PLAsticity, Security and Tolerance to Intermittent Hypoxic Conditioning Following Stroke

NCT05210088 | Withdrawn Phase 1 DMC

• 1 other identifier: 2021-A00104-37
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

By inducing endogenous neuroprotection, hypoxic post-conditioning following stroke may represent a harmless and efficient non-pharmacological innovative neuro-therapeutic modality aiming at inducing neuroplasticity and brain repair, as supported by many preclinical studies. The investigators thus hypothesize that hypoxic post-conditioning represents a safe therapeutic strategy post-stroke. The investigators further hypothesize that hypoxic conditioning could enhance neuroplasticity and function in combination with conventional rehabilitative care. The primary study endpoint will be safety. Safety will be assessed through the clinical review of the adverse events over the duration of the study, every 48 hours by a trained evaluator, blinded for the therapeutic intervention. The investigators will further investigate the potential functional benefits of such a therapeutic approach on motor function, gait, balance, and cognition. The neurophysiological substrates of hypoxic conditioning-triggered neuroplasticity at a subacute delay post-stroke will also be investigated, based on biological and imagery markers.

Conditions

Stroke, Ischemic; Stroke Sequelae

Keywords

Stroke; Hypoxic conditioning; Intermittent hypoxia; Recovery; Biomarkers; Safety

Outcome Measures

Primary Outcomes (1)

• Secondary adverse events

  The safety of such a therapeutic strategy will be assessed by systematic screening for adverse events at each conditioning session and at follow-up visits throughout the duration of exposure (8 weeks) by a trained experimenter, blinded to the therapeutic intervention. All adverse events will be assessed and scored as a composite endpoint according to the NIH CCTAE 5.0 (National Institute of Health Common Terminology Criteria for Adverse Events), including in particular those listed in the sub-sections on "Cardiological Pathologies", "Central Nervous System Pathologies" and "Vascular Pathologies".

  Through study completion, an average of 8 weeks

Secondary Outcomes (14)

• Fugl-Meyer

  Phase 1: Inclusion, 2 months; Phase 2: Inclusion, 2 months, 6 months

• New Functional ambulation category (nFAC) score

  Phase 1: Inclusion, 2 months; Phase 2: Inclusion, 2 months, 6 months

• Prospective collection of number of falls

  Phase 1: Inclusion, 2 months; Phase 2: Inclusion, 2 months, 6 months

• Modified Rankin Scale (mRS)

  Phase 1: Inclusion, 2 months; Phase 2: Inclusion, 2 months, 6 months

• Barthel index

  Phase 1: Inclusion, 2 months; Phase 2: Inclusion, 2 months, 6 months

Other Outcomes (4)

• Biomarkers of hypoxic conditioning - Brain Derived Neurotrophic Factor (BDNF)

  Phase 2: Inclusion, 2 months, 6 months

• Biomarkers of hypoxic conditioning - Erythropoietin (EPO)

  Phase 2: Inclusion, 2 months, 6 months

• Biomarkers of hypoxic conditioning - Hypoxia inducible factor 1

  Phase 2: Inclusion, 2 months, 6 months

Study Arms (3)

PHASE 1- Dose escalation protocol

EXPERIMENTAL

4-step dose-escalation protocol with increasing doses of intermittent hypoxia and continuous reassessment of safety criteria (primary endpoint). Hypoxic conditioning will be performed in three one-hour sessions per week, performed non-consecutively, for 8 weeks. The hypoxic stimulus will be intermittent, and each session will consist of 7 cycles of 5 minutes of hypoxia alternating with 3 minutes of normoxia (FiO2 = 21%). The subjects will be installed in a semi-recumbent position, at rest in a quiet environment. For hypoxic exposure, the inspired fraction of oxygen (FiO2) will be set individually to achieve the targeted level of desaturation (Pulse Oxygen Saturation, SpO2) continuously monitored: 90% for stage 1 (n=1 patient), 85% for stage 2 (n=3 patients), 80% for stage 3 (n=3 patients), 75% for stage 4 (n=3 patients).

Drug: Hypoxia, intermittent

PHASE 2 - Intermittent hypoxia group

ACTIVE COMPARATOR

Group exposed to an intermittent hypoxic stimulus (n=20, target pulsed saturation in dioxygen 75%). The device used is a gas mixer already in use in the unit and used in current clinical practice and research in our team (Altitrainer®, Sport and Medical TEChnologies S.A. (SMTEC S.A.), Switzerland). The hypoxic stimulus will be obtained by having the subject inhale a gas mixture enriched in nitrogen by means of a mask, in variable proportion according to the desired degree of hypoxia. Hypoxic conditioning will be performed in three one-hour sessions per week, performed non-consecutively, for 8 weeks. The hypoxic stimulus will be intermittent, and each session will consist of 7 cycles of 5 minutes of hypoxia alternating with 3 minutes of normoxia (FiO2 = 21%). The subjects will be installed in a semi-recumbent position, at rest in a quiet environment. For hypoxic exposure, the FiO2 will be set individually to achieve the targeted level of desaturation.

Drug: Hypoxia, intermittent

PHASE 2 - Sham (Normoxia) group

SHAM COMPARATOR

Normoxia group (n=10, FiO2 = 21%). The same setting will be used as in the Intermittent hypoxia group, but subjects will breathe ambient air throughout the conditioning procedure.

Other: Normoxia

Interventions

Hypoxia, intermittent DRUG

The device used to generate the intermittent hypoxia stimulus is a gas mixer used in current clinical practice and research (Altitrainer®, SMTEC S.A. Switzerland). The hypoxic stimulus will be obtained by having the subject inhale a gas mixture enriched in nitrogen by means of a mask, in variable proportion according to the desired degree of hypoxia. Hypoxic conditioning will be performed in three one-hour sessions per week, performed non-consecutively, for 8 weeks. The hypoxic stimulus will be intermittent, and each session will consist of 7 cycles of 5 minutes of hypoxia alternating with 3 minutes of normoxia (FiO2 = 21%). The subjects will be installed in a semi-recumbent position, at rest in a quiet environment. For hypoxic exposure, the inspired fraction of oxygen (FiO2) will be set individually to achieve the targeted level of desaturation (Pulse Oxygen Saturation, SpO2) continuously monitored.

Also known as: Hypoxic conditioning, Hypoxia

PHASE 1- Dose escalation protocol; PHASE 2 - Intermittent hypoxia group

Normoxia OTHER

The normoxic stimulus will be obtained by having the subjects inhale via a face mask a normoxic gas mixture with a fixed FiO2 of 21%, delivered by the gas mixing device (Altitrainer®, SMTEC S.A. Switzerland).

PHASE 2 - Sham (Normoxia) group

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with minor cerebral infarction with NIHSS \< or equal to 5 will be included in the protocol;
• Cerebral infarction occurring one month (±1 week) before the planned start of hypoxic exposure;
• Age ≥18 years;
• A first, unilateral, ischemic, supra-tentorial hemispheric stroke, confirmed by magnetic resonance imaging;
• Modified Rankin Scale score between 1 and 3, defining mild to moderate residual functional disability.
• A person affiliated with the social security system or benefits from such a system;
• A person who has given written informed consent.

You may not qualify if:

• Patients who are minors or over 85 years of age, pregnant or breastfeeding women, or women of childbearing potential in the absence of highly effective contraception;
• Stroke of the brainstem or cerebellum ;
• Severe aphasia, limiting the ability to understand the protocol;
• History of central or peripheral neurological pathology;
• Modified Rankin Scale score \>0 before stroke;
• Known severe untreated obstructive sleep apnea syndrome, defined as an apnea-hypopnea index ≥ 30 events per hour of sleep;
• Pre-existing hypoxemic lung disease (such as chronic obstructive pulmonary disease);
• Heart failure, defined as an ejection fraction ≤40% ;
• History of high altitude pathology;
• Scheduled stay at altitude (\> 2500 m) during the study period ;
• Migraine;
• History of rheumatological or orthopedic disease of the lower limbs, amputation of the lower limb.
• Contraindication to magnetic resonance imaging;
• Subjects who cannot be contacted in an emergency;
• Subject under administrative or judicial supervision;

Sponsors & Collaborators

• University Hospital, Grenoble: lead
• Agir pour les maladies chroniques: collaborator

Study Sites (1)

Grenoble Aalpes University Hospital

Grenoble, Veuillez Sélectionner Une Région., 38000, France

Location

Related Publications (3)

• Verges S, Chacaroun S, Godin-Ribuot D, Baillieul S. Hypoxic Conditioning as a New Therapeutic Modality. Front Pediatr. 2015 Jun 22;3:58. doi: 10.3389/fped.2015.00058. eCollection 2015.

  PMID: 26157787 BACKGROUND

• Baillieul S, Chacaroun S, Doutreleau S, Detante O, Pepin JL, Verges S. Hypoxic conditioning and the central nervous system: A new therapeutic opportunity for brain and spinal cord injuries? Exp Biol Med (Maywood). 2017 Jun;242(11):1198-1206. doi: 10.1177/1535370217712691.

  PMID: 28585890 BACKGROUND

• Burtscher J, Syed MMK, Lashuel HA, Millet GP. Hypoxia Conditioning as a Promising Therapeutic Target in Parkinson's Disease? Mov Disord. 2021 Apr;36(4):857-861. doi: 10.1002/mds.28544. Epub 2021 Feb 27.

  PMID: 33638916 BACKGROUND

MeSH Terms

Conditions

Ischemic Stroke; Stroke

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Study Officials

• Sébastien BAI, MD PHD

  CHU Grenoble Alpes

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Masking Details: The patients, as well as the experimenters performing the assessment sessions, will be blinded to the level of hypoxia. Only operators not involved in the monitoring of patients within the protocol and who will set the hypoxia generator device will not be concerned by the blind procedure.
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase I (safety and tolerability) clinical trial (impact on intermediate endpoints) evaluating a chronic (one month) hypoxic conditioning strategy for stroke, single-center, dose-escalation accelerated titration design (Liu S., Contemp. Clin. Trials. 2013) with continuous safety reassessment method. Dose escalation protocol. Dose escalation consisting of 4 successive steps, with increasing doses of hypoxia and continuous reassessment of safety criteria (primary endpoint, see below) Phase 2: Randomised, double-blind, controlled study comparing a group exposed to intermittent hypoxic post-conditioning versus a group exposed for the same duration and under the same conditions to a normoxic stimulus.

Study Record Dates

• First Submitted: October 5, 2021
• First Posted: January 27, 2022
• Study Start: January 1, 2024
• Primary Completion: January 1, 2024
• Study Completion: January 1, 2024
• Last Updated: June 4, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: After the publication of the results of the present study.
• Access Criteria: Data collected for the study, including deidentified individual participant data will be made available to others following the publication of this article, for academic purposes (e.g., meta-analyses) on request to the principal investigator.

Locations

FR (1)