Clinical trial NCT01257750: Treatment of Corneal Neovascularization With Topical Pazopanib
Official title: Safety and Efficacy of Topical Pazopanib in Treatment of Corneal Neovascularization
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Corneal Neovascularization
Keywords: corneal neovascularization
pazopanib
votrient
rosacea
Lead sponsor: Massachusetts Eye and Ear Infirmary
Sponsor class: OTHER
First posted: 2010-12-10
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Heart Rate
timeFrame: 12 Weeks
measure: Mean Arterial Pressure
timeFrame: 12 Weeks
measure: Central Corneal Thickness
timeFrame: 12 Weeks
measure: Intaocular Pressure
timeFrame: 12 Weeks
Secondary outcomes:
measure: Corneal Neovascular Area
timeFrame: Through 12 weeks of Follow-Up
measure: Corneal Invasion Area
timeFrame: 12 Weeks
measure: Corneal Vessel Length
timeFrame: 12 Weeks
measure: Corneal Vessel Caliber
timeFrame: 12 Weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts Eye and Ear Infirmary
state: Massachusetts
Study officials:
affiliation: Mass Eye and Ear Infirmary
name: Reza Dana, MD, MPH, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Amparo F, Sadrai Z, Jin Y, Alfonso-Bartolozzi B, Wang H, Shikari H, Ciolino JB, Chodosh J, Jurkunas U, Schaumberg DA, Dana R. Safety and efficacy of the multitargeted receptor kinase inhibitor pazopanib in the treatment of corneal neovascularization. Invest Ophthalmol Vis Sci. 2013 Jan 17;54(1):537-44. doi: 10.1167/iovs.12-11032.