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

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).

Exploiting moderate hypoxia to benefit patients with brain disease: Molecular mechanisms and translational research in progress

“…Clearly defined prophylactic or therapeutic effects have been attributed to the use of normobaric hypoxia. In contrast to rather few reports on the application of hypoxia in patients suffering from multiple sclerosis, Parkinson's or Huntington's disease, 55,56,65,66 there are several studies suggesting beneficial impacts of hypoxia on cognitive performance, dementia, and Alzheimer's disease 48,67–71 . Moreover, hypoxic exposure has been suggested as a potentially effective treatment for human diseases associated with mitochondrial dysfunction 72 …”

The Hypoxia Response Pathway: A Potential Intervention Target in Parkinson's Disease?

“…115,225 In our recent phase 1 trial (manuscript in preparation), we deployed a dose-finding protocol by administering four different hypoxic conditioning sessions once a week and compared it to placebo. 229 The low-frequency administration allowed for sufficient wash-off of potential lingering effects. We evaluated target engagement (eg, EPO) and measured the acute cardiovascular, respiratory, and symptomatic responses to all hypoxic conditioning sessions.…”

“…As longer hypoxia bouts are associated with increased oxidative stress (see earlier), especially in PD due to reduced hypoxic ventilatory response, intermittent hypoxia with 3‐ to 5‐minute exposures to hypoxia is likely optimal 115,225 . In our recent phase 1 trial (manuscript in preparation), we deployed a dose‐finding protocol by administering four different hypoxic conditioning sessions once a week and compared it to placebo 229 . The low‐frequency administration allowed for sufficient wash‐off of potential lingering effects.…”

Reply to: Hypoxia treatment of Parkinson’s disease may disrupt the circadian system

“…In recent years, increasing attention has been given to hypoxia-based treatment for persons with neurodegenerative and mitochondrial disease, as reflected by the significant rise in publications from basic [ 1 ], preclinical [ 2 ] and clinical [ 3 , 4 ] research groups. Hypoxia treatment is based on the idea of hypoxic conditioning and adaptations induced by hypoxia.…”

“…Hypoxia treatment is based on the idea of hypoxic conditioning and adaptations induced by hypoxia. Recently, we published a protocol paper to assess the safety, feasibility, and acute symptomatic effects of single sessions of continuous and intermittent hypoxia (for 45 min, at FiO2 0.133 and 0.163) in persons with Parkinson’s disease (PD) [ 3 ].…”