Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomised, placebo-controlled trial

Chitnis, Tanuja; Banwell, Brenda; Kappos, Ludwig; Arnold, Douglas L.; Gücüyener, Kıvılcım; Deiva, Kumaran; Скрипченко, Н В; Cui, Liying; Saubadu, Stéphane; Hu, Wenruo; Bénamor, Myriam; Le-Halpere, Annaig; Truffinet, Philippe; Tardieu, Marc; Dubois, Bénédicte; Verhelst, Hélène; Bojinova-Tchamova, Veneta; Mah, Jean K.; Fang, Fang; Hao, Yunpeng; Jiang, Li; Li, Ling; Mao, Ding-An; Qiu, Wei; Tan, Guojun; Wu, Ye; Zhang, Meini; Zhou, Hongyu; Zhou, Shuizhen; Gross‐Paju, Katrin; Cheuret, Emmanuel; Edan, Giles; Vukusic, Sandra; Chrousos, George; Zafeiriou, Dimitrios; Achiron, Anat; Vaknin‐Dembinsky, Adi; Yamout, Bassem; Laurynaitienė, Jūratė; Vaičienė-Magistris, Nerija; Bojkovski, V.; Trajkova, Vesna; Chaouki, S.; Kissani, Najib; Neuteboom, Rinze F.; Palavra, Filipe; Белова, А. Н.; Boyко, Alexey; Evdoshenko, Evgeny; Каирбекова, Е. И.; Malkova, N A; Shumilina, Maria; Скрипченко, Н. В.; Nikolić, Dimitrije; Meca-Lallana, José; Triki, Chahnez; Mhiri, Chokri; Gouider, Riadh; Anlar, Banu; Hız, Ayşe Semra; İdıman, Egemen; Türkoğlu, Recai; Yapıcı, Zühal; Yılmaz, Ünsal; Tantsura, Lyudmyla; Voloshyna, N. N.; Lim, Ming; Wassmer, Evangeline; Cascione, Mark; LaGanke, Christopher; Rathke, Kevin; Scagnelli, John

doi:10.1016/s1474-4422(21)00364-1

Cited by 53 publications

(53 citation statements)

References 31 publications

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“…This phase III, placebo-controlled study (TERIKIDS trial, NCT02201108) has enrolled up to 166 POMS patients that were randomized to either placebo or the full adult teriflunomide dose of 14 mg (1:2 ratio) [ 71 ]. Although teriflunomide treatment resulted in a 34% reduction in risk of relapse, this primary study outcome was not statistically significant when compared to placebo [ 72 ].…”

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

“…The study investigators have listed several reasons that could serve as a potential explanation for the lack of trial significance. One main reason mentioned argues that the placebo group had significantly greater MRI activity during the study, which forced the investigators to switch patients from a double-blind to open-label phase (rescue procedure) [ 72 ]. Therefore, a large number of censored placebo patients did not reach the final study outcome, resulting in a much smaller and stable comparison group that unfavored the teriflunomide treatment [ 72 ].…”

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

“…One main reason mentioned argues that the placebo group had significantly greater MRI activity during the study, which forced the investigators to switch patients from a double-blind to open-label phase (rescue procedure) [ 72 ]. Therefore, a large number of censored placebo patients did not reach the final study outcome, resulting in a much smaller and stable comparison group that unfavored the teriflunomide treatment [ 72 ]. In hindsight, a primary trial outcome of time to first relapse would have mitigated this limitation.…”

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

“…In hindsight, a primary trial outcome of time to first relapse would have mitigated this limitation. The 8-week run-in phase for dosage finding in the teriflunomide arm could be considered as another unfavorable trial design that may have allowed more in-trial activity [ 72 ]. A post-hoc analysis demonstrated a significant reduction in MRI activity, with a 55% reduction in new or newly enlarging T2 lesions and a 75% reduction in gadolinium-enhancing lesions [ 72 ].…”

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

“…The 8-week run-in phase for dosage finding in the teriflunomide arm could be considered as another unfavorable trial design that may have allowed more in-trial activity [ 72 ]. A post-hoc analysis demonstrated a significant reduction in MRI activity, with a 55% reduction in new or newly enlarging T2 lesions and a 75% reduction in gadolinium-enhancing lesions [ 72 ]. Similarly, teriflunomide also demonstrated a significant treatment effect on a combined measure of MRI activity and clinical relapses [ 72 ].…”

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

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Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

et al. 2021

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Pediatric-onset multiple sclerosis (POMS) is a rare neuroinflammatory and neurodegenerative disease that has a significant impact on long-term physical and cognitive patient outcomes. A small percentage of multiple sclerosis (MS) diagnoses occur before the age of 18 years. Before treatment initiation, a careful differential diagnosis and exclusion of other similar acquired demyelinating syndromes such as anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD) is warranted. The recent 2017 changes to the McDonald criteria can successfully predict up to 71% of MS diagnoses and have good specificity of 95% and sensitivity of 71%. Additional measures such as the presence of T1-weighted hypointense lesions and/or contrast-enhancing lesions significantly increase the accuracy of diagnosis. In adults, early use of disease-modifying therapies (DMTs) is instrumental to a better long-term prognosis, including lower rates of relapse and disability worsening, and numerous FDA-approved therapies for adult-onset MS are available. However, unlike their adult counterparts, the development, testing, and regulatory approval of POMS treatments have been significantly slower and hindered by logistic and/or ethical considerations. Currently, only two MS DMTs (fingolimod and teriflunomide) have been tested in large phase III trials and approved by regulatory agencies for use in POMS. First-line therapies not approved by the FDA for use in children (interferon-β and glatiramer acetate) are also commonly used and result in a significant reduction in inflammatory activity when compared with non-treated POMS patients. An increasing number of POMS patients are now treated with moderate efficacy therapies such as dimethyl fumarate and high-efficacy therapies such as natalizumab, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, and/or autologous hematopoietic stem cell transplantation. These high-efficacy DMTs generally provide additional reduction in inflammatory activity when compared with the first-line medications (up to 62% of relapse-rate reduction). Therefore, a number of phase II and III trials are currently investigating their efficacy and safety in POMS patients. In this review, we discuss potential changes in the regulatory approval process for POMS patients that are recommended for DMTs already approved for the adult MS population, including smaller sample size for pharmacokinetic/pharmacodynamic studies, MRI-centered primary outcomes, and/or inclusion of teenagers in the adult trials.

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Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

Section: Use Of Disease-modifying Treatment In Pediatric Multiple Sclerosismentioning

confidence: 99%

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Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

et al. 2021

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Considering the Future of Pediatric Multiple Sclerosis Trials After the CONNECT Open-Label Randomized Trial

2022

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The approach to treatment of relapsing-remitting multiple sclerosis (RRMS) is rapidly evolving, with more than 15 disease-modifying therapies (DMTs) currently licensed for adults. Current treatment algorithms in children with multiple sclerosis (MS) remain heavily reliant on adult MS protocols, and most DMTs in children are prescribed off-label. Convincing evidence has increasingly emerged to support the biological rationale that effective DMTs in adult patients with MS are equally efficacious in children. 1 To date, only 2 randomized clinical trials of DMTs have been published in pediatric-onset MS (POMS). 2,3 This is partly a result of major recruitment challenges due to the low incidence and prevalence of POMS, in addition to challenges of MS diagnosis in children, with an emphasis on exclusion of other mimics, particularly antibody-mediated diseases such as myelin oligodendrocyte glycoprotein and aquaporin-4 antibodies. 4 Both previously published clinical trials in POMS compared newer oral agents (teriflunomide and fingolimod) to either older injectables or placebo. In the TERIKIDS trial, conducted at 57 clinical centers in 22 countries, 109 patients (aged <18 years) were randomly assigned to teriflunomide and 57 to placebo. The study demonstrated similar efficacy of teriflunomide in a pediatric cohort Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Abdel-Mannan O et al. JAMA Network Open.

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Reinterpreting Clinical Trials in Children With Multiple Sclerosis Using a Bayesian Approach

et al. 2022

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Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomised, placebo-controlled trial

Cited by 53 publications

References 31 publications

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

Considering the Future of Pediatric Multiple Sclerosis Trials After the CONNECT Open-Label Randomized Trial

Reinterpreting Clinical Trials in Children With Multiple Sclerosis Using a Bayesian Approach

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