Phase 3, Randomized, Placebo-Controlled, Double-Blinded Trial of the Combined Lysis of Thrombus With Ultrasound and Systemic Tissue Plasminogen Activator (tPA) for Emergent Revascularization in Acute Ischemic Stroke (CLOTBUST-ER)

A Phase 3, Randomized, Placebo-Controlled, Double-Blind Study of the Combined Lysis of Thrombus With Ultrasound and Systemic Tissue Plasminogen Activator (tPA) for Emergent Revascularization (CLOTBUST-ER) in Acute Ischemic Stroke

This is a randomized, placebo-controlled, phase 3 clinical trial to evaluate the efficacy and safety of transcranial ultrasound (US) as an adjunctive therapy to tissue plasminogen activator (tPA) treatment in subjects with acute ischemic stroke.

Study Overview

• Status: Terminated
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Device: Transcranial ultrasound as an adjunctive therapy to tPA; Drug: Standard of care tPA therapy for acute ischemic stroke

Detailed Description

The primary objective of this trial is to provide information regarding the efficacy of a combined treatment with transcranial US and systemic tPA (Target group) compared to systemic tPA alone (Control group) in subjects with acute ischemic stroke. The primary efficacy endpoint is functional outcome at 3 months from stroke onset (modified Rankin Score ordinal shift analysis). The primary safety endpoint is the proportion of subjects in the Target vs Control group experiencing symptomatic intracranial hemorrhage (sICH) within 24 hours of treatment.

• Study Type: Interventional
• Enrollment (Actual): 675
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Washington
    • Redmond, Washington, United States, 98052-2431
      • Cerevast Therapeutics, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or females 18 - 80 years of age
2. Subjects presenting within timeframe for intravenous tPA treatment approved by local regulatory authorities but no more than 4.5 hours from onset of symptoms
3. No signs of intracranial bleeding on assessment by non-contrast CT
4. Subjects with neurological deficits of a total NIHSS score ≥ 10 points
5. Subjects that in the opinion of the treating physician require treatment with full dose IV tPA as standard of care per institutional standards
6. SBP < 185 mmHg and DBP < 105 mmHg at baseline or after treatment of hypertension with medications prior to tPA bolus
7. Pre-morbid modified Rankin score of 0-1
8. Provision of informed consent as demonstrated by the subject's signature or by the signature of the subject's authorized legal representative on the Informed Consent Form in accordance with all local and national regulations
9. Co-signature on the Informed Consent Form by a qualified member of the study staff signifying that, in his/her professional opinion, informed consent has been obtained in accordance with all local and national regulations

10. For subjects in the optional arterial recanalization substudy:

    1. Occlusion located in the intracranial carotid tee through mid M2 or proximal A2, or intracranial vertebrobasilar or P1/proximal P2 segments or tandem lesions
    2. Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min for patients undergoing CTA or MRA

Exclusion Criteria:

1. Subjects with primary intra-arterial thrombolysis
2. Females who are pregnant or breast feeding
3. Subjects receiving other investigational drugs, procedures, or therapies within 30 days prior to study treatment
4. Subjects with any standard contraindication for intravenous tPA therapy
5. Significant concurrent medical/neurological conditions or test values that, in the opinion of the investigator, pose significant risk to the subject and warrant exclusion from the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Target group; A combined treatment with transcranial US and systemic tPA	Device: Transcranial ultrasound as an adjunctive therapy to tPA; tPA per approved labeling administered over 60 minutes; Ultrasonic headframe with active insonation for 120 minutes
Active Comparator: Control group; Systemic tPA alone	Drug: Standard of care tPA therapy for acute ischemic stroke; tPA per approved labeling administered over 60 minutes; Ultrasonic headframe with sham (inactive) insonation for 120 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modified Rankin score ordinal shift analysis	The primary objective of this study is to compare clinical recovery rates (modified Rankin score ordinal shift analysis) at 3 months after stroke onset.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Symptomatic intracerebral hemorrhage	The secondary outcome is a comparison of the rates of symptomatic intracerebral hemorrhage within 0-24 hours from initiation of treatment.	0-24 hours from treatment

Collaborators and Investigators

• Sponsor: Cerevast Therapeutics, Inc.

Publications and helpful links

General Publications

• Alexandrov AV, Kohrmann M, Soinne L, Tsivgoulis G, Barreto AD, Demchuk AM, Sharma VK, Mikulik R, Muir KW, Brandt G, Alleman J, Grotta JC, Levi CR, Molina CA, Saqqur M, Mavridis D, Psaltopoulou T, Vosko M, Fiebach JB, Mandava P, Kent TA, Alexandrov AW, Schellinger PD; CLOTBUST-ER Trial Investigators. Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Neurol. 2019 Apr;18(4):338-347. doi: 10.1016/S1474-4422(19)30026-2.
• Schellinger PD, Alexandrov AV, Barreto AD, Demchuk AM, Tsivgoulis G, Kohrmann M, Alleman J, Howard V, Howard G, Alexandrov AW, Brandt G, Molina CA; CLOTBUSTER Investigators. Combined lysis of thrombus with ultrasound and systemic tissue plasminogen activator for emergent revascularization in acute ischemic stroke (CLOTBUST-ER): design and methodology of a multinational phase 3 trial. Int J Stroke. 2015 Oct;10(7):1141-8. doi: 10.1111/ijs.12536. Epub 2015 Jun 29.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: April 2, 2010
• First Submitted That Met QC Criteria: April 5, 2010
• First Posted (Estimate): April 6, 2010

Study Record Updates

• Last Update Posted (Estimate): April 7, 2015
• Last Update Submitted That Met QC Criteria: April 3, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction
• Other Study ID Numbers: CEREVAST THERAPEUTICS CP-01