The purpose of this phase II study is to further assess the safety of tiopronin in aneurysmal subarachnoid hemorrhage(aSAH) patients in order to obtain preliminary data on the efficacy of tiopronin versus placebo in reducing serum and cerebrospinal fluid (CSF) 3AP levels in this patient population. Funding Source - FDA Office of Orphan Products Development
The annual rate of aSAH in United States is approximately 18 to 24 thousand cases each year. Mortality rates following aSAH range from 30-70% with 10-20% of survivors experiencing severe neurological disability. Following aSAH, a major cause of morbidity and mortality is vasospasm, which causes delayed ischemic neurologic deterioration. There is currently no effective treatment for preventing or ameliorating the damage that occurs following cerebral ischemia. A myriad of neuro-toxins are produced in the ischemic brain resulting in a vicious cycle of cellular death and destruction. The polyamines spermine and spermidine are metabolized by polyamine oxidase (PAO) into putrescine and 3-aminopropanal (3AP). Tiopronin (Thiola) is an FDA approved drug used for the treatment of cystine stones in patients with cystinuria in the U.S. In Europe, it is also used for the treatment of rheumatoid arthritis and bronchial hypersecretion. In previous animal studies, we demonstrated that tiopronin is able to bind and neutralize the toxic effects of 3AP. We have shown in previous studies that aSAH patients have elevated 3AP levels, and higher levels correlate to a poor neurologic outcome. The goals of this phase II multicenter, randomized, double-blinded safety and efficacy trial are to (1) further evaluate the safety of the drug in our patient population at the dose established in phase I; (2) demonstrate that tiopronin crosses the blood-brain barrier; (3) show that both serum and CSF 3AP levels are reduced by administration of tiopronin; and (4) demonstrate that a reduction in 3AP levels is associated with improved neurologic outcome in aSAH patients.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
60
Dosage will be 1 gram, 3 times daily. Drug dosing will be initiated at time of aSAH confirmation, for a length of 14 days or at hospital discharge.
Dosage will be 1 gram, 3 times daily. Drug dosing will be initiated at time of aSAH confirmation, for a length of 14 days or at hospital discharge.
University of Florida
Gainesville, Florida, United States
Columbia University Medical Center
New York, New York, United States
University of Washington
Seattle, Washington, United States
Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels
The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care.
Time frame: Day 7
Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels
The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care.
Time frame: Day 14
Modified Rankin Score (mRS) at Discharge
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
Time frame: At time of discharge, approximately Day 14
Modified Rankin Score (mRS) at 3 Months
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
Time frame: 3 months
Modified Rankin Score (mRS) at 12 Months
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
Time frame: 12 months
Barthel Index at Discharge
Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome.
Time frame: At time of discharge, approximately Day 14
Barthel Index at 3 Months
Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: 3 months
Barthel Index at 12 Months
Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome.
Time frame: 12 months