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SONIC

Nelonemdaz for Patients With Acute Ischemic Stroke Undergoing Endovascular Reperfusion Therapy: A Randomized Phase II Trial

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Year of Publication: 2022

Authors: Ji Man Hong, MD, PhD; Jin Soo Lee, ..., PhD; on behalf of the SONIC Investigators

Journal: Stroke

Citation: https://www.ahajournals.org/doi/pdf/10.1161/STROKEAHA.122.039649

PDF: https://www.ahajournals.org/doi/pdf/10.1...EAHA.122.039649

Clinical Question

To evaluate the safety and efficacy of the neuroprotectant drug nelonemdaz in patients with acute ischemic stroke due to large-vessel occlusion who are receiving endovascular reperfusion therapy.

Bottom Line

In this phase II trial, adjunctive treatment with nelonemdaz did not result in a statistically significant improvement in the proportion of patients with a good functional outcome at 12 weeks compared to placebo. However, the treatment was safe and showed a favorable, non-significant trend toward better outcomes, warranting a larger phase III trial.

        Major Points
        SONIC was a multicenter, randomized, double-blind, placebo-controlled, 3-arm, phase II trial conducted at 7 centers in South Korea.
209 patients with acute ischemic stroke due to large-vessel occlusion undergoing endovascular therapy within 8 hours of onset were randomized 1:1:1 to receive placebo, low-dose nelonemdaz (2750 mg total), or high-dose nelonemdaz (5250 mg total).
The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0-2 at 12 weeks.
The primary outcome did not differ significantly among the groups: 54.1% in the placebo group, 61.5% in the low-dose group, and 63.2% in the high-dose group (P=0.5578).
No serious adverse events related to the drug were reported, and the overall frequency of adverse events was similar across all groups.
A favorable, though not statistically significant, shift in the distribution of mRS scores at 12 weeks was observed in the nelonemdaz treatment groups compared to placebo.

      

Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled, 3-arm, phase II clinical trial

Randomization: 1

Blinding: Double-blind (study investigators and participants blinded to treatment allocation)

Enrollment Period: October 29, 2016, to June 1, 2020

Follow-up Duration: 12 weeks

Centers: 7

Countries: South Korea

Sample Size: 209

Analysis: The primary outcome was analyzed using the chi-squared test on the full analysis set, which included all randomized patients with an available primary end point. Safety was evaluated in the intention-to-treat population.

Inclusion Criteria

Age ≥19 years
Acute ischemic stroke caused by large-vessel occlusion in the anterior circulation (intracranial internal carotid artery, M1 or M2 segment of the middle cerebral artery)
Previously functionally independent
National Institutes of Health Stroke Scale (NIHSS) score of ≥8 on admission
Baseline Alberta Stroke Program Early CT Score (ASPECTS) of ≥6
Eligible for endovascular reperfusion therapy (ERT) within 8 hours from symptom onset

Exclusion Criteria

Simultaneous occlusion in multiple major vascular territories (eg, both MCAs, or both anterior and posterior circulations)

Baseline Characteristics

Characteristic	Control	Active
Group	Placebo (n=61 in FAS)	High-dose nelonemdaz (n=57 in FAS)
Age, mean±SD	70.0±10.1	68.6±11.0
Female, n (%)	24 (39.3)	20 (35.1)
NIHSS, median (IQR)	15 (12-19)	15 (10-18)
Intravenous alteplase (tPA), n (%)	35 (57.4)	33 (57.9)

Arms

Field	Control	Low-dose nelonemdaz	High-dose nelonemdaz
Intervention	Intravenous infusion of 250 mL of saline, with the first dose initiated before thrombectomy, followed by 9 additional doses twice daily at a 12-hour interval for 5 consecutive days.	Intravenous nelonemdaz. Initial infusion of 500 mg, followed by 9 doses of 250 mg twice daily for 5 days (total dose: 2750 mg).	Intravenous nelonemdaz. Initial infusion of 750 mg, followed by 9 doses of 500 mg twice daily for 5 days (total dose: 5250 mg).
Duration	5 days	5 days	5 days

Outcomes

Outcome	Type	Control	Intervention	P-value
The proportion of patients with a modified Rankin Scale (mRS) score of 0-2 at 12 weeks.	Primary	54.1% (33/61)	61.5% (40/65) for low-dose; 63.2% (36/57) for high-dose	0.5578
Favorable shift in mRS scores at 12 weeks (shift analysis)	Secondary	Reference	Low-dose vs Placebo: Common OR 1.55 (90% CI, 0.92-2.60); High-dose vs Placebo: Common OR 1.61 (90% CI, 0.94-2.76)
Barthel index >90 at 12 weeks	Secondary	43.6% (24/55)	Low-dose: 54.8% (34/62); High-dose: 63.0% (34/54)	0.1264 (overall); 0.0480 (high-dose vs placebo)
Serious adverse events	Adverse	Not reported	None reported
Symptomatic intracranial hemorrhage	Adverse	Not reported	Not reported in any group

Subgroup Analysis

Subgroup analysis for the primary outcome showed no significant differences among the variables.

Criticisms

The trial did not demonstrate a statistically significant benefit for its primary endpoint.
A high dropout rate resulted in a smaller full analysis set (183/208) than planned, potentially reducing statistical power.
There were baseline imbalances between groups; the low-dose group was younger and had a higher rate of intravenous alteplase use, which may have biased results.
The P value for statistical significance was set at an unconventional level of ≤0.1.

Funding

GNT Pharma, Republic of Korea

Based on: SONIC (Stroke, 2022)