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DIAS

The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): A Phase II MRI-Based 9-Hour Window Acute Stroke Thrombolysis Trial With Intravenous Desmoteplase

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Year of Publication: 2005

Authors: Werner Hacke, MD; Greg Albers, MD; Yasir Al-Rawi, ..., MD; for The DIAS Study Group

Journal: Stroke

Citation: Stroke. 2005;36:66-73.

Link: https://www.ahajournals.org/doi/pdf/10.1...149938.08731.2c

PDF: https://www.ahajournals.org/doi/pdf/10.1...149938.08731.2c

Clinical Question

To evaluate the safety and efficacy of various doses of intravenous desmoteplase administered between 3 to 9 hours after ischemic stroke onset in patients selected based on a perfusion/diffusion mismatch on MRI.

Bottom Line

Intravenous desmoteplase, when given 3 to 9 hours after stroke onset to patients selected by MRI perfusion/diffusion mismatch, is associated with higher rates of reperfusion and better clinical outcomes compared to placebo. A weight-adjusted dose of 125 μg/kg demonstrated significant efficacy with a low rate of symptomatic intracranial hemorrhage.

        Major Points
        DIAS was a Phase II, randomized, double-blind, placebo-controlled, dose-finding trial that used MRI perfusion/diffusion mismatch (≥20%) to select patients for treatment in an extended time window of 3 to 9 hours.
The trial was conducted in two parts. Part 1 tested high, fixed doses (25-50 mg) and was stopped early due to an unacceptably high rate of symptomatic intracranial hemorrhage (sICH) of 26.7%.
Part 2 tested lower, weight-adjusted doses (62.5, 90, and 125 μg/kg) and found a much lower overall sICH rate of 2.2% in the desmoteplase groups.
The 125 μg/kg dose of desmoteplase resulted in a significantly higher reperfusion rate at 4-8 hours (71.4%) compared to placebo (19.2%; P=0.0012).
The 125 μg/kg dose also led to a significantly higher rate of favorable clinical outcome at 90 days (60.0%) compared to pooled placebo (22.2%; P=0.0090).
Early reperfusion was strongly correlated with favorable clinical outcome at 90 days (P=0.0028).

      

Design

Study Type: Phase II, placebo-controlled, double-blind, randomized, dose-finding trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: January 2001 to October 2003

Follow-up Duration: 90 days

Centers: 44

Countries: Germany, Switzerland, Spain, Austria, France, Singapore, Australia, Belgium, Finland, Norway, United Kingdom

Sample Size: 102

Analysis: Intention-to-treat analysis. Comparisons between treatment groups were based on odds ratios.

Inclusion Criteria

Age 18 to 85 years
National Institute of Health Stroke Scale (NIHSS) scores of 4 to 20
MRI evidence of perfusion/diffusion mismatch of at least 20%
Ability to be treated within 3 to 9 hours of stroke onset

Exclusion Criteria

Pre-stroke modified Rankin Scale (mRS) of >1
History of intracranial hemorrhage (ICH) at any time
Current use of oral anticoagulants or an International Normalized Ratio >1.7
Use of heparin in the previous 48 hours
Platelet count <100,000/mm³
Blood glucose >11 mmol/L (>200 mg/dL)
Diffusion-weighted imaging (DWI) abnormality involving >1/3 of the Middle Cerebral Artery (MCA) territory

Baseline Characteristics

Characteristic	Control	Active
Group	Total Placebo (n=27)	Desmoteplase 125 μg/kg (n=15)
Age, y (median)	68	70
Female, %	48.1	46.7
NIHSS (median)	12	12
Time from onset, min (median)	325	295

Arms

Field	Control	Desmoteplase (Part 1 - Fixed Doses)	Desmoteplase (Part 2 - Weight-Adjusted Doses)
Intervention	Intravenous placebo administered as a bolus over 1 to 2 minutes.	Intravenous desmoteplase at fixed doses of 25 mg, 37.5 mg, or 50 mg.	Intravenous desmoteplase at weight-adjusted doses of 62.5 μg/kg, 90 μg/kg, or 125 μg/kg.
Duration	Single dose	Single dose	Single dose

Outcomes

Outcome	Type	Control	Intervention	P-value
The study had co-primary safety (symptomatic ICH) and efficacy (reperfusion and clinical outcome) endpoints. The most effective and safe dose from Part 2 is highlighted here.	Primary	Placebo: sICH 0/27 (0.0%); reperfusion 5/26 (19.2%); favorable 90-day outcome 6/27 (22.2%)	Desmoteplase 125 μg/kg (best dose): sICH 0/15 (0.0%); reperfusion 10/14 (71.4%); favorable 90-day outcome 9/15 (60.0%)	Reperfusion P=0.0012; favorable clinical outcome P=0.0090 (125 μg/kg vs pooled placebo)
Primary Safety Endpoint: Symptomatic Intracranial Hemorrhage (sICH)	Secondary	0% (Pooled Placebo)	2.2% (Desmoteplase Part 2); 0% in the 125 µg/kg group
Efficacy Endpoint: Reperfusion at 4-8 Hours	Secondary	19.2% (Pooled Placebo)	71.4% (Desmoteplase 125 μg/kg)	0.0012
Efficacy Endpoint: Favorable Clinical Outcome at 90 Days	Secondary	22.2% (Pooled Placebo)	60.0% (Desmoteplase 125 μg/kg)	0.0090
sICH in Part 1	Adverse	0%	26.7% (All fixed doses)
Mortality within 90 days	Adverse	9.1% (Part 2 Placebo)	4.4% (Part 2 Desmoteplase)

Subgroup Analysis

Early reperfusion on MRI was significantly correlated with favorable clinical outcome at 90 days (P=0.0028). 52.5% of patients with reperfusion had a favorable outcome versus 24.6% of those without.

Criticisms

The trial was redesigned after Part 1 was halted due to high rates of symptomatic intracranial hemorrhage, resulting in two distinct parts with different dosing schemes.
The sample size in each dose group was small, particularly in the dose-escalation design of Part 2, which limits statistical power.
Baseline DWI lesion volumes were not well-balanced across the treatment groups in Part 2, which may have confounded the results for the higher-dose desmoteplase groups.
The dose-escalation design of Part 2, while blinded, could have introduced bias in MRI interpretation because the likely dose group was known based on the study phase.

Funding

PAION GmbH, Aachen, Germany

Based on: DIAS (Stroke, 2005)