Dual Thrombolytic Therapy With Mutant Pro-urokinase and Low Dose Alteplase for Ischemic Stroke (DUMAS)

• ClinicalTrials.gov Identifier: NCT04256473
• Recruitment Status: Recruiting
• First Posted: February 5, 2020
• Last Update Posted: June 18, 2021
• Sponsor: Erasmus Medical Center
• Collaborator: DUMAS is sponsored by an unrestricted grant from Thrombolytic Science International, paid to the institution.
• Information provided by (Responsible Party): Nadinda van der Ende, Erasmus Medical Center

Tracking Information

• First Submitted Date: February 3, 2020
• First Posted Date: February 5, 2020
• Last Update Posted Date: June 18, 2021
• Actual Study Start Date: August 10, 2019
• Estimated Primary Completion Date: May 31, 2022 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 4, 2020): Any intracranial hemorrhage according to the Heidelberg Bleeding Classification on MRI [ Time Frame: 24-48 hours post-treatment ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 7, 2020)

• Score on the National Institutes of Health Stroke Scale (NIHSS) [ Time Frame: at 24 hours and 5-7 days post-treatment ]
  The NIHSS measures neurological deficit, ranging from 0 to 42, with higher scores indicating more severe neurological deficit.
• Score on the modified Rankin Scale (mRS) [ Time Frame: at 30 days ]
  The mRS is an ordinal scale ranging from 0 (no symptoms) to 6 (death) measuring the degree of disability or dependence in everyday life.
• Infarct volume on MRI [ Time Frame: at 24-48 hours ]
• Change (pre-treatment vs. post-treatment) in abnormal perfusion volume based on TTP/MTT maps measured with CT perfusion at baseline and MRI [ Time Frame: at 24-48 hours post treatment. ]
• Secondary blood biomarkers of thrombolysis: d-dimer levels and fibrinogen levels. [ Time Frame: 1 hour post-treatment, after 3 hours, and after 24 hours post-treatment, ]
• Symptomatic intracranial hemorrhage (sICH) according to the Heidelberg Bleeding Classification [ Time Frame: within 30 days ]
  sICH is defined as any intracranial hemorrhage followed by a neurological deterioration that can be attributed to that hemorrhage, defined as an increase of >= 4 points on the NIHSS or >= 2 points on a specific NIHSS item.
• Death from any cause [ Time Frame: Within 30 days ]
• Major extracranial hemorrhage according to the ISTH criteria [ Time Frame: within 24 hours of study drug administration ]

Original Secondary Outcome Measures (submitted: February 4, 2020)

• Score on the National Institutes of Health Stroke Scale (NIHSS) [ Time Frame: at 24 hours and 5-7 days post-treatment ]
  The NIHSS measures neurological deficit, ranging from 0 to 42, with higher scores indicating more severe neurological deficit.
• Score on the modified Rankin Scale (mRS) [ Time Frame: at 30 days ]
  The mRS is an ordinal scale ranging from 0 (no symptoms) to 6 (death) measuring the degree of disability or dependence in everyday life.
• Infarct volume on MRI [ Time Frame: at 24-48 hours ]
• Change (pre-treatment vs. post-treatment) in abnormal perfusion volume based on TTP/MTT maps measured with CT perfusion at baseline and MRI [ Time Frame: at 24-48 hours post treatment. ]
• Secondary blood biomarkers of thrombolysis: d-dimer levels and fibrinogen levels. [ Time Frame: 1 hour post-treatment, after 3 hours, and after 24 hours post-treatment, ]
• Symptomatic intracranial hemorrhage (sICH) according to the Heidelberg Bleeding Classification [ Time Frame: within 30 days ]
  sICH is defined as any intracranial hemorrhage followed by a neurological deterioration that can be attributed to that hemorrhage, defined as an increase of >= 4 points on the NIHSS or >= 2 points on a specific NIHSS item.
• Death from any cause [ Time Frame: Within 30 days ]
  Number of participants that died during the study.
• Major extracranial hemorrhage according to the ISTH criteria [ Time Frame: within 24 hours of study drug administration ]
  Number of participants with a major extracranial hemorrhage according tot he ISTH criteria.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dual Thrombolytic Therapy With Mutant Pro-urokinase and Low Dose Alteplase for Ischemic Stroke
• Official Title: Dual Thrombolytic Therapy With Mutant Pro-urokinase (M-pro-urokinase, HisproUK) and Low Dose Alteplase for Ischemic Stroke
• Brief Summary: Randomized controlled phase II trial to test the safety and preliminary efficacy of a dual thrombolytic treatment consisting of a small intravenous (IV) bolus of alteplase followed by IV infusion of mutant pro-urokinase against usual treatment with IV alteplase in patients presenting with ischemic stroke.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Outcomes Assessor); Primary Purpose: Treatment
• Condition: Ischemic Stroke

Intervention

• Drug: mutant pro-urokinase
  Intravenous administration
  Other Name: HisproUK
• Drug: Alteplase
  Intravenous administration
  Other Name: Actilyse

Study Arms

• Experimental: Intervention

  Bolus of IV alteplase (5 mg) followed by continuous infusion of HisproUK 40 mg/hr during 60 minutes.

  Depending on results of interim analyses, the alternate dose may be revised to a lower dose (30mg/hr during 60 minutes) or a higher dose (50mg/hr during 60 minutes).

  Intervention: Drug: mutant pro-urokinase
• Active Comparator: Control
  Usual care with alteplase 0.9 mg/kg in 60 minutes
  Intervention: Drug: Alteplase

• Publications *: van der Ende NAM, Roozenbeek B, Smagge LEM, Luijten SPR, Aerden LAM, Kraayeveld P, van den Wijngaard IR, Lycklama A Nijeholt GJ, den Hertog HM, Flach HZ, Wallace AC, Gurewich V, Del Zoppo GJ, Meurer WJ, Lingsma HF, van der Lugt A, Dippel DWJ; DUMAS Investigators. Dual thrombolytic therapy with mutant pro-urokinase and small bolus alteplase for ischemic stroke (DUMAS): study protocol for a multicenter randomized controlled phase II trial. Trials. 2022 Aug 9;23(1):641. doi: 10.1186/s13063-022-06596-z.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 7, 2020): 200
• Original Estimated Enrollment (submitted: February 4, 2020): 25
• Estimated Study Completion Date: July 31, 2022
• Estimated Primary Completion Date: May 31, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• A clinical diagnosis of ischemic stroke;
• A score of at least 1 on the NIH Stroke Scale;
• CT ruling out intracranial hemorrhage;
• Treatment possible within 4.5 hours from symptom onset or last seen well;
• Meet the criteria for standard treatment for IV alteplase according to national guidelines27;
• Age of 18 years or older;
• Written informed consent (deferred).

Exclusion Criteria:

• Candidate for endovascular thrombectomy (i.e., a proximal intracranial large artery occlusion on CTA);

• Contra-indication for treatment with IV alteplase according to national guidelines27:

  • Arterial blood pressure exceeding 185/110 mmHg and not responding to treatment
  • Blood glucose less than 2.7 or over 22.2 mmol/L
  • Cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuro-imaging
  • Head trauma in the previous 4 weeks
  • Major surgery or serious trauma in the previous 2 weeks
  • Gastrointestinal or urinary tract hemorrhage in the previous 2 weeks
  • Previous intracerebral hemorrhage
  • Use of anticoagulant with INR exceeding 1.7 or APTT exceeding 50 seconds
  • Known thrombocyte count less than 90 x 109 /L
  • Treatment with direct thrombin or factor X inhibitors, unless specific antidotum has been given, i.e. idarucizumab in case of dabigatran use.
• Pre-stroke disability which interferes with the assessment of functional outcome at 90 days, i.e. mRS > 2;
• Known pregnancy or if pregnancy cannot be excluded, i.e. did not have intercourse for > 6 months and no clinical signs of pregnancy, adequate use of any contraceptive method (e.g. intrauterine devices) or sterilization of the subject herself.

• Contra-indication for an MRI scan, i.e.:

  • an MRI incompatible pacemaker, ICD, pacing wires and loop records
  • metallic foreign bodies (e.g. intra-ocular)
  • prosthetic heart valves
  • blood vessel clips, coils or stents
  • an implanted electronic and/or magnetic implant or pump (e.g. neurostimulator)
  • cochlear implants
  • mechanical implants (implanted less than 6 weeks ago)
  • a copper intrauterine device
• Current Participation in any medical or surgical therapeutic trial other than DUMAS.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT04256473
• Other Study ID Numbers: DUMAS-1.1
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Nadinda van der Ende, Erasmus Medical Center
• Original Responsible Party: Nadinda van der Ende, Erasmus Medical Center, Prof. Dr. Dippel
• Current Study Sponsor: Erasmus Medical Center
• Original Study Sponsor: Nadinda van der Ende
• Collaborators: DUMAS is sponsored by an unrestricted grant from Thrombolytic Science International, paid to the institution.
• Investigators: Not Provided
• PRS Account: Erasmus Medical Center
• Verification Date: June 2021