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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

PDF: https://www.ncbi.nlm.nih.gov/pmc/articles/6108339

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

Baseline Characteristics

Characteristic	Alteplase	Saline
Sample Size	249	251
Age - Median (IQR)	59 (51-66) years	59 (51-67) years
Female	105 (42%)	117 (47%)
Male	144 (58%)	134 (53%)
White	144 (58%)	161 (64%)
African American	92 (37%)	78 (31%)
Hispanic/Latino	28 (11%)	32 (13%)
Tobacco use	73 (29%)	59 (24%)
Cocaine use	12 (5%)	18 (7%)
On anticoagulation at registration	20 (8%)	29 (12%)
On antiplatelet at registration	56 (22%)	72 (29%)
Randomization MAP	96 (86-106) mmHg	94 (86-104) mmHg
Randomization GCS total	10 (7-13)	9 (7-12)
Randomization NIHSS	19 (11-32)	20 (11-35)
Stability IVH volume	21.2 (12.7-34.2) mL	22.4 (12.7-39.1) mL
Stability ICH volume	8.3 (2.9-15.2) mL	7.2 (2.3-14.7) mL
Thalamic ICH	149 (60%)	144 (57%)
Primary IVH (no ICH)	19 (8%)	27 (11%)
Ictus to hospital arrival	1.5 (0.8-3.3) hours	1.5 (0.8-3.6) hours
Ictus to first CT	2.3 (1.3-4.6) hours	2.3 (1.4-5.2) hours
Ictus to first EVD	7.1 (4.5-11.9) hours	7.9 (5.1-12.0) hours
Ictus to stability CT	43.1 (25.4-58.8) hours	44.0 (28.2-57.0) hours
Ictus to randomization	51.8 (36.4-65.8) hours	52.2 (41.2-66.8) hours

Arms

Field	Alteplase Group	Control
Intervention	External 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.
Duration	Median 2.5 days (IQR 1.8-3.7) from randomization to end of treatment	Median 4.7 days (IQR 4.0-5.1) from randomization to end of treatment

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-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 assessments	Primary	110 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 location	Secondary	45%	48%	RR 1.08, difference 3.5%	0.420, 95% CI 0.90-1.29
180-day mortality (case fatality)	Secondary	73 of 251 (29%)	46 of 249 (18%)	HR 0.60	0.006, 95% CI 0.41-0.86
mRS 5 (bedbound, severe disability) at 180 days	Secondary	21 of 245 (9%)	42 of 246 (17%)	RR 1.99	0.007, 95% CI 1.22-3.26
Vegetative state (eGOS) at 180 days	Secondary	6 of 245 (3%)	8 of 246 (3%)	RR 1.33	0.787, 95% CI 0.47-3.78
Long-term care facility placement at 180 days	Secondary	29 of 245 (12%)	34 of 246 (14%)	RR 1.18	0.479, 95% CI 0.74-1.88
mRS 0-4 vs 5-6 at 180 days	Secondary	Not specified	Not specified	Secondary planned analysis	Not significant per text
Time to open 3rd and 4th ventricles	Secondary	5 days (IQR 3-7)	2 days (IQR 2-3)		<0.0001
Achievement of 80% IVH removal	Secondary	24 of 251 (10%)	82 of 249 (33%)		Not specified
End of treatment IVH volume	Secondary	11.5 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)	Secondary	All patients combined analysis	All patients combined analysis	Adjusted OR 0.96	<0.0001, 95% CI 0.94-0.97
Association of clot removal with 180-day mortality (per mL clot remaining, adjusted)	Secondary	All patients combined analysis	All patients combined analysis	Adjusted HR 1.03	<0.0001, 95% CI 1.02-1.04
Bacterial ventriculitis (day 0-180)	Adverse	31 of 251 (12%)	17 of 249 (7%)	RR 0.55	0.048, 95% CI 0.31-0.97
Symptomatic bleeding ≤72 hours post last dose	Adverse	5 of 251 (2%)	6 of 249 (2%)	RR 1.21	0.771, 95% CI 0.37-3.91
Serious adverse events (day 0-180)	Adverse	151 of 251 (60%)	114 of 249 (46%)	RR 0.76	0.002, 95% CI 0.64-0.90
Neurological disorders (SAE category)	Adverse	50 of 251 (20%)	39 of 249 (16%)		Not specified
Respiratory disorders (SAE category)	Adverse	34 of 251 (14%)	26 of 249 (10%)		Not specified
General disorders/sudden deaths (SAE category)	Adverse	33 of 251 (13%)	17 of 249 (7%)		Not specified
Cardiac disorders (SAE category)	Adverse	14 of 251 (6%)	6 of 249 (2%)		Not specified
Gastrointestinal bleeding	Adverse	Not specified	Not specified	Most common hemorrhagic event per text
ICP ≤20 mmHg (mean proportion of events)	Adverse	10.2%	9.8%		0.45
CPP <70 mmHg	Adverse	867 of 251 patients (9% of measurements)	644 of 249 patients (7% of measurements)		<0.0001
Ventriculoperitoneal shunt placement	Adverse	44 of 251 (18%)	46 of 249 (18%)		0.78
Withdrawal of care	Adverse	30 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)