What are the recommended trials for stroke treatment?

Major Stroke Trials and Treatment Recommendations

Pivotal Efficacy Trials

The NINDS rt-PA Stroke Trial (1995) remains the landmark study demonstrating that tissue plasminogen activator (tPA/alteplase) significantly improves clinical outcomes when administered within 3 hours of acute ischemic stroke onset. 1, 2

Key Positive Trials

• NINDS rt-PA Trial: Demonstrated efficacy of intravenous tPA within 3 hours, using a global statistic approach evaluating modified Rankin scale, Barthel Index, Glasgow Outcome Scale, and NIHSS at 90 days 1, 2

• ECASS III Trial: Extended the treatment window, showing significant improvement in clinical outcomes when alteplase was administered between 3 and 4.5 hours after stroke onset 2

• STARS Study: Prospective multicenter study of 389 patients showing 35% achieved very favorable outcomes (modified Rankin 0-1) and 43% were functionally independent at 30 days, with 3.3% symptomatic intracerebral hemorrhage rate 3

• SITS-MOST and SITS-ISTR: Observational studies confirming alteplase effectiveness and tolerability within 4.5 hours in routine clinical practice, though outcomes were less favorable in the 3-4.5 hour window compared to <3 hours 2

Negative Trials

• ATLANTIS Study: Failed to show benefit for rt-PA administered between 3 and 5 hours after symptom onset, with increased symptomatic ICH (7.0% vs 1.1%, p<0.001) and fatal ICH (3.0% vs 0.3%, p<0.001) 4

• Multiple neuroprotective compound trials: Despite promising phase II results and reduction of infarct volumes in animal models, none have proven efficacious in phase III trials 1

• Intra-arterial thrombolysis with prourokinase and ancrod: Showed promise but neither achieved marketing approval 1

Combination Therapy Trials

CURE Trial: In acute coronary syndrome patients, clopidogrel plus aspirin reduced cardiovascular death, MI, or stroke compared to aspirin alone, though this was not specifically a stroke treatment trial 5

Combined intravenous and intra-arterial tPA: Preliminary trials tested lower-dose IV tPA followed by angiography and additional intra-arterial tPA with manual clot manipulation for severe strokes with persistent vascular occlusion 1

Trial Design Recommendations from STAIR Guidelines

Phase IIb Trial Considerations 1

Before proceeding to phase III, phase IIb trials must establish:

• Route of administration, dose range, and treatment duration
• Time from stroke onset to treatment initiation (critical variable)
• Pharmacokinetic profile and side effect frequency
• Drug interactions with commonly used medications
• Target population refinement based on stroke subtype
• Evidence of therapeutic activity via clinical and/or surrogate markers

Placebo-controlled, blinded, randomized trials are necessary even at the phase IIb stage 1

Phase III Trial Design 1

Primary endpoint selection:

• Modified Rankin scale score of 0-1 is appropriate for treatments within 3 hours (as in NINDS trial) 1
• Modified Rankin 0-2 may be more appropriate for later treatment windows (as in ECASS II and PROACT II) 1
• Global statistic approach testing multiple predefined outcome measures simultaneously provides most robust treatment differences 1
• 90-day endpoint is standard, though earlier timepoints may avoid confounding from late complications 1

Patient population criteria:

• Baseline stroke severity: Patients with NIHSS <6-7 have high spontaneous improvement rates; those with NIHSS >20-22 have very low full recovery rates even with treatment 1
• Age considerations: Lower limit typically 18 years; upper limit based on drug tolerability and pharmacokinetics 1
• Target INR of 2.5 (range 2.0-3.0) for warfarin in stroke prevention for atrial fibrillation 6

Multimodal Trial Strategies 1

Four broad categories for increasing treatable stroke patients: 1

1. Reducing delays between symptom onset and treatment presentation
2. Using imaging/laboratory measures to identify patients benefiting from delayed interventions
3. Testing novel treatments effective beyond current tPA time window
4. Developing combination therapies enhancing existing treatment efficacy

Multimodal approaches under investigation: 1

• Thrombolysis plus neuroprotection: Testing IV tPA combined with neuroprotective agents versus tPA plus placebo, with neuroprotection given during, after, or before tPA infusion
• Multimodal reperfusion: Mechanical reperfusion techniques, combined IV/intra-arterial thrombolytics, glycoprotein IIb/IIIa agents, and thrombin inhibitors
• Metalloproteinase inhibitors: To reduce hemorrhagic risk associated with reperfusion 1

Critical Pitfalls and Limitations

Common trial failures attributed to: 1

• Testing drugs not truly effective based on preclinical data
• Underpowered phase III trials
• Including patients unlikely to respond to tested drug
• Primary endpoints not evaluating total treatment effects

Time-dependent efficacy: Pooled analyses show alteplase benefit decreases as time from onset to treatment increases, with no significant benefit >4.5 hours and increasing mortality odds with treatment delay 2

Protocol violations in clinical practice: The STARS study reported violations in 32.6% of patients, including treatment >3 hours (13.4%), anticoagulant use within 24 hours (9.3%), and treatment despite BP >185 mmHg (6.7%) 3