Thompson, Richard E.

Importance Anhydramnios from fetal kidney failure causes lethal pulmonary hypoplasia. Serial amnioinfusions have shown promise in mitigating pulmonary disease from bilateral renal agenesis, but efficacy and safety for other causes of fetal kidney failure are unproven. Objective To assess the efficacy of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia in cases of anhydramnios due to fetal kidney failure. Design, Setting, and Participants Prospective, nonrandomized clinical trial conducted at 13 US fetal therapy centers from December 2018 to February 2025. Outcomes for maternal-fetal pairs with anhydramnios before 22 weeks’ gestation due to fetal kidney failure without bilateral renal agenesis are reported; data collection for surviving infants continued until February 13, 2026. Exposure Thirty-two participants underwent serial amnioinfusions with isotonic fluid beginning before 26 weeks’ gestation. Main Outcomes and Measures The primary end point was neonatal survival for 14 days or longer with dialysis access placement. Secondary outcome measures of survival to discharge home and kidney transplant are reported. Results Twenty-nine of 32 participants (91%) had a live birth, with a median (IQR) gestational age at delivery of 34 weeks 1 day (31 weeks 5 days to 34 weeks 6 days). All participants delivered before 37 weeks’ gestation. No unexpected serious maternal adverse events occurred, and the most common maternal complications were preterm prelabor rupture of membranes in 19 participants (56%) and chorioamniotic separation in 10 (29%). The primary outcome occurred in 19 (65.5%) of 29 live-born neonates (95% CI, 45.7%-82.1%). Factors associated with survival to the primary outcome included receiving more amnioinfusions (median [IQR], 14 [9-18] in survivors vs 7 [4-11] in nonsurvivors; P = .01), longer time interval from first amnioinfusion to preterm prelabor rupture of membranes (63.5 [60.5-74.5] days in survivors vs 29.0 [22.0-56.0] days in nonsurvivors; P = .01), gestational age greater than 32 weeks (79% of survivors vs 38% of nonsurvivors; P = .03), and higher birth weight (2029 [1770-2250] g in survivors vs 1635 [1185-1915] g in nonsurvivors; P = .01). Fourteen live-born infants (48%) survived to hospital discharge at a median (IQR) age of 4.7 (3.4-5.7) months. Of the 11 infants surviving to date, 7 (64%) have undergone kidney transplant between ages 2 years to 5 years. Conclusions and Relevance Serial amnioinfusions mitigated lethal pulmonary hypoplasia in neonates with anhydramnios due to fetal kidney failure. Significant neonatal morbidity and mortality independent of early lung function was noted. Factors associated with survival were consistent with the Renal Anhydramnios Fetal Therapy trial’s bilateral renal agenesis cohort, suggesting common mechanistic pathways for mitigating pulmonary hypoplasia. Trial Registration ClinicalTrials.gov Identifier: NCT03101891

BACKGROUND AND OBJECTIVES: It is not clear whether changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials aimed at preventing bleeding in cerebral cavernous malformations (CCM). METHODS: We examined prospective changes in CCM lesion volume in the double-blinded AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We correlated these with symptomatic hemorrhage (SH) events, contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (modified Rankin Scale (mRS)) and subjective (Euro-QoL Visual Analog Scale [EQ-VAS]) functional status. We also simulated sample sizes needed to detect potential effects on lesion volume. RESULTS: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R 2 = 0.68, P < .0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively ( P = .43). All cases with SH had increases in lesion volume and increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS, but there were no overall meaningful correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS, or EQ-VAS (all R/R 2 < 0.5 and Bonferroni corrected P > .05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger case numbers needed to demonstrate an effect on change in lesion volume than those needed to detect an effect on QSM change with α = 0.05 and β = 0.8, and even larger samples to detect effects on the number of cases with increased or decreased lesion volume. CONCLUSION: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with biomarkers of lesional bleeding, nor reflect functional changes, and are not statistically advantageous compared with QSM measures in detecting potential drug effects.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH ( P =0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03652181.

Background: Cerebral cavernous angiomas with symptomatic hemorrhage (CASH) carry highest rebleed rates and are targeted for novel interventions. A multisite clinical trial readiness project (clinicaltrials.gov NCT03652181) aims to identify clinical and functional changes over time in trial eligible CASH patients. Methods: Adult patients from 5 high volume centers with a CASH in the prior year and no planned surgical intervention were enrolled. In addition to demographic, clinical, and imaging review, patients underwent baseline, 1 year and 2 year NIH-stroke scale (NIHSS), modified Rankin scale (mRS), Euro-QOL 5D-3L (EQ-5D-3L) and EQ VAS (visual analog score), and PROMIS 29 assessments. Recurrent symptomatic hemorrhages (SH) were verified. We assessed the hemorrhage rate, change in scores/scales over time, and determined which scales/scores were most affected in patients with SH. Results: 123 patients completed baseline assessments and were prospectively followed (60.9% female; mean age 44.1 years; 39.1% familial; 41.5% brainstem location). As of reporting date, 89 of 104 (86%) and 58 of 76 (76%) cases have completed assessments. There were 16 SHs during 147 patient-years of follow up (10.9% per patient year). At baseline, 111 (90.2%) of patients had NIHSS 0-2 and 77 (62.6%) patients had mRS baseline 0-1 which improved to 40 (95.2 %) and 43 (75.4%) at 2 years. At baseline, 54 (43.9%) of patients had at least one moderate to severely abnormal PROMIS-29 domain compared to 13 (26.5%) at 2 years. EQ-5D-3L baseline demonstrated a moderate proportion of patients reporting some difficulty with pain (48.8%), anxiety (41.5%), and activity (41.5%) which improved to 28%, 30%, and 34% respectively at 2 years. Patients with a prospective SH were more likely than those without recurrent SH at 2 years to display mild functional decline (0.5 SD) of most PROMIS-29 domains, a mRS of 2 or higher and an abnormal EQ- self-care (P<0.05). Other scales/scores were not significantly different between the groups. Conclusion: We report SH rate and functional outcome at baseline and rates of changes during 2 years in trial eligible CASH patients. The PROMIS-29, mRS, and EQ-self-care domains were most discriminative in patients with recurrent SH. No test was 100% specific.

Background: Quantitative susceptibility mapping (QSM) is a measure of iron content, and ≥6% increase in QSM has been correlated with new hemorrhage in previously stable cavernous angiomas. Longitudinal changes in QSM are not known in cavernous angiomas with symptomatic hemorrhage (CASH) with high rates of rebleeding and are the targets of novel pharmacotherapies. In a prospective multisite Trial Readiness project (clinicaltrials.gov NCT03652181), QSM is longitudinally assessed. Methods: Trial eligible subjects with CASH in the prior year and not undergoing lesion resection or radiation, were enrolled. Mean QSM of CASH lesion was acquired at baseline and at 1 and 2 year planned follow-ups. Relative change in mean lesional QSM during each follow-up year was assessed, and any symptomatic hemorrhage (SH), asymptomatic changes (AC; defined as subclinical bleed or growth) in the lesion during the same epoch. Results: Paired QSM assessments were completed to date in 99 CASH lesions (67 year 1, and 32 year 2) and are reported herein. Four SH and 6 ACs occurred during 1 st follow-up year, and 3 SH during 2 nd year. QSM increased in 54 lesion-years, decreased in 44, and remained stable in 1. The % lesional QSM change in year 1 was significantly higher than that observed in year 2 (mean +9.33, SD 37.52 vs. +5.20; SD= 24.86; p=0.05; Spearman correlation ρ -0.36). CAs with clinical SH or AC had a significantly higher % QSM change than lesions without (mean +28.03, SD 17.77 vs. +4.97, SD= 34.75; p=0.0014). All 13 lesions with SH/AC demonstrated a QSM increase ≥6% while 31 of 86 (36%) lesions with no clinical events had a ≥6% QSM increase. Conclusion: QSM change of ≥6% is present in every CASH lesion manifesting a new SH or AC (100% specificity), and is more common than clinical events (3.4X higher sensitivity). The biomarker can hence be used as a more sensitive categorical outcome than SH or AC in clinical trials of novel therapies aimed at bleeding in CASH lesions. Effect of an intervention on % QSM change may also be proposed as a time-averaged difference between 2 arms using a repeated measures analysis implemented as an unadjusted linear mixed model. These results are the basis of application for certification by the U.S F.D.A. of QSM as a monitoring biomarker of drug effect in CASH.

Background: Patients with cerebral cavernous angiomas with symptomatic hemorrhage (CASH) have high risk of disability from recurrent bleeding. Candidate medications to prevent rebleeding in CASH lesions will require multisite clinical trials with standardized data collection. Objective: To report the prevalence and baseline cohort features in CASH patients and establish a research network infrastructure for trials. Methods: This prospective observational cohort study includes adults with radiologically verified CASH lesion within 1-year of consent. Exclusions include prior or planned surgical intervention, spinal location, or prior brain irradiation. Six sites enrolled patients into the screening and clinical assessment portion of the study starting July 2018. Patients also had the option to participate in the follow up biomarker validation at 4 sites. Baseline demographics, clinical and imaging information, and outcomes (mRS, PROMIS-29, NIHSS, and EuroQol-5D) were collected. Biomarker imaging included dynamic contrast enhanced quantitative perfusion (DCEQP) and quantitative susceptibility mapping (QSM) that correlated with symptomatic bleeding. Descriptive statistics were performed and one-sample t-test was used to compare whether mean T-scores for PROMIS-29 domains differed significantly from a reference population. Results: As of May 2020, 849 CASH patients were screened of whom 110 (13%) were eligible and enrolled; 73 also enrolled into the biomarker validation study. Average age at enrollment was 46±16 years at a mean of 4.4 months after symptom onset; 53% were female, 41% were familial, and 43% of CASH lesions were brainstem location. At enrollment, 90% of the cohort had independent functional outcome (mRS ≤ 2 and NIHSS <5). Perceived health problems affecting QoL were reported in >30% (EuroQol-5D). CASH cases had significantly worse anxiety but better depression and social satisfaction scores compared to a general population (all P<0.01). Baseline DCEQP and QSM measures did not differ significantly across sites. Conclusion: We demonstrate feasibility of multisite recruitment of CASH patients and report prevalence of baseline features that will aid in design of clinical trials and inclusion of appropriate outcome measures.

Abstract BACKGROUND More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. OBJECTIVE To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. METHODS The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. EXPECTED OUTCOMES The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. DISCUSSION With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

Abstract BACKGROUND Brain cavernous angiomas with symptomatic hemorrhage (CASH) are uncommon but exact a heavy burden of neurological disability from recurrent bleeding, for which there is no proven therapy. Candidate drugs to stabilize the CASH lesion and prevent rebleeding will ultimately require testing of safety and efficacy in multisite clinical trials. Much progress has been made in understanding the epidemiology of CASH, and novel biomarkers have been linked to the biological mechanisms and clinical activity in lesions. Yet, the ability to enroll and risk-stratify CASH subjects has never been assessed prospectively at multiple sites. Biomarkers and other outcomes have not been evaluated for their sensitivity and reliability, nor have they been harmonized across sites. OBJECTIVE To address knowledge gaps and establish a research network as infrastructure for future clinical trials, through the Trial Readiness grant mechanism, funded by National Institute of Neurological Disorders and Stroke/National Institutes of Health. METHODS This project includes an observational cohort study to assess (1) the feasibility of screening, enrollment rates, baseline disease categorization, and follow-up of CASH using common data elements at multiple sites, (2) the reliability of imaging biomarkers including quantitative susceptibility mapping and permeability measures that have been shown to correlate with lesion activity, and (3) the rates of recurrent hemorrhage and change in functional status and biomarker measurements during prospective follow-up. EXPECTED OUTCOMES We propose a harmonized multisite assessment of enrollment rates of CASH, baseline features relevant to stratification in clinical trials, and follow-up assessments of functional outcomes in relation to clinical bleeds. We introduce novel biomarkers of vascular leak and hemorrhage, with firm mechanistic foundations, which have been linked to clinical disease activity. We shall test their reliability and validity at multiple sites, and assess their changes over time, with and without clinical rebleeds, hence their fitness as outcome instruments in clinical trials. DISCUSSION The timing cannot be more opportune, with therapeutic targets identified, exceptional collaboration among researchers and the patient community, along with several drugs ready to benefit from development of a path to clinical testing using this network in the next 5 years.