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

Parkinson Disease Clinical Trial

— TALISMAN  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05214287
• Other study ID #: 112203
• Secondary ID: NL.77891.091.212
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: February 22, 2022
• Est. completion date: July 12, 2023

Study information

• Verified date: June 2023
• Source: Radboud University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: July 12, 2023
• Est. primary completion date: July 12, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Effect of Drug
• Hypoxia
• Parkinson Disease

Intervention

Drug:
• Hypoxic Gas Mixture
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.

Locations

Country	Name	City	State
Netherlands	Dpt. of Physiology, Radboud University Medical Center	Nijmegen

Sponsors (2)

Lead Sponsor	Collaborator
Radboud University Medical Center	Michael J. Fox Foundation for Parkinson's Research

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serum platelet-derived growth factor receptor ß (PDGFRß)	PDGFRß is a pericyte-released marker of hypoxia and blood-brain barrier integrity. Change from (pre-treatment) baseline. Higher equals more hypoxic-induced adaptive response	60 minutes after intervention
Other	Serum cortisol	Cortisol is a molecular marker of systemic stress. Change from (pre-treatment) baseline. Lower equals less stress.	Directly after intervention, 30 minutes, 60 minutes
Other	Serum erythropoietin (EPO)	Erythropoietin is a marker of cellular hypoxia. Change from (pre-treatment) baseline. Higher equals more hypoxic-induced adaptive response.	60 minutes after intervention
Primary	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
Primary	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
Primary	Blood pressure	Systolic and diastolic blood pressure	Baseline and every 5 mins until 30 mins post-intervention
Primary	Heartrate	Beats/min	Baseline and every 5 mins until 30 mins post-intervention
Primary	Respiratory rate	Breaths/min	Baseline and every 5 mins until 30 mins post-intervention
Primary	Oxygen saturation	Percentage	Baseline and every 5 mins until 30 mins post-intervention
Primary	Feasibility questionnaire	17-item scale, scored 1-10, lower is better. Subscores and total score	After 1st, 5th, 10th post-intervention test
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	MiniBESTest	Change from (pre-treatment) baseline in item subscores and total score. The MiniBESTest is a concise balance test. Higher is better.	30 minutes
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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