Endpoint Biomarkers Research Articles

Long-Term Randomized Controlled Trials of Diet Intervention Reports and Their Impact on Cancer: A Systematic Review.

Most randomized controlled trials (RCTs) assessing the impact of diet on cancer have been short term (<1 year), mostly evaluating breast cancer survivors. Given the many-year interval that is generally required for an intervention to have an impact on cancer risk or prognosis, as well as the fact that lifestyle strategies such as diet modification frequently fail due to lack of adherence over the long term, we focused this systematic review only on longer-term (≥1 year) intervention reports. Diet intervention reports focused on reducing cancer risk in overweight and obese individuals target caloric restriction (every day, some days, or most hours of each day). This study is a systematic review of RCTs lasting at least 1 year, testing dietary interventions with a primary or secondary endpoint of cancer or a biomarker linked to cancer. Fifty-one reports met our review criteria. Twenty of fifty-one (39%) reports are RCTs where the primary endpoint was cancer or a cancer-related biomarker, while the other reports evaluated reports where cancer or a cancer-related biomarker was a secondary endpoint. Thirteen of twenty (65%) primary reports evaluated isocaloric, and the remaining eight evaluated low-calorie diets. All but one of the primary and two secondary isocaloric diet reports evaluated the benefit of a low-fat diet (LFD), with the other three evaluating a Mediterranean diet (MedD). More LCD vs. isocaloric diet primary reports (71% vs. 38%) demonstrated cancer or cancer-related biomarker benefit; the difference in chance of benefit with secondary reports was 85% for LCD vs. 73% for isocaloric diets. Three of three MedD reports demonstrated benefit. Sixty-nine percent (20/29) of the secondary reports came from two large reports: the WHI diet modification trial (15 secondary reports) and the polyp prevention trial (5 secondary reports). Nineteen of twenty-two (86%) primary reports enrolled only women, and three enrolled both men and women. No study that met our criteria enrolled only men, comprising 1447 men in total vs. 62,054 women. Fifteen of twenty (75%) primary reports focus on healthy women or women with breast cancer. Adherence findings are discussed when provided. More long-term RCTs evaluating cancer and cancer-related biomarker endpoints are needed, especially for cancers at sites other than the breast.

The National Cancer Institute Clinical Trials Planning Meeting to Address Gaps in Observational and Intervention Trials for Cancer-Related Cognitive Impairment.

Cancer-related cognitive impairment (CRCI) is a broad term encompassing subtle cognitive problems to more severe impairment. CRCI severity is influenced by host, disease, and treatment factors and affects patients prior to, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a Clinical Trial Planning Meeting (CTPM) to review the state of the science on CRCI and to develop both Phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system (CNS) disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of CRCI, members of the SxQOL SC, patient advocates, representatives from all seven NCI Community Oncology Research Program (NCORP) Research Bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacologic and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three CTPM working groups (longitudinal studies and pharmacologic and behavioral intervention trials) convened for one year to discuss and report on top priorities and to design studies. The CTPM experts concluded sufficient data exist to advance Phase II/Phase III trials utilizing selected pharmacologic and behavioral interventions for the treatment of CRCI in the non-CNS setting with recommendations included herein.

Japanese Subgroup Analyses from EMERGE and ENGAGE, Phase 3 Clinical Trials of Aducanumab in Patients with Early Alzheimer’s Disease

BackgroundGlobal prevalence and incidence of dementia continue to rise at a rapid rate. There is a need for new Alzheimer’s disease (AD) treatments globally. Aducanumab is a human monoclonal antibody that selectively targets aggregated soluble amyloid beta oligomers and insoluble amyloid beta fibrils. In June 2021, aducanumab was approved by the US Food and Drug Administration for the treatment of AD under the accelerated approval pathway.ObjectivesWe evaluated the efficacy, safety, biomarker and pharmacokinetics (PK) of aducanumab in Japanese subgroups in EMERGE and ENGAGE studies.DesignEMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early AD (mild cognitive impairment due to AD or mild AD dementia).SettingThese studies involved 348 sites in 20 countries. PARTICIPANTS: Participants enrolled in Japan included 121 (7.4% of total 1638 in EMERGE) and 100 (6.1% of total 1647 in ENGAGE) patients (aged 50–85 years with confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to AD or mild AD dementia.InterventionParticipants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (6 or 10 mg/kg target dose) or placebo via IV infusion once every 4 weeks over 76 weeks.MeasurementsThe primary outcome measure was change from baseline to Week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; biomarker endpoints (amyloid PET and plasma p-tau181); serum PK profiles and immunogenicity.ResultsResults from the Japanese subgroup analyses were generally consistent with those of the overall study population across endpoints, while a lower mean body weight (kg) and a smaller proportion of ApoE ε4 carriers were observed in the Japanese subgroup population. A treatment effect was observed in favor of aducanumab on the primary and secondary efficacy endpoints at Week 78 in EMERGE, but not ENGAGE. The incidence and type of adverse events in the Japanese subgroups were generally comparable to those observed in the overall study population; amyloid related imaging abnormalities (ARIA) were common treatment-related adverse events that appeared to be related to the aducanumab dose. ARIA incidence was generally lower in the Japanese subgroup compared with the overall population. Consistent with the overall data set, a robust dose-dependent decrease in amyloid beta levels as assessed with amyloid-PET and plasma p-tau181 was observed. Serum PK profiles and immunogenicity of aducanumab in Japanese population were consistent with the non-Japanese population.ConclusionEfficacy, safety, biomarker, and PK profiles of aducanumab were consistent between the Japanese subgroup and the overall population. A positive treatment effect of aducanumab on efficacy endpoints was observed in EMERGE, but not in ENGAGE.

Abstract PO1-08-09: Drynaria fortunie, a nutritional herb for prevention in triple negative breast cancer

Abstract Study Rationale: The triple negative breast cancer (TNBC) lacks the expression of hormone and growth factor receptors and responds only to anthracycline/taxol-based conventional chemotherapy. Major therapeutic limitations include systemic toxicity and acquired resistance to chemo-therapeutics. Relatively non-toxic nutritional herbs from traditional Chinese medicine (TCM) may represent testable alternatives against TNBC. These herbs effectively target multiple signaling pathways (Yang et al: J. Ethno-pharmacology 264: 113249, 2021). Growth inhibitory efficacy of nutritional herbs in a cellular model for TNBC is associated with downregulation of RB, RAS, PI3K and AKT signaling pathways (Telang et al: Pharmaceuticals 14: 1318, 2021). Drynaria fortunie (DF) is a nutritional herb that is used in many TCM herbal formulations. The present study is designed to examine the effects of DF in a cellular model for TNBC and to identify mechanistic leads for its efficacy. Experimental Model, herbal extract and biomarkers: Estrogen receptor negative, progesterone receptor negative and human epidermal growth factor receptor-2 negative MDA-MB-231 human breast cancer cell line represented a cellular model for TNBC. Non-fractionated aqueous extract from the bark of DF represented the test agent. Cell cycle progression, RB signaling and caspase 3/7 activity represented quantitative end point biomarkers. Study Outcome: Treatment with DF at cytostatic concentrations induced S phase arrest and inhibited RB signaling via downregulated expression of cyclin E, CDK2, pRB and E2F1. DF treatment also induced caspase 3/7 activity, a marker for cellular apoptosis. Collectively, these data provide potential mechanistic leads for anti-proliferative and pro-apoptotic effects of DF in the present model. Conclusion: Present data validate a mechanism-driven experimental approach to prioritize efficacious nutritional herbs as testable alternatives for prevention/therapy of TNBC. Citation Format: Nitin TELANG, Hareesh Nair, George Wong. Drynaria fortunie, a nutritional herb for prevention in triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-09.

Niraparib, Dostarlimab, and Bevacizumab as Combination Therapy in Pretreated, Advanced Platinum-Resistant Ovarian Cancer: Findings From Cohort A of the OPAL Phase II Trial.

To report the results of OPAL (ClinicalTrials.gov identifier: NCT03574779) cohort A, a single-arm substudy of niraparib plus dostarlimab and bevacizumab for the treatment of advanced, platinum-resistant ovarian cancer (PROC). Participants with PROC who received 1-2 previous lines of therapy were treated with niraparib (200 or 300 mg once daily), dostarlimab (500 mg once every 3 weeks for four 21-day cycles, followed by 1,000 mg once every 6 weeks), and bevacizumab (15 mg/kg once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1. Safety was also assessed. Exploratory biomarker end points included evaluation of changes in the tumor molecular profile and microenvironment using baseline and on-treatment tumor samples. Of 41 enrolled participants (median age, 66.0 years [range, 37-83 years]), 9.8% had tumors that were BRCA-mutated, 19.5% were homologous recombination (HR)-deficient, and 17.1% were HR repair (HRR)-mutated. As of the cutoff date, all participants discontinued treatment. The ORR was 17.1% (80% CI, 9.8 to 27.0), including one complete response (2.4%); the disease control rate was 73.2% (80% CI, 62.3 to 82.2). Two participants withdrew before first postbaseline scan because of adverse events (AEs). Grade ≥3 treatment-emergent AEs were reported in 92.7% of participants, with the most common being hypertension (26.8%). Response was not correlated with BRCA, HRR, HR deficiency (HRD), or PD-L1 status. Changes suggesting immune activation were observed in on-treatment samples after triplet therapy. Results demonstrated modest activity of niraparib, dostarlimab, and bevacizumab in participants with PROC, many of whom had prognostic factors for poor treatment response. Most participants with response were bevacizumab-naïve. No association was found with HRD, BRCA, or PD-L1 status. AEs were consistent with previous monotherapy reports, except that hypertension was reported more frequently.

Utilization of fluid-based biomarkers as endpoints in disease-modifying clinical trials for Alzheimer’s disease: a systematic review

BackgroundClinical trials in Alzheimer’s disease (AD) had high failure rates for several reasons, including the lack of biological endpoints. Fluid-based biomarkers may present a solution to measure biologically relevant endpoints. It is currently unclear to what extent fluid-based biomarkers are applied to support drug development.MethodsWe systematically reviewed 272 trials (clinicaltrials.gov) with disease-modifying therapies starting between 01–01-2017 and 01–01-2024 and identified which CSF and/or blood-based biomarker endpoints were used per purpose and trial type.ResultsWe found that 44% (N = 121) of the trials employed fluid-based biomarker endpoints among which the CSF ATN biomarkers (Aβ (42/40), p/tTau) were used most frequently. In blood, inflammatory cytokines, NFL, and pTau were most frequently employed. Blood- and CSF-based biomarkers were used approximately equally. Target engagement biomarkers were used in 26% (N = 72) of the trials, mainly in drugs targeting inflammation and amyloid. Lack of target engagement markers is most prominent in synaptic plasticity/neuroprotection, neurotransmitter receptor, vasculature, epigenetic regulators, proteostasis and, gut-brain axis targeting drugs. Positive biomarker results did not always translate to cognitive effects, most commonly the small significant reductions in CSF tau isoforms that were seen following anti-Tau treatments. On the other hand, the positive anti-amyloid trials results on cognitive function were supported by clear effect in most fluid markers.ConclusionsAs the field moves towards primary prevention, we expect an increase in the use of fluid-based biomarkers to determine disease modification. Use of blood-based biomarkers will rapidly increase, but CSF markers remain important to determine brain-specific treatment effects. With improving techniques, new biomarkers can be found to diversify the possibilities in measuring treatment effects and target engagement. It remains important to interpret biomarker results in the context of the trial and be aware of the performance of the biomarker. Diversifying biomarkers could aid in the development of surrogacy biomarkers for different drug targets.

Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger-containing (PIKfyve) inhibitor with a favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis (ALS) models. In this ALS clinical trial, the safety, tolerability, CNS penetrance and modulation of pharmacodynamic target engagement biomarkers were evaluated. This phase 2a, randomized, double-blind, placebo-controlled, biomarker-end-point clinical trial was conducted in four US centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansions were randomly assigned (2:1) to receive twice-daily oral treatment with 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent or serious adverse events attributable to the study drug and tolerability at trial completion or treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod dimesylate and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition [soluble glycoprotein nonmetastatic melanoma protein B (sGPNMB) upregulation] and disease-specific CNS target engagement [poly(GP)] were measured. Between 16 December 2021 and 7 July 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance [n = 9 (90%) apilimod dimesylate; n = 5 (100%) placebo]. At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/ml [standard deviation (SD): 0.937]. At Week 12, apilimod dimesylate increased plasma sGPNMB by >2.5-fold (P < 0.001), indicating PIKfyve inhibition, and lowered CSF poly(GP) protein levels by 73% (P < 0.001), indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker end-points in this phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to result in the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

Day-to-day variability of stress biomarkers during a music intervention in people living with dementia and their family caregivers.

Examination of the variability of stress biomarkers among people living with dementia and their family caregivers can provide evidence of stress reactions and corresponding self-regulation capacities, but no such research has been conducted to date. The aim of this study was to examine day-to-day variability patterns of salivary biomarkers in dyads of people living with dementia and their family caregivers and to investigate differences in variability patterns between music intervention and control groups. This study involved secondary analysis of data collected during a two-group, non-randomized open trial examining the effects of an 8-week music intervention on physiological stress markers. A total of 5791 salivary samples from 34 dyads were used to analyze the variability of morning and evening cortisol and of morning dehydroepiandrosterone sulfate (DHEA-S). The variability indices employed were the intra- and inter-individual standard deviation, coefficient of variation, and intra-class correlation coefficient. We found that family caregivers in the music intervention group had significantly greater coefficients of variation for all three biomarker endpoints than those in the control group. Our findings provide evidence that stress biomarkers in family caregivers with functional self-regulation capacities may be more likely to respond to music intervention. However, stress biomarkers in people living with dementia may not be responsive to music intervention, possibly due to their dysfunctional self-regulation capacities. Future stress biomarker studies involving dyads of people living with dementia and family caregivers should consider biomarker variability patterns in determining the effectiveness of behavioral interventions.

Role of Estimated Glomerular Filtration Rate in Clinical Research: The Never-Ending Matter.

Chronic kidney disease (CKD) burden is crucial both on a global scale and at individual patient level, affecting morbidity and mortality directly and through its effect on both cardiovascular damage and CKD progression to end-stage-kidney-disease (ESKD). Unfortunately, the awareness of CKD is poor, with few CKD patients conscious of the severity of their health status. The principal biomarker of kidney function is estimated glomerular filtration rate (eGFR). We searched the literature and present a review article with the aim of summarizing the role of eGFR in clinical research. In particular, we report the eGFR role as a prognostic, enrichment and endpoint biomarker and its role in the early detection of CKD. eGFR has a major role as a biomarker in clinical research. As a prognostic marker, eGFR reduction is associated with cardiovascular events, ESKD and mortality. As an enrichment biomarker, eGFR values are pivotal for selecting patients to be included in randomized and observational studies; it helps to test a pre-defined drug in early CKD or in more advanced CKD allowing also to avoid screening failures and to shorten the duration of clinical trials. Moreover, eGFR decline (expressed as a percentage of reduction from baseline or continuous slope) can be considered a good endpoint in clinic trials overcoming delays whilst waiting for hard endpoints to develop. eGFR is a strong clinical measure for both observational and intervention studies. It is also helpful in screening the general population for kidney disease and, in particular, to increase awareness of CKD.

Exploring the Utility of Biofluid‐Based Biomarkers in Early‐Onset Alzheimer’s Disease

AbstractBackgroundOne goal of the longitudinal early onset Alzheimer’s disease study (LEADS) is to define fluid biomarker characteristics of early‐onset Alzheimer’s disease (EOAD). In this mid‐study cross sectional analysis, participants have undergone clinical and cognitive assessments, magnetic resonance imaging (MRI), positron emission tomography (PET), lumbar puncture, and blood draws. There is limited data available concerning comprehensive analysis of fluid biomarkers in an EOAD population and this study represents first results from the mid‐study analysis of a large multi‐site cohort.MethodLEADS is an observational study with N = 371 subjects included in the mid‐study analysis (N = 165 with CSF and N = 324 with plasma biomarker data). CSF levels of Aβ1‐40, Aβ1‐42, tTau, pTau181, VILIP‐1, SNAP‐25, neurogranin (Ng), neurofilament light chain (NfL), and YKL‐40 were measured by immunoassay. Plasma levels of Aβ1‐40, Aβ1‐42, NfL, pTau231, and glial fibrillary acid protein (GFAP) were measured by immunoassay. Differences by diagnostic group and Spearman’s correlations with cognitive measures (MOCA, CDR‐SB, ADAS‐Cog) were evaluated for each fluid biomarker. Diagnostic accuracies were determined using area under the curve of receiver operating characteristics curve analysis which included APOE4 carrier status, age and sex in logistic regression models.ResultLevels of CSF Aβ42/40, pTau181, tTau, SNAP25, and Ng in the EOAD group were significantly different from both cognitively normal and early‐onset non‐AD dementia groups; CSF NfL, YKL‐40 and VILIP‐1 did not vary by diagnosis. The combination of APOE ε4 carrier status, age, sex and CSF Aβ42/40 and pTau181 (Figure 1A) or plasma Aβ42/40 and pTau231 (Figure 1B) separated the EOAD group from CN and EOnonAD with Area Under the ROC curves of 0.99 and 0.89 respectively. The diagnostic accuracies of plasma Aβ42/40 or pTau231 were 0.80 and 0.86 respectively. In the pooled analysis, all CSF biomarkers except SNAP25 were correlated with cognition (Figure 2A). Within the EOAD group only CSF Aβ42/40, NfL, Ng, and SNAP25 were correlated with at least one cognitive measure (Figure 2B).ConclusionThis study provides the first comprehensive analysis of fluid biomarkers in sporadic EOAD and will inform clinical trial designs that incorporate fluid biomarkers in patient selection, or as biomarker endpoints.

Mclena‐1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients with Mild Cognitive Impairment Due to Alzheimer’s Disease; Interim progress

AbstractBackgroundAccumulating evidence indicates that inflammation mediated by tumor necrosis factor alpha (TNF alpha), interleukins (e.g. IL‐1 beta, IL‐2, and IL‐6), and chemokines (e.g. IL‐8), is prominent in Alzheimer’s disease (AD) patients. These data suggest that systemic inflammation plays a crucial role in the cause and effects of AD neuropathology. Thus, we propose that modulating systemic inflammation via a pleiotropic immunomodulator is a putative therapeutic intervention if administered at a proper time window during the course of the disease.MethodThis is a Phase II, proof‐of mechanism, placebo‐controlled clinical study on amnestic mild cognitive impairment (aMCI) male and female subjects administered 10 mg/day the immunomodulator, anti‐cancer agent lenalidomide for 12 months on a 1:1 ratio (15 placebo + 15 drug‐treated subjects total) followed by a 6 months washout period. Amyloid loads is measured by FBP PET. The primary endpoints are cognition measured via a large battery cognitive tests every 3 months, and comparison of brain amyloid loads (Florbetapir PET imaging) and neurodegeneration (volumetric MRI) pre‐ and post‐drug treatment. The secondary endpoints are safety, which is evaluated through reported adverse events (AEs), clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital signs, physical and neurological examinations, and electrocardiograms. The tertiary and exploratory objectives will assess blood inflammatory markers after lenalidomide vs. placebo administration.ResultsTo date, 15 participants have signed consent, 7 screen failed, 2 withdrew consent and 6 have completed treatment after 12 months. Adverse events occurred as expected in cancer cohorts. No severe AEs have occurred so far. Importantly, assuming a 1:1 randomization in the blinded phase, several participants have received lenalidomide continuously for 12 months without interruption. Though blinded, the completers appeared to be stable.ConclusionIn the current project we aim to investigate lenalidomide as a possible AD therapy. Our study should allow determining whether or not lenalidomide is safe in subjects suffering neurological disorders, and whether it can alter the clinical course of AD. To date, AEs are as expected and the safety and tolerability are manageable. A second trial coined MCLENA 2 will start soon. It will focus on biomarker endpoints (rather than cognition) following treatment for 6 months

Trials in Progress: The Randomized, Double-Blind, Placebo-Controlled Phase 1b CROSSWALK-a and Phase 2a CROSSWALK-c Trials - Crovalimab for the Treatment and Prevention of Vaso-Occlusive Episodes in Sickle Cell Disease

Background and Significance In sickle cell disease (SCD), a single point mutation in the beta-globin gene results in hemoglobin S (HbS) production, which can polymerize upon deoxygenation. Polymerization distorts the red blood cell (RBC) membrane and generates sickled RBCs, contributing to microvascular occlusions, which may present as acute, painful vaso-occlusive episodes (VOEs). For patients (pts) with SCD, 70% of emergency department visits and 90% of hospitalizations are VOE-related. 1,2 Despite existing treatments for VOE prevention, considerable morbidity and mortality remain; acute VOE treatment is limited to supportive care due to a lack of targeted therapies. Accumulating nonclinical data suggest a multimodal role for complement dysregulation in SCD pathophysiology, including in vaso-occlusion, hemolysis, inflammation, thrombogenicity, endothelial activation, and end-organ damage. 3 Crovalimab is a novel, engineered, anti-complement C5 monoclonal antibody that allows for small-volume subcutaneous (SC) injection after an initial intravenous (IV) loading dose. 4 Here, we describe two randomized, double-blind, placebo-controlled trials evaluating crovalimab in pts with SCD: CROSSWALK-a (Phase 1b; NCT04912869) and CROSSWALK-c (Phase 2a; NCT05075824). Study Design and Methods CROSSWALK-a evaluates the safety of crovalimab in managing acute uncomplicated VOEs. CROSSWALK-c evaluates the efficacy and safety of crovalimab as adjunct therapy in preventing VOEs. Pts 12-55 years old, weighing ≥40 kg with a confirmed diagnosis of sickle cell anemia (homozygous HbSS or heterozygous HbS/β 0 thalassemia) and vaccinated against N. meningitidis, H. influenzae type B and S. pneumoniae are eligible (Fig. 1 and 2). Concurrent SCD-directed therapies are allowed. CROSSWALK-a Pts must present with an acute uncomplicated VOE requiring hospitalization and parenteral opioid analgesics, and have had ≤10 VOEs in the 12 months prior to randomization. Eligible pts will be randomized 2:1 to receive a single IV weight-based tiered dose of crovalimab or placebo, and monitored during hospitalization and in an 84-day observational period followed by a safety follow-up period for a total study duration of 322 days (10.5 months). The primary objective of CROSSWALK-a is to evaluate safety up to Day 84, including: Incidence and severity of adverse eventsIncidence and severity of infusion-related reactions and hypersensitivityChange from baseline in targeted vital signs and clinical laboratory test results Efficacy, pharmacokinetic (PK), pharmacodynamic (PD), immunogenicity, and exploratory biomarker endpoints will also be evaluated. CROSSWALK-c Pts with 2-10 VOEs in the 12 months prior to randomization are eligible. Eligible pts will be randomized 1:1 to receive weight-based tiered doses of crovalimab or placebo, consisting of initial loading doses (IV: Day 1; SC: Day 2 and weekly for Weeks 2-4) and monthly maintenance SC doses Weeks 5-49 for 48 weeks of treatment. The primary objective of CROSSWALK-c is to evaluate crovalimab efficacy vs placebo up to 48 weeks, on the basis of: The annualized rate of medical facility VOEs Key secondary efficacy objectives are: Annualized rate of home VOEsAnnualized rate of acute chest syndromeAnnualized rate of days hospitalized for medical facility VOEsPt-reported fatigue in adults Safety, PK, PD, immunogenicity, and exploratory biomarker endpoints will also be evaluated. Primary results will be published upon trial readout.

Melatonin, an adjuvant for neonatal sepsis: a systematic review and meta-analysis

Link of Video Abstract: https://youtu.be/QMfynOrGWxM Introduction: Neonatal sepsis remains a serious health problem in some countries, especially in developing countries, like Indonesia. The standard treatment for sepsis is the administration of antibiotics. Melatonin, a hormone produced by the pineal gland, has beneficial effects in fighting free radicals, antioxidants, anti-inflammatory, and anti-apoptotic effects. However, in newborns, melatonin is minimally detectable. Adjuvant therapy is required for the deterrence and neonatal sepsis therapy. This study aims to systematically review and perform a meta-analysis of melatonin as an adjunctive therapy in treating neonatal sepsis with the addition of the most recent articles. Methods: Databases of electronics used such as PubMed, Embase, and the Cochrane Central Controlled Trials Register were searched systematically in October 2022 for clinical trials reporting the efficacy of melatonin as adjunctive therapy for neonatal sepsis. We compared treatment responses between groups using serum C-reactive protein (CRP) levels as an endpoint biomarker. Data analysis was performed to appraise the quality of enrolled studies using a comprehensive meta-analysis Revman 5.4 and bias tool risk of the Cochrane Collaboration. Results: Four trials with a total of 175 subjects were listed in the systematic review and meta-analysis. Pooled analysis showed a statistically significant mean difference in serum CRP level (mg/L) between groups 24 hours after adjuvant melatonin therapy (-1.63 mg/L; 95% CI: -3.20 to -0.054; P=0.043). Conclusion: Melatonin as an adjunctive therapy significantly lowers CRP levels. Larger, sample size studies are necessary to establish clear clinical benefits of this treatment.

A randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a progressive, inflammatory liver disease with no approved pharmacological treatment. This Phase IIa, double-blind, placebo-controlled, multicentre trial (ClinicalTrials.gov: NCT03166735) investigated pharmacodynamics and safety of BI 1467335, an amine oxidase copper-containing 3 (AOC3) inhibitor, in adults with NASH from Europe and North America. Participants from 44 centres across the US, Germany, Spain, Belgium, the UK, Netherlands, Canada, France and Ireland were randomised (2:1:1:1:2; 27 July 2017 to 14 June 2019) to daily oral BI 1467335 1 mg (n = 16), 3 mg (n = 16), 6 mg (n = 17), 10 mg (n = 32) or placebo (n = 32) for 12 weeks, with follow-up to Week 16. Primary endpoint was AOC3 activity relative to baseline (%), 24 hours post-dose after 12 weeks’ treatment. Secondary biomarker endpoints included changes from baseline at Week 12 in alanine aminotransferase (ALT) and caspase-cleaved cytokeratin 18 (CK-18 caspase). Mean AOC3 activities relative to baseline at Week 12: 90.4% (placebo; n = 32), 26.5% (1 mg; n = 16), 10.4% (3 mg; n = 16), 5.0% (6 mg; n = 16), 3.3% (10 mg; n = 32). These changes indicated that BI 1467335 dose-dependently inhibited AOC3 activity; ≥3 mg doses achieved >80% inhibition ( < 20% activity) at Week 4. At Week 12 following doses of BI 1467335 ≥ 3 mg, ALT and CK-18 caspase decreased dose-dependently. All tested BI 1467335 doses were well tolerated, with no clinically relevant treatment-emergent safety signals. BI 1467335 strongly inhibited AOC3 in participants with NASH, with doses ≥3 mg dose-dependently reducing the levels of liver injury biomarkers, ALT and CK-18. This trial was registered with ClinicalTrials.gov (NCT03166735) and the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2016-000499-83).

Targeting Pharmacotherapies for Inflammatory and Cardiorenal Endpoints in Kidney Disease.

Inflammation is an important contributor to excess cardiovascular risk and progressive renal injury in people with chronic kidney disease (CKD). Dysregulation of the innate and adaptive immune system is accelerated by CKD and results in increased systemic inflammation, a heightened local vascular inflammatory response leading to accelerated atherosclerosis, and dysfunction of the cardiac and renal endothelium and microcirculation. Understanding and addressing the dysregulated immune system is a promising approach to modifying cardiorenal outcomes in people with CKD. However, targeted pharmacotherapies adopted from trials of non-CKD and cardiorheumatology populations are only beginning to be developed and tested in human clinical trials. Pharmacotherapies that inhibit the activation of the NOD-like receptor protein 3 inflammasome and the downstream cytokines interleukin-1 and interleukin-6 are the most well-studied. However, most of the available evidence for efficacy is from small clinical trials with inflammatory and cardiorenal biomarker endpoints, rather than cardiovascular event endpoints, or from small CKD subgroups in larger clinical trials. Other pharmacotherapies that have proven beneficial for cardiorenal endpoints in people with CKD have been found to have pleiotropic anti-inflammatory benefits including statins, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 agonists. Finally, emerging therapies in CKD such as interleukin-6 inhibition, small-interfering RNA against lipoproteins, aryl hydrocarbon receptor inhibitors, and therapies adopted from the renal transplant population including mammalian target of rapamycin inhibitors and T regulatory cell promoters may have benefits for cardiorenal and inflammatory endpoints but require further investigation in clinical trials.

Design and analysis considerations for early phase clinical trials in hepatitis B (HBV) cure research: the ACTG A5394 study in persons with both HIV and HBV

With growing interest and efforts to achieve a hepatitis B (HBV) cure, HBV therapeutics have increasingly entered the clinical testing phase. In designing an early phase clinical trial aimed at HBV cure, the heterogeneity in participants and the choice of a biomarker endpoint that signals a cure requires careful consideration. We describe the key elements to consider during the development of HBV clinical trials aimed at a functional cure, and how we have addressed them in the design of a phase II AIDS Clinical Trials Group (ACTG) study, A5394 (NCT05551273). The trial we present is for persons with both HIV and HBV, a unique population that has much to gain from an HBV cure. Our decisions on the design elements are specific to the study agent and the targeted population, but our deliberations may be informative in the emerging field of early phase HBV trials aimed at cure.

A rank-based approach to improve the efficiency of inferential seamless phase 2/3 clinical trials with dose optimization

To accelerate clinical development, seamless 2/3 adaptive design is an attractive strategy to combine phase 2 dose selection with phase 3 confirmatory objectives. As the regulatory requirement for dose optimization in oncology drugs shifted from maximum tolerated dose to maximum effective dose, it's important to gather more data on multiple candidate doses to inform dose selection. A phase 3 dose may be selected based on phase 2 results and carried forward in phase 3 study. Data obtained from both phases will be combined in the final analysis. In many disease settings biomarker endpoints are utilized for dose selection as they are correlated with the clinical efficacy endpoints. As discussed in Li et al. (2015), the combined analysis may cause type I error inflation due to the correlation and dose selection. Sidák adjustment has been proposed to control the overall type I error by adjusting p-values in phase 2 when performing the combined p-value test. However, this adjustment could be overly conservative as it does not consider the underlying correlations among doses/endpoints. We propose an alternative approach utilizing biomarker rank-based ordered test statistics which takes the rank order of the selected dose and the correlation into consideration. If the correlation is unknown, we propose a rank-based Dunnett adjustment, which includes the traditional Dunnett adjustment as a special case. We show that the proposed method controls the overall type I error, and leads to a uniformly higher power than Sidák adjustment and the traditional Dunnett adjustment under all potential correlation scenarios discussed.

Longitudinal lumbar puncture adherence in the Alzheimer’s Prevention Initiative Autosomal‐Dominant Alzheimer’s Disease Colombia Trial

AbstractBackgroundCerebrospinal fluid (CSF) biomarkers have potentially important roles in Alzheimer’s disease (AD) treatment and prevention trials. The Alzheimer’s Prevention Initiative Autosomal‐Dominant AD (API ADAD) trial protocol (NCT01998841) includes optional CSF biomarker measurements at baseline, 24 months, and 60 months. We determined the adherence to lumbar puncture (LP) procedures and predictors of dropout rates in trial participants who had a baseline LP.MethodAvailable data from cognitively unimpaired 30–60‐year‐old members of the Presenilin 1 E280A kindred were used to characterize LP participation rates at baseline, LP‐related complications and potential factors associated with adherence to 24‐month follow‐up LPs (age, sex, education, place of residence, puncture site, needle gauge, number of attempts, and traumatic puncture). Logistic regression was used to investigate associations.Result130 (51.6%) of 252 trial individuals consented to participate in the CSF biomarkers substudy. Consent was not associated with age, sex, education or location of residence. 43 (33.1%) participants had 49 LP‐related complications at baseline. The most frequent complications were headache in 25 (19.2%) participants and low back pain in 14 (10,8%) participants. Other baseline LP‐related events were dizziness, photopsia, and tremor. Complications at baseline were not associated with puncture site (L3‐L4 or L4‐L5), needle gauge (22 or 24 G), number of attempts or traumatic puncture. Ninety‐eight (75.4%) of the eligible participants consented to have the 24‐month follow‐up LP. Absence of any baseline LP‐related complications was associated with less attrition in this subsequent LP consent (0R = 0.25; 95%CI 0.10‐0.61), after controlling for age, sex, years of schooling, rural home and city of residence.ConclusionAdherence to 24‐month follow‐up LP in API ADAD trial was 75.4%. This clinical trial is conducted in young people, active at work. Although some participants live far from the city where LP’s are performed or in remote areas, this did not affect their willingness to consent to a second LP. However, the presence of any complication did increase the risk of withdrawal for the subsequent procedure since it impacted ability to work. This information could help to inform the design and statistical power of future AD prevention trials using CSF biomarker endpoints.

Association of Minimal Residual Disease Negativity Rates With Progression Free Survival in Frontline Therapy Trials for Newly Diagnosed Multiple Myeloma: A Meta-analysis.

Current frontline therapies for newly diagnosed multiple myeloma patients have significantly prolonged progression-free survival (PFS). This has led to interest in minimal residual disease negativity (MRDng) as an efficacy-response biomarker and possible surrogate endpoint. A meta-analysis was conducted to explore the surrogacy of MRD for PFS and quantify the relationship between MRDng rates and PFS at the trial level. A systematic search was conducted on phase II and III trials reporting MRDng rates along with median PFS (mPFS) or PFS hazard ratios (HR). Weighted linear regressions were conducted relating mPFS to MRDng rates, and relating PFS HRs to either odds ratios (OR) or rate differences (RD) for MRDng in comparative trials. A total of 14 trials were available for the mPFS analysis. log(MRDng rate) was moderately associated with log (mPFS), with a slope of β=0.37 (95% CI, 0.26 to 0.48) and R2=0.62. A total of 13 trials were available for the PFS HR analysis. Treatment effects on MRDng rates were correlated with the corresponding effects on PFS: log (PFS HR) and log (MRDng OR) had a moderate association with β=-0.36 (95% CI, -0.56 to -0.17) and R2=0.53 (95% CI, 0.21 to 0.77); log (PFS HR) and the MRDng RD had a stronger association with slope β=-0.03 (95% CI, -0.04 to -0.02) and R2=0.67 (95% CI, 0.31 to 0.86). MRDng rates moderately associate with PFS outcomes. MRDng RDs are more strongly associated with HRs than MRDng ORs, with evidence suggestive of potential surrogacy.

A Prospective Natural History Study of Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (S49.008)

A Prospective Natural History Study of Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) (S49.008)