Short Arm Human Centrifuge Therapeutic Training and Rehabilitation (GRACER1)

Study Overview
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Brief Summary
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The study is a single blind randomized controlled trial (RCT) designed to examine the benefit of a short arm human centrifuge intervention program (SAHC) combined with exercise, compared to a standard of care (SOC) rehabilitation program in physically impaired patients with MS, stroke, severe chronic obstructive pulmonary disease (COPD) and elderly people with balance and gait disorders (risk of falls).

Detailed Description
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The patients will be randomly assigned to the short arm human centrifuge training (SAHC intervention), standard of care (SOC training) or a passive control. The SAHC intervention consists of 3 sessions per week. The session duration is 1 hour. The intervention will last 3 months. Aiming to estimate the minimum number of participants required for obtaining reliable results, the investigators performed power analysis. It was conducted in g-power 3.1 to determine a sufficient sample size using an alpha of 0.05, a power of 0.80, and a medium effect size (f = 0.21). Based on the aforementioned assumptions, a total sample size of 26 participants per group was computed. The passive control group will abstain from any exercise. Initially, there will be one session serving as an evaluation and familiarization of the SAHC group participants on the centrifuge. Its aim besides familiarization will be also to individually assess the optimal according to the participant's cardiovascular functioning with cardiac output (CO), stroke volume (SV) mean arterial pressure (MAP) diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR). These criteria are monitored at each training session and are used to dynamically adapt the intervention intensity. More specifically, after 6 training sessions (2 weeks), the centrifugation load will be increased and considering the cardiovascular criteria, centrifugation will be combined with either aerobic exercise (through an ergometer) or resistance training through elastic training bands. Further verification of the dynamic configuration of the intervention will be provided by the electroencephalographic (EEG) assessment. More specifically, resting state EEG (eyes open & closed condition, lying in horizontal position) and centrifugation in three different intensities, mild (corresponding to 0.5,0.7, and 1 g), medium (corresponding to 1.2 and 1.5 g) and high intensity (corresponding to 1.7 and 2 g). Functional connectivity and cortical-network features derived from graph theory will be used by deep learning algorithms (convolutional neural networks) in order to define the optimal centrifuge training. A set of core outcomes as described below will be collected at the following experimental time instances: a) baseline, b) after 4 weeks, c) 8 weeks, d) 3 months, e) 6-month follow-up, g) 12-month follow-up. The outcomes will be collected across the domains of body structure and function, activity, and participation as classified by the world health organization international classification of functioning (ICF), disability and health. The primary outcomes are the following: A set of cardiovascular biosignal sensors described above, Electroencephalographic (EEG) recordings, The functional gait assessment (FGA) and The functioning differences assessed by changes in summary ordinal score on the short physical performance battery (SPPB). The battery consists of three tests: balance, gait ability and leg strength. The score for each test is given in categorical modality (0-4) based on run time intervals, and the total score will range from 0 (worst) to 12 points (best). The SPPB has been shown to be a valid instrument for screening frailty and predicting disability, institutionalization and mortality. A total score of less than 10 points indicates frailty and a high risk of disability and falls. 1 point change in the total score has demonstrated to be of clinical relevance. More primary outcomes include other measures of gaze and postural stability, fatigue, and functional mobility, isokinetic strength and muscle oxygen consumption. Additionally, a set of biomarkers in blood and urine will be collected.

Official Title
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Estimating the Optimal G Level for Training and Rehabilitation on a Short Arm Human Centrifuge

Conditions
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Multiple Sclerosis, Stroke, Pulmonary Disease, Chronic Obstructive, Aged

Intervention / Treatment
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* Device: ARTIFICIAL GRAVITY COMBINED WITH EXERCISE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: both male and female height less than 2 m, healthy or with gait disorder or impaired mobility from multiple sclerosis or stroke, chronic obstructive pulmonary disease (COPD) or elderly Exclusion Criteria: Neurological or psychiatric disorder, vertigo, nausea or chronic pain, participants with a height greater than 2 meters, participants with chronic use of substances or alcoholism, with recent (within 6 months) surgery, current arrhythmia, severe migraines, pregnancy, epilepsy, cholelithiasis or kidney stones, dehydration, recent wounds from surgery, recent fractures (unless recommended by a doctor), acute inflammation or pain and newly inserted metal pins or plates, newly implanted stents .

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Intervention Model: Sequential Assignment
Interventional Model Description: The use of a short arm human centrifuge intervention program (SAHC) combined with exercise, compared to a standard of care (SOC) rehabilitation program in physically impaired patients with MS, stroke, severe Chronic Obstructive Pulmonary Disease (COPD) and elderly people with balance and gait disorders (risk of falls). The patients will be randomly assigned to the centrifuge training (SAHC intervention), SOC training or a passive control group. The SAHC intervention consists of 3 sessions per week. The session duration is 1 hour. The intervention will last for 3 months.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHORT ARM HUMAN CENTRIFUGE<br>SHORT ARM HUMAN CENTRIFUGE IN COMBINATION WITH EXERCISE INTERMITTENT CENTRIFUGATION TOTAL TIME 30 MINUTES | Device: ARTIFICIAL GRAVITY COMBINED WITH EXERCISE<br>* The passive control group will abstain from any exercise. Recordings of the participant's will include cardiovascular functioning cardiac output (CO), stroke volume (SV) mean arterial pressure (MAP) diastolic blood pressure (DBP), systolic blood pressure (SBP), and heart rate (HR), Electroencephalography ( EEG) as well as dynamic force and stance and muscle oxygenation. More specifically, after 6 training sessions (2 weeks), the centrifugation load will be increased and will be combined with either aerobic exercise (through an ergometer) or resistance training through elastic training bands. Functional connectivity and cortical-network features will be used by deep learning algorithms in order to define the optimal centrifuge training .<br>* Other names: standard of care (SOC) rehabilitation program;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular physiological parameter 1 cardiac output (CO) 1-standing | Cardiac output (CO) unit L/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes standing condition | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 1 cardiac output (CO) 2-lying | Cardiac output (CO) unit L/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes lying condition | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 1 cardiac output (CO) 3-mild intensity | Cardiac output (CO) unit L/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes mild intensity centrifugation condition | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 1 cardiac output (CO) 4-medium intensity | Cardiac output (CO) unit L/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes medium intensity centrifugation condition | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 1 cardiac output (CO) 5-high intensity | Cardiac output (CO) unit L/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes high intensity centrifugation condition | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 2, Stroke volume (SV) 1-standing | Stroke volume (SV) unit L/beat, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes standing position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 2, Stroke volume (SV) 2-lying | Stroke volume (SV) unit L/beat, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes lying position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 2, Stroke volume (SV) 3-mild intensity | Stroke volume (SV) unit L/beat, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation of mild intensity (from 0,5 g to 1 g | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 2, Stroke volume (SV) 4-medium intensity | Stroke volume (SV) unit L/beat, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation of medium intensity (from 1,2g to1,5 g | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 2, Stroke volume (SV) 5-high intensity | Stroke volume (SV) unit L/beat, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation of high intensity (from 1,7g to 2 g) | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 3, mean arterial pressure (MAP) 1-standing | Mean arterial pressure (MAP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger at standing position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 3, mean arterial pressure (MAP) 2-lying | Mean arterial pressure (MAP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger at lying position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 3, mean arterial pressure (MAP) 3-mild intensity | Mean arterial pressure (MAP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger after centrifugation with mild intensity (from 0,5 g to 1 g) | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 3, mean arterial pressure (MAP) 4-medium intensity | Mean arterial pressure (MAP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger after centrifugation with medium intensity (from 1,2g to1,5 g) | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 3, mean arterial pressure (MAP) 5-high intensity | Mean arterial pressure (MAP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger after centrifugation with high intensity (from 1,7g to 2 g). | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 4, diastolic blood pressure (DBP) 1-standing | Diastolic blood pressure (DBP) unit mmHg,measured by a non invasive tensortip device attached to the subject's finger after 5 minutes standing position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 4, diastolic blood pressure (DBP) 2-lying | Diastolic blood pressure (DBP) unit mmHg,measured by a non invasive tensortip device attached to the subject's finger after 5 minutes lying position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 4, diastolic blood pressure (DBP) 3-low intensity | Diastolic blood pressure (DBP) unit mmHg,measured by a non invasive tensortip device attached to the subject's finger after centrifugation of mild intensity (from 0,5 g to 1 g). | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 4, diastolic blood pressure (DBP) 4-medium intensity | Diastolic blood pressure (DBP) unit mmHg,measured by a non invasive tensortip device attached to the subject's finger after centrifugation with medium intensity (from 1,2g to1,5 g). | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 4, diastolic blood pressure (DBP) 5-high intensity | Diastolic blood pressure (DBP) unit mmHg,measured by a non invasive tensortip device attached to the subject's finger after centrifugation of high intensity (from 1,7g to 2 g). | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 5, systolic blood pressure (SBP) 1-standing | Systolic blood pressure (SBP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes at standing position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 5, systolic blood pressure (SBP) 2;lying | Systolic blood pressure (SBP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes at lying position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 5, systolic blood pressure (SBP) 3-mild intensity | Systolic blood pressure (SBP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation with mild intensity (from 0,5 g to 1 g). | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 5, systolic blood pressure (SBP) 4-medium intensity | Systolic blood pressure (SBP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation with medium intensity (from 1,2g to1,5 g) | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 5, systolic blood pressure (SBP) 5-high intensity | Systolic blood pressure (SBP) unit mmHg, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation with high intensity (from 1,7g to 2 g) | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 6, heart rate (HR) 1-standing | Heart rate (HR) unit beats/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes at standing position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 6, heart rate (HR) 2-lying | Heart rate (HR) unit beats/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes at lying position | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 6, heart rate (HR) 3-mild intensity | Heart rate (HR) unit beats/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation of mild intensity (from 0,5 g to 1 g). | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 6, heart rate (HR) 4-medium intensity | Heart rate (HR) unit beats/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation with medium intensity (from 1,2g to1,5 g). | The time frame will include: changes from baseline up to 6 months | 
| Cardiovascular physiological parameter 6, heart rate (HR) 5-high intensity | Heart rate (HR) unit beats/min, measured by a non invasive tensortip device attached to the subject's finger after 5 minutes centrifugation of high intensity (from 1,7g to 2 g). | The time frame will include: changes from baseline up to 6 months | 
| Electrical activity of the brain in alpha band, Electroencephalography (EEG)(μV) 1 | Recording of the brain's spontaneous electrical activity using multiple electrodes placed on the scalp with a conductive gel or paste, usually after preparing the scalp area by light abrasion to reduce impedance due to dead skin cells. Electrode locations and names are specified by the International 10-20 system.Each electrode is connected to one input of a differential amplifier, which amplifies the voltage between the active electrode and the reference (typically 1,000-100,000 times, or 60-100 dB of voltage gain) and the amplified signal is digitized via an analog-to-digital converter, after being passed through an anti-aliasing filter. Analog-to-digital sampling typically occurs at 256-512 Hz in clinical scalp EEG; sampling rates of up to 20 kHz will be used . The recording involves the subject with eyes open. | The time frame will include: changes from baseline up to 6 months | 
| Electrical activity of the brain in alpha band, Electroencephalography (EEG)(μV) 2 | Recording of the brain's spontaneous electrical activity using multiple electrodes placed on the scalp with a conductive gel or paste, usually after preparing the scalp area by light abrasion to reduce impedance due to dead skin cells. Electrode locations and names are specified by the International 10-20 system.Each electrode is connected to one input of a differential amplifier, which amplifies the voltage between the active electrode and the reference (typically 1,000-100,000 times, or 60-100 dB of voltage gain) and the amplified signal is digitized via an analog-to-digital converter, after being passed through an anti-aliasing filter. Analog-to-digital sampling typically occurs at 256-512 Hz in clinical scalp EEG; sampling rates of up to 20 kHz will be used . The recording involves the subject with eyes closed. | The time frame will include: changes from baseline up to 6 months | 
| Electrical activity of the brain in alpha band, Electroencephalography (EEG)(μV) 3 | Recording of the brain's spontaneous electrical activity using multiple electrodes placed on the scalp with a conductive gel or paste, usually after preparing the scalp area by light abrasion to reduce impedance due to dead skin cells. Electrode locations and names are specified by the International 10-20 system.Each electrode is connected to one input of a differential amplifier, which amplifies the voltage between the active electrode and the reference (typically 1,000-100,000 times, or 60-100 dB of voltage gain) and the amplified signal is digitized via an analog-to-digital converter, after being passed through an anti-aliasing filter. Analog-to-digital sampling typically occurs at 256-512 Hz in clinical scalp EEG; sampling rates of up to 20 kHz will be used . The recording involves the subject in standing position. | The time frame will include: changes from baseline up to 6 months | 
| Electrical activity of the brain in alpha band, Electroencephalography (EEG)(μV) 4 | Recording of the brain's spontaneous electrical activity using multiple electrodes placed on the scalp with a conductive gel or paste, usually after preparing the scalp area by light abrasion to reduce impedance due to dead skin cells. Electrode locations and names are specified by the International 10-20 system.Each electrode is connected to one input of a differential amplifier, which amplifies the voltage between the active electrode and the reference (typically 1,000-100,000 times, or 60-100 dB of voltage gain) and the amplified signal is digitized via an analog-to-digital converter, after being passed through an anti-aliasing filter. Analog-to-digital sampling typically occurs at 256-512 Hz in clinical scalp EEG; sampling rates of up to 20 kHz will be used . The recording involves the subject in lying position. | The time frame will include: changes from baseline up to 6 months | 
| Electrical activity of the brain in alpha band, Electroencephalography (EEG)(μV) 5 | Recording of the brain's spontaneous electrical activity using multiple electrodes placed on the scalp with a conductive gel or paste, usually after preparing the scalp area by light abrasion to reduce impedance due to dead skin cells. Electrode locations and names are specified by the International 10-20 system.Each electrode is connected to one input of a differential amplifier, which amplifies the voltage between the active electrode and the reference (typically 1,000-100,000 times, or 60-100 dB of voltage gain) and the amplified signal is digitized via an analog-to-digital converter, after being passed through an anti-aliasing filter. Analog-to-digital sampling typically occurs at 256-512 Hz in clinical scalp EEG; sampling rates of up to 20 kHz will be used . The recording involves the subject in centrifugation with mild intensity (from 0,5 g to 1 g). | The time frame will include: changes from baseline up to 6 months | 
| Electrical activity of the brain in alpha band, Electroencephalography (EEG)(μV) 6 | Recording of the brain's spontaneous electrical activity using multiple electrodes placed on the scalp with a conductive gel or paste, usually after preparing the scalp area by light abrasion to reduce impedance due to dead skin cells. Electrode locations and names are specified by the International 10-20 system.Each electrode is connected to one input of a differential amplifier, which amplifies the voltage between the active electrode and the reference (typically 1,000-100,000 times, or 60-100 dB of voltage gain) and the amplified signal is digitized via an analog-to-digital converter, after being passed through an anti-aliasing filter. Analog-to-digital sampling typically occurs at 256-512 Hz in clinical scalp EEG; sampling rates of up to 20 kHz will be used . The recording involves the subject in centrifugation with medium intensity (from 1,2g to1,5 g). | The time frame will include: changes from baseline up to 6 months | 
| Electrical activity of the brain in alpha band, Electroencephalography (EEG)(μV) 7 | Recording of the brain's spontaneous electrical activity using multiple electrodes placed on the scalp with a conductive gel or paste, usually after preparing the scalp area by light abrasion to reduce impedance due to dead skin cells. Electrode locations and names are specified by the International 10-20 system.Each electrode is connected to one input of a differential amplifier, which amplifies the voltage between the active electrode and the reference (typically 1,000-100,000 times, or 60-100 dB of voltage gain) and the amplified signal is digitized via an analog-to-digital converter, after being passed through an anti-aliasing filter. Analog-to-digital sampling typically occurs at 256-512 Hz in clinical scalp EEG; sampling rates of up to 20 kHz will be used . The recording involves the subject in centrifugation of high intensity (from 1,7g to 2 g). | The time frame will include: changes from baseline up to 6 months | 
| The Short Physical Performance Battery assessment score | The functioning differences assessed by changes in summary ordinal score on Balance, gait ability and leg strength. The score for each test is given in categorical modality (0-4) based on run time intervals, and the total score will range from 0 (worst) to 12 points (best). | The time frame will include: changes from baseline up to 6 months | 
| The Functional Gait Assessment (FGA) | questionnaire | changes in 3 months | 
| Gastrocnemius muscle oxygenation | Oxygen saturation (SmO2 (%)) of the gastrocnemius medialis muscle measured with muscle oxygen monitor (MOXY) placed in the gastrocnemius muscle of the dominant leg during centrifugation | The time frame will include: changes in 3 months | 
| Biological samples 1: CATECHOLAMINES | Unit of measurement: μmol from urine and saliva samples will be collected | The time frame will include: changes in 3 months | 
| Biological samples 2: ADIPONECTINE | Unit of measurement: μg/mL from serum | The time frame will include: changes in 3 months | 
| Biological samples 3:BDNF | Unit of measurement: ng/ml from serum | The time frame will include: changes in 3 months | 
| Biological samples 4:MELATONINE | Unit of measurement: pg/mL from saliva | The time frame will include: changes in 3 months | 
| Biological samples 5:ADENOSINE | Unit of measurement: µM from saliva | The time frame will include: changes in 3 months | 
| Biological samples 5:TNF-α | Unit of measurement: pg/mL from serum | The time frame will include: changes in 3 months | 
| Biological samples 6:IL-1β | Unit of measurement: pg/mL from serum | The time frame will include: changes in 3 months | 
| Biological samples 7:High-sensitivity C-reactive Protein (hs-CRP) | Unit of measurement: mg/L from serum | The time frame will include: changes in 3 months | 
| Biological samples 8:Total leucocyte number: | Unit of measurement: number of cells x 10^3/μL from serum | The time frame will include: changes in 3 months | 
| Biological samples 9:sTNF-RII | Unit of measurement: pg/ml from serum | The time frame will include: changes in 3 months | 
| Biological samples 10:D-creatinine | Unit of measurement: mmol/l from serum | The time frame will include: changes in 3 months | 
| Biological samples 11:alpha-amylase | Unit of measurement: IU, from serum | The time frame will include: changes in 3 months | 
| Biological samples 12:secretory immunoglobulin A (sIgA) | Unit of measurement: mg/dL, from serum | The time frame will include: changes in 3 months | 
| Biological samples 13: cortisol (SC) mg/dL | Unit of measurement: mg/dL, from saliva | The time frame will include: changes in 3 months | 
| Biological samples 14: Glucose | Unit of measurement: mg/dL, from serum | The time frame will include: changes in 3 months | 
| Biological samples 15: ACTH | Unit of measurement: ng/liter, from plasma | The time frame will include: changes in 3 months | 
| Biological samples 16: Transcortin (mg/liter) | Unit of measurement: mg/liter, from serum | The time frame will include: changes in 3 months | 
| Biological samples 17: Total antioxidant capacity (TAC) | Unit of measurement: mM Trolox equivalent/l , from saliva | The time frame will include: changes in 3 months | 
| weight in kilograms, height in meters), as appropriate, or to clarify how multiple measurements will be aggregated to arrive at one reported value (e.g., weight | unit: Kg | changes in 3 months | 
| Height | Unit:meters | Day 1only | 
| Body Mass Index | Unit: kg/m^2). | changes in 3 months |