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Tiopronin Trial

A Phase I Clinical Trial of Tiopronin, a Putative Neuroprotective Agent, in Aneurysmal Subarachnoid Hemorrhage

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Year of Publication: 2010

Authors: Grace H. Kim, Christopher P. Kellner, Zachary L. Hickman, ..., E. Sander Connolly Jr

Journal: Neurosurgery

Citation: Neurosurgery. 2010 July; 67(1): 182-186

PDF: https://pmc.ncbi.nlm.nih.gov/articles/PM...nihms228575.pdf

Clinical Question

Is short-term (up to 14 days) administration of tiopronin (N-2-mercaptopropionyl-glycine), an FDA-approved drug that binds and neutralizes the neurotoxic aldehyde 3-aminopropanal, safe in patients with aneurysmal subarachnoid hemorrhage at doses up to the maximum FDA-approved dose of 3 g/day?

Bottom Line

Short-term administration of tiopronin up to 3 g/day for up to 14 days following aneurysmal SAH appears to be safe and well-tolerated, without the serious side effects associated with long-term use for cystinuria. In this Phase I dose-escalation trial of 9 patients using a conventional '3+3' design, no patients experienced adverse events attributable to tiopronin, and the maximum FDA-approved dose of 3 g/day was achieved. While this safety trial was not designed or powered to assess efficacy, favorable outcomes were observed with 8/9 patients achieving good discharge outcomes (mRS 1-3) and 5/6 patients with 12-month data achieving excellent outcomes (mRS 0-1). Importantly, no patients developed cerebral infarction from vasospasm despite 55.6% experiencing vasospasm during their hospital course. These results support proceeding to a Phase II randomized, placebo-controlled trial to determine whether tiopronin crosses the blood-brain barrier, reduces CSF concentrations of the neurotoxin 3-AP, and provides neuroprotection following aneurysmal SAH.

Major Points

  • First-in-human Phase I dose-escalation safety trial of tiopronin in aneurysmal SAH patients
  • Single-center, prospective, nonrandomized, open-label design at Columbia University Medical Center
  • Study period: July 2006 to August 2007
  • 46 patients screened, 9 enrolled (most common exclusion: inability to provide informed consent)
  • Conventional '3+3' dose-escalation study design with three-patient cohorts
  • Starting dose 1 g/day divided three times daily, escalated based on predetermined guidelines
  • Maximum dose 3 g/day selected as highest FDA-approved dose for cystinuria treatment
  • All enrolled patients received study drug within 96 hours of SAH onset
  • Treatment duration from enrollment until SAH day 14
  • All patients Hunt-Hess grades 1-3 on admission (good to intermediate clinical condition)
  • Most patients Fisher grade 2 or 3 (diffuse thin or thick subarachnoid blood)
  • All patients underwent definitive aneurysm treatment (6 surgical clipping, 3 endovascular coiling)
  • Drug Safety Monitoring Committee (DSMC) reviewed all clinical research forms after each dose tier
  • DSMC consisted of non-study neurosurgeon, non-study neurologist, and biostatistician
  • Primary endpoint: occurrence of adverse events attributable to tiopronin administration
  • No patients experienced serious side effects warranting study drug discontinuation
  • One patient (Patient 2, 1 g/day cohort) had tiopronin withheld on SAH day 12 due to fever
  • Fever in Patient 2 continued after drug discontinuation, attributed to ventriculitis by DSMC
  • All other 8 patients completed full 14-day course of tiopronin
  • Maximum dose of 3 g/day achieved with minimum 9 patients per study design requirements
  • Cerebral vasospasm occurred in 55.6% (5/9) patients during ICU course
  • Angiographic vasospasm documented in 3/9 patients
  • Clinical signs of cerebral ischemia in 3/9 patients (2 with angiographic confirmation)
  • Critically: no patients developed cerebral infarction from vasospasm
  • Discharge outcomes: 7/9 favorable (mRS 1-3), 1 poor from ventriculitis (mRS 5), 1 poor from rebleed (mRS 4)
  • 3-month follow-up available for 8 patients: 7 favorable outcomes, 1 poor (Patient 2 with ventriculitis)
  • 12-month follow-up available for 6 patients: 5 with mRS 0-1 (83.3%), indicating excellent recovery
  • Medical complications consistent with typical SAH morbidity: 7 UTIs, 1 pneumonia, 1 sepsis, 1 ventriculitis
  • Pathophysiological rationale: 3-AP is neurotoxic aldehyde produced during cerebral ischemia via polyamine oxidase
  • Elevated CSF 3-AP levels correlate with severity of cerebral injury in aSAH patients
  • Tiopronin shown in preclinical studies to bind/inactivate 3-AP in vitro and reduce infarct volumes in vivo
  • SAH provides ideal model for testing neuroprotective agents due to high incidence of delayed ischemia
  • Study fulfilled 3 of 6 STAIR criteria for neuroprotective drug development
  • Tiopronin currently FDA-approved for cystinuria treatment (different indication)
  • Long-term tiopronin use (>3 months) associated with known side effects not seen in this short-term trial
  • Plans for Phase II randomized, placebo-controlled trial underway

Design

Study Type: Single-center, prospective, nonrandomized, open-label, Phase I dose-escalation safety trial

Randomization:

Blinding: Open-label, not blinded. However, functional outcomes assessed by blinded study coordinator using modified Rankin Scale. Adverse events recorded by study coordinator and reviewed by independent Drug Safety Monitoring Committee

Enrollment Period: July 2006 to August 2007

Follow-up Duration: Primary follow-up to discharge or SAH day 14 (whichever first); extended follow-up obtained for 3 months (8 patients) and 12 months (6 patients)

Centers: 1

Countries: United States

Sample Size: 9

Analysis: Conventional '3+3' dose-escalation design. Cohorts of 3 patients enrolled sequentially. Dose escalation guidelines: (1) If 0/3 experience side effects (SE), dose increases by 1 g for next cohort; (2) If 1/3 experience SE, dose stays same for next cohort; (3) If 2-3/3 experience SE, dose reduces by 500 mg; (4) If 2/6 consecutive patients experience SE, dose reduces by 500 mg; (5) If at 500 mg dose, 2+ patients experience SE, study terminates; (6) If 2+ experience SE at prior dose, highest safe dose used for Phase II; (7) If 0/3 or 1/6 experience SE at reduced dose, that dose used for Phase II; (8) If 3 g/day reached, escalation stops. Primary endpoint: occurrence of adverse events. Secondary endpoints: functional outcome (mRS) at discharge/day 14 and cerebral infarction from vasospasm. Good outcome defined as mRS 1-3, poor as mRS 4-6. All clinical forms reviewed by DSMC after each dose tier. FDA and institutional review board approval obtained. Patients or approved proxies provided informed consent per ethics committee protocol

Inclusion Criteria

  • Age 18 years or older
  • Admitted to hospital with acute subarachnoid hemorrhage within 96 hours of onset
  • SAH diagnosed by head CT or lumbar puncture
  • Aneurysmal etiology of SAH confirmed by CT angiography, conventional angiography, or during surgical intervention
  • Ability of patient to provide informed consent independently

Exclusion Criteria

  • Known hypersensitivity to penicillamine
  • Serum creatinine >1.5 mg/dL on admission
  • Platelet count <100,000/µL on admission
  • White blood cell count <3,500/mm³ on admission
  • AST or ALT >60 U/L on admission, or history of liver failure
  • Pregnancy
  • History of systemic lupus erythematosus
  • History of Goodpasture syndrome
  • History of myasthenia gravis
  • History of pemphigus vulgaris
  • History of nephrotic syndrome
  • History of glomerulonephritis
  • History of renal failure

Baseline Characteristics

Overall Cohort:

  • Number: 9
  • Age range: 43-74 years
  • Female: 8 (89%)
  • Male: 1 (11%)
  • Hunt-Hess Grade 1: 3 (33%)
  • Hunt-Hess Grade 2: 1 (11%)
  • Hunt-Hess Grade 3: 5 (56%)
  • Fisher Grade 1: 1 (11%)
  • Fisher Grade 2: 3 (33%)
  • Fisher Grade 3: 4 (44%)
  • Fisher Grade 4: 1 (11%)
  • Aneurysm treatment - surgical clipping: 6 (67%)
  • Aneurysm treatment - endovascular coiling: 3 (33%)

Cohort 1 (1 g/day):

  • Patients: 3 (Patients 1, 2, 3)
  • Ages: 47, 74, 43 years
  • Female: 3 (100%)

Cohort 2 (2 g/day):

  • Patients: 3 (Patients 4, 5, 6)
  • Ages: 45, 46, 43 years
  • Female: 2 (67%)
  • Male: 1 (33%)

Cohort 3 (3 g/day):

  • Patients: 3 (Patients 7, 8, 9)
  • Ages: 44, 45, 43 years
  • Female: 3 (100%)

Arms

FieldCohort 1: Tiopronin 1 g/dayCohort 2: Tiopronin 2 g/dayCohort 3: Tiopronin 3 g/day
InterventionOral tiopronin (N-2-mercaptopropionyl-glycine, marketed as Thiola) 1 gram per day divided three times daily (approximately 333 mg per dose). Administration began within 96 hours of SAH onset and continued until day 14 after SAH ictus. All patients received standard-of-care treatment for aSAH including definitive surgical or endovascular aneurysm repair, nimodipine, and hypertensive-hypervolemic therapy or endovascular therapy for cerebral vasospasm as clinically indicated. Daily monitoring for known tiopronin side effects. Functional outcome assessed at discharge or day 14 using modified Rankin ScaleOral tiopronin 2 grams per day divided three times daily (approximately 667 mg per dose). Administration began within 96 hours of SAH onset and continued until day 14 after SAH ictus. All patients received standard-of-care treatment for aSAH including definitive surgical or endovascular aneurysm repair, nimodipine, and hypertensive-hypervolemic therapy or endovascular therapy for cerebral vasospasm as clinically indicated. Daily monitoring for known tiopronin side effects. Functional outcome assessed at discharge or day 14 using modified Rankin ScaleOral tiopronin 3 grams per day (maximum FDA-approved dose) divided three times daily (1000 mg per dose). Administration began within 96 hours of SAH onset and continued until day 14 after SAH ictus. All patients received standard-of-care treatment for aSAH including definitive surgical or endovascular aneurysm repair, nimodipine, and hypertensive-hypervolemic therapy or endovascular therapy for cerebral vasospasm as clinically indicated. Daily monitoring for known tiopronin side effects. Functional outcome assessed at discharge or day 14 using modified Rankin Scale
DurationUp to 14 days from enrollmentUp to 14 days from enrollmentUp to 14 days from enrollment

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Occurrence of adverse events attributable to tiopronin administration. Patients monitored daily for development of known significant side effects of tiopronin, all of which are sequelae of long-term (>3 months) treatment. Predefined drop-out criteria included: leukopenia (2 consecutive WBC <3500/mm³), thrombocytopenia (2 consecutive platelets <100,000/mm³), renal failure (2 consecutive creatinine >50% rise), proteinuria (2 consecutive UA >2+ protein plus 24-hr urine protein >200 mg/d), laryngeal edema, hemoptysis, myasthenic syndrome, persistent diarrhea, unexplained fever, pemphigus-type reaction, liver failure, lupus-like drug reactionPrimaryNo control arm - single-arm dose-escalationNo patients experienced serious side effects attributable to tiopronin. All patients completed full course except Patient 2 who had drug withheld on SAH day 12 due to fever of unknown origin. Fever persisted after drug cessation and was attributed by DSMC to presumed ventriculitis, not drug effect. No adverse events warranted study drug discontinuation per predefined drop-out criteria
Functional outcome at discharge or SAH day 14 (whichever occurred first) - modified Rankin Scale, dichotomized as good (mRS 1-3) vs poor (mRS 4-6)SecondaryNo controlGood outcome: 7/9 (78%); Poor outcome: 2/9 (22%). Patient 2: mRS 5 (ventriculitis); Patient 9: mRS 4 (aneurysm rebleed before securing)
Cerebral infarction from vasospasm - assessed by imagingSecondaryNo control0/9 (0%) developed infarction from cerebral vasospasm
Cerebral vasospasm - any evidence during neurologic ICU course (clinical, angiographic, or transcranial Doppler)SecondaryNo control5/9 (55.6%) had evidence of cerebral vasospasm
Angiographic vasospasm - documented on angiographySecondaryNo control3/9 (33%) had documented angiographic vasospasm
Clinical cerebral ischemia - clinical signs of ischemiaSecondaryNo control3/9 (33%) exhibited clinical signs of cerebral ischemia (2 of these had angiographic vasospasm)
3-month modified Rankin Scale (extended follow-up, not in original design)SecondaryNo controlData available for 8/9 patients. Good outcome (mRS 0-2): 7/8 (87.5%); Poor outcome: 1/8 (12.5%, Patient 2 with mRS 5 from ventriculitis)
12-month modified Rankin Scale (extended follow-up, not in original design)SecondaryNo controlData available for 6/9 patients. Excellent outcome (mRS 0-1): 5/6 (83.3%); Poor outcome: 1/6 (16.7%, Patient 2 with mRS 6/death)
Medical complications during hospitalizationAdverseNo controlUrinary tract infections: 7; Pneumonia: 1; Sepsis: 1; Ventriculitis: 1 (Patient 2). All complications consistent with known sequelae of SAH and not attributed to tiopronin
Drug-related adverse eventsAdverseNo controlZero patients experienced drug-related adverse events per predefined criteria. One patient (Patient 2) had tiopronin withheld due to fever, but fever continued and was attributed to ventriculitis by DSMC
Study drug discontinuationAdverseNo control1/9 (11%) had drug temporarily withheld (Patient 2, fever later attributed to ventriculitis). All other 8/9 (89%) completed full 14-day course

Subgroup Analysis

Not applicable for Phase I safety trial. Individual patient data provided in Table 4 showing dose cohort, vasospasm occurrence, complications, and outcomes for each of 9 patients

Criticisms

  • Very small sample size (only 9 patients total, 3 per dose cohort) limits generalizability
  • Single-center study at academic medical center limits external validity
  • Nonrandomized, open-label design without control group prevents efficacy assessment
  • Not blinded - investigators and patients aware of treatment allocation
  • Selection bias: only patients able to provide informed consent eligible (excluded sicker patients)
  • All patients Hunt-Hess grades 1-3 - excluded poorest grade patients who might benefit most
  • Short screening period (July 2006-August 2007) with only 46 patients screened
  • Only 9 of 46 screened patients (19.6%) ultimately enrolled
  • Most common exclusion was inability to provide consent - may exclude most relevant population
  • No measurement of CSF 3-AP levels to confirm target engagement
  • No measurement of tiopronin blood or CSF levels to confirm blood-brain barrier penetration
  • No pharmacokinetic or pharmacodynamic data collected
  • Dose escalation based solely on safety, not on biomarker evidence of target engagement
  • Maximum dose 3 g/day chosen arbitrarily as FDA-approved dose for cystinuria, not based on CNS penetration data
  • Primary endpoint (adverse events) inherently subjective and requires clinical judgment
  • Extended follow-up (3 and 12 months) incomplete - not available for all patients
  • 12-month data only available for 6/9 patients (67%)
  • Concomitant standard SAH treatments (nimodipine, triple-H therapy) confound any efficacy signal
  • Two patients had poor outcomes from non-vasospasm complications (ventriculitis, rebleed)
  • Unable to distinguish potential drug benefit from natural disease course or standard care
  • Favorable outcomes may reflect good-grade patient selection rather than drug effect
  • No comparison to historical controls or matched cohorts
  • Statistical analysis not pre-specified for secondary outcomes
  • No adjustment for multiple comparisons on secondary endpoints
  • Study only fulfilled 3 of 6 STAIR criteria for neuroprotective drug development
  • Preclinical data limited - only in vitro binding and rodent ischemia model
  • Mechanism of action (3-AP neutralization) not directly tested in this trial
  • Assumption that reducing 3-AP will improve outcomes not validated in humans
  • Oral administration may result in variable absorption and bioavailability
  • No assessment of drug compliance or pill counts
  • Treatment started within 96 hours of SAH - variable timing may affect results
  • Vasospasm assessment methods varied (TCD, angiography, clinical) - not standardized
  • Definition of clinical vasospasm subjective
  • No systematic imaging protocol for infarction assessment at fixed timepoints
  • mRS assessment by study coordinator potentially subject to bias (though described as blinded)
  • DSMC review occurred after each dose tier, not continuously
  • Drop-out criteria based on known long-term tiopronin side effects may not capture acute issues
  • Study powered only for safety, not efficacy - cannot draw conclusions about neuroprotection
  • Plans for Phase II trial mentioned but no results published (as of 2010 publication)
  • Generalizability limited by single-center academic setting with experienced vascular neurosurgeons

Funding

Supported in part by Doris Duke Charitable Foundation (Drs. Kim, Kellner, Hickman). FDA and institutional review board approval obtained. Authors reported no personal financial or institutional interest in any drugs, materials, or devices described in the article

Based on: Tiopronin Trial (Neurosurgery, 2010)

Authors: Grace H. Kim, Christopher P. Kellner, Zachary L. Hickman, ..., E. Sander Connolly Jr

Citation: Neurosurgery. 2010 July; 67(1): 182-186

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