Feasibility of an Augmented Two-Day Step Test and Causal Modeling for Post-Exertional Symptom Exacerbation in Post Covid-19 Syndrome

NCT06933017 | Completed

• 2 other identifiers: 2024-EDW-REVEALG075423N
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 2

Brief Summary

This study aims to evaluate exercise capacity and identify causes of Post-Exertional Symptom Exacerbation (PESE) in individuals with Long COVID. The investigators will compare the effectiveness of the Two-Day 6-Minute Incremental Step Test (6MIST) and the Cardiopulmonary Exercise Test (CPET) in detecting PESE. Additionally, the investigators will assess metabolism, mitochondrial function, autonomic symptoms, psychological factors, and physical activity. Participants will complete both the Two-Day 6MIST and the Two-Day CPET, with a one-month gap between them. Each test is performed on two consecutive days to assess the delayed symptom response. The subjective symptoms of PESE will also be measured through questionnaires. To explore potential causes of PESE, the investigators will measure metabolism using indirect calorimetry, bioelectrical impedance analysis and food diaries, mitochondrial dysfunction with NIRS technology, autonomic symptoms using the COMPASS-31 questionnaire, psychological factors with questionnaires and physical activity levels using an activity tracker. This study will determine if the Two-Day Step Test (6MIST) is a feasible alternative to the two-day CPET for measuring PESE and will help uncover underlying mechanisms contributing to symptom exacerbation.

Conditions

Long COVID

Keywords

long covid; PEM; Post-Exertional Malaise; CPET; 6MIST; Fatigue

Outcome Measures

Primary Outcomes (18)

• Difference in oxygen uptake at peak (VO2 peak) between day 1 and day 2 measured with the CPET compared to measured with the Calibre device

  The goal is to show that the Calibre device is a feasible alternative to the CPET.

  From day 1 and day 2 of experimental session 1 to day 1 and day 2 of experimental session 2, one month apart (±10 days)

• Difference in Rate of Perceived Exertion (RPE) measured with the CPET compared to measured with the Calibre device

  Rate of Perceived Exertion is measured with the Borg RPE Scale which is a subjective measurement instrument. The scores range from 6 to 20, in which 6 is equal to no exertion at all and 20 is maximal exertion.

  RPE will be measured during two experimental sessions, each with two days, one month apart. On day 1, RPE is recorded 15 minutes (±15 min) before and after the test. On day 2, RPE is measured 24 hours (±120 min) after test 1 and before test 2.]

• Resting Energy Expenditure (kcal/kg/day), measured through Indirect Calorimetry (IC)

  Measuring Resting Energy Expenditure as part of the Directed Acyclic Graph (DAG).

  Baseline (measured once, during the first study visit)

• Total Energy Expenditure (TEE) in kcal/kg/day, measured through Indirect Calorimetry (IC)

  Measuring Total Energy Expenditure as part of the DAG.

  Baseline (measured once during the first study visit)

• Phase angle (degrees), measured through Bioelectrical Impedance Analysis (BIA)

  Measuring Phase Angle as part of the DAG.

  Baseline (measured once during the first study visit)

• Muscle mass (kg/m2), measured through Bioelectrical Impedance Analysis (BIA)

  Measuring muscle mass as part of the DAG.

  Baseline (measured once during the first study visit)

• Fat mass index (kg/m2), measured through Bioelectrical Impedance Analysis (BIA)

  Measuring fat mass index as part of the DAG.

  Baseline (measured once during the first study visit)

• Fat-free mass index (kg/m²), measured through Bioelectrical Impedance Analysis (BIA)

  Measuring fat free mass index as part of the DAG.

  Baseline (measured once during the first study visit)

• Fat to fat-free mass ratio, measured through bioelectrical impedance analysis (BIA)

  Measuring fat-free mass ratio as part of the DAG.

  Baseline (measured once during the first study visit)

• Hydration (%), measured through Bioelectrical Impedance Analysis (BIA)

  Measuring hydration as part of the DAG.

  Baseline (measured once during the first study visit)

• Ratio of calorie and protein intake to individual need, measured through food diaries

  Adequacy of feeding: the ratio between intake of calories and proteins and the individual need. Record of all food and drinks consumed over a 3-day period as part of the DAG.

  Between day 1 of study visit and day 1 of experimental session

• Mean daily intake of calories, fats, proteins, and carbohydrates, measured through food diaries

  Mean daily intake: calories, fats, proteins, carbohydrates Record of all food and drinks consumed over a 3-day period.

  Between day 1 of study visit and day 1 of experimental session

• Oxygen availability as the partial pressure of oxygen (mitoPO2) (mmHg), measured through Near-infrared spectroscopy (NIRS)

  Measuring oxygen availability as the partial pressure of oxygen as part of the DAG.

  Baseline (measured once during the first study visit)

• Kinesiophobia with the Tampa Scale for Kinesiophobia (TSK)

  The Tampa Scale for Kinesiophobia (TSK) consists of 17 statements, each scored from 1 to 4, with 1 being 'strongly disagree' and 4 being 'strongly agree.' Higher scores indicate greater kinesiophobia. Measuring kinesiophobia as part of the DAG.

  Baseline (measured once during the first study visit)

• Ability to bounce back after stressful events with the Brief Resilience Scale (BRS) Questionnaire

  The Brief Resilience Scale (BRS) consists of 6 statements, each scored from 1 to 4, with 1 being 'strongly disagree' and 4 being 'strongly agree.' Higher scores indicate greater resilience. Measuring resilience as part of the DAG.

  Baseline (measured once during the first study visit)

• Coping style with the Ways of Coping (WAYS) Questionnaire

  Sixty-six statements about a stressful situation that participants experienced in the past week, for which they need to give a score ranging from 0 to 3, with 0 being "does not apply" or "not used," and 3 being "used a great deal". Measuring coping style as part of the DAG.

  Baseline (measured once during the first study visit)

• Autonomic symptoms, measured with the COMPASS-31 questionnaire

  Measuring autonomic symptoms as part of the DAG.

  Baseline (measured once during the first study visit)

• Level of Physical Activity (PA) and sedentary behavior assessed by accelerometry (activity tracker)

  Using an actigraph, with a frequenncy of 60 Hertz, that participants wear at their hip on their dominant side. Measuring physical activity as part of the DAG.

  During 7 days before the first experimental session

Secondary Outcomes (10)

• Change from Day 1 to Day 2 in Oxygen Uptake at First Ventilatory Threshold (VO₂ in ml/min/kg) during experimental session 1 or 2 (CPET)

  From Day 1 to Day 2 during experimental session 1 or 2 (CPET)

• Change from Day 1 to Day 2 in Oxygen uptake at peak (VO2 in ml/min/kg) during experimental session 1 and 2 (CPET & 6MIST))

  From Day 1 to Day 2 during experimental sessions 1 and 2 (CPET & 6MIST)

• Change from Day 1 to Day 2 in Workload (Watts) at first ventilatory threshold during experimental session 1 or 2 (CPET)

  From Day 1 to Day 2 during experimental session 1 or 2 (CPET)

• Change from Day 1 to Day 2 in Workload (Watts) at peak during experimental session 1 or 2 (CPET)

  From Day 1 to Day 2 during experimental session 1 or 2 (CPET)

• Change from Day 1 to Day 2 in Heart Rate (bpm) peak during experimental sessions 1 and 2 (CPET & 6MIST))

  From Day 1 to Day 2 during experimental sessions 1 and 2 (CPET & 6MIST)

Other Outcomes (8)

• Vaccination status of the participant

  Baseline (inquired during the first study visit)

• Date of birth of the participant

  Baseline (inquired during the first study visit)

• Ethnicity of the participant

  Baseline (inquired during the first study visit)

Study Arms (2)

Two day 6-Minute Incremental Step Test (6 MIST)

EXPERIMENTAL

The 6-Minute Incremental Step Test (6MIST) is an incremental pace stationary stepping test wherein the pace increases by 5 steps every 30 seconds using a metronome, lasting a maximum of 6 minutes. Clinical cardio-respiratory variables are simultaneously recorded. A portable metabolic analyzer, the Calibre Biometric Tracker, will be utilized to evaluate VO2 and VE (TV and RR). The Polar Sense of the Polar 10 heart rate monitor will measure HR on a continuous basis. The Train-Red Fyer NIRS Muscle Oxygen Sensor will be utilized to gather oxygenation data from muscle tissue.

Device: Portable mask for respiratory gas analysis

Two day Cardio-Pulmonary Exercise Test (CPET)

ACTIVE COMPARATOR

Prior to the CPET, spirometry is executed to predict the Maximum Voluntary Ventilation (MVV) from the Forced Expiratory Volume in one second (FEV1).The test is performed on a bicycle. The protocol is customized for each patient to achieve a fatigue-limited exercise duration of 8 to12 minutes. The predicted peak wattage is calculated according to a formula and by taking into account the patient's clinical profile. Patients start at 0 watts per minute. The intensity is increased until exhaustion (incremental step protocol) or if the test needs to be stopped for safety reasons. Patients are connected to an electrocardiogram (ECG), oximeter and blood pressure cuff. A mouthpiece is used to collect information about gas exchange.

Device: Cardio-pulmonary exercise test

Interventions

Portable mask for respiratory gas analysis DEVICE

This is a portable mask, which is connected to the SplendoHealth app. The Polar sens 10 heartrate monitor and TrainRed NIRS device are also connected to this app. The three devices (mask, heartrate monitor and NIRS) are measuring respiratory gases, heart rate and muscle tissue oxygenation simultanuously and at the end of the 6 min step test, you get an individual cardiorespiratory fitness report.

Also known as: SplendoHealth app

Two day 6-Minute Incremental Step Test (6 MIST)

Cardio-pulmonary exercise test DEVICE

Golden standard for measuring PEM: the double cardio-pulmonary exercise test on a bike.

Also known as: CPET

Two day Cardio-Pulmonary Exercise Test (CPET)

Eligibility Criteria

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

You may qualify if:

• ≥18 years old
• Long COVID patients following the World Health Organization (WHO) criteria: "the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation"
• Previously active as described in the WHO recommendations for physical activity (minimal 150 minutes/week of moderate intensity aerobic physical activity OR minimal 75 minutes of vigorous intensity activity/week OR an equivalent combination of moderate- and vigorous-intensity activity throughout the week)
• Patient suffers from PESE as defined by the DePaul Symptom Questionnaire PEM (Post-Exertional Malaise) subscale
• Able to understand and sign written informed consent in Dutch, French or English

You may not qualify if:

• Any pre-existing conditions or new medical diagnosis that can alternatively explain the current symptoms
• Being unable to perform a cycle ergometer test as decided upon by the medical study team members
• Suffering from Chronic Obstructive Pulmonary Disease (COPD) GOLD classification category 2,3 or 4 (by the Global Initiative for Chronic Obstructive Lung Disease)
• Allergies to medical adhesive bandages
• Skin conditions aggravated by sunlight including Porphyria
• Participation in other interventional trials
• Mitochondrial diseases
• Pregnancy
• Lactation

Sponsors & Collaborators

• Universitair Ziekenhuis Brussel: lead
• Vrije Universiteit Brussel, Jette, Belgium: collaborator

Study Sites (2)

Universitair Ziekenhuis Brussel

Jette, Brussels Capital, 1090, Belgium

Location

Universitair Ziekenhuis Brussel

Brussels, Jette, 1090, Belgium

Location

MeSH Terms

Conditions

Post-Acute COVID-19 Syndrome; Fatigue

Condition Hierarchy (Ancestors)

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Study Officials

• Elisabeth De Waele, MD, PhD

  Universitair Ziekenhuis Brussel

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Statistician
• Purpose: DEVICE FEASIBILITY
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Feasibility study in a cross-over model. The investigators calculated 40% drop out because this protocol presents considerable challenges for participants to complete.

Study Record Dates

• First Submitted: April 3, 2025
• First Posted: April 17, 2025
• Study Start: March 20, 2025
• Primary Completion: July 3, 2025
• Study Completion: July 3, 2025
• Last Updated: July 8, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

BE (2)