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

September 30, 2025 updated by: E. Sander Connolly

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

60

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Florida
      • Gainesville, Florida, United States, 32611
        • University of Florida
    • New York
      • New York, New York, United States, 10032
        • Columbia University Medical Center
    • Washington
      • Seattle, Washington, United States, 96104
        • University of Washington

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

21 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Sugar Pill, Hunt Hess Grade I-V
Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)
Drug: Placebo
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.
Other Names:
  • placebo, sugar pill
Experimental: Tiopronin, Hunt Hess Grade I-V
Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)
Drug: Tiopronin
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.
Other Names:
  • IUPAC Name:2-(2-sulfanylpropanoylamino)acetic acid
  • CAS Number: 1953-02-2
  • Thiola
  • Thiopronin
  • Thiosol
  • Tioglis
  • Acadione
  • Capen
  • Captimer
  • Epatiol
  • Vincol
  • Mucolysin
  • Sutilan
  • Meprin (detoxicant)
  • Thiolpropionamidoacetic acid
  • N-2-Mercaptopropionyl glycine
  • 2-(2-sulfanylpropanoylamino)ethanoic acid
  • 2-(2-sulfanylpropanoylamino)acetic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels
Time Frame: Day 7
The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care.
Day 7

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels
Time Frame: Day 14
The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care.
Day 14
Modified Rankin Score (mRS) at Discharge
Time Frame: At time of discharge, approximately Day 14
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
At time of discharge, approximately Day 14
Modified Rankin Score (mRS) at 3 Months
Time Frame: 3 months
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
3 months
Modified Rankin Score (mRS) at 12 Months
Time Frame: 12 months
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
12 months
Barthel Index at Discharge
Time Frame: At time of discharge, approximately Day 14
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.
At time of discharge, approximately Day 14
Barthel Index at 3 Months
Time Frame: 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.
3 months
Barthel Index at 12 Months
Time Frame: 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.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

E. Sander Connolly

Collaborators

University of Florida
University of Washington
Food and Drug Administration (FDA)

Investigators

  • Principal Investigator: E Sander Connolly, M.D., Columbia University
  • Principal Investigator: Brian Hoh, M.D., University of Florida
  • Principal Investigator: Louis Kim, M.D., University of Washington

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2010

Primary Completion (Actual)

July 1, 2012

Study Completion (Actual)

July 1, 2013

Study Registration Dates

First Submitted

March 25, 2010

First Submitted That Met QC Criteria

March 26, 2010

First Posted (Estimated)

March 30, 2010

Study Record Updates

Last Update Posted (Estimated)

October 29, 2025

Last Update Submitted That Met QC Criteria

September 30, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AAAA8597
  • 1R01FD003728-01 (U.S. FDA Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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