A randomized phase 1b/2a trial of the effectiveness of intermittent hypoxia interventions in Parkinson*s disease

Intermittent hypoxia interventions are a well-established intervention used by
athletes and individuals with cardiovascular disease, amongst others. The
safety and feasibility of (intermittent) hypoxia intervention and its
short-term effects on Parkinson*s disease (PD) symptoms were assessed in a
previous exploratory phase I trial. However, the net effects of multiple
hypoxia intervention sessions on PD symptoms are unknown. The results of the
previous phase I trial informed the study design of the newly proposed phase
1b-2a safety and efficacy trial.

To explore the safety, feasibility and net symptomatic effects of multiple
intermittent hypoxia intervention sessions in individuals with PD. Secondary
outcomes include exploring induction of relevant neuroprotective pathways as
measured in serum.

The study concerns a two-armed double-blinded randomized controlled trial.

45 minutes of normobaric intermittent hypoxia (FiO2 0.163 for 5 minutes
interspersed with 5 minutes normoxia) will be delivered via a hypoxicator (a
device that titrates decreased fractional oxygen from room air) through an
oxygen mask at participants* homes. Interventions will be conducted 3 times a
week, for 4 weeks in total. An instructor will be present for instructions
during the first session, and will remain present until necessary for safe and
comfortable hypoxia administration. This is followed by remote expert
assistance during the first week of interventions, followed by weekly
videocalls to ascertain adequacy of administration, safety and compliance.
During a pilot phase of the first four participants, participants visit the
hospital in the second week to closely monitor bodily responses to repeated
administration.

The mechanism of action of hypoxia interventions on the cardiovascular and
cardiorespiratory system in humans is relatively well-known in healthy
individuals and fragile individuals with a wide variety of conditions.
Extensive literature exists on hypoxia interventions, including more intense or
longer hypoxia trials than the current. Previous studies inducing intermittent
hypoxia in human individuals have shown significant positive cardiovascular
effects. Importantly, outside PD, IHT is a widely adopted intervention proven
safe in a variety of disciplines, including longer-term and more frequent
interventions in fragile populations such as elderly, individuals with chronic
obstructive pulmonary disease (COPD), and cardiac morbidity. Many studies have
used hypoxicators, including the models like the one that is used in this
protocol.
Cardiorespiratory complications intrinsic to PD have not led to adverse events
in intense aerobic exercise trials and participants are thorougly screened
before study initiation. In PD, our TALISMAN-1 trial seems to indicate hypoxia
administration is safe and feasible after having performed a structured
screening procedure. There is no indication of significant symptom worsening in
TALISMAN-1. Although there are no foreseeable adverse events in this
population, we take extensive safety measures that minimalize the risk of any
adverse events, albeit reversible or irreversible. In addition, the proposed
method of hypoxia administration is the most widely used. Studying this
intervention is warranted by the combination of preclinical evidence, and our
previous study results. There is potential discomfort due to breathing through
a mask or (unexpected and unprecedented) reversible worsening of symptoms.
Primarily, this will lead to physical discomfort. Moments of worsening of
symptoms might also cause psychological discomfort. We anticipate no social,
societal, privacy-related, financial or stigma-related adversity for our
participants.