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

This study has been completed.
Sponsor:
Collaborators:
University of Florida
University of Washington
Information provided by (Responsible Party):
E. Sander Connolly, Columbia University
ClinicalTrials.gov Identifier:
NCT01095731
First received: March 25, 2010
Last updated: July 25, 2014
Last verified: July 2014

March 25, 2010
July 25, 2014
April 2010
July 2012   (final data collection date for primary outcome measure)
Reduction in CSF 3AP Levels [ Time Frame: Up to 14 days after SAH ] [ Designated as safety issue: No ]
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.
Reduction in CSF 3AP Levels [ Time Frame: CSF samples will be taken every day for 14 days after SAH ] [ Designated as safety issue: No ]
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.
Complete list of historical versions of study NCT01095731 on ClinicalTrials.gov Archive Site
  • Improve Neurological Outcome following aSAH [ Time Frame: Up to 12 months after discharge from hospital ] [ Designated as safety issue: No ]

    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)
  • Improve Neurological Outcome following aSAH [ Time Frame: Up to 3 months after discharge from hospital ] [ Designated as safety issue: No ]

    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)
  • Improve Neurological Outcome following aSAH [ Time Frame: At time of discharge from hospital ] [ Designated as safety issue: No ]

    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)
  • Improve Neurological Outcome following aSAH [ Time Frame: 12 months after discharge from hospital ] [ Designated as safety issue: No ]

    Outcome assessments will include:

    • Modified Rankin Scale
    • extended Glasgow Outcome Scale (eGOS)
    • Barthel Index
    • Sickness Impact Profile (SIP)
    • Lawton Physical Self Assessment Test (PSMS)
    • Lawton Instrumental Activities of Daily Living (IADL)
    • NIH Stroke Scale (NIHSS)
    • Telephone Interview Cognitive Status (TICS)
    • Visual Search and Attention Test (VSAT)
  • Improve Neurological Outcome following aSAH [ Time Frame: 3 months after discharge from hospital ] [ Designated as safety issue: No ]

    Outcome assessments will include:

    • Modified Rankin Scale
    • extended Glasgow Outcome Scale (eGOS)
    • Barthel Index
    • Sickness Impact Profile (SIP)
    • Lawton Physical Self Assessment Test (PSMS)
    • Lawton Instrumental Activities of Daily Living (IADL)
    • NIH Stroke Scale (NIHSS)
    • Telephone Interview Cognitive Status (TICS)
    • Visual Search and Attention Test (VSAT)
  • Improve Neurological Outcome following aSAH [ Time Frame: At time of discharge from hospital ] [ Designated as safety issue: No ]

    Outcome assessments will include:

    • Modified Rankin Scale
    • extended Glasgow Outcome Scale (eGOS)
    • Barthel Index
    • Sickness Impact Profile (SIP)
    • Lawton Physical Self Assessment Test (PSMS)
    • Lawton Instrumental Activities of Daily Living (IADL)
    • NIH Stroke Scale (NIHSS)
    • Telephone Interview Cognitive Status (TICS)
    • Visual Search and Attention Test (VSAT)
  • Monitoring of Adverse Events [ Time Frame: Throughout duration of study ] [ Designated as safety issue: Yes ]
    All adverse events, neurological and non-neurological, will be recorded by the study coordinator. A data and safety monitoring board (DSMB) consisting of a non-study neurosurgeon, a non-study neurologist, and a biostatistician will review subject clinical research forms (CRFs) every 3 months or 30 patients. Each patient will be examined as part of clinical care at least once each day.
Not Provided
Not Provided
 
The Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage
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

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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Aneurysmal Subarachnoid Hemorrhage
  • Drug: Tiopronin for Hunt Hess grades I-III
    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
  • Drug: Placebo for Hunt Hess grades I-III
    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 Name: placebo, sugar pill
  • Drug: Placebo for Hunt Hess grades IV-V
    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 Name: placebo, sugar pill
  • Drug: Tiopronin for Hunt Hess grades IV-V
    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
  • Placebo Comparator: Sugar Pill, Hunt Hess Grade I-III
    Good Grade (Hunt Hess I-III), n=15
    Intervention: Drug: Placebo for Hunt Hess grades I-III
  • Experimental: Tiopronin, Hunt Hess Grade I-III
    Good Grade (Hunt Hess I-III), n=15
    Intervention: Drug: Tiopronin for Hunt Hess grades I-III
  • Experimental: Tiopronin, Hunt Hess Grade IV-V
    Poor Grade (Hunt Hess IV-V), n=15
    Intervention: Drug: Tiopronin for Hunt Hess grades IV-V
  • Placebo Comparator: Sugar Pill, Hunt Hess Grade IV-V
    Poor Grade (Hunt Hess IV-V), n=15
    Intervention: Drug: Placebo for Hunt Hess grades IV-V

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
60
July 2013
July 2012   (final data collection date for primary outcome measure)

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
Both
21 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01095731
AAAA8597, 1R01FD003728-01
Yes
E. Sander Connolly, Columbia University
E. Sander Connolly
  • University of Florida
  • University of Washington
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
Columbia University
July 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP