Multiple N-of-1 trials to investigate hypoxia therapy in Parkinson's disease: study rationale and protocol

Jules M Janssen Daalen, Marjan J Meinders, Federica Giardina, Kit C B Roes, Bas C Stunnenberg, Soania Mathur, Philip N Ainslie, Dick H J Thijssen, Bastiaan R Bloem, Jules M Janssen Daalen, Marjan J Meinders, Federica Giardina, Kit C B Roes, Bas C Stunnenberg, Soania Mathur, Philip N Ainslie, Dick H J Thijssen, Bastiaan R Bloem

Abstract

Background: Parkinson's disease (PD) is a neurodegenerative disease, for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that hypoxia-based therapy might have short- and long-term benefits in PD. We present the contours of the first study to assess the safety, feasibility and physiological and symptomatic impact of hypoxia-based therapy in individuals with PD.

Methods/design: In 20 individuals with PD, we will investigate the safety, tolerability and short-term symptomatic efficacy of continuous and intermittent hypoxia using individual, double-blind, randomized placebo-controlled N-of-1 trials. This design allows for dose finding and for including more individualized outcomes, as each individual serves as its own control. A wide range of exploratory outcomes is deployed, including the Movement Disorders Society Unified Parkinson's Disease Rating scale (MDS-UPDRS) part III, Timed Up & Go Test, Mini Balance Evaluation Systems (MiniBES) test and wrist accelerometry. Also, self-reported impression of overall symptoms, motor and non-motor symptoms and urge to take dopaminergic medication will be assessed on a 10-point Likert scale. As part of a hypothesis-generating part of the study, we also deploy several exploratory outcomes to probe possible underlying mechanisms of action, including cortisol, erythropoietin and platelet-derived growth factor β. Efficacy will be assessed primarily by a Bayesian analysis.

Discussion: This evaluation of hypoxia therapy could provide insight in novel pathways that may be pursued for PD treatment. This trial also serves as a proof of concept for deploying an N-of-1 design and for including individualized outcomes in PD research, as a basis for personalized treatment approaches.

Trial registration: ClinicalTrials.gov Identifier: NCT05214287 (registered January 28, 2022).

Keywords: Clinical trial; Disease-modifying; Hypoxia; Mitochondrial dysfunction; Parkinson’s disease; Treatment.

Conflict of interest statement

Bastiaan R. Bloem has received honoraria from serving on the scientific advisory board for Abbvie, Biogen, UCB, and Walk with Path; has received fees for speaking at conferences from AbbVie, Zambon, Roche, GE Healthcare, and Bial; and has received research support from The Netherlands Organisation for Scientific Research, the Michael J. Fox Foundation, UCB, Abbvie, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson Foundation, Verily Life Sciences, Horizon 2020, the Topsector Life Sciences and Health, and the Parkinson Vereniging. The other authors have nothing to disclose.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Design of the self-reported outcomes scoring in the multiple N-of-1 trials of every individual patient

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