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

Aneurysmal Subarachnoid Hemorrhage Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01095731
• Other study ID #: AAAA8597
• Secondary ID: 1R01FD003728-01
• Status: Completed
• Phase: Phase 2
• Start date: April 2010
• Est. completion date: July 2013

Study information

• Verified date: September 2020
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: July 2013
• Est. primary completion date: July 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aneurysmal Subarachnoid Hemorrhage
• Hemorrhage
• Subarachnoid Hemorrhage

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida
United States	Columbia University Medical Center	New York	New York
United States	University of Washington	Seattle	Washington

Sponsors (4)

Lead Sponsor	Collaborator
E. Sander Connolly	Food and Drug Administration (FDA), University of Florida, University of Washington

Country where clinical trial is conducted

United States, 

References & Publications (15)

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. Epub 2002 Apr 9. — View Citation

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. — View Citation

Kassell NF, Sasaki T, Colohan AR, Nazar G. Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke. 1985 Jul-Aug;16(4):562-72. Review. — View Citation

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. — View Citation

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. — View Citation

Mayer S, Kreiter K. Quality of life after subarachnoid hemorrhage. J Neurosurg. 2002 Sep;97(3):741-2; author reply 742. — View Citation

Seiler N. Polyamine oxidase, properties and functions. Prog Brain Res. 1995;106:333-44. Review. — View Citation

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. — View Citation

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. — View Citation

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. Epub 2006 Oct 5. — View Citation

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. Epub 2006 Jan 10. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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

External Links

•   Connolly Cerebrovascular Research Laboratory
•   Principle Investigator: E. Sander Connolly Jr.
•   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