A Phase I/II Trial for Intravitreous Treatment of Severe Ocular Von Hippel-Lindau Disease Using a Combination of the PDGF Antagonist E10030 and the VEGF Antagonist Ranibizumab
- Registration Number
- NCT02859441
- Lead Sponsor
- National Eye Institute (NEI)
- Brief Summary
Background: People with Von-Hippel-Lindau (VHL) disease may experience significant vision loss as a result of retinal capillary hemangiomas (RCH), the most common and often earliest manifestation of VHL.
Objective: To investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease.
Design: Three participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks.
Primary Outcome: The safety of the combination investigational treatment, assessed by tabulation of adverse events reported through Week 52.
- Detailed Description
Objective: Von Hippel-Lindau (VHL) disease 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. The disease affects about 7,000 individuals in the United States. Retinal capillary hemangiomas (RCH) are the most common and often the earliest manifestation of VHL disease and may lead to significant vision loss. In some such eyes, inexorable progression of RCH leads to blindness and phthisis bulbi despite aggressive treatment. Levels of vascular endothelial growth factor (VEGF), a potent mediator of angiogenesis and vascular permeability, have been shown to be elevated in multiple cell types deficient in the VHL protein (pVHL). Platelet-derived growth factor (PDGF), which has an important role in stabilization of immature new vessels during angiogenesis, is upregulated in pVHL-defective cell lines and expressed in other pVHL-defective tumors. Anti-VEGF therapy alone had no beneficial effect on ocular VHL disease in two previous phase 1 studies. The objective of this study is to investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease.
Study Population: Three participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks.
Design: In this phase I/II, single-center, prospective, open label, non-randomized, uncontrolled, single group trial, one eye of eligible participants will be treated with investigational products, E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist. Participants will receive combination investigational treatment consisting of intravitreal injections of E10030 (1.5 mg in 0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) every four weeks from baseline through Week 16 (totaling five treatments) and then every eight weeks through Week 48 (totaling nine treatments from baseline). All participants will be followed for 104 weeks.
Outcome Measures: The primary outcome for the study will be safety of the combination investigational treatment, assessed by tabulation of adverse events reported through Week 52. Secondary outcomes will include tabulation of adverse events at Week 104, and the following measures in the study eye at Week 52 and 104: the proportion of participants experiencing reduction in size of at least one RCH in the absence of other ablative treatment (assessed by fundus photography and fluorescein angiography (FA)); the proportion of participants experiencing moderate vision loss (defined as a loss of greater than or equal to 15 letters from baseline on Electronic Visual Acuity (EVA) testing); mean change in visual acuity; change in size of RCH (measured by fundus photography and FA); change in exudation (measured by fundus photography, optical coherence tomography (OCT) and FA); change in epiretinal proliferation, fibrosis or retinal traction (assessed by OCT and fundus photography); proportion of participants undergoing ablative treatment of RCH or ocular surgery; proportion of participants with successful ablative treatment of RCH; and the proportion of participants with appearance of one or more new RCH.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 3
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description E10030 and Ranibizumab Ranibizumab Intravitreal injections of E10030 and Ranibizumab E10030 and Ranibizumab E10030 Intravitreal injections of E10030 and Ranibizumab
- Primary Outcome Measures
Name Time Method Tabulation of Adverse Events From Baseline to Week 52 The total number of adverse events through Week 52.
- Secondary Outcome Measures
Name Time Method Tabulation of Adverse Events From Baseline to Week 104 The total number of adverse events, excluding natural progression of disease events, through Week 104.
The Proportion of Participants Experiencing Reduction in Size of at Least One Retinal Capillary Hemangioma (RCH), in the Absence of Other Ablative Treatment (Assessed by Fundus Photography and Fluorescein Angiography (FA)) From Baseline to Week 52 The proportion of participants experiencing a reduction in size of at least one RCH in the study eye, in the absence of other ablative treatment as assessed by fundus photography and fluorescein angiography (FA), between Baseline and Week 52.
Proportion of Participants With Successful Ablative Treatment of RCH From Baseline to Week 104 The proportion of participants with successful ablative treatment of RCH in the study eye between Baseline and Week 104.
Proportion of Participants Undergoing Ablative Treatment of RCH or Ocular Surgery From Baseline to Week 104 The proportion of participants undergoing ablative treatment of RCH or ocular surgery in the study eye between Baseline and Week 104.
Mean Change in Visual Acuity Baseline and Week 104 Mean change in visual acuity in the study eye from Baseline as compared to Week 104 as measured using the Electronic Early Treatment of Diabetic Retinopathy Study (ETDRS) Visual Acuity (EVA) Testing protocol. Acuity is measured as letters read using an electronic ETDRS program.
Change in Size of RCH (Measured by Fundus Photography and FA) From Baseline to Week 104 Number of participants who experienced increased, decreased, or mixed change in the size of RCH in the study eye between Baseline and Week 104 (measured by fundus photography and FA).
The Proportion of Participants Experiencing Reduction in Size of at Least One RCH, in the Absence of Other Ablative Treatment (Assessed by Fundus Photography and Fluorescein Angiography [FA]) From Baseline to Week 104 The proportion of participants experiencing a reduction in size of at least one RCH in the study eye, in the absence of other ablative treatment as assessed by fundus photography and fluorescein angiography (FA), between Baseline and Week 104.
The Proportion of Participants Experiencing Moderate Vision Loss (Defined as a Loss of Greater Than or Equal to 15 Letters From Baseline on Electronic Visual Acuity [EVA] Testing) From Baseline to Week 104 The proportion of participants experiencing moderate vision loss in the study eye (defined as a loss of greater than or equal to 15 letters from baseline on Electronic Visual Acuity \[EVA\] testing) between Baseline and Week 104.
Change in Exudation (Measured by Fundus Photography, Optical Coherence Tomography (OCT) and FA) From Baseline to Week 52 Number of participants who experienced increased, decreased, or mixed change in exudation in the study eye between Baseline and Week 52 (measured by fundus photography, optical coherence tomography \[OCT\] and FA).
Change in Exudation (Measured by Fundus Photography, Optical Coherence Tomography [OCT] and FA) From Baseline to Week 104 Number of participants who experienced increased, decreased, or mixed change in exudation in the study eye between Baseline and Week 104 (measured by fundus photography, optical coherence tomography \[OCT\] and FA).
Change in Epiretinal Proliferation, Fibrosis or Retinal Traction (Assessed by OCT and Fundus Photography) From Baseline to Week 104 Number of participants who experienced increased, decreased, or mixed change in epiretinal proliferation, fibrosis or retinal traction in the study eye between Baseline and Week 104 (assessed by OCT and fundus photography).
Proportion of Participants With Appearance of One or More New RCH From Baseline to Week 104 The proportion of participants with appearance of one or more new RCH in the study eye between Baseline and Week 104.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States