Completed Clinical Studies Research Articles

Progresses and Pitfalls of Epigenetics in Solid Tumors Clinical Trials.

Epigenetic dysregulation has long been recognized as a significant contributor to tumorigenesis and tumor maintenance, impacting all recognized cancer hallmarks. Although some epigenetic drugs have received regulatory approval for certain hematological malignancies, their efficacy in treating solid tumors has so far been largely disappointing. However, recent advancements in developing new compounds and a deeper understanding of cancer biology have led to success in specific solid tumor subtypes through precision medicine approaches. Moreover, epigenetic drugs may play a crucial role in synergizing with other anticancer treatments, enhancing the sensitivity of cancer cells to various anticancer therapies, including chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy. In this review, we critically evaluate the evolution of epigenetic drugs, tracing their development from initial use as monotherapies to their current application in combination therapies. We explore the preclinical rationale, completed clinical studies, and ongoing clinical trials. Finally, we discuss trial design strategies and drug scheduling to optimize the development of possible combination therapies.

Empowering beyond Pain: Pain Neuroscience Education Interventions in Breast Cancer Survivorship Care.

Chronic pain is a common consequence of breast cancer (BC) and its treatments. Pain neuroscience education (PNE) is a non-pharmacological intervention that adopts a biopsychosocial approach and has already been proven to be effective for different chronic pain syndromes. The present review aims to critically assess clinical trials comparing the efficacy of PNE to traditional biomedical education (BME) in reducing BC-related pain and improving quality of life. We conducted a literature search in scientific databases, including all studies regarding PNE use specifically for BC-related pain. Ongoing randomized controlled and observational studies were identified from ClinicalTrials.gov and congress proceedings. A total of eight clinical trials met the review criteria. The participants were all administered physical therapy and assigned to receive either BME or PNE interventions. Among the completed clinical studies, one reported no statistically relevant differences between the two groups, whereas the other showed lower levels of pain-related indexes in the PNE population compared to the BME one. While the current literature is inconclusive regarding the effectiveness of PNE for managing BC pain, we strongly support the need for further trials, as PNE could empower BC patients in both prevention of and coping with pain, offering the advantage of having no side effects.

A systematic review and meta-analysis of neuroimaging studies examining synaptic density in individuals with psychotic spectrum disorders

BackgroundPsychotic disorders have long been considered neurodevelopmental disorders where excessive synaptic pruning and cortical volume loss are central to disease pathology. We conducted a systematic review of the literature to identify neuroimaging studies specifically examining synaptic density across the psychosis spectrum.MethodsPRISMA guidelines on reporting were followed. We systematically searched MEDLINE, Embase, APA PsycINFO, Web of Science and The Cochrane Library from inception to December 8, 2023, and included all original peer-reviewed articles or completed clinical neuroimaging studies of any modality measuring synaptic density in participants with a diagnosis of psychosis spectrum disorder as well as individuals with psychosis-risk states. The NIH quality assessment tool for observational cohort and cross-sectional studies was used for the risk of bias assessment.ResultsFive studies (k = 5) met inclusion criteria, comprising n = 128 adults (psychotic disorder; n = 61 and healthy volunteers; n = 67 and specifically measuring synaptic density via positron emission tomography (PET) imaging of the synaptic vesicle glycoprotein 2 A (SV2A). Three studies were included in our primary meta-analysis sharing the same outcome measure of SV2A binding, volume of distribution (VT). Regional SV2A VT was reduced in psychotic disorder participants in comparison to healthy volunteers, including the occipital lobe (Mean Difference (MD)= -2.17; 95% CI: -3.36 to -0.98; P < 0.001 ), temporal lobe (MD: -2.03; 95% CI: -3.19 to -0.88; P < 0.001 ), parietal lobe (MD:-1.61; 95% CI: -2.85 to -0.37; P = 0.01), anterior cingulate cortex (MD= -1.47; 95% CI: -2.45 to -0.49; P = 0.003), frontal cortex (MD: -1.16; 95% CI: -2.18 to -0.15; P = 0.02), amygdala (MD: -1.36; 95% CI: -2.20 to -0.52, p = 0.002), thalamus (MD:-1.46; 95% CI:-2.46 to -0.46, p = 0.004) and hippocampus (MD= -0.96; 95% CI: -1.59 to -0.33; P = 0.003).ConclusionsPreliminary studies provide in vivo evidence for reduced synaptic density in psychotic disorders. However, replication of findings in larger samples is required prior to definitive conclusions being drawn.PROSPEROCRD42022359018.

Twelve Years of Drug Prioritization to Help Accelerate Disease Modification Trials in Parkinson's Disease: The International Linked Clinical Trials Initiative.

In 2011, the UK medical research charity Cure Parkinson's set up the international Linked Clinical Trials (iLCT) committee to help expedite the clinical testing of potentially disease modifying therapies for Parkinson's disease (PD). The first committee meeting was held at the Van Andel Institute in Grand Rapids, Michigan in 2012. This group of PD experts has subsequently met annually to assess and prioritize agents that may slow the progression of this neurodegenerative condition, using a systematic approach based on preclinical, epidemiological and, where possible, clinical data. Over the last 12 years, 171 unique agents have been evaluated by the iLCT committee, and there have been 21 completed clinical studies and 20 ongoing trials associated with the initiative. In this review, we briefly outline the iLCT process as well as the clinical development and outcomes of some of the top prioritized agents. We also discuss a few of the lessons that have been learnt, and we conclude with a perspective on what the next decade may bring, including the introduction of multi-arm, multi-stage clinical trial platforms and the possibility of combination therapies for PD.

Regulatory Considerations in the Approval of Rezafungin (Rezzayo) for the Treatment of Candidemia and Invasive Candidiasis in Adults.

On 22 March 2023, the FDA approved rezafungin (Rezzayo) for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options. Rezafungin is an echinocandin that supports weekly dosing, enabling outpatient parenteral treatment that potentially avoids the need for a central venous catheter. Approval of rezafungin was based on a single adequate and well-controlled phase 3 study designed with a day 30 all-cause mortality primary end point and 20% noninferiority margin, which demonstrated that rezafungin is noninferior to the comparator echinocandin. Nonclinical studies of rezafungin in nonhuman primates identified a neurotoxicity safety signal; however, rezafungin's safety profile in the completed clinical studies was similar to other Food and Drug Administration-approved echinocandins. Here we describe the rationale for this approval and important considerations during the review process for a flexible development program intended to expedite the availability of antimicrobial therapies to treat serious infections in patients with limited treatment options. Clinical Trials Registration . NCT02734862 and NCT03667690.

Update on current and new potential immunotherapies in breast cancer, from bench to bedside.

Impressive advances have been seen in cancer immunotherapy during the last years. Although breast cancer (BC) has been long considered as non-immunogenic, immunotherapy for the treatment of BC is now emerging as a new promising therapeutic approach with considerable potential. This is supported by a plethora of completed and ongoing preclinical and clinical studies in various types of immunotherapies. However, a significant gap between clinical oncology and basic cancer research impairs the understanding of cancer immunology and immunotherapy, hampering cancer therapy research and development. To exploit the accumulating available data in an optimal way, both fundamental mechanisms at play in BC immunotherapy and its clinical pitfalls must be integrated. Then, clinical trials must be critically designed with appropriate combinations of conventional and immunotherapeutic strategies. While there is room for major improvement, this updated review details the immunotherapeutic tools available to date, from bench to bedside, in the hope that this will lead to rethinking and optimizing standards of care for BC patients.

Update on gepants for the treatment of chronic migraine.

Chronic migraine (CM) is a profoundly debilitating condition that has detrimental clinical and social outcomes. Over the past two decades, novel small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists, known as gepants, and CGRP monoclonal antibodies (mAbs) have been developed, ushering in a new era of migraine-specific treatment. In this review, we discuss the literature investigating the role of gepants for the treatment of CM. Numerous completed and ongoing clinical studies have conclusively demonstrated the safety, tolerability, and efficacy of several gepants for the acute treatment of migraine. However, preventive trials involving gepants have focused on patients with episodic migraine, with atogepant being the only gepant approved for CM prevention by the US Food and Drug Administration at the time of writing. Although some preliminary positive results have been reported, further research is still required to achieve additional advancements in the future. In summary, the effectiveness of gepants for treating individuals with CM are highly expected. This review highlights the development and current progress of gepants for the treatment of CM, focusing both on their role as acute abortive agents and preventive measures and on their concomitant use with other antimigraine medications, such as CGRP mAbs or triptans.

Light Exposure as a Nonpharmacological Intervention for Alzheimer’s Disease

AbstractBackgroundIn recent years, significant advances have been made in our understanding of the non‐visible biological impact of light (Vetter et al, 2021). Many of these advances can be traced to the 2002 discovery of a previously unknown retinal photoreceptor known as the intrinsically photosensitive retinal ganglion cell, or ipRGC, which is now known to be connected directly to our master circadian clock in our superchiasmatic nucleus (SCN). Now a growing body of clinical and applied research has shown how light spectrum, intensity, and timing can be used to promote circadian entrainment, leading to significant improvements in human health outcomes, including for people with Alzheimer’s disease and related dementia (ADRD).MethodMany of these clinical studies have used lighting interventions in elder care facilities to evaluate the impact of lighting as a nonpharmacological intervention to improve mood, anxiety, sleep quality, falls and other health metrics for ADRD populations. These studies typically gather light exposure and health metric information during control periods or with control populations using traditional lighting approaches and compare results to periods or populations under “circadian‐enhanced” lighting conditions, which generally means brighter and bluer lighting during the day and dimmer and redder light in the evening and night hours.ResultThe results from these studies have consistently demonstrated significant improvements in circadian entrainment, sleep quality, mood, anxiety, falls and other health metrics for ADRD populations under circadian‐enhanced lighting conditions.ConclusionThis talk will provide an overview of our current understanding of how light exposure impacts human physiology. We will discuss several completed and ongoing clinical studies conducted with ADRD populations, including several studies on which the speaker has been the Principal Investigator. We will cover what questions remain in this area and what studies can be developed in the future to address them. Finally, we will close with a discussion of tools, products, building designs and daily routines that can be applied today by clinicians and caregivers that are most likely to improve the health and wellbeing of ADRD patients based on what is known today about the impact of light exposure.

TMET-02. CLINICAL EFFICACY OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMAS IS DRIVEN BY DISRUPTION OF INTEGRATED METABOLIC AND EPIGENETIC PATHWAYS

Abstract H3K27M-mutant diffuse midline glioma (DMG) patients have no proven effective therapies beyond radiation. ONC201, a mitochondrial protease ClpP agonist, has recently demonstrated efficacy in these patients, but the mechanism behind this remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue samples from patients treated in two completed multi-site clinical studies (n=71). Patients treated with ONC201 monotherapy following initial radiation but prior to recurrence (n=35) demonstrated a median overall survival of 21.7 months and a median progression-free survival of 12.2 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. Similar survival benefits were observed using in utero electroporation and orthotopic mouse models of H3K27M-DMG (median 107 versus 77 days [p=0.02] and median 97 versus 141 days [p=0.004], respectively). Integrated transcriptomic and metabolomic analysis of ONC201-treated H3K27M-DMG cells revealed downregulation of TCA cycle, glycolysis, and pyruvate metabolism genes, most notably oxoglutarate dehydrogenase (OGDH), and concomitant changes in levels of associated metabolites including ɑ-ketoglutarate (ɑ-KG). Interestingly, L-2-hydroxyglutarate (L-2HG), a known inhibitor of the Jumonji C domain family of histone lysine demethylases, was also increased. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuro-glial differentiation genes. Genetic knockdown of OGDH recapitulated ONC201-mediated increases in H3K27me3. In contrast, genetic knockdown of ClpP or lactate dehydrogenase A or overexpression of L-2-hydroxyglutarate dehydrogenase (L-2HGDH), but not D-2HGDH, abrogated ONC201-mediated increases in H3K27me3, demonstrating that ONC201 induces the production of L-2HG in H3K27M-DMG cells leading to increased H3K27me3. Overall, our data demonstrates the efficacy of ONC201 in H3K27M-mutant DMG and supports ONC201 as the first monotherapy to improve outcomes in patients with H3K27M-mutant DMG for whom few therapeutic options currently exist. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction.

Unveiling Mesenchymal Stem Cells' Regenerative Potential in Clinical Applications: Insights in miRNA and lncRNA Implications.

It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs.

Mavacamten: a first-in-class myosin inhibitor for obstructive hypertrophic cardiomyopathy.

Mavacamten is a first-in-class, targeted, cardiac-specific myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic New York Heart Association Classes II and III obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten was developed to target the hyper-contractile phenotype, which plays a critical role in the pathophysiology of the disease. In Phase 2 and 3 clinical trials, mavacamten was well tolerated, reduced left ventricular outflow tract gradients, improved exercise capacity and symptoms, and was associated with improvements in other clinically relevant parameters, such as patient-reported outcomes and circulating biomarkers. In addition, treatment with mavacamten was associated with evidence of favourable cardiac remodelling in multi-modality imaging studies. Mavacamten substantially reduced guideline eligibility for septal reduction therapy candidates with oHCM and drug-refractory symptoms. In this article, the available efficacy and safety data from completed and ongoing clinical studies of mavacamten in patients with symptomatic oHCM are reviewed. Longer term extension studies may help address questions related to the positioning of mavacamten in current oHCM management algorithms, interactions with background therapy, as well as the potential for disease modification beyond symptomatic relief of left ventricular outflow tract obstruction.

A Critical Review to Understand the Role of Ayurveda in Management of Opium Withdrawal

ABSTRACT Addiction is defined as a persistent, uncontrollable psychological or physiological dependence on a substance or behavior. It is a long-term brain condition that results in obsessive drug use despite negative effects. Addiction has general as well as negative social effects on people. Any type of drug addiction that is abruptly stopped can result in a psychosomatic condition. Even though contemporary medicine has developed several methods and molecules to combat these, the desired result is far from reality. Hence, it is the need of the hour to find a better solution to combat this drug addiction by exploring the principles of Ayurveda and also by following the drugs and regimen mentioned by the Acharyas in the classics. The information for this article has been gathered from my personal clinical experiences as well as from several completed clinical studies about drug addiction, withdrawal, and its management that has been incorporated in index and nonindex journals. The Padanshik kram is a special technique mentioned in Ayurveda to stop any substance (dangerous or nondangerous) that is homologous to humans by the process of tapering gradually. To replace and tapper up Sameer Gaj Kesari Ras, Vishtinduk Vati in opium withdrawal treatment can be very much beneficial. Along with the above medication, following methods such as psychological counseling, Abhyanga, Shirodhara, Yoga, meditation, and Satvavajaya Chikitsa can also be very much beneficial. Thus, in addiction and withdrawal due to substances containing opium or its derivatives, the Ayurvedic way of treatment can be one of the most effective modes of treatment.

A review of nanomaterials from synthetic and natural molecules for prospective breast cancer nanotherapy.

Breast cancer being one of the most frequent cancers in women accounts for almost a quarter of all cancer cases. Early and late-stage breast cancer outcomes have improved dramatically, with considerable gains in overall survival rate and disease-free state. However, the current therapy of breast cancer suffers from drug resistance leading to relapse and recurrence of the disease. Also, the currently used synthetic and natural agents have bioavailability issues which limit their use. Recently, nanocarriers-assisted delivery of synthetic and natural anticancer drugs has been introduced to the breast cancer therapy which alienates the limitations associated with the current therapy to a great extent. Significant progress has lately been made in the realm of nanotechnology, which proved to be vital in the fight against drug resistance. Nanotechnology has been successfully applied in the effective and improved therapy of different forms of breast cancer including invasive, non-invasive as well as triple negative breast cancer (TNBC), etc. This review presents a comprehensive overview of various nanoformulations prepared for the improved delivery of synthetic and natural anticancer drugs alone or in combination showing better efficacy and pharmacokinetics. In addition to this, various ongoing and completed clinical studies and patents granted on nanotechnology-based breast cancer drug delivery are also reviewed.

Minimal Residual Disease in Colorectal Cancer: Are We Finding the Needle in a Haystack?

Despite significant advances in the surgical and systemic therapy of colorectal cancer (CRC) in recent decades, recurrence rates remain high. Apart from microsatellite instability status, the decision to offer adjuvant chemotherapy to patients with CRC is solely based on clinicopathologic factors, which offer an inaccurate risk stratification of patients who derive benefit from adjuvant therapy. Owing to the recent improvements of molecular techniques, it has been possible to detect small allelic fractions of circulating tumor DNA (ctDNA), and therefore, to identify patients with minimal residual disease (MRD) after curative-intent therapies. The incorporation of ctDNA identifying MRD in clinical practice may dramatically change the standard of care of CRC, refining the selection of patients who are candidates for escalation and de-escalation of adjuvant chemotherapy, and even for organ-preservation strategies in rectal cancer. In the present review, we describe the current standard of care and the DNA sequencing methodologies and assays, present the data from completed clinical studies and list ongoing potential landmark clinical trials whose results are eagerly awaited, as well as the impact and perspectives for the near future. The discussed data bring optimism for the future of oncologic care through the hope of refined utilization of adjuvant therapies with higher efficacy and safety for patients with both localized and advanced CRC.

Fabry Disease: Current and Novel Therapeutic Strategies. A Narrative Review.

Fabry disease (FD) is an inherited lysosomal storage disorder, leading to multisystemic manifestations and causing significant morbidity and mortality. The aim of this narrative review is to present the current and novel therapeutic strategies in FD, including symptomatic and specific treatment options. A systematic literature search was conducted to identify relevant studies, including completed and ongoing randomized-controlled clinical trials (RCTs), prospective or retrospective cohort studies, case series and case reports that provided clinical data regarding FD treatment. A multidisciplinary symptomatic treatment is recommended for FD patients, personalized according to disease manifestations and their severity. During the last two decades, FD-specific treatments, including two enzyme-replacement-therapies (agalsidase alfa and agalsidase beta) and chaperone treatment with migalastat have been approved for use and allowed for symptoms' stabilization or even disease burden reduction. More therapeutic agents are currently under investigation. Substrate reduction therapies, including lucerastat and venglustat, have shown promising results in RCTs and may be used either as monotherapy or as complementary therapy to established enzymereplacement- therapies. More stable enzyme-replacement-therapy molecules that are associated with less adverse events and lower likelihood of neutralizing antibodies formation have also been developed. Ex-vivo and in-vivo gene therapy is being tested in animal models and pilot human clinical trials, with preliminary results showing a favorable safety and efficacy profile. The therapeutic landscape in FD appears to be actively expanding with more treatment options expected to become available in the near future, allowing for a more personalized approach in FD patients.

Curator – A data curation tool for clinical real-world evidence

ObjectiveThis research aims to establish an efficient, systematic, reproducible, and transparent solution for advanced curation of real-world data, which are highly complex and represent an invaluable source of information for academia and industry. Materials and methodsWe propose a novel software solution that splits the statistical analytical pipeline into two phases. The first phase is implemented through Curator, which performs data engineering and data modelling on deidentified real-world data to achieve advanced curation and provides selected information ready to be analyzed in the second phase by statistical packages. Curator is made of a suite of Python programs and uses MySQL as its database management system. Curator has been utilised with several UK primary and secondary care data sources. ResultsCurator has been used in 25 completed clinical and health economics research studies. Their output has been published in 2 NIHR-funded reports and 33 prestigious international peer-reviewed journals and presented at 38 global conferences. Curator has consistently reduced research time and costs by over 36% and made research more reproducible and transparent. DiscussionCurator fits in well with recent UK governmental guidelines that recognise health data curation as a complex standalone technical challenge. Curator has been used extensively on UK real-world data and can handle several linked datasets. However, for Curator to be accessed by a wider audience, it needs to become more user-friendly. ConclusionCurator has proven to be a cost-effective and trustworthy data curation tool, which should be developed further and made available to third parties.

Cefodizime: pharmacological characteristics and potential for clinical use in lower respiratory tract infections

Cefodizime is a third–generation cephalosporin for parenteral use that has become available for the first time in the Russia. This paper reviews the use of this antibiotic in clinical practice based on the current data on antimicrobial resistance in pathogens causing lower respiratory tract infections and the results of completed clinical studies of its efficacy and safety.

Immunotherapy for the treatment of pediatric brain tumors: a narrative review.

The goal of this narrative review is to report and summarize the completed pediatric immunotherapy clinical trials for primary CNS tumors. Pediatric central nervous system (CNS) tumors are the most common cause of pediatric solid cancer in children aged 0 to 14 years and the leading cause of cancer mortality. Survival rates for some pediatric brain tumors have improved, however, there remains a large portion of pediatric brain tumors with poor survival outcomes despite advances in treatment. Cancer immunotherapy is a growing field that has shown promise in the treatment of pediatric brain tumors that have historically shown a poor response to treatment. This narrative review provides a summary and discussion of the published literature focused on treating pediatric brain tumors with immunotherapy. MEDLINE via PubMed, Embase and Scopus via Elsevier were searched. The search utilized a combination of keywords and subject headings to include pediatrics, brain tumors, and immunotherapies. Manuscripts included in the analysis included completed clinical studies using any immunotherapy intervention with a patient population that consisted of at least half pediatric patients (<18 years) with primary CNS tumors. Conference abstracts were excluded as well as studies that did not include completed safety or primary outcome results. Search results returned 1,494 articles. Screening titles and abstracts resulted in 180 articles for full text review. Of the 180 articles, 18 were included for analysis. Another two articles were ultimately included after review of references and inclusion of newly published articles, for a total of 20 included articles. Immunotherapies included dendritic cell vaccines, oncolytic virotherapy/viral immunotherapy, chimeric antigen receptor (CAR) T-cell therapy, peptide vaccines, immunomodulatory agents, and others. In this review, 20 published articles were highlighted which use immunotherapy in the treatment of primary pediatric brain tumors. To date, most of the studies published utilizing immunotherapy were phase I and pilot studies focused primarily on establishing safety and maximum dose-tolerance and toxicity while monitoring survival endpoints. With established efficacy and toxicity profiles, future trials may progress to further understanding the overall survival and quality of life benefits to pediatric patients with primary brain tumors.

Development of a Quantitative Systems Pharmacology Model to Explore Hemostatic Equivalency of Antithrombin Lowering

Fitusiran is an investigational siRNA therapeutic that targets antithrombin (AT) to rebalance hemostasis in people with hemophilia A (PwHA) or B (PwHB), irrespective of inhibitor status. Phase 3 clinical studies have demonstrated that fitusiran prophylaxis significantly reduced bleeding events compared to on-demand or prophylaxis treatment with factor concentrates or bypassing agents (Srivastava et al. Blood 2021; Young et al. Blood 2021; Kenet et al. ISTH 2022). To better understand the hemostatic equivalency of fitusiran prophylaxis (i.e., AT lowering), a quantitative systems pharmacology (QSP) model was developed to investigate thrombin generation in PwHA and PwHB in the context of AT lowering. QSP modeling is a mechanistic approach that integrates clinical and nonclinical data of the coagulation pathway to simulate the results of multiple in vitro coagulation assays, including the thrombin generation assay (TGA) and to mechanistically understand the readouts of these assays. The QSP model builds on prior published models of the coagulation cascade (Attarwala et al. ISTH 2017; Sridharan et al. Blood 2017), updated to represent reported steady-state levels of coagulation factors and accessory proteins in the plasma of healthy individuals and PwHA and PwHB (Figure 1). In addition, the model was extended to describe the impact of α-2-macroglobulin, a key regulator of thrombin, with increased influence at reduced AT levels that is critical to understand the impact of fitusiran on thrombin generation (Kattula et al. Blood 2020). After representing coagulation dynamics from plasma from healthy individuals, PwHA, and PwHB, the QSP model was applied to simulate TGA and relevant metrics, including thrombin peak height (Figure 1). TGA simulations were performed across different percentages of AT and FVIII. These simulations reproduced experimental TGA data from AT- and FVIII-double depleted plasma that was spiked with different levels of AT and/or FVIII. For these in vitro experiments, Factor VIII (FVIII) and AT-double depleted plasma was generated from congenital FVIII-deficient plasma by immunodepleting AT using an anti-AT antibody and recombinant AT protein was spiked back in to achieve different levels of AT. The QSP simulations also reproduced the reported formation of α-2-macroglobulin complexes with thrombin in each condition. Subsequently, the model was validated using both internal and published TGA and activated partial thromboplastin time (aPTT) datasets that were not used during model development. Next, a large (n=1000) virtual population (VP) of severe PwHA (<1% FVIII) was generated based on calibration of the model to individual patient data from completed fitusiran clinical studies. This analysis considered individual patient pharmacokinetic and AT time courses to describe thrombin peak height associated with different levels of AT reduction from fitusiran prophylaxis within a representative population of severe PwHA. The target therapeutic AT range of fitusiran prophylaxis treatment at steady state is 15-35%. Based on this model, the peak thrombin generated at 15-35% AT was similar to peak thrombin observed at 10-20 IU/kg FVIII in PwHA. In summary, by considering the impact of α-2-macroglobulin, the QSP model provides a mechanistic representation of thrombin generation under conditions of AT lowering, consistent with internal TGA data from donor-derived spiked plasma and clinical TGA data from both PwHA and PwHB. The VP analysis of fitusiran prophylaxis provided hemostatic equivalency with FVIII in a representative population of severe PwHA, with a targeted therapeutic range of AT of 15-35% resulting in a thrombin peak profile which was comparable to 10-20 IU/kg FVIII. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The design and evaluation of hybrid controlled trials that leverage external data and randomization

Patient-level data from completed clinical studies or electronic health records can be used in the design and analysis of clinical trials. However, these external data can bias the evaluation of the experimental treatment when the statistical design does not appropriately account for potential confounders. In this work, we introduce a hybrid clinical trial design that combines the use of external control datasets and randomization to experimental and control arms, with the aim of producing efficient inference on the experimental treatment effects. Our analysis of the hybrid trial design includes scenarios where the distributions of measured and unmeasured prognostic patient characteristics differ across studies. Using simulations and datasets from clinical studies in extensive-stage small cell lung cancer and glioblastoma, we illustrate the potential advantages of hybrid trial designs compared to externally controlled trials and randomized trial designs.