Clinical trial NCT05214287: Multiple N-of-1 Trials of (Intermittent) Hypoxia Therapy in Parkinson's Disease
Official title: An N-of-1 Double-blind Randomized Phase 1 Trial of the Safety and Feasibility of (Intermittent) Hypoxia Therapy in Parkinson's Disease (TALISMAN)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Parkinson Disease
Effect of Drug
Keywords: Parkinson's disease
Treatment
Intermittent hypoxia therapy
IHT
Disease-modifying treatment
Symptomatic therapy
Neurodegenerative Diseases
Synucleinopathies
Oxygen Deficiency
Hypoxia, Brain
Movement Disorders
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Michael J. Fox Foundation for Parkinson's Research
First posted: 2022-01-28
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The investigators will deploy an N-of-1 trial design (also known as single participant cross-over trial) in which multiple treatment pairs of active treatment and placebo are offered to an individual participant in a randomized, double-blind fashion. In an N-of-1 trial, random variation within the treatment effect at the individual level can be better accounted for and methodological power is optimized due to repeated treatment-pairs and the fact that the individual participant acts as their own control. Thanks to this design, in which each treatment-pair should be exchangeable in time, N-of-1 trials are especially suitable to investigate treatments in chronic, symptomatic conditions, where period effects (i.e. changes in disease state) and carry over effects (i.e. lingering hypoxia effects) are small. Given the slowly progressive nature of PD with relative stable symptoms, several N-of-1 trials have already been successfully performed to study symptomatic treatments in PD.
Primary purpose: TREATMENT

Brief summary: In recent years, mitochondrial dysfunction and oxidative stress have been implicated in PD pathophysiology. Intermittent hypoxia therapy (IHT) is an upcoming treatment used by elite athletes as well as fragile individuals in clinical settings that works by improving exercise tolerance, neuroplasticity and inducing hypoxic preconditioning (HPC). HPC might improve the oxidative stress response in PD on the long-term. In addition, preclinical evidence suggests beneficial short-term effects such as influence on dopamine and noradrenalin release. Anecdotal evidence indeed suggests that visiting high-altitude areas improves PD symptoms and it is hypothesized that this effect results from decreased oxygen pressure at high altitudes. The safety and feasibility of (intermittent) hypoxia therapy on PD symptoms will be assessed in an exploratory phase I randomized-controlled trial.

Detailed description: Parkinson's disease (PD) currently affects 10 million people worldwide and its prevalence is projected to exponentially rise further in the absence of disease-modifying therapies. A scarcity of symptomatic treatments is available and the mainstay of therapy has been levodopa for over half a century. Although this treatment suffices for many patients in early phases of PD, treatment burden is significant, as are the adverse effects, wearing-off and dyskinesia that develop with disease progression. Therefore, additional treatment modalities are needed.

Preclinical studies have suggested that moderate hypoxia provokes release of survival-enhancing neurotransmitters, such as dopamine release from the substantia nigra. Clinical and preclinical evidence suggests the effects of hypoxia seem especially robust when applied using intermittent hypoxia therapy (IHT) compared to continuous hypoxia. IHT means that hypoxia is present for relatively short periods (i.e. minutes), interspersed with short periods of recovery at normoxia (i.e. sea-level). The precise working mechanism of IHT on the short term remains unclear, but the immediate clinical effects appear to be related to augmented dopamine release from the substantia nigra. Specifically, IHT may improve parkinsonian symptoms via activation of the Hypoxia Inducible Factor 1 (HIF-1) pathway, which in turn activates tyrosine hydroxylase (TH), which is the main rate-limiting enzyme in the production of dopamine. Several studies have demonstrated that HIF-1 stabilization leads to an increase in TH production, and consequently a rise in cellular dopamine content. IHT is a therapy proven safe and effective in a variety of disciplines, including fragile populations such as individuals with chronic obstructive pulmonary disorder (COPD), cardiac morbidity and spinal cord injury. Long-term application of IHT protocols was associated with improved oxidative stress response and adaptive plasticity in the dopaminergic system of rodents, suggesting that in addition to the acute symptomatic effects, repeated exposure to (intermittent) hypoxia might also exert some long-term neuroprotective effects. The general concept behind a possible (long-term) neuroprotective effect of IHT is the phenomenon of hypoxic conditioning: induction of a sub-toxic hypoxic stimulus to improve the (systemic) tolerance of cells and tissues to subsequent more severe stimuli, either in dose or duration. In this way, key adaptive mechanisms are induced that allow maintenance of cellular homeostasis under low-oxygen conditions. Among these adaptive mechanisms, activation of HIF-1 is the most prominent and most extensively described mechanism. Interestingly, IHT protocols also blocked the neurotoxic effect of agents that induce PD in rodents, preventing development of locomotor deficits, again suggesting some neuroprotective effects. Furthermore, circumstantial anecdotal evidence from individuals with PD suggests that ascending to high-altitude areas (e.g. on holidays) improves motor symptoms of PD, which the investigators recently confirmed in a survey conducted in the holiday context (https://doi.org/10.1002/mdc3.13597). The investigators hypothesize that the positive effect of altitude on the symptoms of PD result from decreased oxygen pressure at high altitude, which serves as an acute bodily stressor that releases survival-enhancing neurotransmitters such as dopamine and noradrenaline and might induce neuroprotective mechanisms.

The investigators will assess the potential of IHT in PD by assessing symptomatic effects of intermittent hypoxia therapy in an exploratory phase I trial. Primary objectives are the safety and feasibility of intermittent hypoxia in PD and assessing the responsiveness of subjective and standardized symptom scales to this intervention. This trial will exploit an aggregated N-of-1 approach, which allows testing multiple high-altitude simulation protocols and outcome measures, analysis of the treatment effect in individuals as it can account for random variation for treatment effects in the individual and enhances methodological power due to repeated treatment pairs.

During a screening procedure, participants undergo pulmonary function testing, carbon monoxide diffusion capacity testing and electrocardiography. If no cardiorespiratory abnormalities are demonstrated, individuals undergo a hypoxic intervention with gradually decreasing FiO2 levels from room air to either FiO2 0.127 or an arterial oxygen saturation (SaO2) of 80%, under vital parameter and blood gas monitoring. If a participant reaches FiO2 0.127 without SaO2 \<80%, the most intense active interventions will contain that FiO2. If a participant has an SaO2 \<80% before FiO2 0.127 is reached but still has an SaO2 of 80% or higher at FiO2 0.133, the most intense active intervention will be FiO2 0.133 instead of 0.127 (see Interventions)

Eligibility criteria: Inclusion criteria:

* Informed consent
* Clinical diagnosis of Parkinson's disease by a movement disorder specialized neurologist with Hoehn and Yahr staging 1.5 to 3.
* 15 individuals with self-reported personal experience of positive altitude effect.
* 5 individuals without self-reported personal experience of positive altitude effect.

Exclusion criteria:

* Individuals with diseases leading to restrictive and obstructive pulmonary diseases, pulmonary diffusion deficits, apnea and cardiac output deficits, such as pulmonary fibrosis, COPD, sleep apnea or excessive alcoholic intake, and congestive heart failure respectively.
* Arterial blood gas abnormalities at screening day (as per normal limits)
* Individuals with shortness of breath or other airway or breathing-related inconvenience related to lack of dopaminergic medication will be excluded.
* Inability to comply to intervention in off-medication condition (for example due to extreme discomfort, distress or severe head tremor due to being OFF, i.e. without dopaminergic medication).
* Individuals with unstable dopaminergic medication dose (changes in the last month)
* Individuals likely to start dopaminergic treatment in the next month, also judged by their treating neurologist
* Individuals with active deep brain stimulation
* Individuals unable to provide informed consent.

Primary outcomes:
measure: Nature and number of adverse events
timeFrame: Until 3 days post-intervention
measure: Self-reported dizziness, discomfort and stress on a ten-point scale
timeFrame: Until 3 days post-intervention
measure: Blood pressure
timeFrame: Baseline and every 5 mins until 30 mins post-intervention
measure: Heartrate
timeFrame: Baseline and every 5 mins until 30 mins post-intervention
measure: Respiratory rate
timeFrame: Baseline and every 5 mins until 30 mins post-intervention
measure: Oxygen saturation
timeFrame: Baseline and every 5 mins until 30 mins post-intervention
measure: Feasibility questionnaire
timeFrame: After 1st, 5th, 10th post-intervention test
Secondary outcomes:
measure: Participant-selected motor symptom
timeFrame: Directly after, as well as 30 and 60 minutes after the intervention and four times once every hour after that. In addition, these will be measured once every morning (i.e. in OFF) for the next three mornings after the intervention.
measure: General impression of PD symptoms
timeFrame: Directly after, as well as 30 and 60 minutes after the intervention and four times once every hour after that. In addition, these will be measured once every morning (i.e. in OFF) for the next three mornings after the intervention.
measure: Urge to take dopaminergic medication
timeFrame: Directly after, as well as 30 and 60 minutes after the intervention and four times once every hour after that. In addition, these will be measured once every morning (i.e. in OFF) for the next three mornings after the intervention.
measure: Timed Up & Go Test
timeFrame: 30 minutes
measure: MiniBESTest
timeFrame: 30 minutes
measure: Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
timeFrame: 30 minutes
measure: Finger tapping
timeFrame: 30 minutes
measure: MDS Non-Motor Symptoms Scale (only items related to stress, fatigue, mood, anxiety, pain)
timeFrame: 30 minutes
measure: Accelerometry during MDS-UPDRS part III, items on pronation-supination and tremor
timeFrame: 30 minutes
measure: Heart Rate Variability (HRV)
timeFrame: 30 minutes
measure: Modified Purdue pegboard test
timeFrame: 30 minutes
Other outcomes:
measure: Serum platelet-derived growth factor receptor β (PDGFRβ)
timeFrame: 60 minutes after intervention
measure: Serum cortisol
timeFrame: Directly after intervention, 30 minutes, 60 minutes
measure: Serum erythropoietin (EPO)
timeFrame: 60 minutes after intervention
Locations:
city: Nijmegen
country: Netherlands
facility: Dpt. of Physiology, Radboud University Medical Center
Study officials:
affiliation: Center of Expertise for Parkinson and Movement Disorders, Radboud university medical center
name: prof. dr. Bastiaan R. Bloem
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Integrative Physiology, Radboud university medical center
name: prof. dr. Dick H.J. Thijssen
role: PRINCIPAL_INVESTIGATOR
References:
citation: Janssen Daalen JM, Meinders MJ, Giardina F, Roes KCB, Stunnenberg BC, Mathur S, Ainslie PN, Thijssen DHJ, Bloem BR. Multiple N-of-1 trials to investigate hypoxia therapy in Parkinson's disease: study rationale and protocol. BMC Neurol. 2022 Jul 14;22(1):262. doi: 10.1186/s12883-022-02770-7.