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

E. Sander Connolly

Status and phase: Completed; Phase 2

Conditions: Aneurysmal Subarachnoid Hemorrhage

Treatments: Drug: Tiopronin; Drug: Placebo

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT01095731

AAAA8597

1R01FD003728-01

Details and patient eligibility

About

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

Full 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.

Enrollment: 60 patients

Sex: All

Ages: 21+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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60 participants in 2 patient groups, including a placebo group

Sugar Pill, Hunt Hess Grade I-V

Placebo Comparator group

Description:

Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)

Treatment:

Drug: Placebo

Tiopronin, Hunt Hess Grade I-V

Experimental group

Description:

Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)

Treatment:

Drug: Tiopronin