Clinical trials in pediatric ALS: a TRICALS feasibility study

Tessa Kliest¹, Ruben P A Van Eijk^{1

2}, Ammar Al-Chalabi^{3

4}, Alberto Albanese⁵, Peter M Andersen⁶, Maria Del Mar Amador^{7

8}, Geir BrÅthen^{9

10}, Veronique Brunaud-Danel¹¹, Lev Brylev^{12

13}, William Camu¹⁴, Mamede De Carvalho^{15

16}, Cristina Cereda¹⁷, Hakan Cetin¹⁸, Delia Chaverri¹⁹, Adriano Chiò^{20

21}, Philippe Corcia²², Philippe Couratier²³, Fabiola De Marchi²⁴, Claude Desnuelle²⁵, Michael A Van Es¹, JesÚs Esteban²⁶, Massimiliano Filosto²⁷, Alberto GarcÍa Redondo²⁶, Julian Grosskreutz²⁸, Clemens O Hanemann²⁹, Trygve HolmØy^{30

31}, Helle HØyer³², Caroline Ingre^{33

34}, Blaz Koritnik³⁵, Magdalena Kuzma-Kozakiewicz³⁶, Thomas Lambert³⁷, Peter N Leigh³⁸, Christian Lunetta^{39

40}, Jessica Mandrioli^{41

42}, Christopher J Mcdermott⁴³, Thomas Meyer⁴⁴, Jesus S Mora⁴⁵, Susanne Petri⁴⁶, MÓnica Povedano⁴⁷, Evy Reviers⁴⁸, Nilo Riva⁴⁹, Kit C B Roes⁵⁰, Miguel Á Rubio^{51

52}, FranÇois Salachas^{7

8}, Stayko Sarafov⁵³, Gianni SorarÙ⁵⁴, Zorica Stevic⁵⁵, Kirsten Svenstrup⁵⁶, Anette Torvin MØller⁵⁷, Martin R Turner⁵⁸, Philip Van Damme^{59

60}, Lucie A G Van Leeuwen¹, Luis Varona⁶¹, Juan F VÁzquez Costa⁶², Markus Weber⁶³, Orla Hardiman⁶⁴, Leonard H Van Den Berg¹

Affiliations

¹ Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, the Netherlands.
² Biostatistics & Research Support, Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, the Netherlands.
³ Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
⁴ Department of Neurology, King's College Hospital, London, UK.
⁵ IRCCS Humanitas Research Hospital Rozzano, Milan, Italy.
⁶ Department of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden.
⁷ Département de Neurologie, Centre de référence SLA Ile de France.
⁸ Hôpital de la Pitié Salpêtrière, AP-HP, Paris, France.
⁹ Department of Neurology, University Hospital of Trondheim, Trondheim, Norway.
¹⁰ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ ALS centre, CHU, University of Lille Nord de France, Lille, France.
¹² Bujanov Moscow City Clinical Hospital, Moscow, Russian Federation.
¹³ Moscow Research and Clinical Center for Neuropsychiatry of the Healthcare Department, Moscow, Russian Federation.
¹⁴ ALS Centre CHU Gui de Chauliac, University of Montpellier, Montpellier, France.
¹⁵ Institute of Physiology-Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
¹⁶ Department of Neurosciences and Mental Health, H Santa Maria-CHLN, Lisbon, Portugal.
¹⁷ Regional Newborn Screening Laboratory, Vittore Buzzi Children's Hospital-University of Milan, Italy.
¹⁸ Department of Neurology, Medical University of Vienna, Vienna, Austria.
¹⁹ Neurology Service, Hospital Universitario La Paz, Madrid, Spain.
²⁰ 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
²¹ Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy.
²² Centre Constitutif SLA, CHRU de Tours - Fédération des centres SLA Tours-Limoges, LitORALS, Tours, France.
²³ Centre Constitutif de reference SLA-Fédération Tours-Limoges, CHU de Limoges, Limoges, France.
²⁴ "Maggiore della Carità" University Hospital, Novara, Italy.
²⁵ Hôpital Pasteur 2 - CHU de Nice, Nice, France.
²⁶ ALS Research Lab - ALS Unit, Instituto de Investigación Sanitaria Hospital 12 de Octubre "i + 12", CIBERER, Madrid, Spain.
²⁷ Department of Clinical and Experimental Sciences, University of Brescia; NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy.
²⁸ Precision Neurology, Dept. of Neurology, Lübeck University Hospital, Lübeck, Germany.
²⁹ University of Plymouth, Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
³⁰ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
³¹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³² Department of Medical Genetics, Telemark Hospital, Skien, Norway.
³³ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
³⁴ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³⁵ Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
³⁶ Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
³⁷ Department of Neurology, Royal Stoke University Hospital, Stoke, United Kingdom.
³⁸ Department of Neuroscience, Brighton and Sussex Medical School, Trafford Centre for Biomedical Research, University of Sussex, Brighton, UK.
³⁹ NEMO Clinical Center, Serena Onlus Foundation, Milan, Italy.
⁴⁰ NEMO LAB, Milan, Italy.
⁴¹ Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.
⁴² Department of Neuroscience, St. Agostino Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.
⁴³ Department of Neuroscience, University of Sheffield, Sheffield Institute for Translational Neuroscience, Sheffield, United Kingdom.
⁴⁴ ALS Outpatient Department, Charité - Universitatsmedizin Berlin, Berlin, Germany.
⁴⁵ ALS Unit/Neurology, Hospital San Rafael, Madrid, Spain.
⁴⁶ Department of Neurology, Hannover Medical School, Hannover, Germany.
⁴⁷ Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
⁴⁸ European Organization for Professionals and Patients with ALS (EUpALS) & ALS Liga Belgium, Leuven, Belgium.
⁴⁹ Department of Neurology, Experimental Neuropathology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
⁵⁰ Department of Health Evidence, Section Biostatistics, Radboud University Medical Centre Nijmegen, Nijmegen, the Netherlands.
⁵¹ Neuromuscular Unit, Department of Neurology, Hospital del Mar, Barcelona, Spain.
⁵² Instituto Hospital del Mar de Investivaciones Médicas (IMIM), Barcelona, Spain.
⁵³ Clinic of General Neurology, Medical University Sofia, University Hospital Alexandrovska, Sofia, Bulgaria.
⁵⁴ Department of Neurosciences, University of Padova, Padova, Italy.
⁵⁵ Clinic of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁵⁶ Department of Neurology, Bispebjerg-Frederiksberg Hospital and Rigshospitalet, University Hospital of Copenhagen, Denmark.
⁵⁷ Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
⁵⁸ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁵⁹ Department of Neurosciences, Laboratory for Neurobiology, KU Leuven and Centre for Brain & Disease Research, VIB, Leuven Brain Institute, Leuven, Belgium.
⁶⁰ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
⁶¹ Department of Neurology, Basurto University Hospital, Vizcaya, Spain.
⁶² ALS Unit and Neuromuscular Disease Unit, Department of Neurology, Hospital La Fe, Valencia, Spain.
⁶³ Neuromoscular Disease Unit/ALS Clinic, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
⁶⁴ Academic Unit of Neurology Trinity College Dublin Ireland, Dublin, Ireland.

PMID: 35172656
PMCID: PMC9662181
DOI: 10.1080/21678421.2021.2024856

Clinical trials in pediatric ALS: a TRICALS feasibility study

Tessa Kliest et al. Amyotroph Lateral Scler Frontotemporal Degener. 2022 Nov.

. 2022 Nov;23(7-8):481-488.

doi: 10.1080/21678421.2021.2024856. Epub 2022 Feb 16.

Authors

Affiliations

¹ Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, the Netherlands.
² Biostatistics & Research Support, Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht, the Netherlands.
³ Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
⁴ Department of Neurology, King's College Hospital, London, UK.
⁵ IRCCS Humanitas Research Hospital Rozzano, Milan, Italy.
⁶ Department of Clinical Sciences, Neurosciences, Umeå University, Umeå, Sweden.
⁷ Département de Neurologie, Centre de référence SLA Ile de France.
⁸ Hôpital de la Pitié Salpêtrière, AP-HP, Paris, France.
⁹ Department of Neurology, University Hospital of Trondheim, Trondheim, Norway.
¹⁰ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
¹¹ ALS centre, CHU, University of Lille Nord de France, Lille, France.
¹² Bujanov Moscow City Clinical Hospital, Moscow, Russian Federation.
¹³ Moscow Research and Clinical Center for Neuropsychiatry of the Healthcare Department, Moscow, Russian Federation.
¹⁴ ALS Centre CHU Gui de Chauliac, University of Montpellier, Montpellier, France.
¹⁵ Institute of Physiology-Instituto de Medicina Molecular, Faculty of Medicine, University of Lisbon, Lisbon, Portugal.
¹⁶ Department of Neurosciences and Mental Health, H Santa Maria-CHLN, Lisbon, Portugal.
¹⁷ Regional Newborn Screening Laboratory, Vittore Buzzi Children's Hospital-University of Milan, Italy.
¹⁸ Department of Neurology, Medical University of Vienna, Vienna, Austria.
¹⁹ Neurology Service, Hospital Universitario La Paz, Madrid, Spain.
²⁰ 'Rita Levi Montalcini' Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy.
²¹ Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy.
²² Centre Constitutif SLA, CHRU de Tours - Fédération des centres SLA Tours-Limoges, LitORALS, Tours, France.
²³ Centre Constitutif de reference SLA-Fédération Tours-Limoges, CHU de Limoges, Limoges, France.
²⁴ "Maggiore della Carità" University Hospital, Novara, Italy.
²⁵ Hôpital Pasteur 2 - CHU de Nice, Nice, France.
²⁶ ALS Research Lab - ALS Unit, Instituto de Investigación Sanitaria Hospital 12 de Octubre "i + 12", CIBERER, Madrid, Spain.
²⁷ Department of Clinical and Experimental Sciences, University of Brescia; NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy.
²⁸ Precision Neurology, Dept. of Neurology, Lübeck University Hospital, Lübeck, Germany.
²⁹ University of Plymouth, Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
³⁰ Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
³¹ Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
³² Department of Medical Genetics, Telemark Hospital, Skien, Norway.
³³ Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
³⁴ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
³⁵ Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
³⁶ Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
³⁷ Department of Neurology, Royal Stoke University Hospital, Stoke, United Kingdom.
³⁸ Department of Neuroscience, Brighton and Sussex Medical School, Trafford Centre for Biomedical Research, University of Sussex, Brighton, UK.
³⁹ NEMO Clinical Center, Serena Onlus Foundation, Milan, Italy.
⁴⁰ NEMO LAB, Milan, Italy.
⁴¹ Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.
⁴² Department of Neuroscience, St. Agostino Estense Hospital, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.
⁴³ Department of Neuroscience, University of Sheffield, Sheffield Institute for Translational Neuroscience, Sheffield, United Kingdom.
⁴⁴ ALS Outpatient Department, Charité - Universitatsmedizin Berlin, Berlin, Germany.
⁴⁵ ALS Unit/Neurology, Hospital San Rafael, Madrid, Spain.
⁴⁶ Department of Neurology, Hannover Medical School, Hannover, Germany.
⁴⁷ Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain.
⁴⁸ European Organization for Professionals and Patients with ALS (EUpALS) & ALS Liga Belgium, Leuven, Belgium.
⁴⁹ Department of Neurology, Experimental Neuropathology Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
⁵⁰ Department of Health Evidence, Section Biostatistics, Radboud University Medical Centre Nijmegen, Nijmegen, the Netherlands.
⁵¹ Neuromuscular Unit, Department of Neurology, Hospital del Mar, Barcelona, Spain.
⁵² Instituto Hospital del Mar de Investivaciones Médicas (IMIM), Barcelona, Spain.
⁵³ Clinic of General Neurology, Medical University Sofia, University Hospital Alexandrovska, Sofia, Bulgaria.
⁵⁴ Department of Neurosciences, University of Padova, Padova, Italy.
⁵⁵ Clinic of Neurology, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia.
⁵⁶ Department of Neurology, Bispebjerg-Frederiksberg Hospital and Rigshospitalet, University Hospital of Copenhagen, Denmark.
⁵⁷ Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
⁵⁸ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁵⁹ Department of Neurosciences, Laboratory for Neurobiology, KU Leuven and Centre for Brain & Disease Research, VIB, Leuven Brain Institute, Leuven, Belgium.
⁶⁰ Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
⁶¹ Department of Neurology, Basurto University Hospital, Vizcaya, Spain.
⁶² ALS Unit and Neuromuscular Disease Unit, Department of Neurology, Hospital La Fe, Valencia, Spain.
⁶³ Neuromoscular Disease Unit/ALS Clinic, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
⁶⁴ Academic Unit of Neurology Trinity College Dublin Ireland, Dublin, Ireland.

PMID: 35172656
PMCID: PMC9662181
DOI: 10.1080/21678421.2021.2024856

Abstract

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.

Keywords: Pediatric amyotrophic lateral sclerosis; clinical trial; clinical trials; ethics; pediatric investigation plan; therapy.

PubMed Disclaimer

Conflict of interest statement

AAC reports consultancies or advisory boards for Amylyx, Apellis, Biogen Idec, Brainstorm, Cytokinetics, GSK, Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, and Wave Pharmaceuticals.

CJM has conducted consultancy for Biogen, Merz, Amylyx, Orphazyme and Orion.

S.P. received honoraria as a speaker/consultant from Biogen GmbH, Roche, Novartis, Teva, Cytokinetics Inc. and Desitin; and grants from DGM e.V, Federal Ministry of Education and Research, German Israeli Foundation for Scientific Research and Development, EU Joint Programme for Neurodegenerative Disease Research.

Figures

**Figure 1**
ALS experts’ opinions (yes or no) on whether a waiver should apply to patients with ALS below the age of 18, n = 49.

See this image and copyright information in PMC

References

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Clinical trials in pediatric ALS: a TRICALS feasibility study

Affiliations

Clinical trials in pediatric ALS: a TRICALS feasibility study

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

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