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: January 28, 2014
Last verified: January 2014
  Purpose

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


Condition Intervention Phase
Aneurysmal Subarachnoid Hemorrhage
Drug: Tiopronin for Hunt Hess grades I-III
Drug: Placebo for Hunt Hess grades I-III
Drug: Placebo for Hunt Hess grades IV-V
Drug: Tiopronin for Hunt Hess grades IV-V
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase II Study of the Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage

Resource links provided by NLM:


Further study details as provided by Columbia University:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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)


Enrollment: 60
Study Start Date: April 2010
Study Completion Date: July 2013
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Sugar Pill, Hunt Hess Grade I-III
Good Grade (Hunt Hess I-III), n=15
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
Experimental: Tiopronin, Hunt Hess Grade I-III
Good Grade (Hunt Hess I-III), n=15
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
Experimental: Tiopronin, Hunt Hess Grade IV-V
Poor Grade (Hunt Hess IV-V), n=15
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 IV-V
Poor Grade (Hunt Hess IV-V), n=15
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

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.

  Eligibility

Ages Eligible for Study:   21 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01095731

Locations
United States, Florida
University of Florida
Gainesville, Florida, United States, 32611
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
United States, Washington
University of Washington
Seattle, Washington, United States, 96104
Sponsors and Collaborators
E. Sander Connolly
University of Florida
University of Washington
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
  More Information

Additional Information:
Publications:

Responsible Party: E. Sander Connolly, Professor of Neurological Surgery, Columbia University
ClinicalTrials.gov Identifier: NCT01095731     History of Changes
Other Study ID Numbers: AAAA8597, 1R01FD003728-01
Study First Received: March 25, 2010
Last Updated: January 28, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Columbia University:
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

Additional relevant MeSH terms:
Hemorrhage
Subarachnoid Hemorrhage
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Retinol acetate
Glycine
Adjuvants, Immunologic
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anticarcinogenic Agents
Protective Agents
Antineoplastic Agents
Therapeutic Uses
Glycine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 22, 2014