#ISC26 Closing Main Event reports on SPAN2, I-ACQUIRE, LAIS, LUMOSA, CONCERN, MeVO, DISTALS and BCI-REHAB trials
Results from eight Late-Breaking Science trials were presented during Friday’s Closing Main Event. The research found:
- SPAN2 eliminates five putative cerebroprotectants.
- I-ACQUIRE constraint-induced movement therapy shows promise in infants with PAIS.
- LAIS showed benefit for loberamisal as neuroprotectant.
- LUMOSA trials show neuroprotection promise for odatroltide.
- CONCERN showed benefit for traditional Chinese medicine in nonlarge, nonmedium vessel occlusion.
- MeVO showed thrombectomy benefit for ischemic stroke in medium vessel occlusion.
- DISTALS showed positive benefit for first DMVO stent retriever.
- BCI-REHAB found brain-computer interface training beats conventional exercise therapy for upper limb hemiplegia.
SPAN2 prevents futile human trials
The second Stroke Preclinical Assessment Network (SPAN2) evaluated five promising candidate cerebroprotective agents using multiple animal models. SPAN2 found that none of the first four putative neuroprotectants achieved the stringent prespecified efficacy boundary for continued evaluation. The remaining candidate, GSK2256294A, also did not exceed the prespecified efficacy boundary after Stage 4. The design followed the previous SPAN1, which was presented at #ISC24.
“We succeeded again in a very rigorous implementation of the network,” said Patrick D. Lyden, MD, FAHA, professor of physiology and neuroscience, neurology and neurosurgery at the Zilkha Neurogenetic Institute at the Keck School of Medicine of University of Southern California. “We showed that a new batch of interventions that looked promising in the hands of their individual developers did not show sufficient efficacy in this rigorous, multilaboratory network. I look at SPAN as having possibly prevented yet more failed clinical trials.”
Patrick D. Lyden, MD, FAHA
SPAN was created to improve the selection of putative cerebroprotectants with rigorous, reproducible late-stage preclinical investigation. The network developed a novel adaptive system for parallel testing of promising interventions across multiple sites. The goal is to develop stroke interventions designed to extend the treatment window and/or improve outcomes compared to reperfusion when combined with thrombolysis, thrombectomy, or both. SPAN1 and SPAN2 were funded by the National Institute of Neurological Disorders and Stroke.
SPAN2 investigated five promising treatments using a nylon filament MCAo model of focal cerebral ischemia:
- BPN-27332, a lipoxygenase inhibitor
- uric acid, a potent scavenger of free radicals
- tatCN19o, a peptide inhibitor of activated Ca2+/CaMKII
- GSK2256294A, an inhibitor of soluble epoxide hydrolase
- NVX-508, an oxygen-carrying compound
All were beneficial in pilot single-laboratory studies.
All SPAN2 assessments were blinded using a triple dummy design. All tests were conducted in four animal models:
- spontaneously hypertensive rats
- aging mice
- mice with diet induced obesity and hyperglycemia
- young mice
All interventions were tested in a four-stage design.
The primary endpoint was a nine-item battery of sensorimotor tests conducted 30 days after treatment. Secondary endpoints included a Bederson Score, a corner test and volumetry by MRI.
“People in science have been aware that we did not have a good track record reproducing results,” Lyden said. “The National Institutes of Health challenged us to set up a network of six laboratories that would implement the utmost possible rigor and data transparency. And as a secondary goal, hopefully find a treatment or two that look so promising they should go on to clinical trials.
“We would like to convert SPAN to a platform, like NeuroNet, so agents can come in and go out with either an efficacy or a futility signal,” Lyden said. “And we would like to tighten the entry criteria to help verify the efficacy signal. NIH has not said whether they will fund SPAN3 or not.”
Movement therapy improves outcomes after perinatal strokes
What may be the first pediatric stroke rehabilitation clinical trial in infants and toddlers with perinatal arterial ischemic stroke (PAIS) and hemiparesis showed meaningful improvements in paretic arm-and-hand skills after four weeks of constraint-induced movement therapy (CIMT) compared to usual care. Patients who received a moderate dose of daily therapy gained 1.82 new skills and those with high-dose therapy 2.27 new skills. Improvements persisted to at least six months post-treatment, with more sustained benefits seen in the high-dose group. Parent assessment of functional improvements showed even greater gains for CIMT therapy over usual care. However, the trial did not meet its pre-specified favorable outcome, ≥ 7-point improvement at the end of treatment and at 6 months post-treatment.
Sharon Ramey, PhD
“Constraint-induced movement therapy had never been tested in a very young group of children who had perinatal stroke occurring either late in the prenatal period or within the first 28 days,” said Sharon Ramey, PhD, Distinguished Scholar and professor of psychology, neuroscience and human development at the Virginia Tech Fralin Biomedical Research Institute. “We now have good evidence that more intensive therapy, a higher dose, can produce some very rapid skill gains, which parents value tremendously. Children maintain the skills they gain and actually increase a little, which is wonderful in the real world of pediatric stroke.”
CIMT was developed in the 1980s-1990s for adult stroke rehabilitation, Ramey said, and has been adapted for pediatric use in cerebral palsy. About 1:1,000 live births have infant stroke, with PAIS being the most common type. Infants with PAIS are typically at high risk for lifelong neuromotor impairment with hemiparesis as the most common impairment. The intervention, I-ACQUIRE, is a multicomponent form of CIMT delivered to infants 8 to 36 months by trained therapists at two doses: a moderate dose of three hours daily five days per week for four weeks or a high dose of six hours daily delivered five days weekly for four weeks. A control group received whatever usual therapy they had received for the pre-baseline month. There were about 72 infants recruited in each arm, 49% female/51% male, across 15 sites.
Nearly all participants were born at full term, more than 2/3 had right-side hemiparesis and about half had seizures/epilepsy. The Pediatric Stroke Outcome Measure showed mild to moderate stroke impairment. Some 80% received about 2.4 hours of weekly physical/occupational therapy during the pre-baseline month.
The primary outcome was the Emerging Behaviors Scale of 30 unilateral skills on the paretic side with a favorable outcome defined as ≥7-point improvement over baseline at end of treatment and six months post-treatment. Secondary endpoints included continuous-scale scores and parent assessment of skills changes.
The trial did not meet the primary favorable outcome at both post-treatment times, said Warren Lo, MD, clinical professor of pediatrics and neurology at the Ohio State University College of Medicine. The secondary endpoints from continuous-scale scores favored those who received I-ACQUIRE. Overall, the number of new skills gained was less than expected, and future analyses are needed to better understand why.
A pre-planned per protocol analysis — considering only children who received the CIMT and were fully compliant to all treatment components — supported the findings on the modified-intention to treat (mITT) end-of-treatment results. Children who received all of the treatment components as intended had larger and noteworthy six-month skills gains if they were in the high-dose CIMT group compared to children in the usual care group and those in the moderate-dose group.
“We were encouraged to discover that usual care also produced measurable gains over a six-month period — gains that were larger than we predicted,” Lo said. “Ultimately, we want to improve these findings to design future trials for children with the intent of developing more effective interventions for children who have strokes.”
The I-ACQUIRE protocol was published simultaneously in Stroke.
Positive results for loberamisal as neuroprotectant after stroke
The largest trial to date of loberamisal showed a 13% absolute improvement in achieving excellent functional outcome following acute ischemic stroke vs. placebo. The neuroprotective agent also showed a 9% absolute benefit vs. placebo for a sliding scale of favorable functional outcomes.
“Neuroprotectants have the potential for improvement in stroke recovery,” said Shuya Li, MD, chief physician at the China National Clinical Research Center for Neurological Diseases at Beijing Tiantan Hospital. “These results tell us that neuroprotective agents are real and are the future of stroke therapy; not just dual targeted agents like loberamisal, but also multiple target agents.
Loberamisal is a novel second-generation small molecule inhibitor of post-synaptic density protein 95 (PSD-95) and neuronal nitric oxide synthase (nNOS) pathways. The dual-acting molecule also selectively potentiates α2-containing GABA A receptor and is resistant to tPA-mediated degradation, suggesting potential for use in addition to or in combination with thrombolytic therapies.
The multicenter Loberamisal for Acute Ischemic Stroke (LAIS) phase 3 trial randomized 998 patients to loberamisal (502) or placebo (496) once daily for 10 days within 48 hours of suspected stroke between July 2024 and April 2025. The trial followed a successful phase 2 trial in 2023 that identified 40 mg daily as the optimal dose.
All patients in LAIS had moderate to severe stroke, a National Institutes of Health Stroke Scale (NIHSS) score of 7-20, and all were treated at 32 stroke centers across China.
The primary outcome was modified Rankin Scale (mRS) score of 0-1 at 90 days. Secondary outcomes included measures of functional outcome, neurological disability and quality of life. Safety outcomes included adverse or serious adverse events and mortality.
At 90 days, 69.7% of loberamisal patients and 56.3% of placebo patients had an mRS score of 0-1, risk ratio (RR) 1.24 (95% CI 1.12-1.36). A prespecified sliding dichotomy scale favored loberamisal, RR 1.23 (95% CI 1.07-1.42). Serious adverse events and deaths were similar between the groups. The loberamisal group showed significant risk reductions in depressive symptoms and anxiety symptoms at 90 days in an exploratory analysis.
“Further studies of the neuroprotectant are warranted to validate the findings and identify optimal patients,” Li said. “We need to refine the clinical application of loberamisal and find valid biomarkers that can indicate the likelihood of clinical benefits.”
Combined thrombolytic/neuroprotectant shows promise to expand stroke treatment window
Two phase 2 trials of LT3001 (odatroltide), a novel molecule-combining thrombolytic and neuroprotectant mechanisms, suggest potential to extend treatment to patients for acute ischemic stroke from the current 4.5 hours up to 24 hours after onset of symptoms with signals of improved functional outcomes compared to placebo. A China-based trial showed mRS 0-2 improvement of 7% vs. placebo in the higher dose. In the global trial, no consistent positive signal was observed, likely due to the small sample size and early stopping. There was no increase in symptomatic intracranial hemorrhage with odatroltide, and mortality was similar across all groups.
“Well over 100 neuroprotective trials have been executed to date but regrettably we still do not have a single neuroprotective compound approved in the U.S. for stroke,” said Thomas Devlin, MD, PhD, FSVIN, director of the CHI Memorial Neuroscience Institute, professor of neurology at Morehouse School of Medicine and principal investigator of the LUMOSA 205 study. “The efficacy signals we’re seeing with LT3001 across a wide variety of patients look particularly strong, which gives us great confidence as we prepare to enter into phase 3 testing.”
Thomas Devlin, MD, PhD, FSVIN
Odatroltide is a three-amino acid thrombolytic peptide modified to target thrombus formation to recanalize and restore flow in occluded blood vessels. The molecule can also scavenge free radicals and inhibit both leukocyte chemotaxis and platelet aggregation to minimize brain tissue damage.
Phase 2 trials were conducted across different populations to better assess potential real-world impact, Devlin said. He added that stroke populations in Asia tend to have a higher incidence of atherosclerosis and plaque deposition within cerebral arteries. U.S. stroke populations, particularly large strokes, tend to have embolic clots originating from the heart.
The two trials, LT3001-202 (China) and LT3001-205 (global), randomized patients within 24 hours after symptom onset. The LT3001-202 trial randomized 195 patients to odatroltide and 102 to placebo. The LT3001-205 trial randomized 43 patients to odatroltide and 45 to placebo.
Disabling symptoms were defined as NIHSS items #5 (arm motor) or #6 (leg motor) >2 at baseline. No patients received thrombolysis before enrollment.
The primary endpoint focused on safety, while efficacy was assessed by the proportion of patients achieving specific mRS scores at 90 days. Targeted subgroups included moderate stroke (NIHSS 6 – 12), large artery atherosclerosis (LAA)-enriched patients (in LT3001-202) and perfusion mismatch-positive patients (in LT3001-205).
Among 118 patients with moderately disabling stroke in China, those in the odatroltide arm showed a 9% improvement in mRS 0-2 for both doses vs. placebo. There was no clear signal in the smaller global trial due to early stopping. In the LAA-enriched moderate stroke subgroup, odatroltide improved both mRS 0-1 and 0-2 by 11% vs. placebo.
Among mismatch-positive patients, odatroltide showed directional improvement of 7% in mRS 0-1 and 10% in mRS 0-2 vs. placebo in the global study. There was no increase in symptomatic intracranial hemorrhage with odatroltide and no significant difference in mortality across groups.
“Given our extended treatment window, LT3001’s strong efficacy signals and excellent safety profile appear particularly promising. On the strength of this evidence, we are well poised for a larger phase 3 trial,” Devlin said.
Traditional Chinese medicine combination showed benefit in disabling stroke
A randomized controlled trial of oral chuanzhi tongluo (CZTL) showed a 25% higher likelihood of modified Rankin Scale (mRS) scores of 0-1 compared to placebo for patients with disabling stroke. Patients in the treatment group showed a 53% relative reduction in 90-day mortality vs. placebo.
“We observed a higher proportion of patients with excellent functional outcome in the chuanzhi tongluo group,” said Dahong Yang, MD, Xinqiao Hospital of Army Medical University in Chongqing, China. “After adjustment for age, NIHSS score, intravenous thrombolysis and time from stroke onset or symptom progression to randomization, the risk ratio was 1.25 with a confidence interval of 1.07 to 1.44 and a p value of 0.004.”
CZTL is a traditional Chinese medicinal compound with four active ingredients:
- Whitmania pigra Whitman, a medicinal leech with anticoagulant, antithrombotic, and anti-inflammatory effects
- Ligusticum chuanxiong Hort, which promotes blood circulation and reduces blood stasis,
- Astragalus membranaceus, with immunoregulatory, antioxidant, and anti-inflammatory effects
- Salvia miltiorrhiza bunge, which improves circulation
Yang noted that the traditional mechanisms of action for all four ingredients have been demonstrated in animal models. In rodent models, CZTL significantly increased blood flow in ears, feet and tails.
The CONCERN trial compared CZTL vs. placebo in a randomized controlled trial in patients with acute ischemic stroke without large or medium vessel occlusion within 24 hours of onset or last known well. Participants were less than 96 hours from last known well or stroke onset, within 24 hours of stroke progression and treated with intravenous thrombolysis with early neurologic degeneration (END) or no neurologic improvement. Participants also had an NIHSS score ≥5 and no evidence of a large or medium vessel occlusion.
A total of 1,268 patients were randomized to CZTL (629 patients) or placebo (639 patients) at 73 hospitals across China. CZTL capsules were administered three times daily for up to 90 days.
The median age of patients was 68, 62% were male, and the median NIHSS score at baseline was 7. The median time from last known well/stroke onset was 12 hours and time from last known well/onset to first treatment was 14 hours.
The proportion of mRS 0-1 in the CZTL group was 38.1% vs. 30.1% in the placebo group with an absolute difference of 8.1%. The 90-day mortality rate was 1.9% for CZTL vs. 4.1% for placebo, hazard ratio 0.47 (95% CI 0.24 – 0.93, p=0.03). There were numerically more intracerebral hemorrhages in the placebo group, but the difference was not statistically significant. Serious adverse events were similar in both groups.
Yang noted that the study was conducted entirely in a Chinese population with a higher rate of intracranial artery stenosis than other populations and had a heterogeneous population. Both may limit the generalizability of the trial.
Thrombectomy improved outcomes for medium vessel occlusion
Thrombectomy improved functional independence scores for patients with moderate-to-severe occlusions of medium-sized arteries by 24% compared to standard medical management. The Endovascular Treatment of Medium Vessel Occlusion (MeVO) Strokes with Moderate or Higher Clinical Severity trial is one of the few major trials of endovascular therapy (EVT) in patients with moderate to severe MeVO.
“We think this trial will help clinicians to make decisions when they have patients with MeVO occlusions,” said Xaozhong Jing, MD, PhD, Wei Hu, MD, department of neurology at the First Affiliated Hospital of the University of Science and Technology of China in Hefei, China. “It is the first MeVO trial that found patients who received endovascular thrombectomy had better outcomes, maybe because we selected patients with moderate to severe deficits.”
Most thrombectomy trials select patients with large vessel occlusions and a wide range of functional deficits, said Raoul Nogueira, MD, Endowed Professor of Neurology and Neurosurgery, chief of cerebrovascular medicine and director of the stroke center at the University of Pittsburgh Medical Center. Earlier trials of medium vessel occlusions included patients with a wider range of stroke-related functional deficits.
The MeVO trial was investigator-initiated and enrolled only patients with moderate to severe stroke, NIHSS score ≥6. Jing added that patients in the trial were also somewhat younger than is seen in many stroke trials with a median age of 71 years.
A total of 564 patients were randomized to thrombectomy (281 patients) or to usual medical care (283 patients) across 48 stroke centers in China. The median NIHSS was 10. Of the total population, 42.8% were women, and 36.6% received intravenous thrombolysis
The primary outcome was functional independence, defined as modified Rankin Scale (mRS) score 0 – 2 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and mortality at 90 days.
Functional independence was seen in 58.6% of the thrombectomy arm and 46.6% of the medical management arm, an adjusted risk ratio of 1.24 (95% CI 1.07 – 1.44, p=0.004). The rates of symptomatic hemorrhage were numerically higher for thrombectomy, 4.7% and 2.2% respectively, but the difference was not statistically significant. Ninety-day mortality was also similar between the two groups, 11.1% and 10.2% respectively.
Positive results for first DMVO stent retriever
The first stent retriever developed specifically to treat distal medium vessel occlusions (DMVO) showed more than three-fold higher successful reperfusion without symptomatic intracranial hemorrhage compared to best medical therapy. No patients treated with the novel device showed symptomatic intracranial hemorrhage within the first 24 hours after treatment.
“Current approaches leave a hole in our therapeutic interventions,” said Rishi Gupta, MD, director of critical care, WellStar Health System. “The Tigertriever can fill that hole.”
Gupta noted that DMVO strokes account for over 25% of ischemic strokes, but most trials and devices have focused on large vessel treatments. He added that DMVO trials to date have failed, at least in part because they have used endovascular devices that were not adapted to the medium vessel environment.
The Tigertriever® 13 is an investigational device in the U.S. designed for use in medium vessels. It is compatible with a 1.3 Fr microcatheter and adjusts in small increments to tailor deployment to the individual anatomy.
The DISTALS trial was designed to evaluate the safety and efficacy of the device in restoring blood flow in patients presenting within 24 hours of onset of an ischemic stroke with disabling neurological deficits due to a DMVO vs. medical management.
A total of 118 patients were randomized across 21 sites in Belgium, Germany, Sweden, and the U.S. The mean age of patients was about 69, about 61% were male and the median NIHSS was 6. More than 75% had a pre-stroke modified Rankin Scale (mRS) score of 0 and all had a mRS of ≤1. About 25% had a previous stroke or TIA and about 75% had hypertension. About half the target vessels were M2 and M3 of the middle cerebral artery. The mean time to last known well was 591 minutes and the mean target vessel diameter was 1.8 mm.
The primary endpoint was successful reperfusion without symptomatic intracranial hemorrhage. Secondary endpoints included disability level at 90 days by mRS shift, NIHSS change to the earlier of day 4 or discharge, quality of life and cognitive function at 90 days. Secondary safety endpoints included all-cause mortality at 90 days, any symptomatic intracranial hemorrhage within 24 hours, and adverse events.
A total of 86.3% of patients in the Tigertriever® 13 arm had successful reperfusion without symptomatic intracranial hemorrhage vs. 27.7% in the medical treatment group, p<0.001. Gupta said there were no symptomatic intracranial hemorrhages within 24 hours of Tigertriever® 13 use, and the single hemorrhage occurred in a patient erroneously treated with a different, nonprotocol device.
Noninvasive brain-computer interface better than conventional stroke rehab
The first randomized controlled trial of a noninvasive brain-computer interface (BCI) device showed a 45.8% greater absolute improvement in upper arm mobility recovery compared to conventional at-home physical therapy for stroke patients with chronic upper limb hemiplegia. The device, IpsiHand, was approved for stroke rehabilitation by the Food and Drug Administration in 2021 based on nonrandomized trials.
It has long been recognized that stroke can impair contralateral motor signaling, resulting in hemiplegia, said Eric C. Leuthardt, MD, MBA, Shi H. Huang Professor of Neurological Surgery, professor of neurosurgery, neuroscience, biomedical engineering and mechanical engineering and material science, and chief of neurotechnology at Washington University. He noted that the brain also generates low-frequency ipsilateral motor signals that persist despite the loss of contralateral motor output that normally initiates and controls muscle movement.
“A stroke patient who can’t move their hand can still think about it, still imagine it,” Leuthardt said. “Some of those signals are generated in the unaffected ipsilateral side of the brain. We want to tap into those signals and remodel neural circuits to allow patients to use the unaffected side of the brain to control their paralyzed hand. This is a noninvasive, zero-risk opportunity to allow patients to improve their motor function.”
Leuthardt is chief scientific officer of Neurolutions, which created and markets IpsiHand.
The device initially uses a robotic exoskeleton to move muscles, digits and limbs in response to ipsilateral signals detected by a headset. Movement by the exoskeleton induces sensory neural responses from the muscles that are moved. Hebbian learning associates ipsilateral motor signaling and the corresponding sensory signals to initiate new neural networks. The new ipsilateral networks allow the patient to replace the headset and exoskeleton with unassisted movement that bypasses compromised contralateral networks.
The BCI-REHAB trial compared at-home BCI therapy vs. a conventional at-home exercise program of five sessions weekly for 12 weeks to improve upper extremity function. Patients had right or upper left extremity hemiparesis/hemiplegia for at least 6 months before enrollment.
A total of 62 participants were included in the primary analysis, 37 using BCI and 25 using conventional exercise therapy. The primary outcome was change in Upper Extremity Fugl-Meyer Assessment from baseline to 12 weeks.
The primary outcome was significantly higher in the BCI group, 6.0, vs. the control group, 1.5, with an estimated treatment difference of 4.5 (95% CI 1.9 –7.1 p=0.0007). Patients in the BCI group showed an estimated response rate of 55.5% vs. 9.6% for the control group, an absolute increase of 45.8% (95% CI 10.9 – 70.8, p=0.0003) and a number needed to treat of 2.2.
“This is the first meaningful, noninvasive therapeutic intervention that can give chronic stroke patients some functional benefit back,” Leuthardt said. “You do this at home, on your own, reducing barriers for stroke intervention that have travel or some kind of hospital or health care setting. This is going to be one of the early entrants that will transform the paradigm of chronic stroke as a fixed-for-life problem. People don’t have to have that sense of doom that this is what they have been confined to. This is now something that we can dynamically treat and interact with.”
