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Superiority of Rt-PA + Tenecteplase in Comparison With Rt-PA Only in Proximal Middle Cerebral Artery Occlusion (DIVA)

Primary Purpose

Nervous System Disorders, Cerebral Artery

Status

Withdrawn

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

rt-PA

tenecteplase

About this trial

This is an interventional treatment trial for Nervous System Disorders

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age between 18 and 85 years
Cerebral infarction in relation with a proximal middle cerebral artery occlusion (M1 ou M2)
NIHSS between 4 and 23
Patient treated with intravenous rt-PA (0,9 mg/kg) within the first 4.5 hours
No recanalization on the MRI performed 1 hour after rt-PA initiation (TIMI 0,1 ou 2a)
Administration of TNK within the first 6 hours
Informed and written consent obtained from the patient or next of kin
Patient insured under the French social security system

Exclusion Criteria:

Contraindication to MRI
Contraindication to rt-PA administration
Contraindication to TNK administration
Contraindication to stroke thrombolysis
Refusal to sign the informed consent
Extensive small arteries disease (>5 microbleed and/or Fazekas score≥3)
Systolic arterial pression> 185 mmHg or diastolic arterial pression > 110 mmHg
Glycemia < 3 mmol/l (0,5g/l) or > 22 mmol/l (4g/l)
Thrombopenia < 100 000/mm3 or INR > 1,5.
Patients treated with new oral anticoagulant.
Seizure as one of acute stroke symptoms
Lumbar or arterial puncture in the previous 7 days or major surgery in the previous 15 days
Carotid occlusion associated with MCA occlusion
Thrombus length > 12mm assessed on gradient echo sequences
Large DWI lesion, defined as ASPECTS < 7 / 10
DWI/PWI Mismatch < 20% (when performed) on MRI 2
Marked FLAIR hypersignal on cortical structure and light hypersignal on caudate or lenticular nucleus assessed on MRI 2.
Parenchymal hemorrhage on MRI 2
Pregnancy or breast feeding
Patient currently included in a biomedical study

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

rt-PA

rt-PA + tenecteplase

Arm Description

Patients treated by thrombolysis with rt -PA within 4h30 of the onset of symptoms to a proximal middle cerebral artery occlusion visible on a MRI 1 are pre- included. A second MRI ( IRM2 ) is performed between 1 hour and 1.5 hours after administration of rt-PA in the usual way . After the treatment by rt-PA, if there is no recanalization (TIMI score: 0,1, 2a), the patient is included. A patient included will be randomized either in the arm "rt-PA treatment only" or in the arm "rt-PA + tenecteplase treatment". If he is included in the arm "rt-PA only", he will not receive any other treatment for the study.

If patient is in the arm "rt-PA + tenecteplase", he will receive tenecteplase (50UI/Kg) treatment. A third MRI will be performed at 24hour that will assess the recanalization status (TIMI), the final volume infarct and the hemorrhagic complications.

Outcomes

Primary Outcome Measures

Clinical outcome ill be assessed at 3-month with the modified Rankin score by a blinded examiner.

The clinical outcome will be assessed at 3-month with the modified Rankin score by a blinded examiner. A score of 0-2 is considered good prognosis and a score 3-6 define a poor prognosis.

Secondary Outcome Measures

Full Information

NCT ID

NCT02338466

First Posted

January 12, 2015

Last Updated

June 19, 2018

Sponsor

University Hospital Center of Martinique

1. Study Identification

Unique Protocol Identification Number

NCT02338466

Brief Title

Superiority of Rt-PA + Tenecteplase in Comparison With Rt-PA Only in Proximal Middle Cerebral Artery Occlusion

Acronym

DIVA

Official Title

Randomized Therapeutic Study Assessing the Superiority of a Sequential Intravenous Thrombolysis Treatment (Rt-PA + Tenecteplase) in Comparison With Rt-PA Standard Treatment in Proximal Middle Cerebral Artery Occlusion (DIVA).

Study Type

Interventional

2. Study Status

Record Verification Date

June 2018

Overall Recruitment Status

Withdrawn

Why Stopped

Departure of the principal investigator and lack of succession

Study Start Date

July 2016 (Anticipated)

Primary Completion Date

July 2018 (Anticipated)

Study Completion Date

September 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University Hospital Center of Martinique

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

Proximal Middle Cerebral Artery (MCA) occlusions constitute the most severe stroke. Intra-venous thrombolysis with rt-PA within the first 4,5 hours is the only proven effective treatment. Prognosis is closely related to the recanalization rate that reaches only 30 to 50%. A new therapeutic strategy consisting in a sequential intravenous (IV) thrombolysis by rt-PA followed by 50UI/kg of IV tenecteplase (TNK) has been proposed in case of no recanalization after rt-PA. A case series of 13 consecutive patients treated by this association has been published in 2011. A high rate of recanalization without hemorrhagic transformation increase has been reported. However, efficiency and safety of this therapeutic have to be assessed in a randomized multi-centric study. Such a study is of great interest since interventional neuroradiology has not already shown superiority regarding IV rt-PA. Moreover interventional neuroradiologists specialists are only available in major hospital and an IV sequential strategy could provide an interesting alternative. Main study objectives: Main Clinical Objective: Sequential thrombolysis should be associated with a significant better outcome at 3-month, assessed by the modified Rankin score (mRS). Main Radiological Objective: Sequential thrombolysis should be associated with a higher rate of recanalization (TIMI 2b/3) at 24-hour.

Detailed Description

This is a Phase 2, multi-center, national, randomized, biomedical study comparing two therapeutic strategies in ischemic stroke associated with proximal middle cerebral artery occlusion. Patients will be included in two randomized arms and the new sequential treatment approach (rt-PA + tenecteplase) will be compared with the standard treatment (rt-PA alone).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Nervous System Disorders, Cerebral Artery

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

rt-PA

Arm Type

Placebo Comparator

Arm Description

Arm Title

rt-PA + tenecteplase

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

rt-PA

Other Intervention Name(s)

Actilyse

Intervention Description

0,9 mg/kg of rt-PA is infused intravenously 60 minutes, with 10% of the total dose administered as an initial intravenous bolus.

Intervention Type

Drug

Intervention Name(s)

tenecteplase

Other Intervention Name(s)

Metalyse

Intervention Description

Tenecteplase is under the form of powder and solvent for solution for injection. The maximum duration of this treatment is 15 seconds by a single bolus intravenous injection (0, 25 mg/kg).

Primary Outcome Measure Information:

Title

Clinical outcome ill be assessed at 3-month with the modified Rankin score by a blinded examiner.

Description

The clinical outcome will be assessed at 3-month with the modified Rankin score by a blinded examiner. A score of 0-2 is considered good prognosis and a score 3-6 define a poor prognosis.

Time Frame

3 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age between 18 and 85 years Cerebral infarction in relation with a proximal middle cerebral artery occlusion (M1 ou M2) NIHSS between 4 and 23 Patient treated with intravenous rt-PA (0,9 mg/kg) within the first 4.5 hours No recanalization on the MRI performed 1 hour after rt-PA initiation (TIMI 0,1 ou 2a) Administration of TNK within the first 6 hours Informed and written consent obtained from the patient or next of kin Patient insured under the French social security system Exclusion Criteria: Contraindication to MRI Contraindication to rt-PA administration Contraindication to TNK administration Contraindication to stroke thrombolysis Refusal to sign the informed consent Extensive small arteries disease (>5 microbleed and/or Fazekas score≥3) Systolic arterial pression> 185 mmHg or diastolic arterial pression > 110 mmHg Glycemia < 3 mmol/l (0,5g/l) or > 22 mmol/l (4g/l) Thrombopenia < 100 000/mm3 or INR > 1,5. Patients treated with new oral anticoagulant. Seizure as one of acute stroke symptoms Lumbar or arterial puncture in the previous 7 days or major surgery in the previous 15 days Carotid occlusion associated with MCA occlusion Thrombus length > 12mm assessed on gradient echo sequences Large DWI lesion, defined as ASPECTS < 7 / 10 DWI/PWI Mismatch < 20% (when performed) on MRI 2 Marked FLAIR hypersignal on cortical structure and light hypersignal on caudate or lenticular nucleus assessed on MRI 2. Parenchymal hemorrhage on MRI 2 Pregnancy or breast feeding Patient currently included in a biomedical study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Julien JOUX, MD

Organizational Affiliation

Centre Hospitalier Universiatire de Martinique

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Superiority of Rt-PA + Tenecteplase in Comparison With Rt-PA Only in Proximal Middle Cerebral Artery Occlusion

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