Clinical Trial Protocol for BEACH: A Phase 2a Study of MW189 in Patients with Acute Nontraumatic Intracerebral Hemorrhage

Patients with acute spontaneous intracerebral hemorrhage (ICH) develop secondary neuroinflammation and cerebral edema that can further damage the brain and lead to increased risk of neurologic complications. Preclinical studies in animal models of acute brain injury have shown that a novel small-molecule drug candidate, MW01-6-189WH (MW189), decreases neuroinflammation and cerebral edema and improves functional outcomes. MW189 was also safe and well tolerated in phase 1 studies in healthy adults. The proof-of-concept phase 2a Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) clinical trial is a first-in-patient, multicenter, randomized, double-blind, placebo-controlled trial. It is designed to determine the safety and tolerability of MW189 in patients with acute ICH, identify trends in potential mitigation of neuroinflammation and cerebral edema, and assess effects on functional outcomes. A total of 120 participants with nontraumatic ICH will be randomly assigned 1:1 to receive intravenous MW189 (0.25 mg/kg) or placebo (saline) within 24 h of symptom onset and every 12 h for up to 5 days or until hospital discharge. The 120-participant sample size (60 per group) will allow testing of the null hypothesis of noninferiority with a tolerance limit of 12% and assuming a “worst-case” safety assumption of 10% rate of death in each arm with 10% significance and 80% power. The primary outcome is all-cause mortality at 7 days post randomization between treatment arms. Secondary end points include all-cause mortality at 30 days, perihematomal edema volume after symptom onset, adverse events, vital signs, pharmacokinetics of MW189, and inflammatory cytokine concentrations in plasma (and cerebrospinal fluid if available). Other exploratory end points are functional outcomes collected on days 30, 90, and 180. BEACH will provide important information about the utility of targeting neuroinflammation in ICH and will inform the design of future larger trials of acute central nervous system injury

Neonatal Survival After Serial Amnioinfusions for Bilateral Renal Agenesis: The Renal Anhydramnios Fetal Therapy Trial

IMPORTANCE: Early anhydramnios during pregnancy, resulting from fetal bilateral renal agenesis, causes lethal pulmonary hypoplasia in neonates. Restoring amniotic fluid via serial amnioinfusions may promote lung development, enabling survival. OBJECTIVE: To assess neonatal outcomes of serial amnioinfusions initiated before 26 weeks\u27 gestation to mitigate lethal pulmonary hypoplasia. DESIGN, SETTING, AND PARTICIPANTS: Prospective, nonrandomized clinical trial conducted at 9 US fetal therapy centers between December 2018 and July 2022. Outcomes are reported for 21 maternal-fetal pairs with confirmed anhydramnios due to isolated fetal bilateral renal agenesis without other identified congenital anomalies. EXPOSURE: Enrolled participants initiated ultrasound-guided percutaneous amnioinfusions of isotonic fluid before 26 weeks\u27 gestation, with frequency of infusions individualized to maintain normal amniotic fluid levels for gestational age. MAIN OUTCOMES AND MEASURES: The primary end point was postnatal infant survival to 14 days of life or longer with dialysis access placement. RESULTS: The trial was stopped early based on an interim analysis of 18 maternal-fetal pairs given concern about neonatal morbidity and mortality beyond the primary end point despite demonstration of the efficacy of the intervention. There were 17 live births (94%), with a median gestational age at delivery of 32 weeks, 4 days (IQR, 32-34 weeks). All participants delivered prior to 37 weeks\u27 gestation. The primary outcome was achieved in 14 (82%) of 17 live-born infants (95% CI, 44%-99%). Factors associated with survival to the primary outcome included a higher number of amnioinfusions (P = .01), gestational age greater than 32 weeks (P = .005), and higher birth weight (P = .03). Only 6 (35%) of the 17 neonates born alive survived to hospital discharge while receiving peritoneal dialysis at a median age of 24 weeks of life (range, 12-32 weeks). CONCLUSIONS AND RELEVANCE: Serial amnioinfusions mitigated lethal pulmonary hypoplasia but were associated with preterm delivery. The lower rate of survival to discharge highlights the additional mortality burden independent of lung function. Additional long-term data are needed to fully characterize the outcomes in surviving neonates and assess the morbidity and mortality burden

Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial

Acute stroke due to supratentorial intracerebral haemorrhage is associated with high morbidity and mortality. Open craniotomy haematoma evacuation has not been found to have any benefit in large randomised trials. We assessed whether minimally invasive catheter evacuation followed by thrombolysis (MISTIE), with the aim of decreasing clot size to 15 mL or less, would improve functional outcome in patients with intracerebral haemorrhage. MISTIE III was an open-label, blinded endpoint, phase 3 trial done at 78 hospitals in the USA, Canada, Europe, Australia, and Asia. We enrolled patients aged 18 years or older with spontaneous, non-traumatic, supratentorial intracerebral haemorrhage of 30 mL or more. We used a computer-generated number sequence with a block size of four or six to centrally randomise patients to image-guided MISTIE treatment (1·0 mg alteplase every 8 h for up to nine doses) or standard medical care. Primary outcome was good functional outcome, defined as the proportion of patients who achieved a modified Rankin Scale (mRS) score of 0-3 at 365 days, adjusted for group differences in prespecified baseline covariates (stability intracerebral haemorrhage size, age, Glasgow Coma Scale, stability intraventricular haemorrhage size, and clot location). Analysis of the primary efficacy outcome was done in the modified intention-to-treat (mITT) population, which included all eligible, randomly assigned patients who were exposed to treatment. All randomly assigned patients were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01827046. Between Dec 30, 2013, and Aug 15, 2017, 506 patients were randomly allocated: 255 (50%) to the MISTIE group and 251 (50%) to standard medical care. 499 patients (n=250 in the MISTIE group; n=249 in the standard medical care group) received treatment and were included in the mITT analysis set. The mITT primary adjusted efficacy analysis estimated that 45% of patients in the MISTIE group and 41% patients in the standard medical care group had achieved an mRS score of 0-3 at 365 days (adjusted risk difference 4% [95% CI -4 to 12]; p=0·33). Sensitivity analyses of 365-day mRS using generalised ordered logistic regression models adjusted for baseline variables showed that the estimated odds ratios comparing MISTIE with standard medical care for mRS scores higher than 5 versus 5 or less, higher than 4 versus 4 or less, higher than 3 versus 3 or less, and higher than 2 versus 2 or less were 0·60 (p=0·03), 0·84 (p=0·42), 0·87 (p=0·49), and 0·82 (p=0·44), respectively. At 7 days, two (1%) of 255 patients in the MISTIE group and ten (4%) of 251 patients in the standard medical care group had died (p=0·02) and at 30 days, 24 (9%) patients in the MISTIE group and 37 (15%) patients in the standard medical care group had died (p=0·07). The number of patients with symptomatic bleeding and brain bacterial infections was similar between the MISTIE and standard medical care groups (six [2%] of 255 patients vs three [1%] of 251 patients; p=0·33 for symptomatic bleeding; two [1%] of 255 patients vs 0 [0%] of 251 patients; p=0·16 for brain bacterial infections). At 30 days, 76 (30%) of 255 patients in the MISTIE group and 84 (33%) of 251 patients in the standard medical care group had one or more serious adverse event, and the difference in number of serious adverse events between the groups was statistically significant (p=0·012). For moderate to large intracerebral haemorrhage, MISTIE did not improve the proportion of patients who achieved a good response 365 days after intracerebral haemorrhage. The procedure was safely adopted by our sample of surgeons. National Institute of Neurological Disorders and Stroke and Genentech. [Abstract copyright: Copyright © 2019 Elsevier Ltd. All rights reserved.

Abstract P447: Intracranial Pressure and Cerebral Perfusion Pressure Monitoring in Spontaneous Intracranial Hemorrhage: A Secondary Analysis of the Mistie III Trial

Introduction: Intracerebral hemorrhage (ICH) management guidelines recommend maintaining intracranial pressure (ICP) &lt;20 and cerebral perfusion pressure (CPP) between 50-70 mmHg. We did subgroup analyses of MISTIE III trial to explore whether minimally invasive surgery (MIS) improves ICP or CPP and whether thresholds are associated with long term outcomes. Methods: MISTIE III was a randomized clinical trial including 499 patients with spontaneous ICH randomized to MIS+Alteplase or standard medical care (SMC). Primary outcomes were any threshold event of ICP &gt;20 and CPP &lt;60/70 mmHg. Secondary outcomes were poor modified Rankin Scale at one year and mortality at 30/365 days. We used multivariable models to investigate factors associated with ICP/CPP events and outcomes. Results: Of 72 patients with ICP monitored for median 92 (72-96) hours, 31 (43.1%) had at least one ICP reading &gt;20 and 52/35 (72.2/34.7%) had at least one CPP reading &lt;70/60 mmHg. Lower intraventricular hemorrhage volume and SMC group were associated with having any ICP threshold event &gt;20 and CPP event &lt;70 mmHg whereas CPP&lt;60 mmHg was associated with end of treatment (EOT) ICH volume, hydrocephalus on diagnostic CT and no prior antiplatelet agent use. On adjusted analyses, percentage of ICP readings &gt;20 were significantly less likely in patients undergoing MIS vs SMC (Coefficient -0.79, 95% Confidence Interval [CI] [(-)1.46-(-)0.11]; p=0.02). Percentage of CPP readings &lt;70 were significantly less frequent in MIS group (Coefficient -1.59 [(-)2.58-(-)0.59]; p=0.002). Patients who underwent successful MIS with EOT ICH volume &lt;15mL also had significantly lower percentage of readings at ICP&lt;20 (p=0.02), and CPP&lt;70 (p=0.05). Lower percentage of CPP readings &lt;60 mmHg was independently associated with lower mortality at 30 and 365 days (p=0.02 and 0.04) and CPP &lt;70 was associated with lower one-year mortality (p=0.04). There were no significant associations with one-year functional outcome. Conclusion: Elevated ICP and inadequate CPP are not infrequent during ICP monitoring for large ICH. Burden of low CPP events predict higher short and long term mortality, but not functional outcomes. CPP may be more significant than ICP. MIS appears to mitigate ICP and CPP threshold events. </jats:p

Abstract TMP19: MRI Characteristics and Predictors of Diffusion Weighted Hyperintense Lesions After Spontaneous Intracerebral Hemorrhage: A Secondary Analysis of MISTIE-III

Introduction: Mechanisms of diffusion weighted hyperintense lesions (DWIHL) after spontaneous intracerebral hemorrhage (ICH) are controversial. We evaluated mechanism and outcome of DWIHL. Methods: Protocolized MRI scans within 7 days from ICH were reviewed from MISTIE-III trial. Imaging analysis included DWIHL, leukoariosis (Fazekas score), enlarged perivascular space (EPVS), and cerebral microbleeds. Multivariable logistic regression analysis was performed to assess predictors and outcomes of having DWIHLs. Favorable outcome was defined as modified Rankin Score 0-3 at 12 months. Results: Of 499 patients, 300 underwent DWI studies (62% lobar ICH; 38% deep ICH) and 178 (59%) had acute DWIHLs (66% lobar; 34% deep). DWIHL locations were perihematomal in 140 (79%); and remote in 96 (54%). In multivariable regression analysis, DWIHLs were associated with initial mean arterial pressure [MAP] (odds ratio [OR]: 1.004; 95% confidence interval [CI]: 1.002-1.01), initial ICH volume (OR: 1.004; 95%CI: 1.001-1.01), NIHSS at randomization (OR: 1.01; 95%CI: 1.01-1.02), hypertension history (OR: 1.41; 95%CI: 1.04-1.93), and Fazekas score (OR: 1.04; 95%CI: 1.01-1.08). Patients with DWIHLs were less likely to have favorable outcome (66% vs. 50%; OR: 0.89; 95%CI: 0.81-0.99) after adjusting for ICH severity; however, the presence of DWIHLs did not confer an independent mortality risk at 12 months. In addition, perihematomal DWIHLs were associated with ICH volume (OR: 1.003; 95%CI: 1.00-1.01), NIHSS (OR: 1.01; 95%CI: 1.00-1.02), deep location (OR: 1.25; 95%CI: 1.10-1.42), and centrum semiovale EPVS score (OR: 0.99; 95% CI: 0.99-1.00). Remote DWIHLs were associated with Fazekas score (OR: 1.17; 95%CI: 1.06-1.29), centrum semiovale EPVS score (OR: 1.01; 95%CI: 1.00-1.01), atrial fibrillation (OR: 1.40; 95%CI: 1.04-1.90), and maximal ΔMAP on first 24 hours (OR: 1.004; 95%CI: 1.001-1.006). Conclusions: DWIHLs were common (59%) in patients after spontaneous ICH, predominantly in lobar locations and were associated with unfavorable neurologic outcome. While perihematomal DWIHLs were associated with ICH severity, remote DWIHLs suggested different mechanisms including acute blood pressure reduction, cardiac emboli, and white matter disease severity. </jats:p

Abstract WMP98: Post-Stroke Depression Predictors Among Intracerebral Hemorrhage Survivors

Introduction: Post-stroke depression (PSD) in ischemic stroke is well-documented in the literature, but much less in intracerebral hemorrhage (ICH). We aimed to evaluate the clinical predictors of PSD in a cohort of ICH patients. Methods: 499 randomized ICH subjects in MISTIE-III trial were followed for 1 year. Center for Epidemiologic Studies Depression Scale (CES-D) was assessed at 180 days (D180) post-ICH. A score of CES-D ≥16 were considered depressed. 300 out of 379 survivors responded. Multivariable logistic regression analysis was performed to identify independent predictors of depression at D180 with adjustment for baseline demographic characteristics, ICH hemisphere and severity, and functional recovery, cognition status and patient disposition at day 30 (Model 1) and day 180 (Model 2). Good functional outcome was defined as modified Rankin Scale (mRS) 0-3 vs. 4-5 (poor mRS), cognitive impairment status was defined as screening Mini-Mental State Examination (MMSE) &lt; 24 and good patient disposition was defined as patient location at home. Prior use of antidepressants was too small to consider. Results: Using CES-D, 106/300 subjects (35%) were considered depressed at day 180. Both models found that female gender, Hispanic ethnicity, and right hemisphere ICH location were statistically significant predictors of PSD. Poor mRS at D180 was statistically significant D180. Early (D30), but not late cognitive impairment was also significant. Conclusion: Almost 4 out of 10 ICH survivors displayed significant depression as defined by CES-D. Race/ethnicity, gender, ICH hemisphere, and poor functional recovery appear to influence post-stroke depression, while later cognitive impairment, volumetric, age, and later home location were less important. </jats:p

Abstract 12: An Evaluation of Functional Outcome at 1 Year of Poor Prognosis Patients in Mistie-III

Introduction: Clinical factors impacting prognosis following Intracerebral Hemorrhage (ICH) have been well described in the literature, with “poor” prognosis often leading to withdrawing life sustaining treatments (WoLST). The MISTIE-III trial data provides an opportunity to review 12 month outcome of “poor" prognosis subjects. Methods: In order to evaluate functional recovery of ICH survivors compared with patients who had WoLST we used a severity index (SI) score for predicting good functional recovery 1 year following ICH. The SI used 6 clinical univariate variables from the MISTIE-III analysis (age &gt; 67, Glasgow Coma Score [GCS] &lt; 8, deep ICH location, stability ICH volume &gt; 45mL, stability intraventricular hemorrhage (IVH) volume&gt;0.4mL) and &gt; 3 comorbidities (hypertension, hyperlipidemia, cardiovascular disease, and end-stage renal disease). Based on the SI scores for subjects who had WoLST, a matched cohort of survivors with “poor" prognosis (mRS 4-5) were tracked for functional recovery for 12 months. Results: Of the participants enrolled in MSITIE-III, 61 had WoLST. Of the non-WoLST ICH survivors, 16 progressed to death during the acute period. Another 48 had died prior to the 1 year (D365) follow up. At the 30 Day (D30) evaluation, there were 263 ICH survivors with “poor" prognosis SI scores having a mRS of 4 or 5 and 94% were still in a treatment facility. By D365, 47% of the “poor prognosis” patients had improved to mRS 0-3 (good outcome) with 98% living at home. Of the remaining, 36% had a mRS of 4 (moderately severe disability) with 64% living at home, and 17% had a mRS of 5 (severe disability) with 31% living at home. Conclusion: For family members of patients sustaining an ICH where clinical factors indicate a “poor" prognosis, the decision to continue or withdraw life sustaining treatment is difficult. Our data shows that ICH patients with clinical factors that are assumed to indicate “poor" prognosis for recovery can, when given time, achieve a favorable outcome. </jats:p

Abstract 7: Cerebral Small Vessel Disease Burden and Association With Post-Surgical Rebleeding and Long-Term Outcome in Intracerebral Hemorrhage Patients From the Mistie III Trial

Objectives: To examine the effect of cerebral small vessel disease (CSVD) markers and CSVD burden on hematoma expansion and long-term functional outcomes in large spontaneous intracerebral hemorrhage (ICH) &gt;30 mL. Method: Retrospective analysis of 288 patients from the MISTIE III trial with qualified MRI sequences. MISTIE III evaluated minimally invasive surgery plus alteplase (vs medical management). We identified 6 CSVD markers including lacunes, cerebral microbleeds (CMB), enlarged perivascular space (EPVS), white matter hyperintensities (WMH), cortical superficial siderosis (cSS), and acute DWI positive lesions. First 5 components were reviewed on day 1 MRI and DWI lesions on day 7. The primary outcome was death or major disability at one year (modified Rankin score 4-6). Secondary outcome was post-surgical rebleeding, defined as symptomatic or asymptomatic hemorrhage expansion within 72 hours post last dose of alteplase. Result: Unfavorable outcome occurred in 65.9% at one year. Post-surgical ICH expansion occurred in 34 (22.9%) of 148 surgical patients. Mean time from symptom onset to first MRI was 0.94 (IQR 0.2-6.3) days. Most individual CSVD markers were more common in patients with unfavorable vs. favorable outcome: CMB≧5 (26.1% vs 15.0%, p=0.03), DWI lesions (65.8%vs 49.6%, p=0.006), cSS (16.8% vs 7.1%, p=0.02) severe WMH (67.7% vs 29.9%, p&lt;0.001) severe EPVS in basal ganglia (19.3% vs 10.2%, p=0.047), and lacunes (11.2% vs 6.3%, p=0.21), In the multivariable adjusted model, cumulative CSVD score (one point for each component: CMB≥5, severe EPVS in basal ganglia, lacunes, severe WMH and cSS) was independently associated with unfavorable outcome (OR 0.56, 95%CI 0.41-0.76, p&lt;0.001; AUC 0.855). We did not find a relationship between either independent CSVD markers or CSVD score with post-surgical ICH expansion. Cumulative CSVD score in multivariable analysis adjusted for predictors of hematoma expansion had OR 0.77 (95% CI 0.50-1.19, p=0.77; AUC 0.659). Conclusion: In large volume ICH patients with long-term follow-up, heavy burden of CSVD at ICH onset remains an independent predictor of unfavorable outcome, and particularly severe white matter hyperintensities. CSVD markers did not show association with post-surgical ICH expansion. </jats:p

Abstract 76: Non-Contrast CT Markers and Pre- and Post-Surgical Hematoma Expansion in the MISTIE III Trial Surgical Cohort

Introduction: A range of findings on non-contrast CT (NCCT) have been found to predict hematoma expansion after spontaneous ICH, but it is unclear whether these findings predict peri-procedural bleeding. We explored whether any specific NCCT marker(s) predict pre- or post-surgical hematoma expansion events. Methods: NCCTs were reviewed for presence of black hole sign, blend sign, swirl sign, and island sign in the surgical cohort from the MISTIE-III trial which evaluated minimally invasive surgery plus alteplase in ICH &gt;30 mL. Hematoma expansion was defined as any expansion ≥6 mL or 33% ICH volume increase during pre-surgical period (Model 1) from diagnostic CT (DiagCT) to 24 hours post DiagCT and from stability CT (StabCT) to 24 hours post last dose of alteplase (Model 2). Blend sign was removed from analysis due to small sample size. Multivariable logistic regression analysis was performed to identify independent predictors of pre-op and post-op hematoma expansion. Results: Of 250 surgical subjects, 5 were excluded due to poor image quality. Expansion events occurred in 82 of 234 (35.0%) subjects in the pre-op interval and in 15 of 226 (7%) in the post-op interval. None of the markers were significant for pre-op expansion, but ICH volume and time from ictus to DiagCT were statistically significant predictors. Swirl sign, ICH volume, and posterior trajectory compared to lateral trajectory were independent predictors of post-op expansion events. Expansion volume pre-op and post-op were weakly associated with presence of swirl sign; Spearmans rho=0.3 p=0.065 and rho=0.60 p=0.047, respectively. Conclusion: This is the first analysis of impact of NCCT markers on re-bleeding post minimally invasive surgery from a large clinical trial. Despite an absence of association between NCCT markers and hematoma expansion in the pre-surgical period perhaps reflecting inclusion criteria for hemorrhage stability, swirl sign was associated with post-surgical rebleeding. </jats:p

Abstract TP131: Association Of Hemoglobin Over The First Week With Clinical Outcomes And Neuroimaging Characteristics In Patients With Spontaneous Intracerebral Hemorrhage

Introduction: Studies have shown independent associations of lower admission hemoglobin (HB) levels with larger spontaneous intracerebral hemorrhage (ICH) volumes and poor outcomes, possibly mediated by hematoma expansion (HE). Objective: We retrospectively investigated the association of HB levels over the first week post ICH with functional outcomes (FO) and neuroimaging findings in patients with spontaneous ICH (&gt;30 mL). We explored whether comorbidities modify the effects of HB. Methods: We analyzed HB levels from subjects enrolled in the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation phase 3 trial (MISTIE III). The exposure was admission HB and the HB nadir in the first week. The primary outcome was good FO at 180 days, defined as modified Rankin Scale of 0-3. Secondary outcomes were good FO at 365 days, 30-day mortality, admission ICH volume, and HE (&gt;6 mL). Linear and logistic regression models were used to test the association of HB with clinical outcomes and neuroimaging findings. All models were adjusted for age, sex, race, treatment (medical Vs. MISTIE), Glasgow Coma Scale, ICH volume, presence of intraventricular hemorrhage, and ICH location (deep Vs. lobar). We investigated effect modification of comorbidities on association of HB with FO. Results: A total of 493 of 499 enrolled patients (61% males, mean age 61(SD=12) years, median ICH volume 41.8 (IQR=30.8-51.5) mL) were included. Patients with good FO at 180 days had a higher admission HB (13.2 Vs. 12.6 g/dl, p=0.001) and a higher nadir HB (11.7 Vs. 10.9 g/dl, p&lt;0.001). In adjusted analyses, each additional g/dl in nadir HB (but not admission HB) was associated with higher odds of good FO at 180 (OR 1.29, p=0.005) and 365 (OR 1.18, P=0.048) days. Baseline (B= -1.16, p=0.02) and nadir HB (B= -1.71, p=0.001) were inversely associated with hematoma volumes, but not with HE. There was evidence of heterogeneity in the effects of diabetes on the association of nadir HB with day 180 FO (OR 0.67; p interaction = 0.045). Conclusions: In patients with ICH &gt; 30 mL, higher nadir HB in the first week was associated with better long-term FO and smaller ICH volumes, but not with HE. Early hemoglobin changes may serve as a prognostic biomarker and a potentially modifiable factor to improve FO. </jats:p