Cts-Clinical and Translational Science最新文献

{"title":"Frequency and Implications of High-Risk Pharmacogenomic Phenotypes Identified in a Diverse Australian Pediatric Oncology Cohort","authors":"Claire Moore,&nbsp;Andreas Halman,&nbsp;Tayla Stenta,&nbsp;Dhrita Khatri,&nbsp;Elizabeth Williams,&nbsp;Roxanne Dyas,&nbsp;Julian Stolper,&nbsp;David A. Elliott,&nbsp;Rachel Conyers","doi":"10.1111/cts.70246","DOIUrl":"https://doi.org/10.1111/cts.70246","url":null,"abstract":"<p>Pharmacogenomics remains underutilized in pediatric oncology, despite the existence of evidence-based guidelines. Implementation of pharmacogenomics-informed prescribing could improve medication safety and efficacy in pediatric oncology patients, who are at high risk of adverse drug reactions. This study examines the prevalence of high-risk pharmacogenomic phenotypes and the prescription of relevant medications in a diverse Australian pediatric oncology cohort, highlighting the potential impact of pharmacogenomic testing in this unique population. Whole genome sequencing data from 180 patients were analyzed to assess 14 genes with evidence-based pharmacogenomic guidelines relevant to pediatric oncology. Over 90% of patients had at least one high-risk phenotype, with 20% presenting four or more. Ondansetron, mercaptopurine, omeprazole, pantoprazole, and voriconazole were commonly prescribed medications that have pharmacogenomic prescribing recommendations, with the latter three showing the highest actionability rates. High-risk phenotypes were most frequently observed for <i>CYP2C19</i> and <i>CYP2D6</i>, with 30% of patients having a high-risk phenotype for both genes. This study underscores the potential utility of pharmacogenomics in pediatric oncology patients across a range of pharmacogenes and commonly prescribed medications. The findings support advocacy for implementing broad, pre-emptive pharmacogenomic testing in oncology patients to improve treatment safety and efficacy.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70246","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143932275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 1 Study Evaluating the Pharmacokinetics, Dose Proportionality, Bioavailability, and Tolerability of Subcutaneous Levothyroxine Sodium (XP-8121)","authors":"Richard Fitch,&nbsp;Diane R. Mould,&nbsp;Valentina Conoscenti,&nbsp;Robbie Huang,&nbsp;Dawn Harper","doi":"10.1111/cts.70244","DOIUrl":"https://doi.org/10.1111/cts.70244","url":null,"abstract":"<p>Levothyroxine sodium has been the cornerstone of hypothyroidism management worldwide, with daily oral administration (PO) recognized as standard of care. Oral administration of levothyroxine, however, poses challenges due to variability in pharmacokinetics (PK), influenced by factors such as gastrointestinal absorption, food/drug interactions, and patient adherence. XP-8121 (levothyroxine for subcutaneous administration) is a ready-to-use, subcutaneous (SC) injection formulation of levothyroxine in Phase 3 development. This Phase 1, single-center, 2-part study aimed to characterize the PK and dose proportionality of XP-8121 SC compared to 600 μg oral Ievothyroxine in healthy adults. Additionally, the study evaluated the safety and tolerability of XP-8121 and incorporated population pharmacokinetic (PPK) modeling to support future development. Part 1 was a randomized, open-label, crossover, fixed-sequence study (<i>n</i> = 30). Dose linearity was evaluated by escalating XP-8121 SC doses up to 1200 μg. Part 2 was an open-label, single-period study (<i>n</i> = 30) evaluating PK characteristics of a single dose of XP-8121 SC (1500 μg), potential clinical exposure range, and dose proportionality. After oral levothyroxine administration, baseline-adjusted levothyroxine concentration increased rapidly in plasma (<i>T</i>_max median: 3.1 h); absorption for all XP-8121 SC doses was slower compared to 600 μg oral levothyroxine, and levels remained elevated for 4–5 days before decreasing. Dose proportionality was confirmed, and safety results were similar between all groups. PPK analysis results suggested that weekly doses of XP-8121 SC at four times the daily oral levothyroxine dose provide similar exposure at steady state (AUC_ss). Overall, these data for XP-8121 provide adequate predictive performance to inform future phase 2 studies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elexacaftor/Tezacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients With Cystic Fibrosis","authors":"Ngoc Hoa Truong,&nbsp;Sihem Benaboud,&nbsp;Naïm Bouazza,&nbsp;Mahassen Barboura,&nbsp;Emmanuelle Bardin,&nbsp;Michel Miralles,&nbsp;Gabrielle Lui,&nbsp;Léo Froelicher-Bournaud,&nbsp;Steeve Rouillon,&nbsp;Tiphaine Bihouee,&nbsp;Stéphanie Bui,&nbsp;Philippe Reix,&nbsp;Marie-Laure Dalphin,&nbsp;Muriel Laurans,&nbsp;Jeanne Languepin,&nbsp;Harriet Corvol,&nbsp;Françoise Troussier,&nbsp;Laurence Weiss,&nbsp;Rames Cinthia,&nbsp;Aurélie Tatopoulos,&nbsp;Eric Deneuville,&nbsp;Raphael Chiron,&nbsp;Nathalie Stremler,&nbsp;Cathy Llerena,&nbsp;Sophie Ramel,&nbsp;Caroline Perisson,&nbsp;Véronique Houdoin,&nbsp;Marie Mittaine,&nbsp;Jean-Marc Treluyer,&nbsp;Isabelle Sermet-Gaudelus,&nbsp;Frantz Foissac,&nbsp;MODUL-CF study group","doi":"10.1111/cts.70245","DOIUrl":"https://doi.org/10.1111/cts.70245","url":null,"abstract":"<p>Elexacaftor/tezacaftor/ivacaftor (ETI) significantly improves treatment outcomes for people with cystic fibrosis (pwCF) with at least one F508del allele. In 2023, the Food and Drug Administration approved ETI for children with CF aged 2–5 years. However, real-world pharmacokinetic-pharmacodynamic data for ETI in pediatric and adult populations are still limited. This study aimed to characterize the population PK of ETI in children with CF (chCF) and evaluate current dosing recommendations. Population PK modeling was conducted using Monolix software on 150 ETI concentrations obtained from therapeutic drug (TDM) monitoring in 96 children with CF aged 2–18 years, as part of the MODUL-CF study. Area under the curve was derived from individual Bayesian pharmacokinetic estimates. A one-compartment model with a lag time, first-order absorption, and elimination best described the PK of elexacaftor/ivacaftor, while the PK of tezacaftor followed a one-compartment model with first-order absorption and elimination. A large between-subject variability was observed. The effect of body weight was significant on apparent clearance and volume of distribution parameters using allometric scaling. Children weighing 30–40 kg who received the adult-recommended dose showed higher drug exposure compared to adults with cystic fibrosis. This is the first study to describe the population pharmacokinetics of ETI in chCF aged 2–18 years, revealing high between-subject variability for all three drugs. In this context, TDM is likely essential for managing ETI exposure levels and guiding dosing adjustments. The appropriateness of current dosing recommendations for children under 12 years old weighing 30–40 kg remains to be clarified.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemoprevention of Gastrointestinal Cancers: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials and Cohort Studies","authors":"Jia En Chan,&nbsp;Suresh Shanmugham,&nbsp;Suresh Kumar,&nbsp;Yeong Yeh Lee,&nbsp;Siew Mooi Ching,&nbsp;Nathorn Chaiyakunapruk,&nbsp;Sajesh K. Veettil","doi":"10.1111/cts.70235","DOIUrl":"https://doi.org/10.1111/cts.70235","url":null,"abstract":"<p>Several meta-analyses have investigated the association between chemopreventive agents (CPAs) and the risk of gastrointestinal cancers, but syntheses of the quality of evidence in aggregate are lacking. This umbrella review aimed to assess the quality of evidence from meta-analyses of randomized controlled trials (RCTs) and cohort studies that examine inverse associations between CPAs and the risk of gastrointestinal cancers or any premalignant conditions. Summary effect sizes from random-effects models, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance, and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs. From 20,296 publications, 577 full-text articles were evaluated for eligibility, and 69 articles that provided 194 unique meta-analyses were included. Among meta-analyses of RCTs (<i>N</i> = 93), 26 reached statistical significance (<i>p</i> &lt; 0.05). Seven inverse associations were graded as either high quality (celecoxib and colorectal adenomas, (<i>N</i> = 4)) or moderate (aspirin and colorectal adenomas, (<i>N</i> = 2) and <i>H-pylori</i> eradication and gastric cancer (<i>N</i> = 1)). Among meta-analyses of cohort studies (<i>N</i> = 101), 60 reached statistical significance. Four inverse associations were graded as either convincing (antivirals with hepatocellular carcinoma (HCC); <i>N</i> = 1) or highly suggestive (aspirin with HCC (<i>N</i> = 2) and colorectal cancer (<i>N</i> = 1)). This review suggests that the associations with the most consistent empirical evidence were confined to those targeting the well-established risk factors of gastrointestinal cancer progression. Despite the limited established evidence, the inverse associations observed between metformin and colorectal, esophageal, and gastric cancers, as well as between statins and HCC and gastric cancer, merit further research.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70235","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrating Sustainability Pillars Into Trial Design Decision-Making: Results of an International Survey","authors":"Pritibha Singh,&nbsp;Oleksandr Sverdlov,&nbsp;Robert A. Beckman,&nbsp;Andrea M. Burden","doi":"10.1111/cts.70241","DOIUrl":"https://doi.org/10.1111/cts.70241","url":null,"abstract":"<p>The pharmaceutical industry is increasingly shifting to decentralized clinical trials (DCTs) conducted at the patient's home, sometimes including trial material home delivery. The traditional clinical trial (CT) is conducted at the investigational site. Research suggests that centralized and decentralized trials have a large carbon footprint, with DCTs potentially providing patient-centric solutions. However, leaders must determine how to integrate environmental, economic, and social sustainability pillars into their portfolios and subsequent downstream trial-level decisions. An online survey was designed and deployed via Eidgenössische Technische Hochschule's (ETH, Swiss Federal Institute of Technology) SurveySelect software to capture perceptions of priorities and tradeoffs when deciding between a DCT and a traditional CT for each pillar. The survey closed on 31st January 2023. A total of 447 participants responded. The findings revealed that the overall cohort prioritized greenhouse gas emissions (22.4%) for environmental impact, trial probability of success (15%) for economic considerations, and patient convenience (23.3%) for social criteria. Overall, the DCT setting was perceived as more sustainable in all pillars. Participants reported tradeoffs centered on patient engagement and bringing new medicines to the market. The results from this survey provide initial insights into international multistakeholder perceptions of the priorities and tradeoffs when choosing between a traditional CT and DCT. The synthesized perceptions inform three key recommendations: the need (1) for simulation studies to guide holistic decision-making across all pillars as empirical data accumulates, (2) to protect the environment, and (3) to protect the supply chain. As empirical data accumulates, these recommendations provide directionality for further research.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70241","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protocol Development for Investigator-Sponsored Clinical Studies","authors":"Lyn Frumkin","doi":"10.1111/cts.70237","DOIUrl":"https://doi.org/10.1111/cts.70237","url":null,"abstract":"<p>Clinical trials with investigator sponsors at academic sites have increased, in part due to studies involving drug repurposing, the process of identifying new uses for existing drugs that are initially conducted in patients rather than healthy participants. In contrast to industry- or government-sponsored trials, investigator-sponsored clinical studies, also known as investigator-initiated trials, are typically conducted at one or several academic centers and are resource-limited by finances and patient numbers. These studies can serve as crucial pilot studies to inform the design of larger, more definitive clinical trials. Drawing from the experience of working with clinical researchers in academic settings, this tutorial presents guidelines for writing clinical protocols for resource-limited investigator-sponsored studies that meet international standards and optimize the detection of meaningful signals or outcomes that can lead to investigation in larger well-controlled trials.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70237","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INT-787, a Novel Farnesoid X Receptor Agonist, in Healthy Volunteers: A Phase 1 Trial","authors":"Thomas Capozza,&nbsp;Jennifer Burkey,&nbsp;Jeroen Van De Wetering,&nbsp;Reinhold Kerb,&nbsp;Jennifer Callahan,&nbsp;Ludmila Kryzhanovskaya,&nbsp;Mary Erickson","doi":"10.1111/cts.70229","DOIUrl":"https://doi.org/10.1111/cts.70229","url":null,"abstract":"<p>Aberrant farnesoid X receptor (FXR) signaling is implicated in cholestatic, inflammatory, and fibrotic liver diseases. In preclinical/clinical studies, semisynthetic bile acid-derived FXR agonists markedly improved hepatic function in various conditions. INT-787, a novel hydrophilic semisynthetic bile acid FXR agonist, has demonstrated a reduction in inflammatory and fibrotic markers and regulation of bile acid/lipid metabolism. This first-in-human, randomized, placebo-controlled phase 1 study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of INT-787 and its equipotent metabolites in healthy volunteers by evaluating single ascending doses (SAD), multiple ascending doses (MAD), and food effect. Participants (<i>n</i> = 130) across all study portions were similar in age, race, and body mass index. In the SAD and MAD portions, the maximum plasma concentration (<i>C</i>_max) and area under the curve (AUC) for total INT-787 generally increased with dose. In the Food Effect portion, the mean <i>C</i>_max of total INT-787 was almost 2-fold higher under fasted conditions compared with fed conditions; AUC_0-inf was unchanged. Steady state for total INT-787 was reached by Day 7. In cohorts receiving ≥ 50 mg doses, the half-life of total INT-787 ranged from 21 to 55 h. INT-787 metabolites exhibited increased concentrations after mealtimes despite morning dosing, consistent with endogenous bile acid behavior. Following single and multiple doses of INT-787, decreases in C4 and increases in FGF-19 levels were observed. Single and multiple oral doses were generally well tolerated; 4 adverse events of mild, transient pruritus not requiring interventions were reported at higher doses. These results warrant further investigation of INT-787 in patients with liver-related disorders.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impacts of Pharmacokinetic Gene Polymorphisms on Steady-State Plasma Concentrations of Simvastatin in Thai Population","authors":"Sayanit Tipnoppanon,&nbsp;Udomsak Udomnilobol,&nbsp;Sarawut Siwamogsatham,&nbsp;Yongkasem Vorasettakarnkij,&nbsp;Chonlaphat Sukasem,&nbsp;Thomayant Prueksaritanont,&nbsp;Pajaree Chariyavilaskul,&nbsp;Varalee Yodsurang,&nbsp;Thanate Srimatimanon,&nbsp;Monpat Chamnanphon,&nbsp;Natchaya Vanwong","doi":"10.1111/cts.70225","DOIUrl":"https://doi.org/10.1111/cts.70225","url":null,"abstract":"<p>Simvastatin, an HMG-CoA reductase inhibitor, is widely used for hypercholesterolemia but may cause myotoxicity linked to its plasma concentration. Pharmacokinetic gene polymorphisms influence inter-individual variability in simvastatin exposure. This study investigated the effects of pharmacokinetic gene polymorphisms on steady-state simvastatin plasma levels in Thai patients. Eighty-nine Thai patients with dyslipidemia or coronary artery disease on simvastatin treatment for at least 2 weeks without dose adjustment were recruited from King Chulalongkorn Memorial Hospital. Simvastatin lactone and acid concentrations were measured 12 h post-dose using UHPLC–MS/MS. Pharmacokinetic gene polymorphisms, including <i>ABCB1, ABCC2, ABCG2, SLCO1B1, SLCO1B3, CYP3A4,</i> and <i>CYP3A5</i>, were genotyped by MassARRAY System. The results showed that patients with the <i>SLCO1B1</i> c.521TC+CC genotype had significantly higher simvastatin acid levels than those with c.521TT (0.53 vs. 0.19 ng/mL, <i>p</i> = 0.03). Similarly, the <i>SLCO1B1</i>*<i>1b/</i>*<i>15</i> genotype was associated with higher simvastatin acid levels than <i>SLCO1B1</i>*<i>1a</i>/*<i>1a</i> (0.58 vs. 0.16 ng/mL, <i>p</i> &lt; 0.001). These findings suggest that <i>SLCO1B1</i> c.521T&gt;C, alone or with c.388A&gt;G (<i>SLCO1B1</i>*<i>1b/</i>*<i>15</i>), reduces OATP1B1 function, leading to elevated simvastatin acid levels and increased myotoxicity risk. This study confirms the association of <i>SLCO1B1</i> rs4149056 (c.521T&gt;C) with higher simvastatin plasma levels in Thai patients. The study highlights the potential role of <i>SLCO1B1</i> genotyping, particularly rs4149056 (c.521T&gt;C) and rs2306283 (c.388A&gt;G), in guiding statin therapy for Thai patients, which could help optimize treatment and reduce adverse effects such as statin-induced myotoxicity.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EDP-323, a First-In-Class, Once-Daily, Oral L-Protein Inhibitor for the Treatment of RSV: Results From a Phase 1 Study in Healthy Adults","authors":"Kimberly Elmore,&nbsp;John DeVincenzo,&nbsp;Michael H. J. Rhodin,&nbsp;Scott T. Rottinghaus,&nbsp;Alaa Ahmad","doi":"10.1111/cts.70231","DOIUrl":"https://doi.org/10.1111/cts.70231","url":null,"abstract":"<p>Respiratory syncytial virus (RSV) remains a significant health concern, particularly for vulnerable populations. Despite preventive strategies, there remains a need for effective antiviral treatments. EDP-323 is a first-in-class, potent oral selective non-nucleoside inhibitor of the large protein (L polymerase) of RSV under investigation for the treatment of RSV infection. This phase 1, randomized, double-blind, placebo-controlled study evaluated the safety and pharmacokinetics of EDP-323. This study included fasted single ascending dose (SAD; EDP-323 50/100/200/400/600/800 mg doses, 3:1 to placebo), fed multiple ascending dose (MAD; EDP-323200/400/600/800 mg doses, 3:1 to placebo), and food effect (EDP-323200 mg dose, 4:1 to placebo) cohorts in healthy adult participants. Key objectives were to assess the safety, tolerability, and pharmacokinetic (PK) profile of EDP-323 in plasma and urine, and to evaluate the effect of food intake on its pharmacokinetics. Among 82 randomized participants (SAD, <i>n</i> = 50; MAD, <i>n</i> = 32), EDP-323 was well tolerated up to the highest tested dose (800 mg once daily for 7 days). Adverse events (AEs) were reported in 14.6% of total participants, with the majority being mild and deemed unlikely related to the study drug. Headache was the most frequent AE (<i>n</i> = 3). PK analysis showed that EDP-323 was rapidly absorbed (<i>T</i>_max = 3.0–5.0 h), with exposures increasing with ascending dose. The half-life of EDP-323 (<i>t</i>_1/2 = 10.8–16.6 h) supported once-daily dosing, and no food effect was observed. EDP-323 demonstrated a favorable safety and PK profile, supporting its potential as a once-daily oral treatment for RSV.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development and Testing of the Protocol Quality Rating Tool (PQRT) to Evaluate Clinical Trial Protocol Document Quality","authors":"Angela K. Lyden,&nbsp;Claire Z. Kalpakjian,&nbsp;Cathie Spino,&nbsp;Susan L. Murphy,&nbsp;Julie C. Lumeng,&nbsp;Anna S. Lok","doi":"10.1111/cts.70240","DOIUrl":"https://doi.org/10.1111/cts.70240","url":null,"abstract":"<p>A high-quality protocol document is essential for the successful and efficient implementation of clinical trials, but there is no consensus on how clinical trial protocol document quality should be evaluated. We used a modified Delphi approach and cognitive interviews to develop a new protocol document quality assessment tool, the <i>Protocol Quality Rating Tool (PQRT)</i>. We compiled a checklist of elements that should be included in a high-quality trial protocol document and asked experts to rate the importance of each element. We developed the <i>PQRT</i> by describing the expected content of each element and identified essential vs. additional (bonus) content to differentiate high- versus low-quality protocol documents and then organized the elements into 18 sections. We revised the <i>PQRT</i> based on feedback from and cognitive interviews with our protocol quality rating team. We then tested the <i>PQRT</i> using ten protocol documents previously approved by the Institutional Review Board. All the protocol quality raters found the tool easy to use and their scores were highly concordant for eight of ten protocol documents. We have developed and tested a simple tool to measure clinical trial protocol document quality and encourage other researchers to evaluate and validate it.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"18 5","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}