Browsing by Author "Lacaze-Masmonteil, Thierry"

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    Adaptive designs in clinical trials: a systematic review-part I
    (2024-10-04) Ben-Eltriki, Mohamed; Rafiq, Aisha; Paul, Arun; Prabhu, Devashree; Afolabi, Michael O. S.; Baslhaw, Robert; Neilson, Christine J.; Driedger, Michelle; Mahmud, Salaheddin M.; Lacaze-Masmonteil, Thierry; Marlin, Susan; Offringa, Martin; Butcher, Nancy; Heath, Anna; Kelly, Lauren E.
    Abstract Background Adaptive designs (ADs) are intended to make clinical trials more flexible, offering efficiency and potentially cost-saving benefits. Despite a large number of statistical methods in the literature on different adaptations to trials, the characteristics, advantages and limitations of such designs remain unfamiliar to large parts of the clinical and research community. This systematic review provides an overview of the use of ADs in published clinical trials (Part I). A follow-up (Part II) will compare the application of AD in trials in adult and pediatric studies, to provide real-world examples and recommendations for the child health community. Methods Published studies from 2010 to April 2020 were searched in the following databases: MEDLINE (Ovid), Embase (Ovid), and International Pharmaceutical Abstracts (Ovid). Clinical trial protocols, reports, and a secondary analyses using AD were included. We excluded trial registrations and interventions other than drugs or vaccines to align with regulatory guidance. Data from the published literature on study characteristics, types of adaptations, statistical analysis, stopping boundaries, logistical challenges, operational considerations and ethical considerations were extracted and summarized herein. Results Out of 23,886 retrieved studies, 317 publications of adaptive trials, 267 (84.2%) trial reports, and 50 (15.8%) study protocols), were included. The most frequent disease was oncology (168/317, 53%). Most trials included only adult participants (265, 83.9%),16 trials (5.4%) were limited to only children and 28 (8.9%) were for both children and adults, 8 trials did not report the ages of the included populations. Some studies reported using more than one adaptation (there were 390 reported adaptations in 317 clinical trial reports). Most trials were early in drug development (phase I, II (276/317, 87%). Dose-finding designs were used in the highest proportion of the included trials (121/317, 38.2 %). Adaptive randomization (53/317, 16.7%), with drop-the-losers (or pick-the-winner) designs specifically reported in 29 trials (9.1%) and seamless phase 2-3 design was reported in 27 trials (8.5%). Continual reassessment methods (60/317, 18.9%) and group sequential design (47/317, 14.8%) were also reported. Approximately two-thirds of trials used frequentist statistical methods (203/309, 64%), while Bayesian methods were reported in 24% (75/309) of included trials. Conclusion This review provides a comprehensive report of methodological features in adaptive clinical trials reported between 2010 and 2020. Adaptation details were not uniformly reported, creating limitations in interpretation and generalizability. Nevertheless, implementation of existing reporting guidelines on ADs and the development of novel educational strategies that address the scientific, operational challenges and ethical considerations can help in the clinical trial community to decide on when and how to implement ADs in clinical trials. Study protocol registration https://doi.org/10.1186/s13063-018-2934-7 .
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    Doxapram versus placebo in preterm newborns: a study protocol for an international double blinded multicentre randomized controlled trial (DOXA-trial)
    (2023-10-10) Poppe, Jarinda A.; Flint, Robert B.; Smits, Anne; Willemsen, Sten P.; Storm, Kelly K.; Nuytemans, Debbie H.; Onland, Wes; Poley, Marten J.; de Boode, Willem P.; Carkeek, Katherine; Cassart, Vincent; Cornette, Luc; Dijk, Peter H.; Hemels, Marieke A. C.; Hermans, Isabelle; Hütten, Matthias C.; Kelen, Dorottya; de Kort, Ellen H. M.; Kroon, André A.; Lefevere, Julie; Plaskie, Katleen; Stewart, Breanne; Voeten, Michiel; van Weissenbruch, Mirjam M.; Williams, Olivia; Zonnenberg, Inge A.; Lacaze-Masmonteil, Thierry; Pas, Arjan B.; Reiss, Irwin K. M.; van Kaam, Anton H.; Allegaert, Karel; Hutten, G. J.; Simons, Sinno H. P.
    Abstract Background Apnoea of prematurity (AOP) is one of the most common diagnoses among preterm infants. AOP often leads to hypoxemia and bradycardia which are associated with an increased risk of death or disability. In addition to caffeine therapy and non-invasive respiratory support, doxapram might be used to reduce hypoxemic episodes and the need for invasive mechanical ventilation in preterm infants, thereby possibly improving their long-term outcome. However, high-quality trials on doxapram are lacking. The DOXA-trial therefore aims to investigate the safety and efficacy of doxapram compared to placebo in reducing the composite outcome of death or severe disability at 18 to 24 months corrected age. Methods The DOXA-trial is a double blinded, multicentre, randomized, placebo-controlled trial conducted in the Netherlands, Belgium and Canada. A total of 396 preterm infants with a gestational age below 29 weeks, suffering from AOP unresponsive to non-invasive respiratory support and caffeine will be randomized to receive doxapram therapy or placebo. The primary outcome is death or severe disability, defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness, at 18–24 months corrected age. Secondary outcomes are short-term neonatal morbidity, including duration of mechanical ventilation, bronchopulmonary dysplasia and necrotising enterocolitis, hospital mortality, adverse effects, pharmacokinetics and cost-effectiveness. Analysis will be on an intention-to-treat principle. Discussion Doxapram has the potential to improve neonatal outcomes by improving respiration, but the safety concerns need to be weighed against the potential risks of invasive mechanical ventilation. It is unknown if the use of doxapram improves the long-term outcome. This forms the clinical equipoise of the current trial. This international, multicentre trial will provide the needed high-quality evidence on the efficacy and safety of doxapram in the treatment of AOP in preterm infants. Trial registration ClinicalTrials.gov NCT04430790 and EUDRACT 2019-003666-41. Prospectively registered on respectively June and January 2020.
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    The Gut Microbiome of Premature Infants: An Ecological Analysis of a Probiotic Intervention Study
    (2021-10) Samara, Jumana; Arrieta, Marie Claire; McCoy, Kathy; Lacaze-Masmonteil, Thierry; Alshaikh, Belal
    Preterm infants are a unique population of patients, as prematurity is the leading cause of death in children under 5 years of age, and survivors are extremely challenged during their early and future life 1. Due to prematurity on every system, challenges faced by preterm infant early and later in life include, and are not limited to respiratory, digestive, immune, neurological, and growth-related conditions that can lead to life threatening complications and an increased risk to several diseases later in life 2-4. Probiotic strains are increasingly used in preterm infants due to their potential to reduce mortality and morbidities in this population. However, due to reduced evidence on safety and efficacy, these are not routinely used in extremely premature infants. The infant gut undergoes important developmental stages that are dependent upon the colonization with microorganism, beginning at birth 5. While it is well established that the premature gut microbiome exhibits profound alterations, the ecological patterns of microbial assembly and succession in preterm infants remained understudied and have only included bacteria. Moreover, it is not well understood how these processes are impacted by probiotics. The goal of my MSc research is to determine if probiotics use changes gut colonization patterns of the gut microbiome during and after treatment, and if the probiotic strains can persist in the gut of extremely premature infants. We showed a successful colonization of probiotics strains in the gut of extremely low birth weight preterm infants in addition to significant ecological changes of bacterial and fungal microbiome during the probiotic’s consumption and up to 6 months after treatment cessation. Our results confirmed that early life colonization with healthy bacteria beneficially impacts the future microbiome in extremely preterm infants.