Therapeutic Trials Research Articles

Pivotal trial characteristics and types of endpoints used to support Food and Drug Administration rare disease drug approvals between 2013 and 2022.

Rare disease drug development faces unique challenges, such as genotypic and phenotypic heterogeneity within small patient populations and a lack of established outcome measures for conditions without previously successful drug development programs. These challenges complicate the process of selecting the appropriate trial endpoints and conducting clinical trials in rare diseases. In this descriptive study, we examined novel drug approvals for non-oncologic rare diseases by the U.S. Food and Drug Administration's Center for Drug Evaluation and Research over the past decade and characterized key regulatory and trial design elements with a focus on the primary efficacy endpoint utilized as the basis of approval. Using the Food and Drug Administration's Data Analysis Search Host database, we identified novel new drug applications and biologics license applications with orphan drug designation that were approved between 2013 and 2022 for non-oncologic indications. From Food and Drug Administration review documents and other external databases, we examined characteristics of pivotal trials for the included drugs, such as therapeutic area, trial design, and type of primary efficacy endpoints. Differences in trial design elements associated with primary efficacy endpoint type were assessed such as randomization and blinding. Then, we summarized the primary efficacy endpoint types utilized in pivotal trials by therapeutic area, approval pathway, and whether the disease etiology is well defined. One hundred and seven drugs that met our inclusion criteria were approved between 2013 and 2022. Assessment of the 107 drug development programs identified 150 pivotal trials that were subsequently analyzed. The pivotal trials were mostly randomized (80%) and blinded (69.3%). Biomarkers (41.1%) and clinical outcomes (42.1%) were commonly utilized as primary efficacy endpoints. Analysis of the use of clinical trial design elements across trials that utilized biomarkers, clinical outcomes, or composite endpoints did not reveal statistically significant differences. The choice of primary efficacy endpoint varied by the drug's therapeutic area, approval pathway, and whether the indicated disease etiology was well defined. For example, biomarkers were commonly selected as primary efficacy endpoints in hematology drug approvals (70.6%), whereas clinical outcomes were commonly selected in neurology drug approvals (69.6%). Further, if the disease etiology was well defined, biomarkers were more commonly used as primary efficacy endpoints in pivotal trials (44.7%) than if the disease etiology was not well defined (27.3%). In the past 10 years, numerous novel drugs have been approved to treat non-oncologic rare diseases in various therapeutic areas. To demonstrate their efficacy for regulatory approval, biomarkers and clinical outcomes were commonly utilized as primary efficacy endpoints. Biomarkers were not only frequently used as surrogate efficacy endpoints in accelerated approvals, but also in traditionally approved rare disease drugs. The choice of primary efficacy endpoints varied by therapeutic area, approval pathway, and understanding of disease etiology.

Biomarkers of disease progression in progressive supranuclear palsy for use in clinical trials

Abstract Progressive supranuclear palsy is a rare neurodegenerative disease with no current disease-modifying treatments approved. Longitudinal research and clinical trials for progressive supranuclear palsy are ongoing and require reliable measures which are sensitive to disease progression. Despite susceptibility to subjective limitations clinical and cognitive assessments are the most used instruments in therapeutic trials in progressive supranuclear palsy. The objective of this review is to identify measures which have been studied longitudinally as measures of progression and which are suitable for use as clinical trial endpoints. We reviewed the measures currently used as trial endpoints, identifying the clinical, cognitive, fluid and imaging measures which have previously been studied longitudinally, and discussing current diagnostic and emerging measures which are yet to be studied longitudinally but which may be sensitive to disease progression. We found that many fluid and imaging measures require further research to validate their use as longitudinal measures of change, including emerging measures which have not yet been studied specifically in progressive supranuclear palsy. We also summarise the sample size estimates required to detect changes in a 2-arm, 52-week therapeutic trial and found that specific MRI volumes require the smallest sample sizes to detect change.

Balance recovery and its link to vestibular agnosia in traumatic brain injury: a longitudinal behavioural and neuro-imaging study

BackgroundVestibular dysfunction causing imbalance affects c. 80% of acute hospitalized traumatic brain injury (TBI) cases. Poor balance recovery is linked to worse return-to-work rates and reduced longevity. We previously showed that white matter network disruption, particularly of right inferior longitudinal fasciculus, mediates the overlap between imbalance and impaired vestibular perception of self-motion (i.e., vestibular agnosia) in acute hospitalized TBI. However, there are no prior reports tracking the acute-longitudinal trajectory of objectively measured vestibular function for hospitalized TBI patients. We hypothesized that recovery of vestibular agnosia and imbalance is linked and mediated by overlapping brain networks.MethodsWe screened 918 acute major trauma in-patients, assessed 146, recruited 39 acutely, and retested 34 at 6 months. Inclusion criteria were 18–65-year-old adults hospitalized for TBI with laboratory-confirmed preserved peripheral vestibular function. Benign paroxysmal positional vertigo and migraine were treated prior to testing. Vestibular agnosia was quantified by participants’ ability to perceive whole-body yaw plane rotations via an automated rotating-chair algorithm. Subjective symptoms of imbalance (via questionnaires) and objective imbalance (via posturography) were also assessed.ResultsAcute vestibular agnosia predicted poor balance recovery at 6 months. Recovery of vestibular agnosia and linked imbalance was mediated by bihemispheric fronto-posterior cortical circuits. Recovery of subjective symptoms of imbalance and objective imbalance were not correlated.ConclusionVestibular agnosia mediates balance recovery post-TBI. The link between subjective dizziness and brain injury recovery, although important, is unclear. Therapeutic trials of vestibular recovery post-TBI should target enhancing bi-hemispheric connectivity and linked objective clinical measures (e.g., posturography).

Development of the Lee Symptom Scale-Skin Sclerosis for chronic GVHD-associated sclerosis.

Sclerosis is a highly morbid manifestation of chronic GVHD (cGVHD), associated with distressing symptoms and significant long-term disability. A patient-reported outcome measure (PRO) for cGVHD-associated sclerosis is essential to advance therapeutic trials. We aimed to develop a PRO for adults with cGVHD-associated sclerosis and evaluate and refine its content validity. Adults age ≥18 years with cGVHD-associated sclerosis participated in semi-structured interviews to identify salient symptoms and functions. Sclerosis-relevant symptoms and functions from existing PROs were also used to prompt discussion of topics not spontaneously mentioned. Symptoms and functions (subcodes) of importance were clustered and mapped to overarching domains (codes) using inductive analysis, and candidate items were developed. Cognitive interviews were employed to evaluate content validity of the items, response options, recall period, and respondent instructions.Thirty-five open-ended interviews, conducted to saturation, revealed the breadth of the patient experience with cGVHD-associated sclerosis including 5 overarching domains: (1) skin changes, (2) symptoms, (3) emotional and social functioning, (4) mobility restrictions, and (4) activity limitations. A pool of 54 items was tested and iteratively refined through cognitive debriefing interviews (n=25). Phrasing changes were made to improve relevance and comprehension. One item was removed and two items were added to address respondent feedback, resulting in 55 items. Results support the relevance, comprehensibility, and comprehensiveness of the provisional Lee Symptom Scale-Skin Sclerosis. Concept elicitation and cognitive interviewing have informed the development of the Lee Symptom Scale-Skin Sclerosis. Psychometric testing and determination of minimal clinically important difference are underway in an external cohort to validate the PRO.

Vitamin C for the common cold and pneumonia.

This article provides an overview of vitamin C for preventing and treating respiratory infections. Studies in a wide variety of animals have shown vitamin C to be protective against infections. In controlled trials in the general human population, >1 g/day vitamin C did not prevent common colds. However, in 5 trials with participants undertaking heavy physical activity, vitamin C halved the incidence of colds. In 15 trials (N = 6244), regular supplementation of ≥1 g/day of vitamin C decreased the severity of colds by 15%. Results of therapeutic trials, in which vitamin C was initiated after common cold symptoms began, have been inconsistent. However, two therapeutic trials found that 6-8 g/day of vitamin C was twice as effective at reducing the duration of colds than 3-4 g/day. In three controlled trials, vitamin C prevented pneumonia, but the contexts were atypical: participants were schoolboys in a boarding school in the UK before WW-II, soldiers hospitalized for influenza A, and US marine recruits. It is unlikely that vitamin C would reduce the risk of pneumonia in the general population, however, four trials reported a treatment benefit for pneumonia patients, although the findings encourage further research rather than providing firm evidence of efficacy. Vitamin C has been tested for COVID-19 and sepsis with conflicting results. Given the evidence that vitamin C reduces the severity and duration of the common cold, and the safety and low cost, it is not unreasonable for individuals to test whether 6-8 g/day is beneficial at the individual level.

A smart tool for non expert clinicians for the dissemination of the MDS criteria for progressive supranuclear palsy.

Due to the variety of clinical phenotypes and the massive clinical overlap with other neurodegenerative diseases, the diagnosis of Progressive Supranuclear Palsy (PSP) remains a major challenge. Notwithstanding, early and reliable clinical diagnosis of PSP is highly warranted for estimation of prognosis, appropriate allocation to therapeutic trials and development of new diagnostic tools. As reliable biomarkers are lacking, PSP diagnosis relies on the application of the clinical criteria promoted by the International Parkinson and Movement Disorder Society (MDS). Despite providing a framework including all the main PSP cornerstones (ocular dysfunction and postural instability, akinesia and cognitive dysfunction), the application of the MDS PSP criteria is complex and not straightforward to apply in a clinical setting. Herein we propose a practical tool, including a video-guided slide-set and a smartsheet, to disseminate the MDS PSP clinical criteria among healthy practitioners and increase confidence in non expert clinicians towards suspicion and diagnosis of PSP. The video-guided slide set may serve as a teaching resource for both general neurologists and practitioners, while the smartsheet may represent a valid support in attributing the degree of diagnostic certainty and phenotype based on the identified clinical features. Application of our tool may improve early recognition of patients in primary and secondary care and determine a prompt referral to third level movement disorder centers for consideration in clinical trials testing disease-modifying treatments.

Real-life experience with disease-modifying drugs in hereditary transthyretin amyloid polyneuropathy: A clinical and electrophysiological appraisal.

New treatments have dramatically improved the prognosis for Hereditary Transthyretin Amyloid Polyneuropathy (ATTRv-PN). However, there is a lack of routine follow-up studies outside of therapeutic trials. Our aim was to report the long-term clinical and electrophysiological evolution of a cohort of ATTRv-PN patients and to determine which biomarkers are most sensitive to change. We retrospectively collected neuropathy impairment scale (NIS), polyneuropathy disability scale (PND), overall neuropathy limitation scale (ONLS), rash built overall disability scale (RODS), electrodiagnostic data, motor unit number index (MUNIX), troponin and N-terminal pro-brain natriuretic peptide levels. Electrophysiological worsening was defined as a 20% decrease in previous values. Thirty-five patients, with a median age of 58 (interquartile ranges 42-71) years, were followed for a median of 36 (24-48) months. All patients received a transthyretin stabiliser, gene silencer or liver transplant. Overall assessment of the cohort showed clinical, biological and electrophysiological stability. However, on an individual basis, NIS worsened in 45% of patients (14/31), ONLS in 46% (13/28), PND in 28% (9/32) and RODS in 39% (11/28) at the last follow-up. Motor amplitude sum score decreased in 33% (11/33), amplitude recorded on tibialis anterior muscle in 44% (12/27), sensory amplitude sum score in 39% (11/28) and MUNIX sum score in 27% (7/26). Overall effectiveness of ATTRv-PN treatments in routine care is good. However, individual assessments show up to 40% deterioration over time. Electrophysiological measures are valuable monitoring tools but are not more sensitive to change than clinical scores. Results must be confirmed in larger cohorts.

In vivo mapping of sodium homeostasis disturbances in individual ALS patients: A brain 23Na MRI study.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by significant heterogeneity among patients. 23Na MRI maps abnormal sodium homeostasis that reflects metabolic alterations and energetic failure contributing to the neurodegenerative process. In this study, we investigated disease severity at the individual level in ALS patients using brain 23Na MRI. 1H and 23Na brain MRI were collected prospectively from 28 ALS patients. Individual map of abnormal total sodium concentration (TSC) was computed using voxel-based statistical mapping for each patient compared to a local database of 62 healthy controls. Clinical data included the revised ALS functional rating scale (ALSFRS-R), ALSFRS-R slope, ALSFRS-R at 6-month and survival time. Individual maps quantifying voxels with TSC increase evidenced a high heterogeneity between patients consistent with clinical presentation. The main areas involved were the corticospinal tracts. Half of patients showed abnormal TSC increase within more than 1% of whole brain voxels. Patients with TSC increase had worse clinical severity: higher ALSFRS-R slope (p = 0.02), lower ALSFRS-R at 6-month (p = 0.04), and shorter survival (p = 0.04). ALS patients with limited TSC increase had slower progression of disability or predominant lower motor neuron phenotype or shorter disease duration. This study mapping sodium homeostasis disturbances at the individual level in ALS patients through 23Na MRI evidenced heterogeneity of TSC increase among patients associated with clinical presentation and disease severity. These findings suggest that TSC increase detected at the individual level by 23Na MRI may be a useful marker of the clinical heterogeneity of ALS patients, a factor that is likely to greatly influence the results of therapeutic trials.

Efficacy of anticoccidial drugs and their impacts on growth performance on caecal coccidiosis in broiler chicken

Coccidiosis is a fatal disease of poultry. In order to combat caecal coccidiosis of broiler, this study was designed to evaluate the comparative efficacy of sulfaclozine, toltrazuril and amprolium. 50 pcs of day old broiler chick were randomized and divided into five groups. The chicks of group T0 kept as non-infected, non-medicated control. The group Ti were kept as infected non treated and other three groups such as T1, T2, T3 were treated with sulfaclozine, toltrazuril and amprolium at a dose rate of 10 mg/kg body weight orally, respectively on day 21 and 24 of age. In chicks of group T1, sulfaclozine was given at rate of 10mg/kg body weight orally. Similarly chicks of group T2 were treated with toltrazuril 10 mg/kg and group T3 were treated with amprolium at the rate of 10 mg/kg body weight orally, respectively. After treatment, the efficacy, body weight, morbidity and mortality were studied. From the present research treatment there were sharp decline of OPG counts in all groups. But the decline was very significant (P<0.05) in Group T3 which was 1.37±0.002 thousand. This study also suggested that the mean initial weight of chicks for all groups were almost similar, which was 37 g and above as recorded on day 1. The pre-infection body weight values at day 10 recorded for all groups were almost similar which was more than 217 g. Significant (P<0.01) increase of body weight was recorded on day 21 following which the highest increase (780.21±1.29 g) was seen in Group T0 chicken (healthy control). After treatment (on day 24), there were significant increase in body weight of all groups used for therapeutic trial with the maximum mean weight gain in Group T3 (790.83±2.10g) which was the nearest value to Group T0 (healthy control). The clinical signs of caecal coccidiosis appeared on day 15 and became severe on day 21. A total of 6 chicks died during the experimental period from Group Ti (untreated affected group) and found 60% mortality. Only 3 birds died in Group T1 treated with sulfaclozine and 2 birds died in group T2 treated with toltrazuril and 2 birds died in group T3 group treated with amprolium.

Cognitive decline profiles associated with lewy pathology in the context of Alzheimer’s disease neuropathologic change

BackgroundAlzheimer’s disease neuropathologic change (ADNC) and Lewy pathology (LP) often coexist in cognitively impaired individuals. These pathologies’ relative distribution and severity may modify these individuals’ clinical presentation, cognitive profile, and prognosis. Therefore, we examined the contributions of LP and concomitant ADNC to disease survival and profiles of cognitive decline in preclinical and clinical stages in a large neuropathologically diagnosed group.MethodsWe evaluated 597 participants with LP and 491 participants with intermediate/high ADNC in the absence of LP from the National Alzheimer Coordinating Center (NACC) database. At baseline, 237 participants were cognitively normal (CN), 255 were diagnosed with mild cognitive impairment (MCI), and 596 with dementia. Cognition was assessed using three cognitive domain scores (i.e., Memory, Executive, and Language) from the NACC Uniform Dataset (UDS) neuropsychological test battery, MMSE, and Clinical Dementia Rating (CDR). Multivariate adaptive regression splines were used to evaluate associations between baseline cognitive scores and mean annual rate of change over two years. The likelihood of progression to MCI or dementia was assessed using Cox hazard models.ResultsNeocortical LP, independent of the clinical diagnosis, was associated with lower Executive and higher Language and Memory scores at baseline, whereas Braak V-VI neurofibrillary tangle pathology was associated with lower Memory and Language scores. Similarly, neocortical LP was associated with faster Executive decline, whereas Braak V-VI neurofibrillary tangle pathology was associated with faster Memory and Language decline. A clinical diagnosis of Lewy Body Dementia (i.e., a strong LP phenotype) was associated with the LP cognitive profile and shorter disease duration. Progression to incident MCI or dementia was primarily associated with the degree of tau pathology; neocortical LP or a diagnosis of Lewy Body Dementia only predicted progression when those with intermediate/high ADNC were excluded.ConclusionsLP and ADNC differentially affected cross-sectional and longitudinal cognitive profiles in a large autopsy sample. Concomitant Braak V-VI neurofibrillary tangle pathology had a strong impact on clinical progression in those with LP, regardless of the initial stage. Thus, LB and ADNC co-pathology interact to affect cognitive domains that may be used to track Lewy Body disease longitudinally and as outcome measures in therapeutic trials.

Neuronal ceroid lipofuscinoses type 7 (CLN7): a case series reporting cross sectional and retrospective clinical data to evaluate validity of standardized tools to assess disease progression, quality of life, and adaptive skills

BackgroundThis study evaluated the clinical characteristics of neuronal ceroid lipofuscinosis type 7 or CLN7 disease spectrum to characterize the clinical, electrophysiologic and neuroimaging phenotypes.MethodsWe performed a single-center cross sectional data collection along with retrospective medical chart review in patients with a genetic diagnosis of CLN7. This study received ethical approval by the University of Texas Southwestern Medical Center Institutional Review Board. A total of 8 patients were included between the ages of 4 to 6 years. All patients had a genetic diagnosis of CLN7 with homozygous or compound heterozygous mutations in the MFSD8 gene. The information collected includes patient demographics, developmental history, neurological events including seizures and neurodevelopmental regression along with further evaluation of brain magnetic resonance imaging and electrophysiological findings. The clinical phenotype is described through cross sectional and retrospective data collection and standardized tools assessing quality of life and functional skills.ResultsOur findings in this cohort of CLN7 patients indicated that development is initially normal with onset of clinical symptoms as early as two years of age. Language problems were noted prior to or at the onset of seizures in all cases. Gait problems were noted prior to seizure onset in 3 of 8 patients, and at or within 6 months after the onset of seizures in 5 of 8 patients. All patients followed a progressive course of language, motor, and neurocognitive deterioration. Congruent with the medical history, our patients had significantly low scores on adaptive abilities. Natural history data such as this can be used to support future clinical trial designs.ConclusionsThis study provides a comprehensive description of CLN7 disease, highlighting clinical data alongside standardized neuropsychological assessments, neuroimaging, and electrophysiologic data. It emphasizes the value of importance of standardized tools for understanding disease phenotype and their potential use as endpoints in future clinical trials. The findings established can provide a baseline for developing future prospective natural history studies and potential therapeutic clinical trials.

An Assessment of Sex and Gender Considerations in Migraine Calcitonin Gene-Related Peptide Clinical Trials.

Published guidelines for conducting clinical trials for migraine therapeutics recommend recruiting participants based on disease epidemiology and including sex/gender-based subpopulation analyses. These recommendations aim to improve the quality and generalizability of migraine clinical trials. The aim of this study was to summarize participant demographics in migraine clinical trials for FDA-approved calcitonin gene-related peptide (CGRP)-targeting drugs (receptor antagonists [gepants], CGRP peptide or receptor monoclonal antibodies [mAbs]) and assess the use of sex/gender-based subpopulation analyses in these studies. We conducted a review of industry-sponsored migraine clinical trials for FDA-approved CGRP-targeting medications. Demographic data (sex and/or gender) from phase II or III trials were abstracted, and the use of sex/gender-based analyses was recorded. Fourteen trials of gepants were included in this analysis. Participants who were identified as females or women were more likely to participate in these trials (87.0 ± 2.2%). Twenty-four trials of CGRP mAbs were reviewed. These studies also reported that participants were predominantly identified as female or women (84.9 ± 2.3%). None of the clinical trials reviewed reported sex/gender-based analyses of their results. This study suggests that men are underrepresented in migraine CGRP clinical trials. Greater attention to sex and gender is needed in migraine clinical trial design so that they better align with current recommendations made by headache societies and regulatory agencies.

Contribution of long-lived plasma cells to antibody-mediated allograft rejection.

Persistent alloantigens derived from allograft tissues can be recognized by the host's alloreactive immune system. This process enables cognate B cells to differentiate into plasma cells, which secrete donor-specific antibodies that are key drivers of antibody-mediated allograft rejection. A subset of these plasma cells can survive for extended periods in a suitable survival niche and mature into long-lived plasma cells (LLPCs), which are a cellular component of humoral memory. The current understanding of LLPCs is limited due to their scarcity, heterogeneity, and absence of unique markers. However, accumulating evidence indicates that LLPCs, unlike conventional short-lived plasma cells, can respond to extrinsic signals from their survival niches and can resist cell death associated with intracellular stress through cell-intrinsic mechanisms. Notably, they are refractory to traditional immunosuppressants and B cell depletion therapies. This resistance, coupled with their longevity, may explain why current treatments targeting antibody-mediated rejection are often ineffective. This review offers insights into the biology of LLPCs and discusses ongoing therapeutic trials that target LLPCs in the context of antibody-mediated allograft rejection.

Cerebrospinal Fluid and Serum Neuron-Specific Enolase in Niemann-Pick Disease Type C1.

Niemann-Pick disease, type C1 (NPC1) is an ultra rare, autosomal recessive disorder characterized by impaired intracellular cholesterol trafficking. This study assessed neuron-specific enolase (NSE) as a biomarker for disease status and treatment response in individuals with NPC1. We also evaluated the concordance between serum and cerebrospinal fluid (CSF) NSE measurements. A total of 34 individuals with NPC1 were included in this analysis. Overall, 10 participants were used to compare concurrent samples of CSF and serum NSE. NSE levels were correlated with indexes of disease severity (Annual Severity Increment Score [ASIS] and age of neurological onset) and disease burden (NPC Neurological Severity Score [NSS]). NSE was elevated in CSF, but paired CSF/serum samples were not correlated (rs = -0.16, p = 0.64). Additionally, no significant correlations were observed between serum NSE levels and clinical measures of either disease burden or severity. CSF NSE values showed a significant positive association with the ASIS (rs = 0.37, p = 0.0291) but no association with age of neurological onset or NPC NSSs. Longitudinal analysis of nine participants showed a significant (p = 0.0317) decrease in CSF NSE levels after initiation of intrathecal 2-hydroxypropyl-β-cyclodextrin (IT HPβCD) therapy. This study suggests that CSF NSE may have some utility as a biomarker in NPC1 therapeutic trials.

A Global Perspective of GBA1-Related Parkinson's Disease: A Narrative Review.

Parkinson's disease (PD) is considered to be the second most prominent neurodegenerative disease and has a global prevalence. Glucocerebrosidase (GBA1) gene mutations represent a significant hereditary risk factor for the development of PD and have a profound impact on the motor and cognitive progression of the disease. The aim of this review is to summarize the literature data on the prevalence, type, and peculiarities of GBA1 mutations in populations of different ethnic backgrounds. We reviewed articles spanning the 2000-2024 period. GBA1-related PD has a worldwide distribution. It has long been recognized that pathogenic GBA1 mutations are particularly common in certain ethnic populations, including PD patients of Ashkenazi Jewish ancestry. Moreover, a considerable number of studies focused on European ancestry patients from Europe and North America have revealed a high proportion (up to 15%) of carriers among the PD population. GBA1 mutations also appear to play an important role in patient groups with an East Asian background, although the frequency of specific variants may differ as compared to those of European ancestry. Notably, the assessment of underrepresented populations in other parts of Asia (including India) and Latin America is in the spotlight of current research, while a variant with a newly described pathogenic mechanism has been reported in Sub-Saharan Africans. Given the importance of GBA1 mutations for PD genetics and clinical phenotype, a focused assessment of the prevalence and type of GBA1 variants in distinct ethnic populations will possibly inform ongoing PD-related clinical studies and facilitate upcoming therapeutic trials.

Peripartum cardiomyopathy in the twenty-first century: a review of the pathophysiology and clinical trials for novel disease-specific therapeutics.

Peripartum cardiomyopathy is an idiopathic and nonischemic systolic dysfunction with onset toward the end of pregnancy and up to 5months postpartum. Its clinical phenotype overlaps with pregnancy-associated cardiomyopathy rendering both a continuum of the same disease. Incidence varies geographically and is highest in areas where risk factors are prevalent. The understanding of its pathophysiology is constantly evolving, but a proposed two-hit model of dysfunctional vasculogenesis and genetic predisposition exacerbated by the hemodynamic stressors of pregnancy is widely accepted. The catalysis of the cleavage of prolactin into an anti-angiogenic fragment provoked by unbalanced oxidative stress forms the bedrock of its pathogenesis. Furthermore, miRNA signaling, placenta-produced factors, and a potential underlying genetic susceptibility convene to disrupt cardiac and endothelial metabolic homeostasis. The role of anti-adrenergic and anti-sarcomeric antibodies, nutritional deficiency, and mutated viral cardiotropes are understudied. There are limited randomized controlled trials for disease-specific drugs; however, most trials are targeted at the D2 receptor agonist bromocriptine. Positive primary endpoints in a large German clinical trial led to its approved use in Europe, but the U.S.A. still renders it experimental with ongoing trials evaluating its long-term efficacy and safety. Despite its popularity since the 1900s, multiple gaps in evidence regarding long-term management after myocardial recovery, management of subsequent pregnancies, optimal anticoagulation strategy, and alternative pathophysiological pathways remain unknown.

Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies.

As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrixduring fibrosis impairs the structure andfunction of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only forfibrosis but also for the development of antifibrotic therapies.

The Global Kidney Patient Trials Network and the CAPTIVATE Platform Clinical Trial Design

Chronic kidney disease (CKD) is a global health priority affecting almost 1 billion people. New therapeutic options and clinical trial innovations such as adaptive platform trials provide an opportunity to efficiently test combination therapies. To describe the design and baseline results of the Global Kidney Patient Trials Network (GKPTN) and the design and structure of the global adaptive platform clinical trial Chronic Kidney Disease Adaptive Platform Trial Investigating Various Agents for Therapeutic Effect (CAPTIVATE) to find new therapeutic options and treatments for people with kidney disease. The GKPTN is a multicenter registry that started in May 2020 and is ongoing, while CAPTIVATE is a multicenter, multifactorial, phase 3, placebo-controlled adaptive platform randomized clinical trial that includes patients with CKD. The first participant was randomized in September 2024. The GKPTN recruits patients from kidney and endocrinology practices, and CAPTIVATE aims to recruit patients from GKPTN sites where possible. Both the GKPTN and CAPTIVATE recruit patients with nondialysis CKD. CAPTIVATE will test several investigational agents or combinations of agents, beginning with a mineralocorticoid receptor antagonist. The GKPTN monitors clinical characteristics, treatment, and outcomes to identify eligible clinical trial participants and provide a contemporary global picture of patients with CKD. The primary outcome of CAPTIVATE is to identify investigational agents or combinations of agents to reduce the rate of chronic estimated glomerular filtration rate (eGFR) decline. The default maximum sample size per treatment arm in each domain, based on bayesian simulations, is 500 participants, providing approximately 90% power to detect a clinically meaningful improvement of 2.6 mL/min/1.73 m2 in eGFR at the end of the 104-week study period. The GKPTN has enrolled 4334 patients across 119 sites in 8 countries (US, Australia, Argentina, China, Italy, Canada, Spain, and Japan). The mean (SD) participant age at enrollment was 64.5 (16.2) years, 2542 participants (58.7%) were female, and diabetic kidney disease was most frequently reported among patients for CKD etiology (1875 [43.3%]). Among the participants, the mean (SD) eGFR was 52.9 (29.3) mL/min/1.73 m2, and the median urinary albumin-to-creatinine ratio was 89 mg/g (coefficient of variation, 20-420 mg/g). In the GKPTN cohort, the mean eGFR decline was steeper among participants with a baseline eGFR of 60 mL/min/1.73 m2 or more (-2.29 [95% CI, -3.14 to -1.44]) compared with those with an eGFR of less than 60 mL/min/1.73 m2 (-1.16 [95% CI, -1.77 to -1.44]) and was progressively steeper in more severe albuminuria subgroups. The GKPTN registry and the CAPTIVATE trial have the potential to expand and optimize therapeutic options for people with CKD using an adaptive platform clinical trial design. ClinicalTrials.gov Identifiers: NCT04389827 and NCT06058585.

Heterogeneity in Pancreatitis: Recognizing Heterogeneity and Its Role in the Management of Pancreatitis. Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

Both the clinical management and study of recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP) is complicated by significant heterogeneity in the etiology, mechanisms, symptoms, and complications of pancreatitis. The National Institutes of Diabetes and Digestive and Kidney Disease (NIDDK) recently convened a workshop to address current knowledge and knowledge gaps in the field. Preclinical models that better replicate human disease are important for development of new therapies. Pain is often the most common and most difficult symptom to treat, as the causes are multifactorial and effective treatment may vary depending on whether pain is neuropathic or nociceptive in origin, and the placebo effect can complicate evaluation of the efficacy of medical and procedural interventions. Novel technologies like functional MRI and virtual reality may offer novel means for assessing and treating pain, respectively. Clinical trial designs will need to consider best approaches to addressing the heterogeneity of CP, including careful attention to designing eligibility criteria, and establishing accepted and validated core outcomes criteria for the field. The latter may be informed by consensus in pain research. Recruitment of participants into clinical trials has been challenging, often requiring multiple centers. Establishment of a clinical trials network would facilitate greater opportunities for therapeutic trials in pancreatitis.

Therapeutic Clinical Trial Eligibility and Enrollment among Women with Breast Cancer: Implications for Understanding Trial Disparities.

Therapeutic clinical trials frequently lack diverse representation, hindering generalizability and exacerbating preexisting disparities in clinical outcomes. This study explored associations between breast cancer patient demographics, clinical trial eligibility, and enrollment in a National Cancer Institute (NCI)-designated cancer center. This prospective cohort study included patients with breast cancer screened for therapeutic clinical trials from July 2020 to January 2024. Eligibility was determined by the provider and study coordinator. Patient characteristics were abstracted from the electronic medical record. Rurality and neighborhood disadvantage were mapped by address using rural-urban commuting area codes and area deprivation index (ADI), respectively. Likelihood of eligibility and enrollment by race, rurality, and neighborhood disadvantage were evaluated using risk ratios (RR) and 95% confidence intervals (CIs) from modified Poisson regression models. Of 343 patients screened for therapeutic trials, the mean age was 56 years (SD 13), 33% were Black/other race, 22% lived in highly disadvantaged areas, and 16% in rural areas. Most patients were screened for one trial (87%). Overall, 54% of patients were eligible for trials, and of those, 58% enrolled. Similar likelihoods of eligibility and enrollment were seen by race and rurality. Though not significant, patients living in highly disadvantaged areas trended toward higher likelihood of enrollment (RR 1.24, 95% CI 0.99-1.55). Over half of trial-eligible patients, even across race, rurality, or neighborhood disadvantage, enrolled, surpassing the national average. In contrast to national trends, there was higher enrollment among patients of higher ADI.