Glenzocimab Efficacy and Safety Added to Intravenous Thrombolysis With or Without Mechanical Thrombectomy in Patients With Acute Ischemic Stroke—ACTISAVE: A Prospective, Randomized, Double-Blind Study

Abstract

BACKGROUND:

Glenzocimab, a platelet glycoprotein VI antagonist, is a novel agent that inhibits platelet activation and aggregation. Its safety was demonstrated in the ACTIMIS trial (Acute Ischemic Stroke Interventional Study; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03803007) for patients with stroke receiving thrombolysis, with or without mechanical thrombectomy, and results suggested a reduction in intracranial hemorrhages and mortality. The ACTISAVE trial was designed as a confirmatory study to evaluate the efficacy and safety of glenzocimab in acute ischemic stroke.

METHODS:

ACTISAVE (Acute Ischemic Stroke Study Evaluating Glenzocimab Used as Add-On Therapy Versus Placebo) was an international, randomized, double-blind, placebo-controlled phase 2/3 study in patients with stroke, treated by thrombolysis within 4.5 hours of symptoms onset with or without mechanical thrombectomy. The study was conducted at 54 primary and comprehensive stroke centers located in 10 countries. Patients were randomized 1:1 to glenzocimab (1000 mg-IV) or placebo. The primary outcome was the modified Rankin Scale (mRS) score of 4 to 6 at day 90. Key secondary outcome was the mRS score of 0 to 2 at day 90. Mortality, mRS shift, National Institutes of Health Stroke Scale score, quality of life, and safety outcomes were assessed.

RESULTS:

Between September 2021 and October 2023, 438 patients were randomized, 421 treated, and included as randomized in the primary analysis set. Median age was 73 (63–80) years, and 43% were female. Thrombolysis was performed 2.3 hours (median) after symptom onset and followed by mechanical thrombectomy in 36% of patients. The assigned treatment began a median of 1.2 (interquartile range, 0.8–1.6) hours after thrombolysis initiation. Prethrombolysis National Institutes of Health Stroke Scale score median was 9 (6–15). At day 90, there was no statistically significant difference in the primary outcome between the treatment groups: the incidence of poor outcome (mRS score 4–6 versus 0–3) was 21.6% in the glenzocimab group compared with 15.3% placebo group (odds ratio, 1.51 [95% CI, 0.90–2.54]; P=0.120). No statistically significant difference in secondary outcomes was observed. There were no major safety signals with any intracerebral hemorrhage occurring respectively in 60 (28.6%) and 63 (29.9%) patients in glenzocimab and placebo arms.

CONCLUSIONS:

ACTISAVE failed to confirm a beneficial effect of glenzocimab on mRS in patients with acute ischemic stroke treated by thrombolysis.

REGISTRATION:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT05070260.

Acute ischemic stroke (AIS) treatment currently focuses on rapid recanalization of the occluded artery. Thrombolysis and, more recently, mechanical thrombectomy have increased the proportion of patients successfully returning to normal life, as assessed by modified Rankin Scale (mRS) ordinal scores of 0 to 1, measured 3 months after the initial stroke.^1,2 However, recanalization strategies may fail due to factors such as incomplete recanalization, reocclusion caused by secondary clot formation,³ absent or incomplete tissue reperfusion,⁴ and ischemia-induced inflammation. Clinically, intracerebral bleeding is more frequent in patients with poor recanalization.⁵ In randomized clinical trials using bridging therapy with best available recanalization strategies, only 50% of patients reached functional independence, defined by an mRS score of 0 to 2.^6,7 In addition, none of the current therapeutic options have significantly reduced the mortality of AIS.^8,9

Glenzocimab, a monoclonal antibody fragment (Fab) directed against platelet receptor GPVI (glycoprotein VI),¹⁰ inhibits ex vivo platelet aggregation to both collagen¹⁰ and fibrin¹¹ in a dose-dependent manner. As a result, it may ameliorate some of the causes of poor outcomes after reperfusion therapies^12,13 and is consequently being developed for the treatment of AIS.¹⁴ Its safety was evaluated in a phase 1 trial in healthy volunteers¹⁵ and in a phase 1b/2a trial (ACTIMIS study [Acute Ischemic Stroke Interventional Study]; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03803007).¹⁴

Both studies confirmed the favorable safety profile of a single dose of glenzocimab 1000 mg infused over 6 hours, showing no increase in attributable adverse events or bleeding-related events compared with placebo. In the ACTIMIS trial, the proportion of patients with poor outcomes, defined as mRS scores 4 to 6 (moderate or severe disability or death), was significantly lower in glenzocimab-treated patients compared with those receiving a placebo. In addition, Kaplan-Meier analysis demonstrated a significant reduction in all-cause mortality in the glenzocimab group compared with placebo, occurring in the first week after stroke onset and persisted through month 3. Mortality was a consistent differentiating factor between treatment groups in both the overall population and subgroups, linked to a reduction in intracranial hemorrhages.

The ACTISAVE study (Acute Ischemic Stroke Study Evaluating Glenzocimab Used as Add-On Therapy Versus Placebo) was designed to confirm the results of the ACTIMIS study and to provide pivotal data on the efficacy of glenzocimab for AIS.

Methods

All data and supporting materials have been provided with the published article. The study was funded by the study sponsor, Acticor Biotech (Paris, France), and a grant from Bpifrance to cover part of the study costs.

Study Design and Oversight

ACTISAVE was an international, randomized, double-blind, placebo-controlled, parallel-group, phase 2/3 study designed to evaluate the efficacy and safety of a fixed dose of glenzocimab. The treatment was administered in patients receiving intravenous thrombolysis within 4.5 hours after the AIS symptoms onset, and included mechanical thrombectomy for eligible patients, compared with the standard-of-care alone. The study was conducted in 54 comprehensive and primary stroke centers in 10 countries (Belgium, the Czech Republic, Denmark, France, Germany, Israel, Slovakia, Spain, the United Kingdom, and the United States). The trial protocol is available in the Supplemental Material.

The study was conducted in accordance with Good Clinical Practice guidelines, the Declaration of Helsinki, and national laws and regulations. Independent central and, where applicable, local ethics committees approved the study protocol and all subsequent amendments. A written informed consent from patients or legal representatives, or an emergency consent, when applicable and necessary, was obtained in every case before study initiation. If patients could not consent themselves at the time of randomization, reconsent was always sought as soon as possible. The study sponsor, Acticor Biotech (Paris, France), provided the trial drug (glenzocimab and placebo), monitored the trial, and supervised analysis of the data with oversight from the Study Scientific Committee. An Independent Data Monitoring Committee was established before the first randomization. One preplanned Independent Data Monitoring Committee meeting occurred once the first 100 patients were treated and followed-up until 3 months to review all available safety data consisting of symptomatic and nonsymptomatic intracerebral hemorrhages (ICHs), serious adverse events, suspected unexpected serious adverse reactions, bleeding-related events, treatment-emergent adverse events (TEAEs), and more generally any safety data that needed to be evaluated during the study. Ad-hoc meetings could be triggered in case of any urgent safety concern.

Modification to the Study Protocol

The design of the ACTISAVE study evolved during its conduct, originally setting the mRS score ordinal shift at day 90 as the primary outcome with a planned sample size of 1000 patients. During the course of the study, results from ACTIMIS were released, prompting protocol modifications.¹⁴ Without unblinding of outcome data, a dual primary end point of mRS score shift or binary mRS score 4 to 6 compared with mRS score 0 to 3 was selected. In addition, mortality became a key secondary end point. These changes were made without altering the sample size. However, subsequent consultation with regulatory authorities led to a final protocol amendment, designating binary mRS score 4 to 6 versus mRS score 0 to 3 as the primary end point, and binary mRS score 0 to 2 versus mRS score 3 to 6 as the key secondary end point. These amendments occurred without any study data unblinding. The sample size was adjusted to 400 evaluable patients to align with the new study objectives.

Patients

Eligible patients were ≥18 years of age, had a diagnosis of AIS (either in the anterior or posterior circulation), and were treated within 4.5 hours of symptom onset by intravenous thrombolysis using either alteplase or tenecteplase. Eligible patients could undergo a mechanical thrombectomy in case of a large vessel occlusion. They were also required to have a prethrombolysis National Institutes of Health Stroke Scale (NIHSS) score of ≥6—a proportion of patients were randomized with an NIHSS score of ≥4 before the protocol was amended. The use of effective birth control methods and a negative pregnancy test were required for women of childbearing potential.

Patients were not eligible if they were comatose or presented with an NIHSS score >25, had a previous AIS within the past 3 months, prestroke mRS score ≥2, stroke of hemorrhagic origin, known severe or terminal renal impairment (grade 4 and 5), known ongoing anticoagulant therapy, concomitant dual antiplatelet therapy, ongoing treatment with a monoclonal antibody, or life expectancy <3 months.

The complete list of inclusion/exclusion criteria is included in the Supplemental Appendix and Table S1.

Randomization and Masking

ACTISAVE was a double-blind study with quadruple masking (patient, caregiver, outcome assessor, and investigator). Sponsor’s staff and contract research organization personnel remained blinded to the study treatment until final evaluation of the results.

Patients were randomized in a 1:1 ratio between glenzocimab and placebo arms using a central electronic procedure. An Interactive Web Response Systems was deployed to provide randomization and drug shipment management. Each participant was assigned a trial identity code number. Permuted block randomization (size=4) was used to create a randomization list to allocate subjects to the treatment arm. The randomization was stratified according to the type of recanalization therapy applied (thrombolysis alone or thrombolysis with mechanical thrombectomy), randomization occurred after initiation of thrombolysis, and the decision to treat by mechanical thrombectomy. Within each recanalization therapy category, a minimization program accounted for the following factors: prethrombolysis NIHSS score (<10 versus ≥10), age category (<65, 65–79, ≥80 years), and type of thrombolytic agent (alteplase versus tenecteplase) to ensure balanced treatment group composition.

Procedures

Glenzocimab or matching placebo was administered as a 6-hour intravenous infusion, with ¼ of the dose administered in 15 minutes and three-fourths of the dose in 5 hours and 45 minutes. The study drug was administered as soon as possible, and no later than 2 hours after the start of thrombolysis. After treatment, patients had several follow-up visits: at 24 hours (± 3 hours) for clinical evaluation and safety imaging; at day 7 (±3 days or at discharge) for a follow-up visit; at 30-day (±3 days), and 60-day (±3 days) posttreatment evaluations; at 90-day (±7days) posttreatment evaluation corresponding to the end of study visit. The 30- and 60-day visits could be conducted remotely. The final mRS score evaluation at the end of the study visit.

Outcomes

The dichotomized primary outcome of ACTISAVE was poor outcome based on the mRS score, defined as a score of 4 to 6 (versus 0–3) at day 90. The key secondary efficacy end point was a favorable outcome, defined as an mRS score of 0 to 2 (versus 3–6) at day 90. Other secondary end points included all-cause mortality, ordinal mRS score shift, severe outcome defined as an mRS score 5 to 6 (versus 0–4) at day 90, excellent outcome defined as an mRS score 0 to 1 (versus 2–6) at day 90, utility-weighted mRS score at day 90, symptomatic and nonsymptomatic ICHs, NIHSS score change from baseline to 24 hours, and recanalization (assessed only in patients undergoing Mechanical Thrombectomy on angiogram by expanded Thrombolysis in Cerebral Ischemia [eTICI] score). Utility-weighted mRS score weights were defined based on the MOST study (Multi-Arm Optimization of Stroke Thrombolysis; URL: https://www.clinicaltrials.gov; Unique identifier: NCT03735979).¹⁶ Safety end points included TEAEs, serious TEAEs, suspected unexpected serious adverse reactions, fatal TEAEs, and bleeding-related TEAEs other than ICHs. Predefined subgroups for outcomes evaluation were defined using stratification and minimization factors (treatment by mechanical thrombectomy yes/no, NIHSS score below/over or equal to 10, age groups <65; 65–79; ≥80 years old).

All imaging data were centrally reviewed by a blinded, independent neuroradiologist (Keosys Medical Imaging Software & Services, St. Herblain, France). In case of discrepancies between the central review and local investigator regarding intracranial hemorrhage occurrence or Heidelberg classification, a blinded adjudication committee consisting of 3 independent vascular neurologists with radiological expertise was set up to arbitrate any emergent discrepancy. The ACTISAVE study results manuscript follows the CONSORT reporting guidelines (Consolidated Standards of Reporting Trials).¹⁷

Statistical Analysis

The sample size was determined with the assumption of a low drop-out rate at day 90 (≈1 or 2%). Calculations were based on expected odds ratios, enrolling 400 patients, ≈140 subjects undergoing mechanical thrombectomy (MT+ strata), and 260 subjects receiving only thrombolysis (MT− strata). For the primary end point (mRS score 4–6), we assumed a nominal 1-sided alpha level of 0.025 (for superiority) and an expected common odds ratio of 0.4 in both the MT+ and MT− strata based on MT+ data from ACTIMIS (ie, an mRS score 4–6 rate of 39.5% in the placebo group versus 20.7% in the glenzocimab group for the MT+ stratum, and 17% in the placebo group versus 7.6% in the glenzocimab group for the MT− stratum). The power of the stratified CMH analysis was ≈90.8%.

Analyses were performed on the full analysis set, defined as all randomized patients who received at least some dose during the infusion, even if they discontinued prematurely. The primary analysis of poor outcome (mRS score 4–6 versus 0–3) was conducted using a logistic regression model that included treatment (glenzocimab versus placebo), mechanical thrombectomy status (with or without), baseline NIHSS score (NIHSS score ≥10, NIHSS score <10), and age at informed consent (<65, 65–79 and ≥80 years) as covariates. The treatment effect was estimated as an odds ratio along with its 95% CI. Missing data for primary analysis were imputed according to the following prespecified rules: Patients with no mRS score recorded during the study were imputed as 5; for all other patients, a multiple imputation approach was used assuming a missing at random mechanism and using an imputation model that includes treatment, actual stratification factors, and mRS score assessed at day 30 and 60. Binary response was then derived from the imputed data. Sensitivity analyses are further detailed in the protocol. A similar analysis was performed for the mRS score 0 to 2. Additional details regarding statistical analyses are included in the Supplemental Appendix. Tests were conducted at 1-sided alpha level of 0.025, and 95% CIs were provided. All analyses were performed using SAS software version 9.4 or higher (SAS Institute, NC).

Results

Trial Participants

From September 2021 through October 2023, a total of 444 patients with AIS treated within 4.5 hours of symptom onset were screened, of whom 438 were enrolled. Out of the 436 randomized, some were not treated for various reasons (Figure 1), leading to 419 patients who were randomized and treated in the study. Out of those, 211 were assigned to receive glenzocimab, and 208 were assigned to receive a placebo (Figure 1). A total of 204 (96.7%) participants in the glenzocimab group and 202 (97.1%) in the placebo group completed the trial at 90 days and had an mRS score evaluation. There were 16 deaths in the glenzocimab group and 10 deaths in the placebo group. In addition, 2 participants were treated without randomization, 1 receiving glenzocimab and 1 receiving a placebo. These patients were included in the safety set analysis.

Figure 1.

Study overview (CONSORT diagram). Completers set is defined as patients with an evaluation of modified Rankin Scale (mRS) score at day 90. Lost-to-follow-up patients were included in the full analysis set by using multiple implementations of the mRS score at day 90. AE indicates adverse events; CONSORT, Consolidated Standards of Reporting Trials; and IMP, Investigational Medicinal Products.

Baseline characteristics of the participants in both trial arms are described in Table 1. The mean age of participants was 70.9±12.4 years in the glenzocimab group and 70.8±13.0 years in the placebo group. In the glenzocimab group, 56% of patients were men, compared with 58% in the placebo group. Medical history showed differences between the groups, with fewer dyslipidemia, hypertension, and cardiac disease, and more cases of diabetes and a higher incidence of concomitant antithrombotic treatment in the glenzocimab group compared with the placebo group. Pre-intravenous thrombolysis NIHSS score was similar between arms, with a median (interquartile range) of 9 (6–16) in glenzocimab group versus 9 (6–14) in placebo. In a predefined subgroup of patients receiving mechanical thrombectomy, the median of pre-intravenous thrombolysis NIHSS score was 3 points higher in the glenzocimab arm (Table S2). Baseline characteristics were generally similar between the 2 treatment groups across most prespecified subgroups (Tables S2 through S4 for details on standard-of-care, baseline severity, and age). Thrombolysis start to study drug (hours) was median (interquartile range) 1.3 (0.8–1.7) and 1.1 (0.8–1.6) for glenzocimab and placebo, respectively. In the mechanical thrombectomy subgroup, patients receiving glenzocimab had a lower rate of dyslipidemia and cardiac disease, higher rates of diabetes, and more concomitant antithrombotic treatments compared with those receiving placebo. Differences in the rate of cardiac disease between the 2 trial arms were also observed across all age subgroups. Specifically, in the 65 to 79 years subgroup, participants receiving glenzocimab had a higher incidence of concomitant antithrombotic treatment compared with those receiving placebo.

Table 1.

Baseline Characteristics (FAS Population)

Primary Outcome

The distribution of the mRS score at day 90 by treatment group is presented in Figure 2A. At day 90, the incidence of poor outcome (mRS score 4–6 versus 0–3) was not significantly different with 21.6% in glenzocimab group compared with 15.3% in placebo group (odds ratio, 1.51 [95% CI, 0.90–2.54]; P=0.120; 1-sided alpha=0.025; Figure 2B). Supportive analyses, including per-protocol, completers, and randomized analyses, showed consistent results (see Table S5). Similar results were found in subgroup analyses based on recanalization treatment, baseline severity, and age (Figure 2B).

Figure 2.

Primary end point results: modified Rankin Scale (mRS) at day 90. A, mRS scores at 3 months by study treatment group. B, Primary outcome: poor outcome odds ratio (OR) at 3 months. A, Only patients with mRS score data are shown—completers set. B, OR were calculated on the full analysis set. Missing mRS scores were imputed using a mixture of worst-case imputation and missing at random multiple imputation techniques. Treatment effect and P values are presented after handling missing values. OR was also evaluated in prespecified subgroups according to standard-of-care, baseline severity, and age at screening. MAR indicates missing at random; NIHSS, National Institutes of Health Stroke Scale; and p het, P value for heterogeneity.

Secondary Efficacy Outcomes

Other mRS score end points at day 90, including favorable outcome (mRS score 0–2 versus 3–6), severe outcome (mRS score 5–6 versus 0–4), mRS score ordinal shift, and utility-weighted mRS score, did not show any differences between the 2 groups (Figure S1; Table S6). Excellent outcome (mRS score 0–1 versus 2–6) occurred in 49.0% of the glenzocimab group compared with 46.5% in the placebo group (odds ratio, 1.13 [95% CI, 0.75–1.70]; Figure S2). Similar trends were observed in subgroup analyses.

During the 90-day follow-up, a total of 26 deaths occurred, with 16 (7.6%) in the glenzocimab arm and 10 (4.8%) in the placebo arm. One patient who died was randomized to glenzocimab but mistakenly treated with a placebo; hence, in the safety set, the 26 deaths were distributed 15 (7.1%) in the glenzocimab arm and 11 (5.2%) in the placebo arm. Among them, 14 and 8 deaths were respectively classified as stroke-related deaths by investigators. There were no significant differences between groups in the analyses of all-cause mortality across different populations and subgroups (Table S7). Similarly, no differences were observed for NIHSS score end points (Table S8). Among patients who underwent mechanical thrombectomy, eTICI end points favored placebo: 83.9% achieved eTICI 2b to 3 with glenzocimab compared with 96.6% with placebo (odds ratio, 0.16 [95% CI, 0.03–0.82]); 73.2% achieved eTICI recanalization grades 2b67 to 3 with glenzocimab compared with 87.9% with placebo (odds ratio, 0.37 [95% CI, 0.13–1.00]); and 58.9% achieved 2c to 3 with glenzocimab compared with 79.3% with placebo (odds ratio, 0.34 [95% CI, 0.15–0.81]; Table S9).

Secondary Safety Outcomes

Table 2 presents the frequency of ICH and Heidelberg classification at 24 hours throughout the study period. Similar outcomes were observed between the 2 treatment arms. There were no significant between-group differences in the incidence of patients with at least 1 ICH, symptomatic ICH, nonsymptomatic ICH, and hemorrhagic transformation across the study period in the overall population and in prespecified subgroups (Table S10).

Table 2.

ICH Frequency and Heidelberg Classification (Safety Population)

Table 3 shows that 84.8% of participants in the glenzocimab group and 81.5% in the placebo group reported ≥1 TEAEs during the trial. Serious TEAEs occurred in 30.5% of the glenzocimab arm and 24.6% of the placebo arm. There was a total of 81 bleeding-related events (other than ICHs) reported, with 55 occurring in the glenzocimab group and 26 in the placebo group. Among these events, only 8 were classified as major (6 in glenzocimab arm and 2 in the placebo arm). During the trial, 17 cases of suspected unexpected serious adverse reactions were reported in the glenzocimab group, involving 15 participants. Among them, 13 cases of ICH (8 symptomatic and 6 asymptomatic), 1 case of vasogenic cerebral edema, 1 case of epilepsy, 1 case of hematoma, and 1 case of embolism are reported.

Table 3.

Adverse Events (Safety Population)

Discussion

The ACTISAVE study evaluated the efficacy of glenzocimab treatment in patients with AIS treated by thrombolysis, with or without mechanical thrombectomy. We observed no significant differences in 90-day functional outcomes between those treated with glenzocimab versus placebo. This outcome was consistent across preplanned subgroup analyses, and the binary evaluation of mRS score at 90 days even suggested potentially favorable outcomes for placebo in some analyses, although the evidence was not conclusive. Similar results were observed in the per-protocol population.

Those unexpected results did not replicate the ACTIMIS study outcomes, where a reduction of ICH and mortality rate was observed in the glenzocimab arm. It is possible that differing patient populations in the 2 trials led to markedly different outcomes, notably with a higher overall proportion of patients returning to relatively normal life in the ACTISAVE study. The estimated poor outcome rate in the placebo arm was higher than the observed rate, resulting in a narrowing of the estimated effect size. Although the estimated poor outcome rate was based on previous ACTIMIS data, we cannot exclude that the evolution of mechanical thrombectomy procedures and consequent improved outcomes reduced the possibility of observing a treatment effect.

Analyses of the preplanned primary and secondary end points in subgroups revealed a possible trend toward more unfavorable outcomes in glenzocimab versus placebo in patients who underwent mechanical thrombectomy in addition to thrombolysis. In this subgroup, in addition to a relatively small sample size, there was an imbalance between arms across baseline characteristics, particularly in diabetic status and baseline NIHSS score, which are known predictors of mechanical thrombectomy success and long-term outcomes. NIHSS score minimization was performed on a cutoff value of 10 and did not allow proper NIHSS score balance in the mechanical thrombectomy strata. Given the substantial impact of thrombectomy success on clinical outcome, the lower rate of postmechanical thrombectomy recanalization as measured by the eTICI score may have been a major determinant of poorer mRS score outcomes in the glenzocimab group. These results suggest that the design of any future trials targeting postrecanalization perfusion and inflammation with glenzocimab should be designed to ensure balance in recanalization between groups.

The ACTISAVE results are representative of the challenge of evaluating new treatment options added on to existing effective treatments in patients with AIS, where patient heterogeneity presenting diverse baseline characteristics, such as cause, thrombus localization, or glycemia, complicates the comparison of treatment arms within trials. Recently, ESCAPE-NEXT (Efficacy and Safety of Nerinetide in Acute Ischemic Stroke in Patients Undergoing Endovascular Thrombectomy Without Previous Thrombolysis; URL: https://www.clinicaltrials.gov; Unique identifier: NCT04462536) has also failed to show efficacy despite promising preclinical and clinical data. We have to point out that while a higher number of deaths in the glenzocimab arm compared with placebo arm in the population who underwent mechanical thrombectomy in addition to thrombolysis could be explained by imbalance at baseline, it could also be due to unexpected worsening due to treatment. This effect could be generic to antiplatelet agents or more specific to glenzocimab. Two other trials, MOST¹⁶ and GREEN (Glenzocimab for Reperfusion in the Setting of Endovascular Therapy for Brain Infarction; URL: https://www.clinicaltrials.gov; Unique identifier: NCT05559398), respectively, evaluating argatroban/eptifibatide and glenzocimab in patients undergoing mechanical thrombectomy within 24 hours of symptom onset, were stopped for futility. Those results could be indicative of a relatively modest impact of antiplatelet agents at the acute phase of ischemic stroke, at least in patients treated by other recanalization therapies.

Limitations of the Study

ACTISAVE presents several limitations that restrict the conclusions and insights that can be drawn from it. Its diversity and moderate sample size resulted in imbalances in baseline characteristics, particularly in the thrombectomy group, where the small sample size and further imbalance in thrombectomy success limit our ability to interpret results on the mRS score in this subgroup. ACTISAVE was originally intended to confirm the findings of ACTIMIS regarding poor outcomes. However, notable improvement in the overall proportion of patients returning to normal life, possibly reflecting the quality of care provided in the clinical centers, hampered our ability to discern any effect on patients with an mRS score of 4 to 6. Glenzocimab was not administered until a median of 1.3 hours after the start of thrombolysis. While this was still within the half-life of thrombolytic activity in some patients, and before thrombectomy in all patients in that subgroup, it is possible that the delay may have reduced any beneficial synergistic effect of GPVI inhibition and thrombolysis. Finally, both the sample size and primary outcomes were altered during ACTISAVE based on relevant results from ACTIMIS and feedback from regulatory agencies. The focus of ACTISAVE remained on the prevention of poor outcome throughout these changes, and all changes were made when investigators and sponsors were blinded to any study results, but could have partially led to a study not appropriately powered.

Conclusions

ACTISAVE failed to confirm a beneficial effect of glenzocimab on clinical outcome in patients with AIS treated with reperfusion therapy. The ongoing clinical trial LIBERATE (A Phase II, Randomised, Double-Blind, Placebo-Controlled Trial to Investigate the Efficacy and Safety of Glenzocimab and the Mechanism of Inhibiting Platelet GPVI as a Treatment for ST-Elevation Myocardial Infarction; URL: https://www.isrctn.com/; Unique identifier: ISRCTN15443962) in ST-segment–elevation myocardial infarction, will offer additional insights into the efficacy of glenzocimab in a different indication. The good safety profile established in ACTIMIS and confirmed in ACTISAVE allows for further exploration of glenzocimab as a safe antiplatelet agent. Care will be needed to evaluate if ACTISAVE results were not, at least in some population, due to potential safety concerns. Data derived from ACTISAVE might be useful in shaping patient selection and design of any future efficacy trials involving glenzocimab or other GPVI targeting treatments.

ARTICLE INFORMATION

Acknowledgments

The authors thank patients and their families who have agreed to join the ACTISAVE study (Acute Ischemic Stroke Study Evaluating Glenzocimab Used as Add-On Therapy Versus Placebo). Our acknowledgements go to the investigators, nurses, study coordinators, and all the personnel on site, and the sponsor team that conducted a study of high quality. The authors also acknowledge the role of the contract research organization involved in the conduct of the trial (Worldwide Clinical Trial, Aixial, Keosys, Kayentis, QPS) and are grateful to the Scientific Advisory Board and to the members of the Data Safety Monitoring Board for their dedication and advice.

Disclosures

Dr Köhrmann has received speaker’s honoraria and compensation for advisory board participation from: Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, Bristol Myers Squibb (BMS), AstraZeneca, Sanofi, Novartis, Biogen, and Acticor. Dr Köhrmann is a member of the supervisory board of CompuGroup Medical SE & Co. Dr Sibon reports consultant activities for Bayer, BMS/Pfizer, Boehringer Ingelheim, Medtronic, Novartis, Novo Nordisk, Bioprojet, AstraZeneca, Alexion, and speaker activities for AstraZeneca, Bayer, BMS/Pfizer, Boehringer Ingelheim, Medtronic, Novartis, Novo Nordisk. E. Drumez was a contractor for Acticor Biotech. Dr Binay, Dr Bougamra, Dr Comenducci, A. Meilhoc, Dr Sari, and Dr Toledano are employees of Acticor Biotech. Drs Avenard, Pletan, and Grouin are consultants to Acticor Biotech. Drs Avenard, Binay, and Pletan are General Managers of Acticor Biotech. Dr Avenard, Dr Binay, Dr Bougamra, Dr Comenducci, A. Meilhoc, Dr Pletan, Dr Sari, and Dr Toledano hold share interest in Acticor Biotech. Dr Grotta is a consultant for Frazer Ltd and Alva Health, and a DSMB, advisory board member for Acticor and Prolong Pharma, and receives a grant from Genentech. Drs Köhrmann and Grotta were international coordinators of the ACTISAVE study; Drs Berrouschot, Serena, Bornstein, Iversen, Kalladka, Krastev, Molina, Peeters, Šaňák, and Sibon were national coordinators of the ACTISAVE study; Drs Della Schiava, Tembl, Masjuan, Soda, Richard, and Eichlova were investigators in the ACTISAVE study.

Supplemental Material

List of Investigators

Tables S1–S10

Figures S1–S3

Study Protocol

Statistical Analysis Plan

Funding Statement

The main funder, who provided the trial drug (glenzocimab), was the study sponsor with oversight from the Study Scientific Committee. The study sponsor and the Study Scientific Committee jointly coordinated study design, data monitoring, data analysis and interpretation, writing the study report, and the decision to publish the results. The sponsor received a grant from BPIfrance to cover part of the study costs. However, this funding body was not involved in the study design, data analysis, interpretation, or the decision to publish the results. The sponsor and the Study Scientific Committee were both blinded throughout the conduct of the study until enrollment was complete, and the data were analyzed.