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

NCT05214287 | Completed Phase 1 DMC

• 4 other identifiers: 112203NL.77891.091.212021-005480-412021-12410
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (7)

• 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 Outcomes (11)

• Participant-selected motor symptom

  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

  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

  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

  30 minutes

• MiniBESTest

  30 minutes

Other Outcomes (3)

• Serum platelet-derived growth factor receptor β (PDGFRβ)

  60 minutes after intervention

• Serum cortisol

  Directly after intervention, 30 minutes, 60 minutes

• Serum erythropoietin (EPO)

  60 minutes after intervention

Study Arms (5)

Intermittent with 5x5-minutes, FiO2 0.163

EXPERIMENTAL

Delivered intermittently, with FiO2 0.163 and room-air, each 5 minutes, for 5 cycles/session

Drug: Hypoxic Gas Mixture

Intermittent with 5x5-minutes, FiO2 0.127 or 0.133

EXPERIMENTAL

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

Continuous for 45 minutes, FiO2 0.163

EXPERIMENTAL

Delivered via the hypoxicator

Drug: Hypoxic Gas Mixture

Continuous for 45 minutes, FiO2 0.127 or 0.133

EXPERIMENTAL

FiO2 0.127 or 0.133 (depending on SaO2 during screening procedure at FiO2 0.127, see study procedures)

Drug: Hypoxic Gas Mixture

Continuous for 45 minutes, FiO2 0.209

PLACEBO COMPARATOR

Delivered via an open three-way valve in the circuitry from hypoxicator to the participant

Drug: Hypoxic Gas Mixture

Interventions

Hypoxic Gas Mixture DRUG

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.

Also known as: Hypoxicator

Continuous for 45 minutes, FiO2 0.127 or 0.133; Continuous for 45 minutes, FiO2 0.163; Continuous for 45 minutes, FiO2 0.209; Intermittent with 5x5-minutes, FiO2 0.127 or 0.133; Intermittent with 5x5-minutes, FiO2 0.163

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Michael J. Fox Foundation for Parkinson's Research: collaborator

Study Sites (1)

Dpt. of Physiology, Radboud University Medical Center

Nijmegen, 6525EX, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 35836147 DERIVED

MeSH Terms

Conditions

Parkinson Disease; Neurodegenerative Diseases; Synucleinopathies; Hypoxia; Hypoxia, Brain; Movement Disorders

Interventions

nitrox

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• prof. dr. Bastiaan R. Bloem

  Center of Expertise for Parkinson and Movement Disorders, Radboud university medical center

  PRINCIPAL INVESTIGATOR

• prof. dr. Dick H.J. Thijssen

  Department of Integrative Physiology, Radboud university medical center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The administration and sequence of intervention(s) will not be disclosed to the participant. However, due to the n-of-1 design, all participants will be exposed to all treatment modalities as well as the control condition arm, which makes concealed allocation not applicable other than the unconcealed intervention sequence. The investigators will assess success of masking by asking a participant in what sequence the different treatments were probably administered. For safety and monitoring purposes, the intervention is not blinded for the lab technician, who will administer and monitor the intervention. All outcomes will be assessed directly before and after the stimulus by an independent and blinded assessor.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: December 28, 2021
• First Posted: January 28, 2022
• Study Start: February 22, 2022
• Primary Completion: July 12, 2023
• Study Completion: July 12, 2023
• Last Updated: July 21, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: Data will be made available within 1.5 years after study completion date.
• Access Criteria: Access to and use of data are supervised by the Michael J. Fox Foundation.

Locations

NL (1)