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

NCT01095731 | Completed Phase 2 Results DMC

• 2 other identifiers: AAAA85971R01FD003728-01
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 3

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

Conditions

Aneurysmal Subarachnoid Hemorrhage

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  Day 7

Secondary Outcomes (7)

• Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels

  Day 14

• Modified Rankin Score (mRS) at Discharge

  At time of discharge, approximately Day 14

• Modified Rankin Score (mRS) at 3 Months

  3 months

• Modified Rankin Score (mRS) at 12 Months

  12 months

• Barthel Index at Discharge

  At time of discharge, approximately Day 14

Study Arms (2)

Sugar Pill, Hunt Hess Grade I-V

PLACEBO COMPARATOR

Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)

Drug: Placebo

Tiopronin, Hunt Hess Grade I-V

EXPERIMENTAL

Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)

Drug: Tiopronin

Interventions

Tiopronin DRUG

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.

Also known as: 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

Tiopronin, Hunt Hess Grade I-V

Placebo DRUG

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.

Also known as: placebo, sugar pill

Sugar Pill, Hunt Hess Grade I-V

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• E. Sander Connolly: lead
• University of Florida: collaborator
• University of Washington: collaborator
• Food and Drug Administration (FDA): collaborator

Study Sites (3)

University of Florida

Gainesville, Florida, 32611, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

University of Washington

Seattle, Washington, 96104, United States

Location

Related Publications (16)

• Linn FH, Rinkel GJ, Algra A, van Gijn J. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke. 1996 Apr;27(4):625-9. doi: 10.1161/01.str.27.4.625.

  PMID: 8614919 BACKGROUND

• Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke. 1997 Mar;28(3):660-4. doi: 10.1161/01.str.28.3.660.

  PMID: 9056628 BACKGROUND

• Mayer S, Kreiter K. Quality of life after subarachnoid hemorrhage. J Neurosurg. 2002 Sep;97(3):741-2; author reply 742. doi: 10.3171/jns.2002.97.3.0741. No abstract available.

  PMID: 12296671 BACKGROUND

• Kassell NF, Sasaki T, Colohan AR, Nazar G. Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke. 1985 Jul-Aug;16(4):562-72. doi: 10.1161/01.str.16.4.562.

  PMID: 3895589 BACKGROUND

• Solenski NJ, Haley EC Jr, Kassell NF, Kongable G, Germanson T, Truskowski L, Torner JC. Medical complications of aneurysmal subarachnoid hemorrhage: a report of the multicenter, cooperative aneurysm study. Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med. 1995 Jun;23(6):1007-17. doi: 10.1097/00003246-199506000-00004.

  PMID: 7774210 BACKGROUND

• Shohami E, Nates JL, Glantz L, Trembovler V, Shapira Y, Bachrach U. Changes in brain polyamine levels following head injury. Exp Neurol. 1992 Aug;117(2):189-95. doi: 10.1016/0014-4886(92)90126-b.

  PMID: 1499692 BACKGROUND

• Ivanova S, Botchkina GI, Al-Abed Y, Meistrell M 3rd, Batliwalla F, Dubinsky JM, Iadecola C, Wang H, Gregersen PK, Eaton JW, Tracey KJ. Cerebral ischemia enhances polyamine oxidation: identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death. J Exp Med. 1998 Jul 20;188(2):327-40. doi: 10.1084/jem.188.2.327.

  PMID: 9670045 BACKGROUND

• Dogan A, Rao AM, Hatcher J, Rao VL, Baskaya MK, Dempsey RJ. Effects of MDL 72527, a specific inhibitor of polyamine oxidase, on brain edema, ischemic injury volume, and tissue polyamine levels in rats after temporary middle cerebral artery occlusion. J Neurochem. 1999 Feb;72(2):765-70. doi: 10.1046/j.1471-4159.1999.0720765.x.

  PMID: 9930751 BACKGROUND

• Seiler N. Polyamine oxidase, properties and functions. Prog Brain Res. 1995;106:333-44. doi: 10.1016/s0079-6123(08)61229-7.

  PMID: 8584670 BACKGROUND

• Ivanova S, Batliwalla F, Mocco J, Kiss S, Huang J, Mack W, Coon A, Eaton JW, Al-Abed Y, Gregersen PK, Shohami E, Connolly ES Jr, Tracey KJ. Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5579-84. doi: 10.1073/pnas.082609299. Epub 2002 Apr 9.

  PMID: 11943872 BACKGROUND

• Cockroft KM, Meistrell M 3rd, Zimmerman GA, Risucci D, Bloom O, Cerami A, Tracey KJ. Cerebroprotective effects of aminoguanidine in a rodent model of stroke. Stroke. 1996 Aug;27(8):1393-8. doi: 10.1161/01.str.27.8.1393.

  PMID: 8711808 BACKGROUND

• Wood PL, Khan MA, Moskal JR. Neurochemical analysis of amino acids, polyamines and carboxylic acids: GC-MS quantitation of tBDMS derivatives using ammonia positive chemical ionization. J Chromatogr B Analyt Technol Biomed Life Sci. 2006 Feb 2;831(1-2):313-9. doi: 10.1016/j.jchromb.2005.12.031. Epub 2006 Jan 10.

  PMID: 16406747 BACKGROUND

• Wood PL, Khan MA, Moskal JR, Todd KG, Tanay VA, Baker G. Aldehyde load in ischemia-reperfusion brain injury: neuroprotection by neutralization of reactive aldehydes with phenelzine. Brain Res. 2006 Nov 29;1122(1):184-90. doi: 10.1016/j.brainres.2006.09.003. Epub 2006 Oct 5.

  PMID: 17026969 BACKGROUND

• Fisher CM, Kistler JP, Davis JM. Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery. 1980 Jan;6(1):1-9. doi: 10.1227/00006123-198001000-00001.

  PMID: 7354892 BACKGROUND

• Lindell A, Denneberg T, Hellgren E, Jeppsson JO, Tiselius HG. Clinical course and cystine stone formation during tiopronin treatment. Urol Res. 1995;23(2):111-7. doi: 10.1007/BF00307941.

  PMID: 7676533 BACKGROUND

• Ironside N, Christophe B, Bruce S, Carpenter AM, Robison T, Yoh N, Cremers S, Landry D, Frey HP, Chen CJ, Hoh BL, Kim LJ, Claassen J, Connolly ES. A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage. J Neurosurg. 2019 Jul 12;133(2):351-359. doi: 10.3171/2019.4.JNS19478. Print 2020 Aug 1.

  PMID: 31299655 DERIVED

Related Links

• The Columbia University Medical Center Department of Neurosurgery Website
• The University of Florida Department of Neurosurgery Website
• The University of Washington Department of Neurosurgery Website
• Principle Investigator: E. Sander Connolly Jr.
• Connolly Cerebrovascular Research Laboratory

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Aneurysm; Hemorrhage; Brain Ischemia

Interventions

Tiopronin; Sugars

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins; N-substituted Glycines; Glycine; Carbohydrates

Results Point of Contact

• Title: E. Sander Connolly Jr., MD
• Organization: Columbia University Irving Medical Center

esc5@cumc.columbia.edu

212-305-0376

Study Officials

• 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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurological Surgery

Study Record Dates

• First Submitted: March 25, 2010
• First Posted: March 30, 2010
• Study Start: April 1, 2010
• Primary Completion: July 1, 2012
• Study Completion: July 1, 2013
• Last Updated: October 29, 2025
• Results First Posted: October 29, 2025

Record last verified: 2025-09

Locations

US (3)