Aneurysmal Subarachnoid Hemorrhage
Conditions
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
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.
Interventions
DRUGTiopronin
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.
DRUGPlacebo
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.
Sponsors
University of Florida
University of Washington
Food and Drug Administration (FDA)
E. Sander Connolly
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | Day 7 | The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Modified Rankin Score (mRS) at Discharge | At time of discharge, approximately Day 14 | The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability). |
| Modified Rankin Score (mRS) at 3 Months | 3 months | The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability). |
| Modified Rankin Score (mRS) at 12 Months | 12 months | The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability). |
| Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | Day 14 | The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care. |
| Barthel Index at 3 Months | 3 months | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. |
| Barthel Index at 12 Months | 12 months | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. |
| Barthel Index at Discharge | At time of discharge, approximately Day 14 | Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome. |
Countries
United States
Participant flow
Pre-assignment details
60 participants enrolled and one withdrew consent prior to randomization, resulting in allocation of 59 participants.
Participants by arm
| Arm | Count |
|---|---|
| Tiopronin, Hunt Hess Grade I-V Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)
Tiopronin: 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. | 30 |
| Sugar Pill, Hunt Hess Grade I-V Good Grade (Hunt Hess I-III) and Poor Grade (Hunt Hess IV-V)
Placebo: 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. | 29 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Tiopronin, Hunt Hess Grade I-V | Sugar Pill, Hunt Hess Grade I-V | Total |
|---|---|---|---|
| Age, Customized 40 - 80 years | 30 Participants | 29 Participants | 59 Participants |
| Diabetes Mellitus | 3 Participants | 3 Participants | 6 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Hispanic | 8 Participants | 4 Participants | 12 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown/Not reported | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 19 Participants | 32 Participants |
| Region of Enrollment United States | 30 participants | 29 participants | 59 participants |
| Sex/Gender, Customized Female | 17 Participants | 22 Participants | 39 Participants |
| Sex/Gender, Customized Male | 12 Participants | 5 Participants | 17 Participants |
| Sex/Gender, Customized Unknown/Not reported | 1 Participants | 2 Participants | 3 Participants |
| Smoker | 18 Participants | 15 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 29 | 3 / 27 |
| other Total, other adverse events | 13 / 29 | 16 / 27 |
| serious Total, serious adverse events | 6 / 29 | 9 / 27 |
Outcome results
Primary
Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels
The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care.
Time frame: Day 7
Population: CSF samples were successfully collected on day 7 in 12 and 13 participants in the tiopronin and sugar pill arms, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tiopronin, Hunt Hess Grade I-V | Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | 11.1 nmol/mL | Standard Deviation 11.8 |
| Sugar Pill, Hunt Hess Grade I-V | Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | 12.9 nmol/mL | Standard Deviation 17.6 |
Secondary
Barthel Index at 12 Months
Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tiopronin, Hunt Hess Grade I-V | Barthel Index at 12 Months | 94 score on a scale | Standard Deviation 24 |
| Sugar Pill, Hunt Hess Grade I-V | Barthel Index at 12 Months | 98 score on a scale | Standard Deviation 5 |
Secondary
Barthel Index at 3 Months
Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome.
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tiopronin, Hunt Hess Grade I-V | Barthel Index at 3 Months | 83 score on a scale | Standard Deviation 33 |
| Sugar Pill, Hunt Hess Grade I-V | Barthel Index at 3 Months | 85 score on a scale | Standard Deviation 28 |
Secondary
Barthel Index at Discharge
Barthel index is a scale used to measure dependency in performing daily activities. Scores range from 0 (total dependency) to 100 (no dependency). A higher score indicates a better outcome.
Time frame: At time of discharge, approximately Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tiopronin, Hunt Hess Grade I-V | Barthel Index at Discharge | 37 score on a scale | Standard Deviation 53 |
| Sugar Pill, Hunt Hess Grade I-V | Barthel Index at Discharge | 30 score on a scale | Standard Deviation 38 |
Secondary
Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels
The level of 3-aminopropanal (3-AP) in cerebrospinal fluid (CSF) measured in nmol/mL. CSF samples taken as a standard of care.
Time frame: Day 14
Population: CSF samples were successfully collected on day 14 in 13 and 9 participants in the tiopronin and sugar pill arms respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tiopronin, Hunt Hess Grade I-V | Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | 14.7 nmol/mL | Standard Deviation 18.8 |
| Sugar Pill, Hunt Hess Grade I-V | Cerebrospinal Fluid 3-aminopropanal (CSF-3AP) Levels | 9.9 nmol/mL | Standard Deviation 10.3 |
Secondary
Modified Rankin Score (mRS) at 12 Months
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
Time frame: 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tiopronin, Hunt Hess Grade I-V | Modified Rankin Score (mRS) at 12 Months | 2 score on a scale |
| Sugar Pill, Hunt Hess Grade I-V | Modified Rankin Score (mRS) at 12 Months | 2 score on a scale |
Secondary
Modified Rankin Score (mRS) at 3 Months
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
Time frame: 3 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tiopronin, Hunt Hess Grade I-V | Modified Rankin Score (mRS) at 3 Months | 3 score on a scale |
| Sugar Pill, Hunt Hess Grade I-V | Modified Rankin Score (mRS) at 3 Months | 2 score on a scale |
Secondary
Modified Rankin Score (mRS) at Discharge
The Modified Rankin Score (mRS) is a disability scale with possible scores ranging from 0 (no symptoms) to 5 (severe disability).
Time frame: At time of discharge, approximately Day 14
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tiopronin, Hunt Hess Grade I-V | Modified Rankin Score (mRS) at Discharge | 4 score on a scale |
| Sugar Pill, Hunt Hess Grade I-V | Modified Rankin Score (mRS) at Discharge | 4 score on a scale |