Multiple N-of-1 Trials of (Intermittent) Hypoxia Therapy in Parkinson's Disease

Study Overview
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Brief Summary
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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
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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)

Official Title
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An N-of-1 Double-blind Randomized Phase 1 Trial of the Safety and Feasibility of (Intermittent) Hypoxia Therapy in Parkinson's Disease (TALISMAN)

Conditions
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Parkinson Disease, Effect of Drug

Intervention / Treatment
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* Drug: Hypoxic Gas Mixture


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intermittent with 5x5-minutes, FiO2 0.163<br>Delivered intermittently, with FiO2 0.163 and room-air, each 5 minutes, for 5 cycles/session | Drug: Hypoxic Gas Mixture<br>* Using a commercially available hypoxicator, varying gas mixtures as described will be administered via a tight-fitting oxygen mask. In the circuitry, a three-way valve is placed that allows for the intermittent administration of hypoxia: the valve either passes the hypoxic mixture from the hypoxicator or room air.<br>* Other names: Hypoxicator;|
| Experimental: Intermittent with 5x5-minutes, FiO2 0.127 or 0.133<br>Delivered intermittently, with FiO2 0.127 or 0.133 (depending on SaO2 during screening procedure at FiO2 0.127, see study procedures) and room-air, each 5 minutes, for 5 cycles/session | Drug: Hypoxic Gas Mixture<br>* Using a commercially available hypoxicator, varying gas mixtures as described will be administered via a tight-fitting oxygen mask. In the circuitry, a three-way valve is placed that allows for the intermittent administration of hypoxia: the valve either passes the hypoxic mixture from the hypoxicator or room air.<br>* Other names: Hypoxicator;|
| Experimental: Continuous for 45 minutes, FiO2 0.163<br>Delivered via the hypoxicator | Drug: Hypoxic Gas Mixture<br>* Using a commercially available hypoxicator, varying gas mixtures as described will be administered via a tight-fitting oxygen mask. In the circuitry, a three-way valve is placed that allows for the intermittent administration of hypoxia: the valve either passes the hypoxic mixture from the hypoxicator or room air.<br>* Other names: Hypoxicator;|
| Experimental: Continuous for 45 minutes, FiO2 0.127 or 0.133<br>FiO2 0.127 or 0.133 (depending on SaO2 during screening procedure at FiO2 0.127, see study procedures) | Drug: Hypoxic Gas Mixture<br>* Using a commercially available hypoxicator, varying gas mixtures as described will be administered via a tight-fitting oxygen mask. In the circuitry, a three-way valve is placed that allows for the intermittent administration of hypoxia: the valve either passes the hypoxic mixture from the hypoxicator or room air.<br>* Other names: Hypoxicator;|
| Placebo Comparator: Continuous for 45 minutes, FiO2 0.209<br>Delivered via an open three-way valve in the circuitry from hypoxicator to the participant | Drug: Hypoxic Gas Mixture<br>* Using a commercially available hypoxicator, varying gas mixtures as described will be administered via a tight-fitting oxygen mask. In the circuitry, a three-way valve is placed that allows for the intermittent administration of hypoxia: the valve either passes the hypoxic mixture from the hypoxicator or room air.<br>* Other names: Hypoxicator;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nature and number of adverse events | Actively reported during intervention and passively for up to 3 days after the intervention, adverse events will be collected. | Until 3 days post-intervention | 
| Self-reported dizziness, discomfort and stress on a ten-point scale | Every 10 minutes up to one hour post-intervention, one time next morning post-intervention, 10-point Likert scale, lower is better. | Until 3 days post-intervention | 
| Blood pressure | Systolic and diastolic blood pressure | Baseline and every 5 mins until 30 mins post-intervention | 
| Heartrate | Beats/min | Baseline and every 5 mins until 30 mins post-intervention | 
| Respiratory rate | Breaths/min | Baseline and every 5 mins until 30 mins post-intervention | 
| Oxygen saturation | Percentage | Baseline and every 5 mins until 30 mins post-intervention | 
| Feasibility questionnaire | 17-item scale, scored 1-10, lower is better. Subscores and total score | After 1st, 5th, 10th post-intervention test | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant-selected motor symptom | Change from (pre-treatment) baseline in the symptom that improved most during previous positive altitude effect (if applicable), or other symptom of choice. Self-reported severity scores on a Likert-scale. 10-point Likert scale allowing half points. Lower is better. | 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. | 
| General impression of PD symptoms | Change from (pre-treatment) baseline on 10-point Likert scale allowing half points. Lower is better. | 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. | 
| Urge to take dopaminergic medication | Change from (pre-treatment) baseline on 10-point Likert scale allowing half points. Lower is better. | 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. | 
| Timed Up & Go Test | Change from (pre-treatment) baseline in total time and steps. The Timed Up & Go Test is a test that evaluates primarily gait functioning. Lower is better. | 30 minutes | 
| MiniBESTest | Change from (pre-treatment) baseline in item subscores and total score. The MiniBESTest is a concise balance test. Higher is better. | 30 minutes | 
| Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III | The MDS-UPDRS part III is the gold standard for motor assessment in Parkinson's disease. Change form (pre-treatment) baseline in item subscores and total scores. Lower is better. | 30 minutes | 
| Finger tapping | Change from (pre-treatment) baseline in number of taps during 10-second trials on both hands, one session each. Finger tapping is considered a measure of bradykinesia. Higher is better. | 30 minutes | 
| MDS Non-Motor Symptoms Scale (only items related to stress, fatigue, mood, anxiety, pain) | The most important potentially adaptive non-motor symptoms mentioned in this gold standard for non-motor symptom screening are selected. Likert scale 1-10 (allowing half points). Change from (pre-treatment) baseline. Lower is better. | 30 minutes | 
| Accelerometry during MDS-UPDRS part III, items on pronation-supination and tremor | During the MDS-UPDRS part III, accelerometry allows for quantification of therapeutic effects in addition to the MDS-UPDRS part III. Lower amplitude is better in tremor, higher frequency and rotational power is better in pronation-supination. Change from (pre-treatment) baseline. | 30 minutes | 
| Heart Rate Variability (HRV) | Average HRV during intervention and post intervention. HRV is a marker of cardiovascular stress. Change form (pre-treatment) baseline. Lower equals more stress. | 30 minutes | 
| Modified Purdue pegboard test | Change from (pre-treatment) baseline in number of pins per side. The Purdue pegboard test is primarily a measure of bradykinesia, hypokinesia and fine motor skills. Higher is better. | 30 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's disease, Treatment, Intermittent hypoxia therapy, IHT, Disease-modifying treatment, Symptomatic therapy, Neurodegenerative Diseases, Synucleinopathies, Oxygen Deficiency, Hypoxia, Brain, Movement Disorders