: There is no known therapy for Cerebral Amyloid Angiopathy (CAA), an important cause of hemorrhagic stroke and other clinical syndromes in the elderly. The pathologic basis of CAA-related stroke is deposition of the Amyloid B-peptide (AB) in cerebral vessels, and resultant degeneration of the vessel wall. We propose a multi-center, phase II pilot study of the safety, tolerability, and preliminary efficacy of NC-758 for secondary prevention of recurrent CAA-related intracerebral hemorrhage. NC-758 is a small molecule designed to compete with glycosaminoglycans for binding to AB. Preliminary studies have demonstrated that this compound penetrates to the CNS, inhibits AB fibril formation and AB-induced cellular toxicity, and reduces severity of CAA in a transgenic mouse model without evidence for major intrinsic toxicity. The proposed trial builds on progress by the Principal Investigator in the diagnosis and staging of CAA. Participants will be survivors of lobar hemorrhagic stroke, considered at high-risk for recurrence based on baseline gradient-echo MRI scan, or apolipoprotein-E genotype. An anticipated 280 patients will be screened at 20 participating sites, and 210 patients randomized to receive low-dose NC-758, high-dose NC-758, or placebo. Patients will be treated for a 16-month period, and followed for adverse clinical events, laboratory abnormalities, and recurrent stroke or decline in cognitive, functional, or neurologic status. At 8 and 16 months of treatment, subjects will undergo follow-up MRI scans to determine the appearance of new hemorrhagic lesions during treatment. The proposed sample size is calculated to have high likelihood of detecting major adverse effects associated with NC-758, and for detecting a 50% reduction in appearance of new symptomatic and asymptomatic hemorrhages. In addition to testing a promising agent for CAA, the proposed study will generate the organization and pilot data to serve as a springboard for future trials of emerging anti-amyloid treatments. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS041409-01A1
Application #
6576291
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Gilbert, Peter R
Project Start
2003-02-01
Project End
2006-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$379,235
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Salat, David H; Smith, Eric E; Tuch, David S et al. (2006) White matter alterations in cerebral amyloid angiopathy measured by diffusion tensor imaging. Stroke 37:1759-64
Zhang-Nunes, Sandy X; Maat-Schieman, Marion L C; van Duinen, Sjoerd G et al. (2006) The cerebral beta-amyloid angiopathies: hereditary and sporadic. Brain Pathol 16:30-9
Greenberg, Steven M; Rosand, Jonathan; Schneider, Alexander T et al. (2006) A phase 2 study of tramiprosate for cerebral amyloid angiopathy. Alzheimer Dis Assoc Disord 20:269-74
Rosand, Jonathan; Muzikansky, Alona; Kumar, Ashok et al. (2005) Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy. Ann Neurol 58:459-62
Greenberg, Steven M; Eng, Jessica A; Ning, MingMing et al. (2004) Hemorrhage burden predicts recurrent intracerebral hemorrhage after lobar hemorrhage. Stroke 35:1415-20
Greenberg, Steven M; Gurol, M Edip; Rosand, Jonathan et al. (2004) Amyloid angiopathy-related vascular cognitive impairment. Stroke 35:2616-9