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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01FD003728-01 | U.S. FDA Grant/Contract | View source |
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| Name | Class |
|---|---|
| University of Florida | OTHER |
| University of Washington | OTHER |
| Food and Drug Administration (FDA) | FED |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sugar Pill, Hunt Hess Grade I-V | Placebo Comparator | Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V) |
|
| Tiopronin, Hunt Hess Grade I-V | Experimental | Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tiopronin | Drug | 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. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care. | Day 7 |
| Measure | Description | Time Frame |
|---|---|---|
| Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care. | Day 14 |
| Modified Rankin Score (mRS) at Discharge |
Not provided
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Florida | Gainesville | Florida | 32611 | United States | ||
| Columbia University Medical Center |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 8614919 | Background | 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. doi: 10.1161/01.str.27.4.625. | |
| 9056628 | Background | 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. doi: 10.1161/01.str.28.3.660. |
| Label | URL |
|---|---|
| The Columbia University Medical Center Department of Neurosurgery Website | View source |
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60 participants enrolled and one withdrew consent prior to randomization, resulting in allocation of 59 participants.
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| ID | Title | Description |
|---|---|---|
| FG000 | Tiopronin, Hunt Hess Grade I-V | Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V) 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. |
| FG001 | Sugar Pill, Hunt Hess Grade I-V | Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V) 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Tiopronin, Hunt Hess Grade I-V | Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V) 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. |
| BG001 | Sugar Pill, Hunt Hess Grade I-V |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care. | CSF samples were successfully collected on day 7 in 12 and 13 participants in the tiopronin and sugar pill arms, respectively. | Posted | Mean | Standard Deviation | nmol/mL | Day 7 |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tiopronin, Hunt Hess Grade I-V | Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V) 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Terminal Extubation (withdrawal of care) | General disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fever | General disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| E. Sander Connolly Jr., MD | Columbia University Irving Medical Center | 212-305-0376 | esc5@cumc.columbia.edu |
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| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| D000783 | Aneurysm |
| D006470 | Hemorrhage |
| D002545 | Brain Ischemia |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D008625 | Tiopronin |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D000603 | Amino Acids, Sulfur |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D000596 | Amino Acids |
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|
| Placebo | Drug | 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. |
|
|
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
| At time of discharge, approximately Day 14 |
| Modified Rankin Score (mRS) at 3 Months | The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability). | 3 months |
| Modified Rankin Score (mRS) at 12 Months | The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability). | 12 months |
| Barthel Index at Discharge | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. | At time of discharge, approximately Day 14 |
| Barthel Index at 3 Months | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. | 3 months |
| Barthel Index at 12 Months | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. | 12 months |
| New York |
| New York |
| 10032 |
| United States |
| University of Washington | Seattle | Washington | 96104 | United States |
| 12296671 | Background | Mayer S, Kreiter K. Quality of life after subarachnoid hemorrhage. J Neurosurg. 2002 Sep;97(3):741-2; author reply 742. doi: 10.3171/jns.2002.97.3.0741. No abstract available. |
| 3895589 | Background | Kassell NF, Sasaki T, Colohan AR, Nazar G. Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke. 1985 Jul-Aug;16(4):562-72. doi: 10.1161/01.str.16.4.562. |
| 7774210 | Background | 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. doi: 10.1097/00003246-199506000-00004. |
| 1499692 | Background | 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. doi: 10.1016/0014-4886(92)90126-b. |
| 9670045 | Background | 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. doi: 10.1084/jem.188.2.327. |
| 9930751 | Background | 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. doi: 10.1046/j.1471-4159.1999.0720765.x. |
| 8584670 | Background | Seiler N. Polyamine oxidase, properties and functions. Prog Brain Res. 1995;106:333-44. doi: 10.1016/s0079-6123(08)61229-7. |
| 11943872 | Background | 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. doi: 10.1073/pnas.082609299. Epub 2002 Apr 9. |
| 8711808 | Background | 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. doi: 10.1161/01.str.27.8.1393. |
| 16406747 | Background | 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. doi: 10.1016/j.jchromb.2005.12.031. Epub 2006 Jan 10. |
| 17026969 | Background | 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. doi: 10.1016/j.brainres.2006.09.003. Epub 2006 Oct 5. |
| 7354892 | Background | 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. doi: 10.1227/00006123-198001000-00001. |
| 7676533 | Background | 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. doi: 10.1007/BF00307941. |
| 31299655 | Derived | Ironside N, Christophe B, Bruce S, Carpenter AM, Robison T, Yoh N, Cremers S, Landry D, Frey HP, Chen CJ, Hoh BL, Kim LJ, Claassen J, Connolly ES. A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage. J Neurosurg. 2019 Jul 12;133(2):351-359. doi: 10.3171/2019.4.JNS19478. Print 2020 Aug 1. |
| The University of Florida Department of Neurosurgery Website | View source |
| The University of Washington Department of Neurosurgery Website | View source |
| Principle Investigator: E. Sander Connolly Jr. | View source |
| Connolly Cerebrovascular Research Laboratory | View source |
Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V) 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex/Gender, Customized | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Diabetes Mellitus | Count of Participants | Participants |
|
| Smoker | Count of Participants | Participants |
|
Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)
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.
|
|
| Secondary | Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care. | CSF samples were successfully collected on day 14 in 13 and 9 participants in the tiopronin and sugar pill arms respectively. | Posted | Mean | Standard Deviation | nmol/mL | Day 14 |
|
|
|
| Secondary | Modified Rankin Score (mRS) at Discharge | The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability). | Posted | Median | Inter-Quartile Range | score on a scale | At time of discharge, approximately Day 14 |
|
|
|
| Secondary | Modified Rankin Score (mRS) at 3 Months | The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability). | Posted | Median | Inter-Quartile Range | score on a scale | 3 months |
|
|
|
| Secondary | Modified Rankin Score (mRS) at 12 Months | The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability). | Posted | Median | Inter-Quartile Range | score on a scale | 12 months |
|
|
|
| Secondary | Barthel Index at Discharge | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. | Posted | Mean | Standard Deviation | score on a scale | At time of discharge, approximately Day 14 |
|
|
|
| Secondary | Barthel Index at 3 Months | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. | Posted | Mean | Standard Deviation | score on a scale | 3 months |
|
|
|
| Secondary | Barthel Index at 12 Months | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. | Posted | Mean | Standard Deviation | score on a scale | 12 months |
|
|
|
| 4 |
| 29 |
| 6 |
| 29 |
| 13 |
| 29 |
| EG001 | Sugar Pill, Hunt Hess Grade I-V | Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V) 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. | 3 | 27 | 9 | 27 | 16 | 27 |
| Ventriculitis | Nervous system disorders | Systematic Assessment |
|
| Hypoxia | General disorders | Systematic Assessment |
|
| Cardiopulmonary Arrest | General disorders | Systematic Assessment |
|
| Neurological Deterioration | Nervous system disorders | Systematic Assessment |
|
| Acidosis | General disorders | Systematic Assessment |
|
| Staphylococcus aureus Infection | Infections and infestations | Systematic Assessment |
|
| Fever | General disorders | Systematic Assessment |
|
| Prolonged Intubation | General disorders | Systematic Assessment |
|
| Proteinuria | Renal and urinary disorders | Systematic Assessment |
|
| Fever of unknown origin | General disorders | Systematic Assessment |
|
| Thrombosis | Vascular disorders | Systematic Assessment |
|
| Seizure | Nervous system disorders | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | Systematic Assessment |
|
| Hypernatremia | General disorders | Systematic Assessment |
|
| Hyponatremia | General disorders | Systematic Assessment |
|
| Acute Respiratory Distress Syndrome | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Headache | Nervous system disorders | Systematic Assessment |
|
| Leukopenia | Immune system disorders | Systematic Assessment |
|
| Laryngeal edema | General disorders | Systematic Assessment |
|
| Rash | General disorders | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Systematic Assessment |
|
| Arrhythmia | Cardiac disorders | Systematic Assessment |
|
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| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D000602 |
| Amino Acids, Peptides, and Proteins |
| D034442 | N-substituted Glycines |
| D005998 | Glycine |
| D002241 | Carbohydrates |