Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

Nina-Maria Wilpert; Davide Tonduti; Ylenia Vaia; Heiko Krude; Catherine Sarret; Markus Schuelke

doi:10.2147/NDT.S379703

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review

Neuropsychiatr Dis Treat. 2023 Oct 20:19:2195-2216. doi: 10.2147/NDT.S379703. eCollection 2023.

Authors

Nina-Maria Wilpert^{1

2}, Davide Tonduti³, Ylenia Vaia³, Heiko Krude⁴, Catherine Sarret⁵, Markus Schuelke^{1

2

6}

Affiliations

¹ Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Department of Pediatric Neurology, Berlin, Germany.
² Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health (BIH), Center for Chronically Sick Children, Berlin, Germany.
³ Unit of Pediatric Neurology, C.O.A.L.A. (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children's Hospital, Università Degli Studi Di Milano, Milan, Italy.
⁴ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Institute of Experimental Pediatric Endocrinology, Berlin, Germany.
⁵ Centre de Compétence des Leucodystrophies et Leucoencéphalopathies de Cause Rare, Centre Hospitalier Universitaire de Clermont-Ferrand, Clermont-Ferrand, France.
⁶ Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), NeuroCure Clinical Research Center, Berlin, Germany.

Abstract

Introduction: The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life.

Methods: We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials.

Results: We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints.

Discussion: We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.

Keywords: MCT8 deficiency; SLC16A2; Triac; movement disorders; stakeholder engagement; ultra-rare disease.

Grants and funding

NMW was supported by the DFG Research Unit 2841 “Beyond the Exome”. HK und MS were supported by the DFG P06 of TRR 296 “Local control of TH action” (LocoTact).