The Effects of Tiopronin on 3-Aminopropanal Level & Neurologic Outcome After Aneurysmal Subarachnoid Hemorrhage

Completed

Phase 2 Results N/A

Trial Description

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.

Conditions

Interventions

  • Placebo Drug
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Sugar Pill, Hunt Hess Grade I-III
    Description: Good Grade (Hunt Hess I-III), n=15
    ARM 2: Kind: Experimental
    Label: Sugar Pill, Hunt Hess Grade IV-V
    Description: Poor Grade (Hunt Hess IV-V), n=15
  • Tiopronin (Thiola )Drug
    Other Names: IUPAC Name:2-(2-sulfanylpropanoylamino)acetic acid; CAS Number: 1953-02-2; Thiola; Thiopronin; Thiosol; Tioglis; Acadione; Capen; Captimer; Epatiol; Vincol; Mucolysin; Sutilan; Meprin (detoxicant); Thiolpropionamidoacetic acid; N-2-Mercaptopropionyl glyci
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Tiopronin, Hunt Hess Grade I-III
    Description: Good Grade (Hunt Hess I-III), n=15
    ARM 2: Kind: Experimental
    Label: Tiopronin, Hunt Hess Grade IV-V
    Description: Poor Grade (Hunt Hess IV-V), n=15
  • Tiopronin for Hunt Hess grades I-III Drug
    Other Names: IUPAC Name:2-(2-sulfanylpropanoylamino)acetic acid; CAS Number: 1953-02-2; Thiola; Thiopronin; Thiosol; Tioglis; Acadione; Capen; Captimer; Epatiol; Vincol; Mucolysin; Sutilan; Meprin (detoxicant); Thiolpropionamidoacetic acid; N-2-Mercaptopropionyl glyci
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Tiopronin, Hunt Hess Grade I-III
    Description: Good Grade (Hunt Hess I-III), n=15
  • Placebo for Hunt Hess grades I-III Drug
    Other Names: placebo, sugar pill
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Sugar Pill, Hunt Hess Grade I-III
    Description: Good Grade (Hunt Hess I-III), n=15
  • Placebo for Hunt Hess grades IV-V Drug
    Other Names: placebo, sugar pill
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Sugar Pill, Hunt Hess Grade IV-V
    Description: Poor Grade (Hunt Hess IV-V), n=15
  • Tiopronin for Hunt Hess grades IV-V Drug
    Other Names: IUPAC Name:2-(2-sulfanylpropanoylamino)acetic acid; CAS Number: 1953-02-2; Thiola; Thiopronin; Thiosol; Tioglis; Acadione; Capen; Captimer; Epatiol; Vincol; Mucolysin; Sutilan; Meprin (detoxicant); Thiolpropionamidoacetic acid; N-2-Mercaptopropionyl glyci
    Intervention Desc: 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.
    ARM 1: Kind: Experimental
    Label: Tiopronin, Hunt Hess Grade IV-V
    Description: Poor Grade (Hunt Hess IV-V), n=15

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
  • Purpose: Treatment
  • Endpoint: Bio-availability Study
  • Intervention: Parallel Assignment

Patient Involvement

Take 1 gram of tiopronin or placebo 3 times daily until discharge from hospital. Have CSF obtained for 3AP levels during hospitalization.Provide follow up information at 3 months and 12 months by telephone interview or hospital visit, by family member or care-giver if necessary. Outcome assessments will include:Modified Rankin Scale, extended Glasgow Outcome Scale (eGOS), Barthel Index, Sickness Impact Profile (SIP), Lawton Physical Self Assessment Test (PSMS), Lawton Instrumental Activities of Daily Living (IADL), NIH Stroke Scale (NIHSS), Telephone Interview Cognitive Status (TICS), and Visual Search and Attention Test (VSAT).

Outcomes

Type Measure Time Frame Safety Issue
Primary Reduction in CSF 3AP Levels
Secondary Improve Neurological Outcome following aSAH, measured using the following scales: Modified Rankin Scale extended Glasgow Outcome Scale (eGOS) Barthel Index Sickness Impact Profile (SIP) Lawton Physical Self Assessment Test (PSMS) Lawton Instrumental Activities of Daily Living (IADL) NIH Stroke Scale (NIHSS) Telephone Interview Cognitive Status (TICS) Visual Search and Attention Test (VSAT)
Secondary Improve Neurological Outcome following aSAH Up to 12 months after discharge from hospital No
Secondary Monitoring of Adverse Events Up to 12 months after hospital stay Yes

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