Intermittent Hypoxic-hyperoxic Training in Patients With Cardiovascular Pathology After COVID-19 Infection.

• ClinicalTrials.gov Identifier: NCT05379608
• Recruitment Status: Recruiting
• First Posted: May 18, 2022
• Last Update Posted: November 22, 2023
• Sponsor: I.M. Sechenov First Moscow State Medical University
• Information provided by (Responsible Party): I.M. Sechenov First Moscow State Medical University

Tracking Information

• First Submitted Date: April 30, 2022
• First Posted Date: May 18, 2022
• Last Update Posted Date: November 22, 2023
• Actual Study Start Date: December 10, 2021
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 16, 2022)

• Change in the levels of proinflammatory cytokines. [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  This outcome will be assessed by taking blood samples from a peripheral vein before and after IHHT to determine and compare the levels of proinflammatory cytokines such as Interleukin-1, Interleukin-6, Interleukin-18 and Tumor necrosis factor.
• Change of the endothelial function [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  This outcome will be assessed via taking blood samples from a peripheral vein before and after IHHT to determine and compare the levels of endothelin-1 and nitric oxide. Measurement of endothelial function will be done by using Flow Mediated Dilation (FMD). The technique involves ultrasound measurement of arterial dilation in response to a 5-minute occlusion of the brachial artery with a blood pressure cuff.
• Changes in indicators of diastolic dysfunction. [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  This outcome will be assessed via transthoracic echocardiography (EchoCG). Transthoracic EchoCG will be performed to assess the heart structure and function: unidimensional (M-mode), two-dimensional (B-mode) and Doppler. Diastolic function of the left ventricle will be assessed using pulse-wave, constant-wave, and tissue Doppler studies. Received data will be compared to the initial one before the IHHT sessions started and the conclusion about diastolic dysfunction will be made.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 16, 2022)

• Change in exercise tolerance after intermittent hypoxic-hyperoxic training. [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  Exercise tolerance will be determined via using a six-minute walk test . The six-minute walk test will measure the distance an individual is able to walk over a total of six minutes on a hard, flat surface.
• Change in maximum level of oxygen consumption after intermittent hypoxic-hyperoxic training. [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  Exercise tolerance will be determined via using a spiroergometry to determine the patient's oxygen consumption. The spiroergometric test will be performed under continuous stepwise increasing load. The duration of each load step is 5 min; the initial load level is 25 W, followed by an increase in load at each step by the same amount. The results of the test will be used to evaluate the achievement of the maximum level of oxygen consumption (in l/min or ml/min/kg body weight). Received data will be compared to the initial one before the IHHT sessions started and the conclusion will be made.
• Change in the levels of ferritin. [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  This outcome will be assessed by taking blood samples from a peripheral vein before and after IHHT to determine and compare the levels of long-term inflammatory markers such as ferritin.
• Change in the levels of C-reactive protein. [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  This outcome will be assessed by taking blood samples from a peripheral vein before and after IHHT to determine and compare the levels of long-term inflammatory markers such as C-reactive protein.
• Change in the levels of D-dimer. [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  This outcome will be assessed by taking blood samples from a peripheral vein before and after IHHT to determine and compare the levels of long-term inflammatory markers such as D-dimer.
• Change in the levels of fibrinogen. [ Time Frame: In 6 months after the reception of 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. ]
  This outcome will be assessed by taking blood samples from a peripheral vein before and after IHHT to determine and compare the levels of long-term inflammatory markers such as fibrinogen.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Intermittent Hypoxic-hyperoxic Training in Patients With Cardiovascular Pathology After COVID-19 Infection.
• Official Title: Intermittent Hypoxic-hyperoxic Training for the Rehabilitation in Patients With Cardiovascular Pathology After COVID-19 Infection.

Brief Summary

Aim of this prospective, interventional, single-center, randomized study is to evaluate the efficacy and safety of intermittent hypoxic-hyperoxic training (IHHT) as a rehabilitation method in patients with cardiovascular pathology in the early period after coronavirus infection.

The study will include 60 patients with cardiovascular pathology who underwent confirmed by laboratory tests COVID-19 infection 1-3 months ago with the degree of lung lesion CT3, CT4, who were admitted to the University Clinical Hospital No. 4 of I.M. Sechenov First Moscow State Medical University. The patients will be divided into 2 groups (intervention and control groups).

Intervention group will inhale hypoxic gas mixtures (10-12% O2) followed by exposure to a hyperoxic gas mixture with 30-35% O2 5 times a week for 3 weeks, while control group will undergo a simulated IHHT.

All the patients will undergo identical laboratory and instrumental testing before IHHT, after the last IHHT procedure, in a month after the last IHHT procedure and in 6 months.

Estimated result of the study is to confirm or refute the hypothesis of the study that a three-week course of IHHT in patients with cardiovascular pathology in the early period after coronavirus infection can improve exercise tolerance, as well as the quality of life and psychoemotional status, and affect the dynamics of laboratory and instrumental parameters.

Detailed Description

Aim of this prospective, interventional, single-centered, randomized study is to evaluate the efficacy and safety of intermittent hypoxic-hyperoxic training as a rehabilitation method in patients with cardiovascular pathology in the early period after coronavirus infection.

The study will include 60 patients with cardiovascular pathology who underwent confirmed by laboratory tests COVID-19 infection (polymerase chain reaction (PCR) testing, enzyme-linked immunosorbent assay (positive result at least 1 time)) 1-3 months ago with the degree of lung lesion CT3, CT4, who were admitted to the University Clinical Hospital No. 4 of I.M. Sechenov First Moscow State Medical University.

Patients will be randomized via the random number table method into two groups, comparable by gender, age and comorbidity:

Intermittent hypoxic-hyperoxic training (intervention group) group, 30 patients who will receive 15 IHHT sessions, 40-minutes long each (5 workouts per week) for 3 weeks. Patients in the IHHT group will inhale hypoxic gas mixtures (10-12% O2) followed by exposure to a hyperoxic gas mixture with 30-35% O2.

A control group of 30 patients will undergo a simulated IHHT course with the same "exposure" time and number of sessions. Patients of this group will breathe normoxic gas mixture using the same equipment; ordinary humidified air is supplied through the mask during the entire session.

Patients eligible for inclusion will undergo the following investigations:

• Anamnesis and complaints collection; physical examination;
• Assessment of the quality of life and psycho-emotional status using the Short Form-36 (SF36) and Hospital Anxiety and Depression Scale (HADS) questionnaires, as well as the six-minute walk test;
• General and biochemical blood tests , urine analysis, , determination of markers of inflammation (ferritin, C-reactive protein, D-dimer, fibrinogen, interleukin-1, interleukin-6, interleukin-18 and tumor necrosis factor), the level of Endothelin-1 and nitric oxide (NO) in the blood;
• Electrocardiography, a flow mediated dilatation procedure for endothelial function assessment,transthoracic echocardiography to identify the structural and functional features of the myocardium, spiroergometry to determine the patient's oxygen consumption.

The statistical processing will be performed using the Python Software Foundation version 3.8 for Windows (Delaware, USA).

Estimated result of the study is to confirm or refute the hypothesis of the study that a three-week course of IHHT in patients with cardiovascular pathology in the early stages after suffering a coronavirus infection can improve exercise tolerance, as well as the quality of life and psychoemotional status, and affect the dynamics of laboratory and instrumental parameters.

• Study Type: Interventional
• Study Phase: Not Applicable

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Masking Description:

participant and the specialists who will carry out investigations (blood and urine analysis, electrocardiography, a flow mediated dilatation procedure, transthoracic echocardiography).

Primary Purpose: Supportive Care

Condition

• COVID-19
• Chronic Heart Failure
• Hypertension
• Arrhythmia
• Conduct Disorder
• Chronic Coronary Syndrome
• Endothelial Dysfunction
• Diastolic Dysfunction
• Oxygen Consumption
• Quality of Life
• Exercise Tolerance

Intervention

• Procedure: Intermittent hypoxic-hyperoxic training

  IHHT will be carried out using the ReOxy normobaric hypoxic therapy apparatus (Bitmos GmbH, Germany, 26790/10221, 04/10/2019).

  Each patient will undergo a hypoxic test to assess the individual response to hypoxia. The minimum safe SpO2 value is 82%, and the maximum allowable heart rate increase during exercise is + 50% of the starting value. When these parameters are reached, an automatic switch to the supply of a hyperoxic gas mixture (35-40% oxygen) occurs till the SpO2 level is 100%. During each training session a hypoxic gas mixture is supplied to the patient in an intermittent mode, alternating with the supply of a hyperoxic gas mixture. On average, each workout includes 6 of the above cycles. The total time of inhalation of a hypoxic gas mixture during one procedure is 20-30 minutes.

• Procedure: Intermittent hypoxic-hyperoxic training/control

  IHHT will be carried out using the ReOxy normobaric hypoxic therapy apparatus (Bitmos GmbH, Germany, 26790/10221, 04/10/2019).

  A control group of 30 patients will undergo a simulated IHHT course (with the same "exposure" time and number of sessions as intervention group - 15 sessions, 40-minutes long each, 5 workouts per week for 3 weeks). Patients of this group will breathe normoxic gas mixture (ordinary humidified air is supplied through the mask) during the entire session.

Study Arms

• Experimental: intervention group
  The patients with cardiovascular pathology who underwent confirmed by laboratory tests COVID-19 infection 1-3 months ago with the degree of lung lesion CT3, CT4, who were admitted to the University Clinical Hospital No. 4 of I.M. Sechenov First Moscow State Medical University will be included in the study.
  Intervention: Procedure: Intermittent hypoxic-hyperoxic training
• Placebo Comparator: control group
  The patients with cardiovascular pathology who underwent confirmed by laboratory tests COVID-19 infection 1-3 months ago with the degree of lung lesion CT3, CT4, who were admitted to the University Clinical Hospital No. 4 of I.M. Sechenov First Moscow State Medical University will be included in the study.
  Intervention: Procedure: Intermittent hypoxic-hyperoxic training/control

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 16, 2022): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 30, 2024
• Estimated Primary Completion Date: December 31, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Written informed consent to participate in the study;
2. Age 40 and over;
3. Male and female;

4. One or more cardiovascular pathologies in the anamnesis:

   • a reliably confirmed diagnosis of hypertension, stage I-III (the diagnosis was made in accordance with the National Clinical Guidelines - 2019);
   • stable angina pectoris I-III functional class, confirmed by complaints, anamnesis and physical examination and with the help of diagnostic tests (bicycle ergometry or daily electrocardiography monitoring);
   • confirmed diagnosis of arrhythmias and conduction disorders based on electrocardiography data and 24-hour Holter monitoring (premature depolarization, supraventricular tachycardia, atrial fibrillation, sick sinus syndrome, atrioventricular block I-II, bundle branch blocks);
   • chronic heart failure stage I-IIB, I-III functional class (New York Heart Association Functional Classification), confirmed by the presence of clinical signs and at least one of two criteria: myocardial dysfunction of left ventricle or / and an increase in the level of the N-terminal fragment of brain natriuretic peptide over 125 pg / ml;
   • the presence of signs of systolic or diastolic dysfunction of the left ventricle according to echocardiography.
5. COVID-19 infection confirmed by laboratory tests (polymerase chain reaction testing, enzyme-linked immunosorbent assay (positive result at least 1 time) with a CT degree of 3 or higher.

Non-inclusion criteria:

1. Acute infectious diseases, tuberculosis;
2. Chronic somatic diseases in the acute stage;
3. Congenital anomalies of the heart and large vessels;
4. Valvular heart defects (congenital and acquired);
5. Severe atherosclerosis of the lower extremities'vessels (chronic ischemia of the lower extremities,stage 3-4);
6. Acute decompensated heart failure (II-IV class according to Killip classification);
7. Chronic heart failure IV functional class (New York Heart Association Functional Classification classification);
8. Secondary arterial hypertension;
9. Acute coronary syndrome within 4 weeks before the start of the study;
10. Life-threatening rhythm and conduction disturbances;
11. Bronchial asthma with the development of respiratory failure II-III degree;
12. Acute cerebrovascular accident within the last 4 months;
13. Chronic kidney disease (glomerular filtration rate<30 ml / min / 1.73 m2 via CKD-EPI (chronic kidney disease epidemiology collaboration) formula);
14. Pregnancy;
15. Mental illness (severe dementia, schizophrenia, severe depression, manic-depressive psychosis);
16. Oncology, diagnosed within a year or receiving a course of radiation / chemotherapy for cancer at the present time;
17. Severe cognitive impairment (MOS) and clinically significant anxiety and / or depression (HADS) interfering with observation;
18. Individual intolerance to oxygen deficiency.

Exclusion Criteria:

1. Refusal to further participation in the study;
2. Acute psychotic reactions arising in the process of the study;
3. Exacerbation of chronic diseases, requiring a change in patient management tactics and preventing his or her further participation in the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Philipp Kopylov; + 7 (903) 687 72 64; kopylov_f_yu@staff.sechenov.ru

Contact: Alina Bektimirova; + 7 (925) 520 29 39; bekalina@mail.ru

• Listed Location Countries: Russian Federation

Administrative Information

• NCT Number: NCT05379608
• Other Study ID Numbers: AB -1771
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: No, as it is prohibited by Local Ethics Committee of I.M. Sechenov First Moscow State Medical University. Any necessary information may be provided after official request to Study Principal Investigator

• Current Responsible Party: I.M. Sechenov First Moscow State Medical University
• Original Responsible Party: Same as current
• Current Study Sponsor: I.M. Sechenov First Moscow State Medical University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Philipp Kopylov; I.M. Sechenov First Moscow State Medical University (Sechenov University)

• PRS Account: I.M. Sechenov First Moscow State Medical University
• Verification Date: November 2023