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

2014-08-27 03:54:09 | BioPortfolio


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.

Study Design

Primary Purpose: Treatment


Von Hippel-Lindau Syndrome




National Institutes of Health Clinical Center, 9000 Rockville Pike
United States




National Institutes of Health Clinical Center (CC)

Results (where available)

View Results


Published on BioPortfolio: 2014-08-27T03:54:09-0400

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Medical and Biotech [MESH] Definitions

A ubiquitin-protein ligase that mediates OXYGEN-dependent polyubiquitination of HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT. It is inactivated in VON HIPPEL-LINDAU SYNDROME.

An autosomal dominant disorder caused by mutations in a tumor suppressor gene. This syndrome is characterized by abnormal growth of small blood vessels leading to a host of neoplasms. They include HEMANGIOBLASTOMA in the RETINA; CEREBELLUM; and SPINAL CORD; PHEOCHROMOCYTOMA; pancreatic tumors; and renal cell carcinoma (see CARCINOMA, RENAL CELL). Common clinical signs include HYPERTENSION and neurological dysfunctions.

A benign tumor of the nervous system that may occur sporadically or in association with VON HIPPEL-LINDAU DISEASE. It accounts for approximately 2% of intracranial tumors, arising most frequently in the cerebellar hemispheres and vermis. Histologically, the tumors are composed of multiple capillary and sinusoidal channels lined with endothelial cells and clusters of lipid-laden pseudoxanthoma cells. Usually solitary, these tumors can be multiple and may also occur in the brain stem, spinal cord, retina, and supratentorial compartment. Cerebellar hemangioblastomas usually present in the third decade with INTRACRANIAL HYPERTENSION, and ataxia. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2071-2)

A recombinant humanized monoclonal antibody fragment that binds VEGF-A to prevent its binding to VEGFR-1 and VEGFR-2 receptors. This activity reduces vessel permeability and angiogenesis in the treatment of neovascular age-related MACULAR DEGENERATION.

Condition with a variable constellation of phenotypes due to deletion polymorphisms at chromosome location 22q11. It encompasses several syndromes with overlapping abnormalities including the DIGEORGE SYNDROME, VELOCARDIOFACIAL SYNDROME, and CONOTRUNCAL AMOMALY FACE SYNDROME. In addition, variable developmental problems and schizoid features are also associated with this syndrome. (From BMC Med Genet. 2009 Feb 25;10:16) Not all deletions at 22q11 result in the 22q11deletion syndrome.

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