The Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage
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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 CSF 3AP levels in this patient population.
| 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 |
- 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.
- 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)
- Monitoring of Adverse Events [ Time Frame: Up to 12 months after hospital stay ] [ 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.
| Enrollment: | 60 |
| Study Start Date: | April 2010 |
| Estimated 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:
|
|
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:
|
|
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 BBB; (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 |
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| 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 |
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: | August 1, 2012 |
| 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 May 23, 2013