A phase 2 study of tramiprosate for cerebral amyloid angiopathy.
OBJECTIVE
No treatments have been identified to lower the risk of intracerebral hemorrhage due to cerebral amyloid angiopathy (CAA). A potential approach to prevention is the use of agents that interfere with the pathogenic cascade initiated by the beta-amyloid peptide (Abeta). Tramiprosate (3-amino-1-propanesulfonic acid) is a candidate molecule shown in preclinical studies to reduce CAA in a transgenic mouse model.


METHODS
We performed a 5-center phase 2 double-blinded trial to evaluate the safety, tolerability, and pharmacokinetics of tramiprosate in subjects with lobar intracerebral hemorrhage. Twenty-four subjects age > or =55 years with possible or probable CAA were randomized to receive 12 weeks of tramiprosate at 1 of 3 oral doses (50, 100, or 150 mg twice daily). Subjects were followed for clinical adverse effects, laboratory, vital sign, electrocardiogram, cognitive, or functional changes, appearance of new symptomatic or asymptomatic hemorrhages, and pharmacokinetic parameters.


RESULTS
Enrolled subjects were younger (mean age 70.8+/-5.4, range 61 to 78) and had more advanced baseline disease (measured by number of previous hemorrhages) than consecutive subjects in a CAA natural history cohort. No concerning safety issues were encountered with treatment. Nausea and vomiting were the most common adverse events and were more frequent at high doses. Nine subjects had new symptomatic or asymptomatic hemorrhages during treatment; all occurred in subjects with advanced baseline disease, with no apparent effect of drug dosing assignment.


CONCLUSIONS
These data suggest that tramiprosate can be given safely to subjects with suspected CAA and support future efficacy trials.
Greenberg
Steven M
SM
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. sgreenberg@partners.org
Rosand
Jonathan
J
Schneider
Alexander T
AT
Creed Pettigrew
L
L
Gandy
Samuel E
SE
Rovner
Barry
B
Fitzsimmons
Brian-Fred
BF
Smith
Eric E
EE
Edip Gurol
M
M
Schwab
Kristin
K
Laurin
Julie
J
Garceau
Denis
D
D000368:Aged; D019540:Area Under Curve; D016657:Cerebral Amyloid Angiopathy / Q000150:complications / Q000188:drug therapy*; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018755:GABA Agonists / Q000009:adverse effects* / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D013654:Taurine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D018755:GABA Agonists; D013654:Taurine; C001355:tramiprosate