Hypoxic conditioning in Parkinson's disease: randomized controlled multiple N-of-1 trials

Abstract

Preclinical evidence suggests positive symptomatic and neuroprotective effects of hypoxic conditioning in Parkinson's disease (PD). This study (NCT05214287) investigated the safety, feasibility, short-term symptomatic and downstream effects of hypoxic conditioning in individuals with PD. 20 individuals with PD (mean age 62, 10 women, Hoehn-Yahr 1.5-3) completed randomized controlled double-blinded multiple N-of-1 trials. Each participant underwent five different 45-minute hypoxia interventions in duplicate: continuous hypoxia at FiO₂ 0.163 and 0.127, intermittent (five-minute intervals interspersed with normoxia) at FiO₂ 0.163 and 0.127, and placebo. Primary outcomes were safety and feasibility as measured by adverse events, vital parameter disturbances, participant-rated discomfort and feasibility questionnaires. Secondary outcomes were short-term participant-rated and assessor-rated symptom scores. Exploratory indicators of target engagement were serum erythropoietin, brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), neurofilament light-chain (NfL), platelet-derived growth factor-receptor-β (PDGFRβ) and cortisol. Secondary outcomes were evaluated using frequentist and Bayesian analysis. 20 participants completed the protocol. The trial met its primary endpoints for safety and feasibility. 95 adverse events occurred, including one moderate and three serious events. Adverse events were not dose-dependent and occurred at comparable incidence following hypoxia and placebo. Hypoxic conditioning was well-tolerated. Low-F_IO₂ protocols caused significant oxygen desaturations in two participants. Participants considered longer-term application feasible. Intermittent hypoxia at F_IO₂ 0.163 modestly improved most participant-rated symptoms for several hours compared to placebo, but not assessor-rated scales. One hour after intervention, serum markers did not differ between interventions. Hypoxic conditioning is safe and feasible in individuals with PD, and specific protocols may be associated with short-term symptom improvement. These findings inform and support follow-up studies of longer-term safety and efficacy of hypoxic conditioning.

Fig. 1. CONSORT diagram of study participants through the protocol.

OFF-medication without dopaminergic medication, PFT pulmonary function testing, ECG electrocardiogram, SaO₂ arterial oxygen saturation.

Fig. 2. Adverse events per intervention protocol and in categories.

“Other” adverse events included mostly self-limiting paresthesia in one or more extremity (6, occurring in both the placebo as active intervention group), vagal symptoms (2) and a sensitive throat (2).

Fig. 3. Change in participant-reported symptoms after single sessions of hypoxic conditioning.

Change in the participant-selected symptom (usually the most prominent Parkinsonian symptom (A), urge to take dopaminergic medication (B) and global symptom impression (C). Three symptom scales were rated on a 10-point Likert scale pre- and post-intervention. The delta between the pre-intervention measurement and all subsequent post-intervention assessments is depicted in these figures. 0 min is the first post-intervention assessment, taken directly after the intervention, then 30 min post intervention, et cetera, until the last measurement 3 days post intervention.

Fig. 4. Study protocol for every participant per week.

As an example, the contents of week 1 are highlighted. All subsequent intervention weeks are identical in events and measurements. The visits for Set 1 (in brown) and Set 2 (in blue) are identical in design and interventions, apart from each set being randomized separately.