry * Full thickness or lamellar keratoplasty within 90 days prior to study entry * Other ocular surgeries within 60 days prior to study entry * Ocular or periocular malignancy * Soft Contact lens (excluding bandage contact lens) use within 2 weeks prior to study entry * Persistent epithelial defect (\>1mm and ≥14 days duration) within 2 weeks prior to study entry * Intravitreal or periocular steroids within 4 weeks prior to study entry * Change in dose/frequency of topical steroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to study entry * Poorly controlled Hypertension: systolic blood pressure (BP) \> 150 or diastolic BP \> 90 * Medical history of uncontrolled diabetes mellitus, with hemoglobin A1c (HbA1c) \>7% * Women 45 years of age or younger that are of child bearing potential as defined by: * No history of a hysterectomy * No history of a bilateral oophorectomy (ovariectomy) * No history of a bilateral tubal ligation * Not post-menopausal * Subjects using hormone replacement therapy (HRT) that have experienced total cessation of menses for ≤ 1 year, OR, in questionable cases, have a follicle stimulating hormone (FSH) value \<40 mIU/mL and an estradiol value \> 40pg/mL (\>140 pmol/L) OR have documented evidence OR have had documented evidence of menopause based on FSH and estradiol concentrations prior to initiation of HRT. Signs of current infection, including fever and current treatment with antibiotics * Participation in another simultaneous medical investigation or trial STUDY
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intaocular Pressure | 12 Weeks | Intaocular pressure is the measurement of pressure within the eye. Intaocular pressure was measured throughout the study to assess subjects for ocular adverse events. |
| Heart Rate | 12 Weeks | Heart rate through was measured throughout the study to assess subjects for systemic adverse events. |
| Mean Arterial Pressure | 12 Weeks | Mean arterial pressure was measured throughout the study to assess subjects for systemic adverse events.. |
| Central Corneal Thickness | 12 Weeks | Pachymetry was used to measure the central corneal thickness of each study subject. Central corneal thickness was measured throughout the study to assess subjects for ocular adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Corneal Neovascular Area | Through 12 weeks of Follow-Up | Corneal neovascular area is the measurement of the area of the cornea where new blood vessels are forming. The mean Change in Corneal Neovascular Area from Baseline to 12 Week Time Point is reported below. |
| Corneal Invasion Area | 12 Weeks | Corneal Invasion area is the measurement of the fraction of the total corneal area that is invaded by blood vessels. The mean Change in Corneal invasion area from baseline to 12 Week Time Point is reported below. |
| Corneal Vessel Length | 12 Weeks | Corneal vessel length is the measurement of the length of the extent of vessels from end to end. The mean change in corneal vessel length from Baseline to 12 Week Time Point is reported below. |
| Corneal Vessel Caliber | 12 Weeks | Corneal vessel caliber is the measurement of the diameter of the corneal blood vessels. The mean change in the corneal vessel caliber from baseline to 12 week time point is reported below. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited and consented at the Massachusetts Eye and Ear Infirmary Cornea Department from November 2010 - October 2011.
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib This is a single site, open label, safety and efficacy study of pazopanib (5mg/ml) where all 20 patients with corneal neovascularization in a single arm will receive pazopanib in one eye.
Frequency and Duration: 4 times per day for 3 weeks | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Pazopanib |
|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 19 |
| Central Corneal Thickness | 572 microns STANDARD_DEVIATION 135 |
| Heart Rate | 70.4 Beats per Minute STANDARD_DEVIATION 8.1 |
| Intraocular Pressure | 15.7 mm Hg STANDARD_DEVIATION 5.9 |
| Mean Arterial Pressure | 92.0 mm Hg STANDARD_DEVIATION 1.7 |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 12 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
Central Corneal Thickness
Pachymetry was used to measure the central corneal thickness of each study subject. Central corneal thickness was measured throughout the study to assess subjects for ocular adverse events.
Time frame: 12 Weeks
Population: All enrolled patients were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pazopanib | Central Corneal Thickness | 590 Microns | Standard Deviation 162 |
Primary
Heart Rate
Heart rate through was measured throughout the study to assess subjects for systemic adverse events.
Time frame: 12 Weeks
Population: All enrolled patients were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pazopanib | Heart Rate | 68.7 Beats per Minutes | Standard Deviation 7.6 |
Primary
Intaocular Pressure
Intaocular pressure is the measurement of pressure within the eye. Intaocular pressure was measured throughout the study to assess subjects for ocular adverse events.
Time frame: 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pazopanib | Intaocular Pressure | 16.9 mmHg | Standard Deviation 5.3 |
Primary
Mean Arterial Pressure
Mean arterial pressure was measured throughout the study to assess subjects for systemic adverse events..
Time frame: 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pazopanib | Mean Arterial Pressure | 90.7 mmHG | Standard Deviation 1.4 |
Secondary
Corneal Invasion Area
Corneal Invasion area is the measurement of the fraction of the total corneal area that is invaded by blood vessels. The mean Change in Corneal invasion area from baseline to 12 Week Time Point is reported below.
Time frame: 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pazopanib | Corneal Invasion Area | 3.9 millimeters squared | Standard Deviation 1.8 |
Secondary
Corneal Neovascular Area
Corneal neovascular area is the measurement of the area of the cornea where new blood vessels are forming. The mean Change in Corneal Neovascular Area from Baseline to 12 Week Time Point is reported below.
Time frame: Through 12 weeks of Follow-Up
Population: Mean Change in Corneal Neovascular Area (measuring the area of the corneal vessels) from Baseline to 12 Week Time Point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pazopanib | Corneal Neovascular Area | 1.5 millimeters squared | Standard Deviation 0.8 |
Secondary
Corneal Vessel Caliber
Corneal vessel caliber is the measurement of the diameter of the corneal blood vessels. The mean change in the corneal vessel caliber from baseline to 12 week time point is reported below.
Time frame: 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pazopanib | Corneal Vessel Caliber | 0.0003 millimeters | Standard Deviation 0.0005 |
Secondary
Corneal Vessel Length
Corneal vessel length is the measurement of the length of the extent of vessels from end to end. The mean change in corneal vessel length from Baseline to 12 Week Time Point is reported below.
Time frame: 12 Weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pazopanib | Corneal Vessel Length | 38.0 millimeters | Standard Deviation 17.2 |