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CLEAR Eptifibatide

The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke: The CLEAR Stroke Trial

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Year of Publication: 2008

Authors: Arthur M. Pancioli, Joseph Broderick, Thomas Brott, ..., and the CLEAR Trial Investigators

Journal: Stroke

Citation: Stroke. 2008;39(12):3268–3276. doi:10.1161/STROKEAHA.108.517656

Link: https://doi.org/10.1161/STROKEAHA.108.517656

PDF: https://www.ahajournals.org/doi/reader/1...EAHA.108.517656

Clinical Question

Is combination therapy with low-dose rt-PA and eptifibatide safe in acute ischemic stroke patients treated within 3 hours of onset?

Bottom Line

Low-dose rt-PA plus eptifibatide was safe and did not increase symptomatic ICH compared to standard-dose rt-PA, despite higher risk baseline features.

Major Points

  • Randomized 3:1 trial of 69 patients on combination therapy vs 25 on standard rt-PA
  • Dose-escalation design: rt-PA 0.3 mg/kg (Tier 1) and 0.45 mg/kg (Tier 2) + eptifibatide
  • Symptomatic ICH: 1.4% in combo group vs 8.0% in rt-PA-only group
  • No significant efficacy benefit; Barthel Index slightly favored standard rt-PA
  • Trial halted early due to acceptable safety profile

Design

Study Type: Multicenter, randomized, double-blind, dose-escalation safety trial

Randomization: 1

Blinding: Double-blind (drug preparation and administration)

Enrollment Period: July 2003 – April 2007

Follow-up Duration: 90 days

Centers: 19

Countries: USA

Sample Size: 94

Analysis: Logistic regression with covariate adjustment; intention-to-treat for safety

Inclusion Criteria

  • Age 18–80 years
  • NIHSS >5
  • Initiation of therapy within 3 hours of symptom onset
  • Serious, measurable neurologic deficit

Exclusion Criteria

  • Recent stroke or head trauma
  • Prior ICH or vascular malformation
  • Elevated INR or anticoagulant use
  • CT showing large infarction or hemorrhage
  • Severe comorbid illness or renal failure
  • Recent surgery, trauma, or bleeding
  • Pregnancy, seizure at onset, or uncorrected hypertension

Baseline Characteristics

Age: 71.4 (combo) vs 61.2 (control)

Sex - Female: 43%

NIHSS Score: 14 (combo) vs 10 (control)

Baseline mRS = 0: 75% (combo) vs 96% (control)

Time to Treatment: Median 2.5h (both groups)

Arms

FieldCombination TherapyControl
InterventionLow-dose rt-PA (0.3 or 0.45 mg/kg) + eptifibatide (75 μg/kg bolus, 0.75 μg/kg/min for 2h)Standard rt-PA (0.9 mg/kg per NINDS protocol)
DurationSingle treatmentSingle treatment

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Symptomatic intracranial hemorrhage within 36 hoursPrimary2/25 (8.0%)1/69 (1.4%)6.55%0.17
Barthel Index ≤95 at 90 daysSecondary72%46%0.04
mRS 0–1 or return to baseline at 90 daysSecondary48%30%0.14
Symptomatic ICHAdverse8.0%1.4%0.17
Any ICHAdverse20%12%0.32
Death at 90 daysAdverse12%22%0.38

Subgroup Analysis

Trend toward lower symptomatic ICH in combination group despite older age and higher stroke severity

Criticisms

  • Significant baseline imbalance in NIHSS and age
  • Small sample size limits efficacy interpretation
  • Complex blinding protocol caused treatment delays
  • Trial not powered for clinical outcome comparison

Funding

NINDS Specialized Programs of Translational Research in Acute Stroke; rt-PA and eptifibatide supplied by Genentech and Schering Plough

Based on: CLEAR Eptifibatide (Stroke, 2008)

Authors: Arthur M. Pancioli, Joseph Broderick, Thomas Brott, ..., and the CLEAR Trial Investigators

Citation: Stroke. 2008;39(12):3268–3276. doi:10.1161/STROKEAHA.108.517656

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