Clinical trial NCT01095731: The Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage
Official title: Phase II Study of the Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Aneurysmal Subarachnoid Hemorrhage
Keywords: 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
Thiolpropionamidoacetic acid
Mercaptopropionyl glycine
2 MPG
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: University of Florida
name: University of Washington
name: Food and Drug Administration (FDA)
First posted: 2010-03-30
Enrollment: 60
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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

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 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

Primary outcomes:
measure: Reduction in CSF 3AP Levels
timeFrame: Up to 14 days after SAH
Secondary outcomes:
measure: Improve Neurological Outcome following aSAH
timeFrame: Up to 12 months after discharge from hospital
measure: Improve Neurological Outcome following aSAH
timeFrame: Up to 3 months after discharge from hospital
measure: Improve Neurological Outcome following aSAH
timeFrame: At time of discharge from hospital
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: Columbia University
name: E Sander Connolly, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Florida
name: Brian Hoh, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Louis Kim, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Seiler N. Polyamine oxidase, properties and functions. Prog Brain Res. 1995;106:333-44. doi: 10.1016/s0079-6123(08)61229-7.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.