EYE001 to Treat Retinal Tumors in Patients With Von Hippel-Lindau Syndrome

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Brief Title

EYE001 to Treat Retinal Tumors in Patients With Von Hippel-Lindau Syndrome

Official Title

Pilot Study of Intravitreal Injection of EYE001 (Anti-VEGF Pegylated Aptamer) for Advanced Ocular Disease of Von Hippel-Lindau (VHL) Disease

Brief Summary

      This study will test the ability of the experimental drug EYE001 to reduce retinal thickening
      and improve vision in patients with Von Hippel-Lindau syndrome (VHL). Angiomas (blood vessel
      tumors) commonly develop in the back of the eye on the retina and the optic nerve in patients
      with VHL. Although the tumors are not cancerous, they may cause significant vision loss.
      Current treatments, including laser therapy, cryotherapy, and vitrectomy, may not be
      successful or possible for all patients. EYE001 decreases production of VEGF, a growth factor
      that is important for the formation of new blood vessels and that is elevated in VHL.
      Preliminary findings from studies of other retinal diseases suggest that EYE001 can reduce
      retinal thickening and improve vision.

      Patients 18 years of age and older with retinal angiomas due to VHL in one or both eyes and
      central vision loss of 20/40 or worse may be eligible for this study. Participants will
      undergo the following tests and procedures:

        -  Medical history, physical examination, electrocardiogram (EKG) and blood tests.

        -  Eye examination, including eye pressure measurement and dilation of the pupils to
           examine the retina.

        -  Fluorescein angiography to evaluate the eye's blood vessels. For this test, a yellow dye
           is injected into an arm vein and travels to the blood vessels in the eyes. Pictures of
           the retina are taken using a camera that flashes a blue light into the eye. The pictures
           will reveal if any dye has leaked from the vessels into the retina, indicating possible
           blood vessel abnormality.

        -  Optical coherence tomography to measure retinal thickness. The eyes are examined through
           a machine that produces cross-sectional pictures of the retina. These measures are
           repeated during the study to determine changes, if any, in retinal thickening.

        -  Electroretinogram (ERG) to measure electrical responses generated from within the
           retina. For this test, the patient sits in a dark room for 30 minutes with his or her
           eyes patched. Then, a small silver disk electrode is taped to the forehead, the eye
           patches are removed, the surface of the eye is numbed with eye drops, and contact lenses
           are placed on the eyes. The patient looks inside an open white globe that emits a series
           of light flashes for about 20 minutes. The contact lenses sense small electrical signals
           generated by the retina when the light flashes.

        -  Stereoscopic color fundus photography to examine the back of the eye. The pupils are
           dilated with eye drops to examine and photograph the back of the eye.

        -  EYE001 injections to treat ocular angiomas. Patients receive EYE001 injections through a
           needle into the eye's vitreous (gel-like substance that fills the inside of the eye).
           Six injections are given over a 30-week period. Before each injection, the surface of
           the eye is numbed with anesthetic eye drops. This is followed by injection of another
           anesthetic into the lower portion of they eye in the clear tissue surrounding the white
           of the eye. After a few minutes, the EYE001 is injected into the vitreous. Patients
           receive EYE001 injections at the first visit (during enrollment) and again at 6, 12, 18,
           24, and 30 weeks after the first injection.

      At each injection visit, participants repeat most of the tests described above to evaluate
      the response to treatment and return a week later for another eye examination. After the last
      injection, patients whose vision has improved may receive three more treatments at visits 36,
      42, and 48. All participants will return for examinations at week 54 and at 2 months after
      their final injection.
    

Detailed Description

      Von Hippel-Lindau (VHL) is an autosomal dominant heritable disorder in which multiple benign
      and malignant neoplasms and cysts of specific histopathologies develop in the kidney, adrenal
      gland, pancreas, brain, spinal cord, eye, inner ear, epididymis, and broad ligament. Retinal
      angioma may be one of the earliest manifestations of VHL disease and may lead to a
      significant decrease in visual acuity of the affected individual. These tumors rarely regress
      spontaneously. The main cause of vision loss is retinal edema, specifically macular edema
      secondary to enlargement of peripheral retinal angiomas or angiomas found on or around the
      optic disk. Treatment of retinal angiomas depends on the location and size of the lesions but
      typically consists of photocoagulation or cryotherapy. However, there is no proven effective
      therapy for the treatment of VHL ocular lesions on or surrounding the optic nerve or lesions
      in the peripheral retina too large to respond to the traditional therapies. The genetic
      mutation found in VHL disease up-regulates the production of vascular endothelial growth
      factor (VEGF). Immunochemical studies of the VHL ocular lesions, as well as others found
      elsewhere in the body show marked increase in VEGF. This open-label study will pilot the use
      of anti-VEGF therapy (EYE001) in 5 patients to investigate the potential efficacy as a
      treatment for retinal angiomas associated with VHL. Patients will receive 6 intravitreal
      injections of study drug over a 30-week period, then return for a follow-up visit 1 year
      after initiating injections. The primary outcomes will be improvement in best corrected
      visual acuity of 15 letters or more at 1 year, reduction in retinal thickening and leakage at
      one year, changes in ERG amplitude and implicit time, and adverse events including local and
      systemic toxicities.
    

Study Phase

Phase 1

Study Type

Interventional




Condition

Hippel-Lindau Disease

Intervention

EYE001


Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

5

Start Date

March 2003

Completion Date

November 2005


Eligibility Criteria

        INCLUSION CRITERIA:

        Patient must understand and sign the informed consent.

        Patient must be at least 18 years of age.

        Patient must have retinal angiomas secondary to VHL in one or both eyes.

        Patient must have either optic nerve tumors or peripheral tumors that have caused central
        vision loss of 20/40 or worse.

        Patient must have clear ocular media and adequate papillary dilation to permit good quality
        stereoscopic fundus photography.

        Patients must be post menopausal, surgically sterile for at least 12 months prior to study
        entry, or agree to use at least two effective forms of birth control.

        All women of childbearing potential must have a negative serum pregnancy test at baseline
        and immediately prior to each injection and for at least 60 days following the last dose of
        EYE001.

        Patient must have lab values indicative of adequate hematological function (hemoglobin
        greater than or equal to 10 g/dl, platelet count less than or equal to 130 x 10(9)/I, WBC
        3.8-10.8 x 10(9)/I) within one month of baseline.

        Patients must have lab values indicative of adequate liver function (serum bilirubin less
        than or equal to 1.5 mg/dl, SGOT/ALT, SGPT/AST, GGT and alkaline phosphotase within 2 x
        ULN) within one month of baseline.

        Patients must have lab values indicative of adequate renal function serum creatinine less
        than or equal to 2.0 mg/dl and BUN within 2.0 x ULN within one month of baseline.

        EXCLUSION CRITERIA:

        Significant media opacities, including cataract that precludes quality fundus photographs
        of the posterior pole.

        History or evidence of severe cardiac disease (electrocardiogram abnormalities, clinical
        history of unstable angina, acute coronary syndrome, myocardial infarction,
        revascularization procedure within 6 months prior to baseline, atrial or ventricular
        tachyarrythmias requiring ongoing treatment).

        History of stroke within 12 months of study entry.

        History of or current acute ocular or periocular infection (including any history of ocular
        herpes zoster).

        Any major surgical procedure within one month of study entry.

        Known serious allergies to fluorescein dye.
      

Gender

All

Ages

N/A - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00056199

Organization ID

030101

Secondary IDs

03-EI-0101


Study Sponsor

National Eye Institute (NEI)


Study Sponsor

, , 


Verification Date

November 2005