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

Feasibility Study of the Augmented Two-Day 6-Minute Incremental Step Test and Causal Exploration Through a Directed Acyclic Graph and Structural Equation Model for Post-Exertional Symptom Exacerbations in Long COVID Patients

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.

Study Overview

• Status: Completed
• Conditions: Long COVID
• Intervention / Treatment: Device: Portable mask for respiratory gas analysis; Device: Cardio-pulmonary exercise test

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Brussels
    • Jette, Brussels, Belgium, 1090
      • Universitair Ziekenhuis Brussel
  • Jette
    • Brussels, Jette, Belgium, 1090
      • Universitair Ziekenhuis Brussel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• ≥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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Device Feasibility
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Two day 6-Minute Incremental Step Test (6 MIST); 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; 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.; Other Names: SplendoHealth app
Active Comparator: Two day Cardio-Pulmonary Exercise Test (CPET); 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; Golden standard for measuring PEM: the double cardio-pulmonary exercise test on a bike.; Other Names: CPET

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
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)
Change from Day 1 to Day 2 in Ventilation (VE) (Tidal Volume (TV) and Respiration Rate (RR)) during experimental sessions 1 and 2 (CPET 1 6MIST)	From Day 1 to Day 2 during experimental sessions 1 and 2 (CPET & 6MIST
Change from Day 1 to Day 2 in VE/VO2 slope during experimental sessions 1 and 2 (CPET and 6 MIST)	From Day 1 to Day 2 during experimental sessions 1 and 2 (CPET & 6MIST
Change from Day 1 to Day 2 in VO2/HR slope (= O2 pulse) during experimental sessions 1 and 2 (CPET and 6 MIST)	From Day 1 to Day 2 during experimental sessions 1 and 2 (CPET & 6MIST
Change from Day 1 to Day 2 in Respiratory Exchange Ratio (RER) = VCO2/VO2 during experimental sessions 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 Cardiorespiratory Optimal Point (COP) = VO2/VE during experimental session 1 or 2 (CPET)	From Day 1 to Day 2 during experimental session 1 or 2 (CPET)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vaccination status of the participant	Is the participant vaccinated or not, and with which vaccine.	Baseline (inquired during the first study visit)
Date of birth of the participant	Date of birth of the participant. This is needed to make sure the participant is older than 18.	Baseline (inquired during the first study visit)
Ethnicity of the participant	What is the ethnicity of the participant. (White, Hispanic/Latino, Black/African/African American, Asian, Native American/Indigenous)	Baseline (inquired during the first study visit)
BMI (kg/m²)		Baseline (calculated during the first study visit)
Hospitalization for COVID-19	Has the participant been hospitalized for his or her COVID infection, yes or no. If yes, has the participant been hospitalized in the ICU or not.	Baseline (inquired during the first study visit)
Educational level of the participant	The highest degree of the participant.	Baseline (inquired during the first study visit)
Employement status of the participant	The current employment status of the participant (employed full time or part-time, unemployed looking for work, unemployed not looking for work, self-employed, unable to work, student, retired).	Baseline (inquired during the first study visit)
Native language of the participant	Native language of the participant (Dutch, French, English, German, Arabic, Other)	Baseline (inquired during the first study visit)

Collaborators and Investigators

• Sponsor: Universitair Ziekenhuis Brussel
• Collaborators: Vrije Universiteit Brussel, Jette, Belgium
• Investigators: Principal Investigator: Elisabeth De Waele, MD, PhD, Universitair Ziekenhuis Brussel

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2025
• Primary Completion (Actual): July 3, 2025
• Study Completion (Actual): July 3, 2025

Study Registration Dates

• First Submitted: April 3, 2025
• First Submitted That Met QC Criteria: April 16, 2025
• First Posted (Actual): April 17, 2025

Study Record Updates

• Last Update Posted (Estimated): July 8, 2025
• Last Update Submitted That Met QC Criteria: July 7, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Fatigue; long covid; CPET; PEM; Post-Exertional Malaise; 6MIST
• Additional Relevant MeSH Terms: Post-Infectious Disorders; COVID-19; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Recurrence; Symptom Flare Up; Post-Acute COVID-19 Syndrome
• Other Study ID Numbers: 2024-EDW-REVEAL; G075423N (Other Identifier: Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No