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

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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.


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.


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.


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.

Downloadable materials

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

Article Information

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.

© AANS, except where prohibited by US copyright law.



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    Flowchart showing patient randomization and allocation process.

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    Bar graphs showing comparisons of CSF 3-AP levels between tiopronin (dark gray) and placebo (light gray) arms on (A) admission; (B) post-SAH day 7 ± 1; and (C) post-SAH day 14 ± 1 or hospital discharge.




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