Crizanlizumab for Treatment of Retinal Vasculopathy With Cerebral Leukoencephalopathy (RVCL)

RVCL - Retinal Vasculopathy Cerebral Leukoencephalopathy Clinical Trial

Official title:

A Trial of Crizanlizumab for the Treatment of Retinal Vasculopathy With Cerebral Leukoencephalopathy (RVCL)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04611880
• Other study ID #: 202008079
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 25, 2021
• Est. completion date: August 25, 2027

Study information

• Verified date: February 2023
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 2 trial that will test the efficacy and safety of crizanlizumab for the treatment of retinal vasculopathy with cerebral leukoencephalopathy (RVCL), a very rare and uniformly fatal genetic condition that affects the microvasculature, especially of the brain and eye. There currently is no treatment for RVCL. A maximum of 20 patients will be enrolled.

Description:

Retinal vasculopathy with cerebral leukoencephalopathy (RVCL) is a very rare and uniformly fatal genetic condition that affects the microvasculature, especially of the brain and eye. Symptoms begin in adulthood (usually in the mid-30s to early 40s) and include loss of vision, mini-strokes, and dementia. Other patients have suffered from microvascular disease involving the kidneys, osteonecrosis, and gut ischemia. Some of these features of microvascular occlusive disease resemble ischemic events that occur during sickle cell disease. Currently, there is no effective treatment for RVCL.

The goal of this study is to test the efficacy of RVCL patients treated with crizanlizumab, a humanized monoclonal anti-P-selectin antibody that prevents leukocyte adhesion to the vascular endothelium, thereby limiting risk of microvascular occlusion. P-selectin is mobilized to the surface of activated vascular endothelial cells and promotes leukocyte adhesion to the blood vessel wall. The Miner laboratory has preliminarily observed a correlation with levels of soluble P-selectin and the number of brain lesions in patients with RVCL. Since leukocyte adhesion to the vascular endothelium promotes microvascular occlusion, we will determine if crizanlizumab will help to limit ischemia and brain lesions in patients with RVCL. This may lead to the development of fewer ischemic brain and eye lesions.

Up to 20 RVCL patients will receive intravenous infusions of crizanlizumab 5 mg/kg at weeks 1 and 3. Thereafter, patients will receive crizanlizumab 5 mg/kg every 28 days for a total of 24 total months. Monitoring will include standard-of-care serial MRI as well as standard-of-care eye disease monitoring at pre-defined intervals. High-risk medication monitoring will include blood work monitoring (CBC/CMP) 1 month after initiation of treatment and every 3 months thereafter. Standard-of-care assessments will be performed including radiological and physical examinations as well as eye imaging and examinations. Patients will be followed for at least 2 years after completion of crizanlizumab administration.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: August 25, 2027
• Est. primary completion date: January 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 25 Years to 75 Years

Eligibility

Inclusion Criteria:

1. A diagnosis of RVCL with confirmation by genetic test

2. At least 25 years of age with imaging evidence of brain or eye disease at the time of study registration

3. Normal hematologic function defined as: White blood cell count (WBC) > 4x109/L, Absolute neutrophil count (ANC) >1.5x109/L and Platelets > 100x109/L

4. Females of childbearing potential (FCBP) must agree to refrain from becoming pregnant while on study drug and for 3 months after discontinuation from study drug, and must agree to use adequate contraception including hormonal contraception, (i.e. birth control pills, etc), barrier method contraception (i.e. condoms), or abstinence during that time-frame

5. Able to understand and willing to sign an Internal Review Board (IRB)-approved written informed consent document (or that of legally authorized representative, if applicable)

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Exclusion Criteria:

1. Acute bacterial, fungal, or viral infection

2. Known HIV, untreated latent tuberculosis (TB), or active hepatitis B or C infection or zoster

3. Pregnant and/or breastfeeding. Negative serum pregnancy test required prior to starting study treatment. For females of child-bearing potential (FCBP), a negative urine pregnancy test is required before each infusion.

4. Known hypersensitivity to one or more of the study agents

5. Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of study drug

6. Liver function tests (LFTs) higher than 3x the upper limit of normal within the last 30 days

7. Treatment with other monoclonal antibody medications within the last 30 days

8. Treatment with various forms of anticoagulation within last 30 days, including but not limited to clopidogrel or coumadin or direct thrombin inhibitors

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Related Conditions & MeSH terms

• Leukoencephalopathies
• RVCL - Retinal Vasculopathy Cerebral Leukoencephalopathy
• Vascular Diseases

Intervention

Drug:
• Crizanlizumab
Drug: crizanlizumab is a humanized monoclonal anti-P-selectin antibody that prevents leukocyte adhesion to the vascular endothelium, thereby limiting risk of microvascular occlusion. It is administered intravenously.

Locations

Country	Name	City	State
United States	Perelman School of Medicine; University of Pennsylvania	Philadelphia	Pennsylvania
United States	Andria Ford	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (5)

Ford AL, Chin VW, Fellah S, Binkley MM, Bodin AM, Balasetti V, Taiwo Y, Kang P, Lin D, Jen JC, Grand MG, Bogacki M, Liszewski MK, Hourcade D, Chen Y, Hassenstab J, Lee JM, An H, Miner JJ, Atkinson JP. Lesion evolution and neurodegeneration in RVCL-S: A monogenic microvasculopathy. Neurology. 2020 Oct 6;95(14):e1918-e1931. doi: 10.1212/WNL.0000000000010659. Epub 2020 Sep 4. Erratum In: Neurology. 2021 May 11;96(19):919. — View Citation

Hasan M, Fermaintt CS, Gao N, Sakai T, Miyazaki T, Jiang S, Li QZ, Atkinson JP, Morse HC 3rd, Lehrman MA, Yan N. Cytosolic Nuclease TREX1 Regulates Oligosaccharyltransferase Activity Independent of Nuclease Activity to Suppress Immune Activation. Immunity. 2015 Sep 15;43(3):463-74. doi: 10.1016/j.immuni.2015.07.022. Epub 2015 Aug 25. — View Citation

Kavanagh D, Spitzer D, Kothari PH, Shaikh A, Liszewski MK, Richards A, Atkinson JP. New roles for the major human 3'-5' exonuclease TREX1 in human disease. Cell Cycle. 2008 Jun 15;7(12):1718-25. doi: 10.4161/cc.7.12.6162. Epub 2008 Jun 16. — View Citation

McEver RP, Cummings RD. Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest. 1997 Dec 1;100(11 Suppl):S97-103. No abstract available. — View Citation

Wood KC, Hebbel RP, Granger DN. Endothelial cell P-selectin mediates a proinflammatory and prothrombogenic phenotype in cerebral venules of sickle cell transgenic mice. Am J Physiol Heart Circ Physiol. 2004 May;286(5):H1608-14. doi: 10.1152/ajpheart.01056.2003. Epub 2004 Jan 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in lesion pattern on Fluid-Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) in RVCL patients.	Volume change in lesions of FLAIR MRI between baseline and one year is assessed.	year

External Links

•   RVCL Research and Treatment Center