The Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage
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| ClinicalTrials.gov Identifier: NCT01095731 |
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Recruitment Status :
Completed
First Posted : March 30, 2010
Last Update Posted : September 3, 2020
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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 or disease | Intervention/treatment | Phase |
|---|---|---|
| Aneurysmal Subarachnoid Hemorrhage | Drug: Tiopronin Drug: Placebo | Phase 2 |
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 (Clinical Trial) |
| Actual Enrollment : | 60 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, 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 |
| Study Start Date : | April 2010 |
| Actual Primary Completion Date : | July 2012 |
| Actual Study Completion Date : | July 2013 |
| Arm | Intervention/treatment |
|---|---|
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Placebo Comparator: Sugar Pill, Hunt Hess Grade I-III
Good Grade (Hunt Hess I-III), n=15
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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 Name: placebo, sugar pill |
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Experimental: Tiopronin, Hunt Hess Grade I-III
Good Grade (Hunt Hess I-III), n=15
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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:
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Experimental: Tiopronin, Hunt Hess Grade IV-V
Poor Grade (Hunt Hess IV-V), n=15
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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:
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Placebo Comparator: Sugar Pill, Hunt Hess Grade IV-V
Poor Grade (Hunt Hess IV-V), n=15
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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 Name: placebo, sugar pill |
- Reduction in CSF 3AP Levels [ Time Frame: Up to 14 days after SAH ]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.
- Improve Neurological Outcome following aSAH [ Time Frame: Up to 12 months after discharge from hospital ]
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 ]
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 ]
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)
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| Ages Eligible for Study: | 21 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01095731
| 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 | |
| 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:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | E. Sander Connolly, Professor of Neurological Surgery, Columbia University |
| ClinicalTrials.gov Identifier: | NCT01095731 |
| Other Study ID Numbers: |
AAAA8597 1R01FD003728-01 ( U.S. FDA Grant/Contract ) |
| First Posted: | March 30, 2010 Key Record Dates |
| Last Update Posted: | September 3, 2020 |
| Last Verified: | September 2020 |
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Tiopronin Thiola Meprin Thiolpropionamidoacetic acid Mercaptopropionyl glycine aneurysm aneurysmal subarachnoid hemorrhage haemorrhage neuroprotection 3-aminopropanal 3AP polyamine oxidase spermine |
spermidine vasospasm cerebral ischemia neurosurgery neurological intensive care unit NICU FDA Thiopronin Thiosol Tioglis Acadione Capen Captimer Epatiol Vincol |
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Subarachnoid Hemorrhage Hemorrhage Pathologic Processes Intracranial Hemorrhages Cerebrovascular Disorders Brain Diseases Central Nervous System Diseases Nervous System Diseases Vascular Diseases Cardiovascular Diseases Acetic Acid Retinol acetate |
Glycine Glycine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs Anti-Bacterial Agents Anti-Infective Agents Adjuvants, Immunologic Immunologic Factors Anticarcinogenic Agents Protective Agents Antineoplastic Agents |