This study will examine whether he drug ranibizumab can slow or stop the growth of angiomas
(blood vessel tumors) in patients with Von Hippel-Lindau syndrome (VHL). Angiomas commonly
develop in the back of the eye on the retina and the optic nerve in patients with VHL.
Although these 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. Ranibizumab decreases production of VEGF, a growth factor that is
important for the formation of new blood vessels and that is elevated in patients with VHL.
Preliminary findings from other studies suggest that ranibizumab can reduce retinal
thickening caused by vessel and tumor growth 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 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 show 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.
- 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.
- 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.
- Ranibizumab injections to treat ocular angiomas. Ranibizumab is injected through a
needle into the eye's vitreous (gel-like substance that fills the inside of the eye).
Seven injections are given over a 28-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 the eye in the clear tissue surrounding the white
of the eye. After a few minutes, the ranibizumab is injected into the vitreous.
Patients receive ranibizumab injections at the first visit (during enrollment) and
again at 4, 8, 12, 16, 20 and 24 weeks after the first injection. At the 28-week visit,
the doctor will determine if further treatment is needed. Patients can continue to have
injections every 4 weeks until 1 year of follow-up (54 weeks).
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.
Von Hippel-Lindau Syndrome (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 an anti-VEGF therapy, ranibizumab (rhuFab V2) in 5 participants to
investigate the potential efficacy as a treatment for retinal angiomas associated with VHL.
Participants will receive 7 intravitreal injections of study drug over a 6 month period,
with the option of up to seven additional injections at the same dose and schedule during
follow-up for a maximum period of 1 year after the initiation of treatment. The primary
outcome will be a change in the best corrected visual acuity of 15 letters or more eight
weeks after a participant receives the final study injection. The secondary outcomes will be
a reduction in retinal thickening and leakage eight weeks after the participants receives
the final study injection, and adverse events including local and systemic toxicities.
- INCLUSION CRITERIA:
1. Participant must understand and sign the informed consent.
2. Participant must be at least 18 years of age.
3. Participant must have retinal angiomas secondary to VHL in one or both eyes.
4. Participant must have either optic nerve tumors or peripheral tumors that have
caused central vision loss of 20/40 or worse.
5. Participant must have clear ocular media and adequate papillary dilation to
permit good quality stereoscopic fundus photography.
6. All women of childbearing potential must have a negative urine pregnancy test at
baseline, and be willing to undergo urine pregnancy testing immediately prior to
each injection, and monthly for at least 2 months following the last dose of
7. Women of child-bearing potential who are sexually active and men who are
sexually active are required to use two forms of birth control during the course
of the study.
1. History (within past 5 years) or evidence of severe cardiac disease (apparent in
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).
2. History of stroke within 12 months of study entry.
3. History within the past five years of a chronic ocular or periocular infection
(including any history of ocular herpes zoster).
4. Current acute ocular or periocular infection.
5. Any major surgical procedure within one month of study entry.
6. Known serious allergies to fluorescein dye.
7. Previous participation in a clinical trial (for either eye) involving anti-angiogenic
drugs (pegaptanib, ranibizumab, anecortave acetate, Protein Kinase C inhibitors,
8. Previous intravitreal drug delivery (e.g., intravitreal corticosteroid injection or
device implantation) in the study eye.
9. History of vitrectomy surgery in the study eye.
10. History of glaucoma filtering surgery in the study eye.
11. History of corneal transplant in the study eye.