A phase II randomized controlled trial of tiopronin for aneurysmal subarachnoid hemorrhage

View More View Less
  • 1 Department of Neurological Surgery, Columbia University Medical Center;
  • 2 Division of Laboratory Medicine, Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center;
  • 3 Department of Medicine, Columbia University Medical Center;
  • 4 Department of Neurology, Columbia University Medical Center, New York, New York;
  • 5 Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia;
  • 6 Department of Neurosurgery, University of Florida, Gainesville, Florida; and
  • 7 Department of Neurological Surgery, University of Washington, Seattle, Washington
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

OBJECTIVE

Delayed cerebral ischemia (DCI) is a significant contributor to poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). The neurotoxin 3-aminopropanal (3-AP) is upregulated in cerebral ischemia. This phase II clinical trial evaluated the efficacy of tiopronin in reducing CSF 3-AP levels in patients with aSAH.

METHODS

In this prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial, 60 patients were assigned to receive tiopronin or placebo in a 1:1 ratio. Treatment was commenced within 96 hours after aSAH onset, administered at a dose of 3 g daily, and continued until 14 days after aSAH or hospital discharge, whichever occurred earlier. The primary efficacy outcome was the CSF 3-AP level at 7 ± 1 days after aSAH.

RESULTS

Of the 60 enrolled patients, 29 (97%) and 27 (93%) in the tiopronin and placebo arms, respectively, received more than one dose of the study drug or placebo. At post-aSAH day 7 ± 1, CSF samples were available in 41% (n = 12/29) and 48% (n = 13/27) of patients in the tiopronin and placebo arms, respectively. No difference in CSF 3-AP levels at post-aSAH day 7 ± 1 was observed between the study arms (11 ± 12 nmol/mL vs 13 ± 18 nmol/mL; p = 0.766). Prespecified adverse events led to early treatment cessation for 4 patients in the tiopronin arm and 2 in the placebo arm.

CONCLUSIONS

The power of this study was affected by missing data. Therefore, the authors could not establish or refute an effect of tiopronin on CSF 3-AP levels. Additional observational studies investigating the role of 3-AP as a biomarker for DCI may be warranted prior to its use as a molecular target in future clinical trials.

Clinical trial registration no.: NCT01095731 (ClinicalTrials.gov)

ABBREVIATIONS aSAH = aneurysmal SAH; DCI = delayed cerebral ischemia; DSMB = data and safety monitoring board; EVD = external ventricular drain; mITT = modified intention to treat; mRS = modified Rankin Scale; SAH = subarachnoid hemorrhage; UPLC-MS/MS = ultra performance liquid chromatography–tandem mass spectrometry; 3-AP = 3-aminopropanal.

Supplementary Materials

    • Supplementary Fig. 1 and Supplementary Tables 1–3 (PDF 752 KB)

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Correspondence Natasha Ironside: Columbia University Medical Center, New York, NY. ironsidenatasha@gmail.com.

INCLUDE WHEN CITING Published online July 12, 2019; DOI: 10.3171/2019.4.JNS19478.

Disclosures Dr. Claassen owns stock in iCE Neurosystems, and once received a speaker’s honorarium from UCB. Dr. Kim owns stock in Spi Surgical, LLC, and SPIWay LLC.

  • 1

    Alleyne CH Jr: Aneurysmal subarachnoid hemorrhage: have outcomes really improved? Neurology 74:14861487, 2010

  • 2

    Anderson DJ, Crossland J, Shaw GG: The actions of spermidine and spermine on the central nervous system. Neuropharmacology 14:571577, 1975

    • Search Google Scholar
    • Export Citation
  • 3

    Astrup J, Siesjö BK, Symon L: Thresholds in cerebral ischemia—the ischemic penumbra. Stroke 12:723725, 1981

  • 4

    Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, : Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 40:9941025, 2009

    • Search Google Scholar
    • Export Citation
  • 5

    de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ: Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 78:13651372, 2007

    • Search Google Scholar
    • Export Citation
  • 6

    Dioguardi N, Ideo G, De Franchis R, Ronchi G: [Controlled clinical trial of 2-mercapto-propionyl-glycine in chronic hepatopathies.] Minerva Med 67:676681, 1976 (Italian)

    • Search Google Scholar
    • Export Citation
  • 7

    Dorhout Mees SM, Algra A, Vandertop WP, van Kooten F, Kuijsten HA, Boiten J, : Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial. Lancet 380:4449, 2012

    • Search Google Scholar
    • Export Citation
  • 8

    Dreier JP, Woitzik J, Fabricius M, Bhatia R, Major S, Drenckhahn C, : Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain 129:32243237, 2006

    • Search Google Scholar
    • Export Citation
  • 9

    Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller T, Ley KF, : Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation. Neurosurgery 53:123135, 2003

    • Search Google Scholar
    • Export Citation
  • 10

    Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V: Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 8:355369, 2009

    • Search Google Scholar
    • Export Citation
  • 11

    Giller CA, Giller AM, Landreneau F: Detection of emboli after surgery for intracerebral aneurysms. Neurosurgery 42:490494, 1998

  • 12

    Glantz L, Nates JL, Trembovler V, Bass R, Shohami E: Polyamines induce blood-brain barrier disruption and edema formation in the rat. J Basic Clin Physiol Pharmacol 7:110, 1996

    • Search Google Scholar
    • Export Citation
  • 13

    Grubb RL Jr, Raichle ME, Eichling JO, Gado MH: Effects of subarachnoid hemorrhage on cerebral blood volume, blood flow, and oxygen utilization in humans. J Neurosurg 46:446453, 1977

    • Search Google Scholar
    • Export Citation
  • 14

    Hoh BL, Topcuoglu MA, Singhal AB, Pryor JC, Rabinov JD, Rordorf GA, : Effect of clipping, craniotomy, or intravascular coiling on cerebral vasospasm and patient outcome after aneurysmal subarachnoid hemorrhage. Neurosurgery 55:779789, 2004

    • Search Google Scholar
    • Export Citation
  • 15

    Hunt WE, Hess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28:1420, 1968

    • Search Google Scholar
    • Export Citation
  • 16

    Ichikawa H, Imaizumi K, Tazawa Y, Obara Y, Ishikawa Y, Tobari I, : Effect of tiopronin on senile cataracts. A double-blind clinical study. Ophthalmologica 180:293298, 1980

    • Search Google Scholar
    • Export Citation
  • 17

    Ivanova S, Batliwalla F, Mocco J, Kiss S, Huang J, Mack W, : Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal. Proc Natl Acad Sci U S A 99:55795584, 2002

    • Search Google Scholar
    • Export Citation
  • 18

    Ivanova S, Botchkina GI, Al-Abed Y, Meistrell M III, Batliwalla F, Dubinsky JM, : Cerebral ischemia enhances polyamine oxidation: identification of enzymatically formed 3-aminopropanal as an endogenous mediator of neuronal and glial cell death. J Exp Med 188:327340, 1998

    • Search Google Scholar
    • Export Citation
  • 19

    Jaja BNR, Saposnik G, Lingsma HF, Macdonald E, Thorpe KE, Mamdani M, : Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: the SAHIT multinational cohort study. BMJ 360:j5745, 2018

    • Search Google Scholar
    • Export Citation
  • 20

    Joly D, Rieu P, Méjean A, Gagnadoux MF, Daudon M, Jungers P: Treatment of cystinuria. Pediatr Nephrol 13:945950, 1999

  • 21

    Kim GH, Kellner CP, Hickman ZL, Zacharia BE, Starke RM, Hwang BY, : A phase I clinical trial of tiopronin, a putative neuroprotective agent, in aneurysmal subarachnoid hemorrhage. Neurosurgery 67:182186, 2010

    • Search Google Scholar
    • Export Citation
  • 22

    Kirkpatrick PJ, Turner CL, Smith C, Hutchinson PJ, Murray GD, STASH Collaborators: Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial. Lancet Neurol 13:666675, 2014

    • Search Google Scholar
    • Export Citation
  • 23

    Li W, Yuan XM, Ivanova S, Tracey KJ, Eaton JW, Brunk UT: 3-Aminopropanal, formed during cerebral ischaemia, is a potent lysosomotropic neurotoxin. Biochem J 371:429436, 2003

    • Search Google Scholar
    • Export Citation
  • 24

    Lovelock CE, Rinkel GJ, Rothwell PM: Time trends in outcome of subarachnoid hemorrhage: Population-based study and systematic review. Neurology 74:14941501, 2010

    • Search Google Scholar
    • Export Citation
  • 25

    Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, : Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 10:618625, 2011

    • Search Google Scholar
    • Export Citation
  • 26

    Macdonald RL, Pluta RM, Zhang JH: Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 3:256263, 2007

    • Search Google Scholar
    • Export Citation
  • 27

    Mahoney FI, Barthel DW: Functional evaluation: the Barthel Index. Md State Med J 14:6165, 1965

  • 28

    Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ: Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol 8:635642, 2009

    • Search Google Scholar
    • Export Citation
  • 29

    Ostrowski RP, Colohan AR, Zhang JH: Molecular mechanisms of early brain injury after subarachnoid hemorrhage. Neurol Res 28:399414, 2006

    • Search Google Scholar
    • Export Citation
  • 30

    Pak CY, Fuller C, Sakhaee K, Zerwekh JE, Adams BV: Management of cystine nephrolithiasis with alpha-mercaptopropionylglycine. J Urol 136:10031008, 1986

    • Search Google Scholar
    • Export Citation
  • 31

    Rankin J: Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 2:200215, 1957

  • 32

    Reilly C, Amidei C, Tolentino J, Jahromi BS, Macdonald RL: Clot volume and clearance rate as independent predictors of vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg 101:255261, 2004

    • Search Google Scholar
    • Export Citation
  • 33

    Sandvei MS, Mathiesen EB, Vatten LJ, Müller TB, Lindekleiv H, Ingebrigtsen T, : Incidence and mortality of aneurysmal subarachnoid hemorrhage in two Norwegian cohorts, 1984-2007. Neurology 77:18331839, 2011

    • Search Google Scholar
    • Export Citation
  • 34

    Sany J, Combe B, Verdie-Petibon D, Tagemouati A, Daures JP: [Long-term tolerability of tiopronin (Acadione) in the treatment of rheumatoid arthritis. Apropos of 140 personal cases.] Rev Rhum Mal Osteoartic 57:105111, 1990 (French)

    • Search Google Scholar
    • Export Citation
  • 35

    Schulz KF, Altman DG, Moher D: CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. J Pharmacol Pharmacother 1:100107, 2010

    • Search Google Scholar
    • Export Citation
  • 36

    Sehba FA, Bederson JB: Mechanisms of acute brain injury after subarachnoid hemorrhage. Neurol Res 28:381398, 2006

  • 37

    Sokolowski JD, Chen CJ, Ding D, Buell TJ, Raper DM, Ironside N, : Endovascular treatment for cerebral vasospasm following aneurysmal subarachnoid hemorrhage: predictors of outcome and retreatment. J Neurointerv Surg 10:367374, 2018

    • Search Google Scholar
    • Export Citation
  • 38

    Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, : CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176181, 2003

    • Search Google Scholar
    • Export Citation
  • 39

    Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, : Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke 41:23912395, 2010

    • Search Google Scholar
    • Export Citation
  • 40

    Yundt KD, Grubb RL Jr, Diringer MN, Powers WJ: Autoregulatory vasodilation of parenchymal vessels is impaired during cerebral vasospasm. J Cereb Blood Flow Metab 18:419424, 1998

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 122 122 122
Full Text Views 54 54 54
PDF Downloads 14 14 14
EPUB Downloads 0 0 0