The Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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Phase II Study of the Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage

Conditions
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Aneurysmal Subarachnoid Hemorrhage

Intervention / Treatment
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* Drug: Tiopronin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Admitted to a recruiting center with aneurysmal subarachnoid hemorrhage Ability to initiate study drug treatment within 96 hours of aSAH onset. Ability to provide either informed or surrogate consent Exclusion Criteria: Hypersensitivity to penicillamine Creatinine level greater than 1.5/mm^3 on admission Platelet count of less than 100,000/mm^3 on admission White blood cell count of less than 3.5/mm^3 on admission AST or ALT of greater than 60/L on admission or history of liver failure Pregnancy History of lupus, Goodpasture's syndrome, myasthenia gravis, pemphigus, nephrotic syndrome, glomerulonephritis, or renal failure Patients considered unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Sugar Pill, Hunt Hess Grade I-III<br>Good Grade (Hunt Hess I-III), n=15 | Drug: Placebo<br>* 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.<br>* Other names: placebo, sugar pill;|
| Experimental: Tiopronin, Hunt Hess Grade I-III<br>Good Grade (Hunt Hess I-III), n=15 | Drug: Tiopronin<br>* 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.<br>* Other names: 2-(2-sulfanylpropanoylamino)acetic acid;|
| Experimental: Tiopronin, Hunt Hess Grade IV-V<br>Poor Grade (Hunt Hess IV-V), n=15 | Drug: Tiopronin<br>* 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.<br>* Other names: 2-(2-sulfanylpropanoylamino)acetic acid;|
| Placebo Comparator: Sugar Pill, Hunt Hess Grade IV-V<br>Poor Grade (Hunt Hess IV-V), n=15 | Drug: Placebo<br>* 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.<br>* Other names: placebo, sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in CSF 3AP Levels | CSF samples taken as a standard of care at each institution will be tested for routine parameters. A small portion of this sample will be saved and sent to Columbia University Medical Center to measure 3AP levels. | Up to 14 days after SAH | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improve Neurological Outcome following aSAH | Outcome assessments will include: Modified Rankin Scale Barthel Index Lawton Physical Self Assessment Test (PSMS) Lawton Instrumental Activities of Daily Living (IADL) NIH Stroke Scale (NIHSS) Telephone Interview Cognitive Status (TICS) | Up to 12 months after discharge from hospital | 
| Improve Neurological Outcome following aSAH | Outcome assessments will include: Modified Rankin Scale Barthel Index Lawton Physical Self Assessment Test (PSMS) Lawton Instrumental Activities of Daily Living (IADL) NIH Stroke Scale (NIHSS) Telephone Interview Cognitive Status (TICS) | Up to 3 months after discharge from hospital | 
| Improve Neurological Outcome following aSAH | Outcome assessments will include: Modified Rankin Scale Barthel Index Lawton Physical Self Assessment Test (PSMS) Lawton Instrumental Activities of Daily Living (IADL) NIH Stroke Scale (NIHSS) Telephone Interview Cognitive Status (TICS) | At time of discharge from hospital | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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aneurysm, aneurysmal, subarachnoid, hemorrhage, haemorrhage, neuroprotection, 3-aminopropanal, 3AP, polyamine oxidase, spermine, spermidine, vasospasm, cerebral ischemia, neurosurgery, neurological intensive care unit, NICU, Tiopronin, Thiola, FDA, Thiopronin, Thiosol, Tioglis, Acadione, Capen, Captimer, Epatiol, Vincol, Mucolysin, Sutilan, Meprin, Thiolpropionamidoacetic acid, Mercaptopropionyl glycine, 2 MPG