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

Phase 2

Completed

• Conditions: Aneurysmal Subarachnoid Hemorrhage
• Interventions: Drug: Placebo; Drug: Tiopronin

• Registration Number: NCT01095731
• Lead Sponsor: E. Sander Connolly

Brief Summary

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

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2010-03-25
• Study First Submitted QC: 2010-03-26
• Study First Posted: 2010-03-30
• Study Start: 2010-04
• Primary Completion: 2012-07
• Study Completion: 2013-07
• Status Verified: 2020-09
• Last Update Submitted: 2020-09-01
• Last Update Posted: 2020-09-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sugar Pill, Hunt Hess Grade I-III	Placebo	Good Grade (Hunt Hess I-III), n=15
Sugar Pill, Hunt Hess Grade IV-V	Placebo	Poor Grade (Hunt Hess IV-V), n=15
Tiopronin, Hunt Hess Grade I-III	Tiopronin	Good Grade (Hunt Hess I-III), n=15
Tiopronin, Hunt Hess Grade IV-V	Tiopronin	Poor Grade (Hunt Hess IV-V), n=15

Primary Outcome Measures

Name	Time	Method
Reduction in CSF 3AP Levels	Up to 14 days after SAH	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.

Secondary Outcome Measures

Name	Time	Method
Improve Neurological Outcome following aSAH	At time of discharge from hospital	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)

Trial Locations

Locations (3)

Columbia University Medical Center; 🇺🇸 New York, New York, United States

University of Washington; 🇺🇸 Seattle, Washington, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States