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CLEAR III

Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Haemorrhage - Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

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Year of Publication: 2017

Authors: Daniel F Hanley, Karen Lane, Nichol McBee, ..., and CLEAR III Investigators

Journal: The Lancet

Citation: Lancet. 2017 February 11; 389(10069): 603-611

Link: https://doi.org/10.1016/S0140-6736(16)32410-2

Clinical Question

In patients with intraventricular hemorrhage and a routine external ventricular drain, does irrigation with alteplase improve functional outcomes compared to irrigation with saline?

Bottom Line

In the CLEAR III trial, intraventricular alteplase via external ventricular drain did not substantially improve functional outcomes at the mRS 0-3 cutoff compared to saline (48% vs 45%, p=0.554). However, alteplase significantly reduced 180-day mortality (18% vs 29%, p=0.006) and ventriculitis (7% vs 12%, p=0.048), though with an increase in severely disabled survivors (mRS 5: 17% vs 9%, p=0.007). Protocol-based use of alteplase with external ventricular drain appears safe, with similar symptomatic bleeding rates. The amount of clot removal was associated with better outcomes, suggesting future investigation should focus on more complete and rapid IVH removal via improved surgical protocols.

Major Points

  • First phase III randomized, double-blind, placebo-controlled trial of intraventricular thrombolysis
  • 500 patients randomized 1:1 at 73 sites across 8 countries from 2009-2015
  • Patients had ICH <30 mL with IVH obstructing 3rd/4th ventricles requiring EVD placement
  • Median IVH volume 21.8 mL, median ICH volume 7.9 mL, 59% thalamic location
  • Primary outcome (mRS 0-3 at 180 days): 48% alteplase vs 45% saline (RR 1.06, 95% CI 0.88-1.28, p=0.554)
  • Adjusted difference accounting for IVH size and thalamic location: 3.5% (RR 1.08, 95% CI 0.90-1.29, p=0.420)
  • 180-day mortality significantly lower with alteplase: 18% vs 29% (HR 0.60, 95% CI 0.41-0.86, p=0.006)
  • Greater proportion with mRS 5 (bedbound) in alteplase group: 17% vs 9% (RR 1.99, 95% CI 1.22-3.26, p=0.007)
  • No difference in vegetative state (eGOS): 3% both groups (p=0.787)
  • Ventriculitis significantly lower with alteplase: 7% vs 12% (RR 0.55, 95% CI 0.31-0.97, p=0.048)
  • Serious adverse events lower with alteplase: 46% vs 60% (RR 0.76, 95% CI 0.64-0.90, p=0.002)
  • Symptomatic bleeding similar between groups: 2% both (RR 1.21, 95% CI 0.37-3.91, p=0.771)
  • Alteplase group received median 5 doses vs 12 for saline, 3rd and 4th ventricles opened faster with alteplase
  • Only 33% alteplase and 10% saline patients achieved 80% IVH removal
  • Amount of clot removal associated with better outcomes: adjusted OR 0.96 per mL remaining (p<0.0001)
  • 98% retention to day 180, excellent follow-up
  • Adaptive randomization after first 100 patients based on IVH volume and ICH location
  • Video-recorded mRS assessments sent to core laboratory for blinded central adjudication
  • Trial was neutral on primary outcome, cannot be recommended to improve functional outcome

Design

Study Type: Investigator-initiated, multicenter, prospective, randomized, double-blind, placebo-controlled phase III trial

Randomization: 1

Blinding: Double-blind. All participants, trial personnel (except local and central pharmacists and unblinded statistician) masked to treatment. Treatment allocation emailed directly to unblinded pharmacist only. Investigational product (alteplase) and placebo (saline) appeared identical, both clear and colorless. Independent panel of experts at Robertson Centre for Biostatistics (University of Glasgow) performed blinded central adjudication of video-recorded mRS assessments. Masking assessed by external monitor.

Enrollment Period: September 18, 2009 to January 13, 2015

Follow-up Duration: 180 days primary; additional assessments at 30 days and 365 days

Centers: 73

Countries: Brazil, Canada, Germany, Hungary, Israel, Spain, United Kingdom, United States

Sample Size: 500

Analysis: Intention-to-treat analysis. Primary outcome: difference in proportion of mRS ≤3 at 180 days, adjusted for stratification variables (IVH volume and ICH location) using weighted average across six strata. Weights proportional to stratum size pooled across groups. 95% CI computed by bias-corrected accelerated (BCa) bootstrap method adhering to covariate-adaptive design. Kaplan-Meier analysis for survival with log-rank test. Logistic regression relating clot removal to outcomes, adjusted for age, GCS, IVH size, ICH volume and location. Multivariable logistic regression for conditional treatment effects. Area under curve (AUC) of IVH time course from stability to end of treatment calculated with trapezoidal rule, normalized by time elapsed. Sample size: 250 per group provides 82% power to detect 13% absolute difference in mRS 0-3 (from 22% to 35%), based on phase II CLEAR data extrapolation and Monte Carlo simulations. Pocock-Simon covariate adaptive randomization after first 100 patients (80/20 weighted coin) balancing IVH size (<20, 20-50, >50 mL) and ICH location (thalamic vs other). No correction for multiplicity in secondary analyses (hypothesis generating). Statistical analyses using STATA 13.0+ and R 3.2. Two-sided tests with alpha 0.05.

Inclusion Criteria

  • Age 18-80 years
  • Known symptom onset within 24 hours of initial CT scan
  • Confirmed intraventricular hemorrhage obstructing 3rd or 4th ventricle
  • Supratentorial intracerebral hemorrhage volume ≤30 mL measured by ABC/2 method
  • Routinely placed external ventricular drain (EVD) as clinical care decision for obstructive hydrocephalus
  • Clot stability documented: no measured expansion >5 mL on repeat CT at least 6 hours after EVD placement
  • Randomization within 72 hours of ictus
  • Historical modified Rankin Scale score ≤1
  • No limitations to care
  • No ongoing coagulopathy
  • No suspicion of aneurysm, arteriovenous malformation, or other vascular anomaly (unless ruled out by angiography or treated ≥3 months prior)
  • Written informed consent obtained

Exclusion Criteria

  • Infratentorial hemorrhage
  • Pregnancy
  • Clotting disorders
  • Platelet count <100,000
  • INR >1.4
  • ICH/IVH enlargement that cannot be stabilized within treatment time window
  • Ongoing internal bleeding (retroperitoneal, gastrointestinal, genitourinary, respiratory)
  • Multi-focal superficial bleeding at vascular access sites or recent surgical sites
  • Prior enrollment in the study
  • Planned or simultaneous participation in another interventional trial between screening and day 30
  • Any condition posing significant hazard if investigational therapy initiated
  • Not expected to survive to day 180 due to comorbidities
  • DNR/DNI status prior to randomization

Arms

FieldAlteplase GroupControl
InterventionExternal ventricular drainage (EVD) plus intraventricular alteplase (rt-PA, Genentech Inc). Dose: 1 mg in 1 mL administered every 8 hours for up to 12 doses via EVD. CT scans obtained every 24 hours during dosing. Treatment continued until stopping point: (1) 3rd and 4th ventricles open; (2) IVH mass effect relieved; (3) estimated 80% IVH resolution; or (4) 12 doses given. First dose given after randomization, median 3.0 hours (IQR 1.7-5.5) post-randomization. Median 5 doses given (IQR 3-8). EVD managed per American Heart Association guidelines for ICH. Catheter irrigation with saline permitted if needed; replacement at neurosurgical discretion.External ventricular drainage (EVD) plus intraventricular 0.9% normal saline (placebo). Dose: 1 mL administered every 8 hours for up to 12 doses via EVD. Identical administration protocol, CT schedule, and stopping points as alteplase group. Saline prepared by unblinded pharmacist to appear identical to alteplase (both clear and colorless). First dose given median 3.1 hours (IQR 1.7-5.7) post-randomization. Median 12 doses given (IQR 9-12). EVD managed identically to alteplase group.
DurationMedian 2.5 days (IQR 1.8-3.7) from randomization to end of treatmentMedian 4.7 days (IQR 4.0-5.1) from randomization to end of treatment

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Proportion of patients with modified Rankin Scale (mRS) score 0-3 (good functional outcome, independence) versus 4-6 (poor outcome, dependence or death) at 180 days, centrally adjudicated by blinded independent panel at University of Glasgow using video-recorded assessmentsPrimary110 of 245 (45%, 95% CI not provided)117 of 246 (48%, 95% CI not provided)3.00%0.554
Primary outcome adjusted for IVH size and thalamic ICH locationSecondary45%48%RR 1.08, difference 3.5%0.420, 95% CI 0.90-1.29
180-day mortality (case fatality)Secondary73 of 251 (29%)46 of 249 (18%)HR 0.600.006, 95% CI 0.41-0.86
mRS 5 (bedbound, severe disability) at 180 daysSecondary21 of 245 (9%)42 of 246 (17%)RR 1.990.007, 95% CI 1.22-3.26
Vegetative state (eGOS) at 180 daysSecondary6 of 245 (3%)8 of 246 (3%)RR 1.330.787, 95% CI 0.47-3.78
Long-term care facility placement at 180 daysSecondary29 of 245 (12%)34 of 246 (14%)RR 1.180.479, 95% CI 0.74-1.88
mRS 0-4 vs 5-6 at 180 daysSecondaryNot specifiedNot specifiedSecondary planned analysisNot significant per text
Time to open 3rd and 4th ventriclesSecondary5 days (IQR 3-7)2 days (IQR 2-3)<0.0001
Achievement of 80% IVH removalSecondary24 of 251 (10%)82 of 249 (33%)Not specified
End of treatment IVH volumeSecondary11.5 mL (IQR 5.8-23.1)5.9 mL (IQR 1.9-13.0)<0.0001
Association of clot removal with mRS 0-3 (per mL clot remaining, adjusted)SecondaryAll patients combined analysisAll patients combined analysisAdjusted OR 0.96<0.0001, 95% CI 0.94-0.97
Association of clot removal with 180-day mortality (per mL clot remaining, adjusted)SecondaryAll patients combined analysisAll patients combined analysisAdjusted HR 1.03<0.0001, 95% CI 1.02-1.04
Bacterial ventriculitis (day 0-180)Adverse31 of 251 (12%)17 of 249 (7%)RR 0.550.048, 95% CI 0.31-0.97
Symptomatic bleeding ≤72 hours post last doseAdverse5 of 251 (2%)6 of 249 (2%)RR 1.210.771, 95% CI 0.37-3.91
Serious adverse events (day 0-180)Adverse151 of 251 (60%)114 of 249 (46%)RR 0.760.002, 95% CI 0.64-0.90
Neurological disorders (SAE category)Adverse50 of 251 (20%)39 of 249 (16%)Not specified
Respiratory disorders (SAE category)Adverse34 of 251 (14%)26 of 249 (10%)Not specified
General disorders/sudden deaths (SAE category)Adverse33 of 251 (13%)17 of 249 (7%)Not specified
Cardiac disorders (SAE category)Adverse14 of 251 (6%)6 of 249 (2%)Not specified
Gastrointestinal bleedingAdverseNot specifiedNot specifiedMost common hemorrhagic event per text
ICP ≤20 mmHg (mean proportion of events)Adverse10.2%9.8%0.45
CPP <70 mmHgAdverse867 of 251 patients (9% of measurements)644 of 249 patients (7% of measurements)<0.0001
Ventriculoperitoneal shunt placementAdverse44 of 251 (18%)46 of 249 (18%)0.78
Withdrawal of careAdverse30 of 251 (12%)27 of 249 (11%)0.70

Subgroup Analysis

Forest plot analysis of prespecified subgroups showed no significant interactions (all p>0.05 for interaction terms). Subgroups analyzed: age (<65 vs ≥65), sex, race (White, African American, Other), IVH volume (<20, 20-50, >50 mL), GCS (mild 13-15, moderate 9-12, severe 3-8), ICH location (thalamic vs non-thalamic), time from symptom onset to randomization (<48, 48-60, >60 hours). All adjusted for age, sex, thalamic ICH, stability ICH/IVH volume, and GCS. Post-hoc analyses suggested larger IVH volumes (>20 mL) showed differential clot removal with alteplase but this did not translate to improved functional outcomes at mRS 0-3 cutoff.

Criticisms

  • Trial neutral on primary functional outcome (mRS 0-3), cannot recommend intervention to improve outcomes
  • First phase III trial of IVH thrombolysis - evidence-based standards for patient selection and treatment endpoints did not exist at study design
  • Open-label EVD management (not blinded) could introduce bias in catheter management decisions
  • Poor adherence to 80% IVH removal endpoint: only 33% alteplase and 10% saline patients achieved this, limiting test of hypothesis
  • Current guidelines do not mandate use, number, or location of EVD catheters - substantial variation in neurosurgical practice
  • Not all severity factors known, imbalances in unmeasured severity could have existed
  • Small sample from most aggressive end of treatment spectrum - patients whose physicians used EVD
  • Control intervention (EVD with saline) represents aggressive care not offered to all IVH patients
  • Survival and good outcomes in controls (45% mRS 0-3) better than general IVH population expectations
  • May not represent true general IVH population - convenience sample bias possible
  • Increased proportion with mRS 5 (bedbound) in alteplase group raises concern about survival with severe disability
  • No difference in vegetative state but divergent findings within severe disability segments need clarification
  • Single EVD placement not standardized for optimal clot removal - multiple catheters or better placement may improve outcomes
  • Treatment endpoint of 80% removal subjective, may vary by assessor
  • Dose selection (1 mg q8h) based on phase II studies with limited samples
  • Exclusion of infratentorial hemorrhage limits generalizability to posterior fossa IVH
  • Age limit 18-80 excludes very elderly who comprise significant portion of IVH population
  • Pre-morbid mRS ≤1 requirement excludes patients with baseline disability
  • Clot stability criteria may delay treatment - could benefit from more rapid treatment
  • Multiple participating sites may have heterogeneity in practices despite standardization attempts
  • Only 27% had dual EVD catheters - better bilateral drainage may improve outcomes
  • Median 5 doses alteplase vs 12 saline - earlier stopping in alteplase group may reflect protocol-driven decisions
  • 3rd and 4th ventricle opening occurred faster with alteplase but didn't translate to improved function
  • Knowledge about risk/benefit in general population limited - only patients receiving EVD studied

Funding

National Institutes of Health (NIH), National Institute of Neurological Disorders and Stroke (NINDS), grant 5U01 NS062851-05 (to DFH). Additional support from NIH/NINDS grants R01NS046309 and 5U01 NS080824-02 (to DFH). Drug (alteplase) provided at no cost by Genentech Inc. US FDA Orphan Products Development program supported high-risk idea development. NIH/NINDS-appointed DSMB (Bob S Carter chair, Kyra J Becker, James C Torner, Alex B Valadka, P Gilbert NINDS liaison) approved changes to analysis plan and publication.

Based on: CLEAR III (The Lancet, 2017)

Authors: Daniel F Hanley, Karen Lane, Nichol McBee, ..., and CLEAR III Investigators

Citation: Lancet. 2017 February 11; 389(10069): 603-611

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