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Pharmacokinetics and Safety of Single and Multiple Doses of Peficitinib (ASP015K) in Healthy Chinese Subjects

DRUG DESIGN DEVELOPMENT AND THERAPY 2022年第0期16卷 1365-1381页

作者： Gao, Xin He, Xuemei Oshima, Hiroyuki Miyatake, Daisuke Otsuka, Yukio Kato, Kota Cai, Chunxiao Wojtkowski, Tomasz Song, Nan Kaneko, Yuichiro Shi, Aixin Chinese Acad Med Sci Clin Trial Ctr Beijing Hosp Natl Ctr Gerontol Beijing 100730 Peoples R China Chinese Acad Med Sci Inst Geriatr Med Beijing 100730 Peoples R China Astellas Pharma Inc Clin Pharmacol & Exploratory Dev Tokyo Japan Astellas Pharma Inc Anal & Pharmacokinet Res Labs Ibaraki Japan Astellas China Investment Co Ltd Dev Med Dept Beijing Peoples R China Astellas Pharma US Inc Data Sci Dev Northbrook IL USA Astellas China Investment Co Ltd Dev Div Biostat & Stat Programming Beijing Peoples R China Astellas Pharma Inc Dev Japan Asia Data Sci Biostat Grp Tokyo Japan

Objective: To investigate the pharmacokinetics and safety of peficitinib (Janus kinase inhibitor for the treatment of rheumatoid arthritis) in healthy Chinese subjects following single and multiple doses. Methods: This open-label, randomized study was conducted at one site in China. Subjects received peficitinib 50, 100 or 150 mg as a single dose on Day 1 (fasted) and once daily from Days 8 to 13 in the multiple-dose period (fed). Blood samples were collected before administration each day, and up to 72h post administration. Pharmacokinetic assessments included area under the concentration curve (AUC), half-life (t1/2), maximum concentration (Cmax), and time to maximum concentration (tmax) of peficitinib and its metabolites (H1, H2 and H4). Treatment-emergent adverse events (TEAEs) were evaluated. Results: Thirty-six subjects were enrolled (12 per dose group). After a single dose of peficitinib, median tmax was 1.0???1.5h and mean t1/2 was 7.4???13.0h for all doses. In the multiple-dose period, median tmax was 1.5???2.0h. Dose-proportional increases in Cmax and AUC24h were observed for peficitinib and its metabolites following single and multiple doses, with minimal drug accumulation. The major metabolite was H2, with a systemic exposure of >150% of the parent AUC. Drug-related TEAEs were experienced by 5 (13.9%) and 12 (33.3%) subjects in the single- and multiple-dose periods, respectively. Following multiple doses of peficitinib, TEAEs were more frequent in higher than lower dose groups but were mild in severity with no related discontinuation or death. Conclusion: Following single and multiple doses of peficitinib in healthy Chinese subjects, peficitinib demonstrated rapid absorption and was well tolerated at all doses.

关键词： rheumatoid arthritis treatment dose-proportionality tsDMARDs

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NO SAFETY CONCERNS OBSERVED WHEN THE ADJUVANTED RECOMBINANT ZOSTER VACCINE (RZV) AND THE COVID-19 MRNA-1273 BOOSTER WERE CO-ADMINISTERED IN ≥ 50-YEAR-OLDS

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INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES 2023年 130卷 S55-S56页

作者： Naficy, A. Pirrotta, P. Kuxhausen, A. Miller, J. Leav, B. Mwakingwe-Omari, A. GSK Clin Sci Viral Vaccines Rockville MD USA GSK Vaccine Clin Safety & Pharmacovigilance Global Safety Wavre Belgium GSK Clin Evidence Generat Biostat & Stat Programming Rockville MD USA Moderna Clin Dev Cambridge MA USA

Intro The US CDC recommends that COVID-19 vaccines may be coadministered with other age-appropriate vaccines. There is limited data assessing outcomes, including reactogenicity, on such co-administration. For the first time, we present interim safety data of RZV administered concomitantly or sequentially with an mRNA-1273 booster vaccine.

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Reducing Patient Burden in Clinical Trials Through the Use of Historical Controls: Appropriate Selection of Historical Data to Minimize Risk of Bias

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THERAPEUTIC INNOVATION & REGULATORY SCIENCE 2020年第4期54卷 850-860页

作者： Lim, Jessica Wang, Li Best, Nicky Liu, Jeen Yuan, Jiacheng Yong, Florence Zhang, Lanju Walley, Rosalind Gosselin, Alice Roebling, Robert Viele, Kert GSK Clin Stat 1250 S Collegeville Rd Collegeville PA 19426 USA AbbVie Data & Stat Sci N Chicago IL USA GSK Adv Biostat & Data Analyt Uxbridge Middx England Allergan Stat Sci & Programming Irvine CA USA Pfizer Biostat Worldwide Res & Dev Cambridge MA USA UCB Ctr Excellence Stat Innovat Slough Berks England Sanofi Biostat & Programming Paris France UCB Global Clin Dev & Med Affairs Monheim Germany Berry Consultants Austin TX USA

Historical data have been used to augment or replace control arms in some rare disease and pediatric clinical trials. With greater availability of historical data and new methodology such as dynamic borrowing, the inclusion of historical data in clinical trials is an increasingly appealing approach for larger disease areas as well, as this can result in increased power and precision and can minimize the burden on patients in clinical trials. However, sponsors must assess whether the potential biases incurred with this approach outweigh the benefits and discuss this trade-off with the regulatory agencies. This paper discusses important points for the appropriate selection of historical controls for inclusion in the analysis of primary and/or key secondary endpoint(s) in clinical trials. The general steps are as follows: (1) Assess whether a trial is a suitable candidate for this approach. (2) If it is, then carefully identify appropriate historical trials to minimize selection bias. (3) Refine the historical control set if appropriate, for example, by selecting subsets of studies or patients. Identification of trial settings that are amenable to historical borrowing and selection of appropriate historical data using the principles discussed in this paper has the potential to lead to more efficient estimation and decision making. Ultimately, this efficiency gain results in lower patient burden and gets effective drugs to patients more quickly.

关键词： TransCelerate Historical controls Clinical trials Selection bias

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The Hospital Recovery Scale: A clinically useful endpoint in patients hospitalized with influenza

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CONTEMPORARY CLINICAL TRIALS 2022年 123卷 106952-106952页

作者： van Duijnhoven, Wilbert Van Dromme, Ilse Haesendonckx, Steven Witek, James Leopold, Lorant Janssen Pharmaceut NV Stat & Decis Sci Beerse Belgium Janssen Pharmaceut NV Clin Biostat Beerse Belgium Janssen Pharmaceut NV Stat Programming Beerse Belgium Janssen Res & Dev Med Dept Titusville NJ USA Janssen Pharmaceut NV Biostat Stat & Decis Sci Turnhoutseweg 30 B-2340 Beerse Belgium

Background: Currently, no single best primary endpoint exists for measuring the efficacy of treatments in seriously ill patients with respiratory infections, such as influenza, who require hospitalization. The Hospital Recovery Scale is an ordinal endpoint used to evaluate treatment outcomes in clinical studies of hospitalized patients infected with influenza. Methods: To determine whether Hospital Recovery Scale outcomes correspond to those for other clinical endpoints in patients hospitalized due to influenza, data from the phase 3 randomized, double-blind ZORO clinical trial (NCT01231620) were analyzed. Randomized influenza-infected patients were divided into sub-groups of interest based on prespecified baseline and infection-related characteristics, as well as randomized treatment arms (intravenous zanamivir 300 mg or 600 mg, or oral oseltamivir 75 mg). Clinical endpoints relevant to this population were included to analyze differences in outcomes between the subgroups, and cor-respondence of these endpoints and hospital recovery endpoint was evaluated. Results: Data from 488 patients were analyzed. There were strong correlations (rho s > 0.8) between the Hospital Recovery Scale assessed on the day after completion of a 5-day antiviral therapy (Day 6) and both time to hospital discharge and time to intensive care unit discharge, and moderate to strong correlations (0.6 < rho s < 0.8) between the Hospital Recovery Scale on Day 6 and several other relevant clinical endpoints. Conclusions: The Hospital Recovery Scale is applicable as a primary endpoint in trials to evaluate new therapies for severely ill patients hospitalized due to influenza, and may have utility in other severe respiratory illnesses such as COVID-19.

关键词： Hospitalization Hospital Recovery Scale Influenza Ordinal endpoint Respiratory infection

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A Methodology Report for the Life's Snapshot Cohort Study to Investigate the Long-Term Efficacy of a Violence Intervention

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VIOLENCE AGAINST WOMEN 2022年第1期28卷 316-344页

作者： Coker, Ann L. Bush, Heather M. Brancato, Candace Huang, Zhengyan Clear, Emily R. Follingstad, Diane R. Univ Kentucky Coll Med Dept Obstet & Gynecol Lexington KY 40506 USA Univ Kentucky Coll Publ Hlth Dept Biostat Lexington KY 40506 USA Univ Kentucky Dept Stat DATAQUeST Data Qual & Stat Programming Lexington KY 40506 USA Univ Kentucky Coll Publ Hlth Dept Hlth Management & Policy Lexington KY 40506 USA Univ Kentucky Dept Psychiat Lexington KY 40506 USA

Engaged bystander interventions are recognized as "promising" programming to reduce sexual violence (SV), yet little is known of the long-term (>12-month) impact of programming on SV and related forms of gender-based violence. Funded by NIH as a prospective cohort study, Life's Snapshot recruited and followed three waves of high school seniors who had participated in a large high-school cluster-randomized controlled trial to evaluate the effectiveness of the Green Dot bystander intervention. This report provides the study design, recruitment methodology, recruitment and retention rates, survey items, and psychometric properties of measures included in the initial and annual electronic surveys with 24-48 months follow-up.

关键词： teen dating violence sexual violence bystander intervention methodology prospective cohort

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Neutralizing antibody correlates of sequence specific dengue disease in a tetravalent dengue vaccine efficacy trial in Asia

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VACCINE 2022年第41期40卷 5912-5923页

作者： Qi, Li Sun, Yanqing Juraska, Michal Moodie, Zoe Magaret, Craig A. Heng, Fei Carpp, Lindsay N. Gilbert, Peter B. Sanofi Biostat & Programming 55 Corp Dr Bridgewater NJ 08807 USA Univ N Carolina Dept Math & Stat 9201 Univ City Blvd Charlotte NC 28223 USA Fred Hutchinson Canc Ctr Vaccine & Infect Dis Div 1100 Fairview Ave North Seattle WA 98109 USA Univ North Florida Dept Math & Stat 1 UNF Dr Jacksonville FL 32224 USA Univ Washington Dept Biostat 3980 15th Ave NE Seattle WA 98109 USA Fred Hutchinson Canc Ctr Vaccine & Infect Dis Div 1100 Fairview Ave NorthM2-C206 Seattle WA 98109 USA Google New York New York NY 10011 USA

In the CYD14 trial of the CYD-TDV dengue vaccine in 2-14 year-olds, neutralizing antibody (nAb) titers to the vaccine-insert dengue strains correlated inversely with symptomatic, virologically-confirmed dengue (VCD). Also, vaccine efficacy against VCD was higher against dengue prM/E amino acid sequences closer to the vaccine inserts. We integrated the nAb and sequence data types by assessing nAb titers as a correlate of sequence-specific VCD separately in the vaccine arm and in the placebo arm. In both vaccine and placebo recipients the correlation of nAb titer with sequence-specific VCD was stronger for dengue nAb contact site sequences closer to the vaccine (p = 0.005 and p = 0.012, respectively). The risk of VCD in vaccine (placebo) recipients was 6.7- (1.80)-fold lower at the 90th vs 10th percentile of nAb for viruses perfectly matched to CYD-TDV, compared to 2.1- (0.78)-fold lower at the 90th vs 10th percentile for viruses with five amino acid mismatches. The evidence for a stronger sequence-distance dependent correlate of risk for the vaccine arm indicates departure from the Prentice criteria for a valid sequence-distance specific surrogate endpoint and suggests that the nAb marker may affect dengue risk differently depending on whether nAbs arise from infection or also by vaccination. However, when restricting to baselineseropositive 9-14 year-olds, the correlation pattern became more similar between the vaccine and placebo arms, supporting nAb titers as an approximate surrogate endpoint in this population. No sequencespecific nAb titer correlates of VCD were seen in baseline-seronegative participants. Integrated immune response/pathogen sequence data correlates analyses could help increase knowledge of correlates of risk and surrogate endpoints for other vaccines against genetically diverse pathogens. Trial registration: EU Clinical Trials Register 2014-001708-24;registration date 2014-05-26.(c) 2022 Elsevier Ltd. All rights reserved.

关键词： Immune correlate of protection Neutralising antibodies Sieve analysis Sequence analysis Surrogate endpoint Vaccine efficacy trial

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Single-Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC-122) in Subjects With Mild, Moderate, or Severe Renal Impairment

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CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT 2020年第7期9卷 785-796页

作者： Li, Yan MacGorman, Kimberly Liu, Liangang Chen, Jian Hoffmann, Matthew Palmisano, Maria Zhou, Simon Celgene Corp Translat Dev & Clin Pharmacol 86 Morris Ave Summit NJ 07920 USA Celgene Corp Biostat & Stat Programming Summit NJ 07920 USA Celgene Corp Nonclin Dev Summit NJ 07920 USA

CC-122 (Avadomide) is a nonphthalimide analogue of thalidomide that has multiple pharmacological activities including immune modulation of several immune cell subsets, antigrowth activity, antiproliferative activity, and antiangiogenic activity. CC-122 as monotherapy and in combination with other agents is being evaluated for multiple indications including hematologic malignancies and advanced solid tumors. Given that renal clearance is one of the major routes of elimination for CC-122 and its clearance/exposure could be affected by renal impairment, a total of 50 subjects with various degrees of renal function were enrolled in an open-label, single-dose study to evaluate the impact of renal impairment on CC-122 pharmacokinetic disposition. The study showed that following administration of a single oral dose of 3 mg CC-122, renal impairment reduced both the apparent total plasma clearance and renal clearance of CC-122, but it had less impact on CC-122 absorption, as demonstrated by similar T-max and C-max among groups with various degrees of renal function. Compared with exposure in subjects with normal renal function, total plasma exposure to CC-122 increased by similar to 20%, similar to 50%, and similar to 120% in subjects with mild, moderate, and severe renal insufficiency, respectively. Results from this study combined with modeling/simulation suggest that dose adjustments are necessary in patients with moderate or severe but not with mild renal impairment. Finally, a single dose of 3 mg CC-122 was safe and well tolerated by healthy subjects and subjects with mild, moderate, and severe renal impairment.

关键词： avadomide CC-122 renal impairment pharmacokinetics safety tolerability

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Sargramostim (rhu GM-CSF) Improves Survival of Non-Human Primates with Severe Bone Marrow Suppression after Acute, High-Dose, Whole-Body Irradiation

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RADIATION RESEARCH 2021年第2期195卷 191-199页

作者： Clayton, Nicholas P. Khan-Malek, Richard C. Dangler, Charles A. Zhang, Donghui Ascah, Alexis Gains, Malcolm Gardner, Brent Mockbee, Colleen Keutzer, Joan M. McManus, John Authier, Simon Sanofi Genzyme Global Rare Dis Cambridge MA USA Sanofi Global Biostat & Programming Bridgewater NJ USA Sanofi Preclin Safety Framingham MA USA Liminal Biosci Laval PQ Canada Partner Therapeut Inc Lexington MA USA Charles River Labs 445 Boul Armand Frappier Laval PQ H7V 4B3 Canada

Exposure to acute, high-dose, whole-body ionizing radiation results in bone marrow failure (hematopoietic acute radiation syndrome with resultant infection, bleeding, anemia, and increased risk of death). Sargramostim (yeast-derived rhu GM-CSF), a yeast-derived, molecularly cloned, hematopoietic growth factor and pieiotropic cytokine supports proliferation, differentiation, maturation and survival of cells of several myeloid lineages. We evaluated the efficacy of sargramostim in non-human primates (rhesus macaques) exposed to whole-body ionizing radiation at a 50-60% lethal dose. The primary end point was day 60 survival. Non-human primates received daily subcutaneous sargramostim (7 mcg/kg/day) or control. To reflect the anticipated setting of a nuclear or radiologic event, treatment began 48 h postirradiation, and non-human primates received only moderate supportive care (no whole blood transfusions or individualized antibiotics). Sargramostim significantly increased day 60 survival to 78% (95% confidence interval, 61-90%) vs. 42% (26-59%;P = 0.0018) in controls. Neutrophil, platelet and lymphocyte recovery rates were accelerated and infection rates decreased. Improved survival when sargramostim was started 48 h postirradiation, without use of intensive supportive care, suggests sargramostim may be effective in treating humans exposed to acute, high-dose whole-body, ionizing radiation in a scenario such as a mass casualty event. (C) 2021 by Radiation Research Society

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An innovative phase 2 proof-of-concept trial design to evaluate SAR445088, a monoclonal antibody targeting complement C1s in chronic inflammatory demyelinating polyneuropathy

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JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM 2023年第2期28卷 276-285页

作者： Querol, Luis Lewis, Richard A. Hartung, Hans-Peter Van Doorn, Pieter A. Wallstroem, Erik Luo, Xiaodong Alonso-Alonso, Miguel Atassi, Nazem Hughes, Richard A. C. Hosp Santa Creu & Sant Pau Dept Neurol Neuromuscular Dis Unit Barcelona Spain Ctr Invest Biomed Red Enfermedades Raras CIBERER Madrid Spain Cedars Sinai Med Ctr Los Angeles CA USA Heinrich Heine Univ Fac Med Dept Neurol Dusseldorf Germany Univ Sydney Brain & Mind Ctr Sydney NSW Australia Med Univ Vienna Dept Neurol Vienna Austria Palacky Univ Olomouc Dept Neurol Olomouc Czech Republic Univ Med Ctr Erasmus MC Rotterdam Netherlands Sanofi R&D Neurol Dev Cambridge MA USA Sanofi R&D Biostat & Programming Bridgewater NJ USA UCL UCL Queen Sq Inst Neurol London England

Background and AimsChronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disease of the peripheral nerves, with significant unmet treatment needs. Clinical trials in CIDP are challenging;thus, new trial designs are needed. We present design of an open-label phase 2 study (NCT04658472) evaluating efficacy and safety of SAR445088, a monoclonal antibody targeting complement C1s, in CIDP. MethodsThis phase 2, proof-of-concept, multicenter, open-label trial will evaluate the efficacy, and safety of SAR445088 in 90 patients with CIDP across three groups: (1) currently treated with standard-of-care (SOC) therapies, including immunoglobulin or corticosteroids (SOC-Treated);(2) refractory to SOC (SOC-Refractory);and (3) naive to SOC (SOC-Naive). Enrolled participants undergo a 24-week treatment period (part A), followed by an optional treatment extension for up to an additional 52 weeks (part B).In part A, the primary endpoint for the SOC-Treated group is the percentage of participants with a relapse after switching from SOC to SAR445088. The primary endpoint for the SOC-Refractory and SOC-Naive groups is the percentage of participants with a response, compared to baseline. Secondary endpoints include safety, tolerability, immunogenicity, and efficacy of SAR445088 during 12-week overlapping period (SOC-Treated). Part B evaluates long-term safety and durability of efficacy. Data analysis will be performed using Bayesian statistics (predefined efficacy thresholds) and historical data-based placebo assumptions to support program decision-making. InterpretationThis innovative trial design based on patient groups and Bayesian statistics provides an efficient paradigm to evaluate new treatment candidates across the CIDP spectrum and can help accelerate development of new therapies.

关键词： Bayesian analysis CIDP complement classical pathway complement C1s SAR445088 trial design

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SPA: Single patient acceleration in oncology dose-escalation trials

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CONTEMPORARY CLINICAL TRIALS 2021年 105卷 106378-106378页

作者： Mi, Gu Bian, Yuanyuan Wang, Xuejing Zhang, Wei Eli Lilly & Co Lilly Corp Ctr Stat Data & Analyt Indianapolis IN 46285 USA Sanofi Biostat & Programming 640 Mem Dr Cambridge MA 02139 USA

Efficient identification of the optimal dose and dosing scheme is one of the most critical and challenging tasks in early-phase oncology trials. The results are far-reaching because advancing a sub-optimal dose to late-stage development may not only jeopardize patients' safety or fail to deliver desired efficacy, but also be costly to sponsors as refined doses must be evaluated further before seeking regulatory approval. A good dose-escalation design is anticipated to yield high accuracy of selecting the correct dose while using fewer patients and keeping the trial duration short. Recently, treating a single patient at each lower dose level until certain events are triggered to switch to larger cohorts has gained much popularity. We name this approach "Single Patient Acceleration" (SPA), which is essentially a variant of the Accelerated Titration Design (ATD) by Simon et al. [25]. Although literature on novel dose-escalation methods is abundant in the past decade, there is a surprisingly lack of research on evaluating the ATD/SPA framework. In this article, we conduct comprehensive simulations to evaluate the performance of dose-escalation designs with or without SPA, and show that SPA improves design efficiency with similar or better accuracy to those without the "single patient" component under certain circumstances (e.g., slow initial enrollment, or the true maximum tolerated dose is at higher candidate dose levels). Potential safety concerns as a cost of efficiency improvement are also investigated in a quantitative manner to illustrate a comprehensive benefit-risk profile of SPA. Practical considerations and recommendations in using SPA are also discussed.

关键词： Dose-escalation Accelerated titration Single patient acceleration Early-phase oncology trials

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