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

July 7, 2025 updated by: Universitair Ziekenhuis Brussel

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
25

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
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
Time Frame: 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)
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
Time Frame: 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.]
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)
Time Frame: Baseline (measured once, during the first study visit)
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)
Time Frame: Baseline (measured once during the first study visit)
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)
Time Frame: Baseline (measured once during the first study visit)
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)
Time Frame: Baseline (measured once during the first study visit)
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)
Time Frame: Baseline (measured once during the first study visit)
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)
Time Frame: Baseline (measured once during the first study visit)
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)
Time Frame: Baseline (measured once during the first study visit)
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)
Time Frame: Baseline (measured once during the first study visit)
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
Time Frame: Between day 1 of study visit and day 1 of experimental session

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
Time Frame: Between day 1 of study visit and day 1 of experimental session
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)
Time Frame: Baseline (measured once during the first study visit)
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)
Time Frame: Baseline (measured once during the first study visit)
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
Time Frame: Baseline (measured once during the first study visit)
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
Time Frame: Baseline (measured once during the first study visit)
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
Time Frame: Baseline (measured once during the first study visit)
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)
Time Frame: During 7 days before the first experimental session
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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
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)
Time Frame: From Day 1 to Day 2 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))
Time Frame: From Day 1 to Day 2 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 Workload (Watts) at first ventilatory threshold during experimental session 1 or 2 (CPET)
Time Frame: From Day 1 to Day 2 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)
Time Frame: From Day 1 to Day 2 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))
Time Frame: From Day 1 to Day 2 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)
Time Frame: From Day 1 to Day 2 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 VE/VO2 slope during experimental sessions 1 and 2 (CPET and 6 MIST)
Time Frame: From Day 1 to Day 2 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 VO2/HR slope (= O2 pulse) during experimental sessions 1 and 2 (CPET and 6 MIST)
Time Frame: From Day 1 to Day 2 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 Respiratory Exchange Ratio (RER) = VCO2/VO2 during experimental sessions 1 or 2 (CPET)
Time Frame: From Day 1 to Day 2 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 Cardiorespiratory Optimal Point (COP) = VO2/VE during experimental session 1 or 2 (CPET)
Time Frame: From Day 1 to Day 2 during experimental session 1 or 2 (CPET)
From Day 1 to Day 2 during experimental session 1 or 2 (CPET)

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Vaccination status of the participant
Time Frame: Baseline (inquired during the first study visit)
Is the participant vaccinated or not, and with which vaccine.
Baseline (inquired during the first study visit)
Date of birth of the participant
Time Frame: Baseline (inquired during the first study visit)
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
Time Frame: Baseline (inquired during the first study visit)
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)
Time Frame: Baseline (calculated during the first study visit)
Baseline (calculated during the first study visit)
Hospitalization for COVID-19
Time Frame: Baseline (inquired during the first study visit)

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
Time Frame: Baseline (inquired during the first study visit)
The highest degree of the participant.
Baseline (inquired during the first study visit)
Employement status of the participant
Time Frame: Baseline (inquired during the first study visit)
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
Time Frame: Baseline (inquired during the first study visit)
Native language of the participant (Dutch, French, English, German, Arabic, Other)
Baseline (inquired during the first study visit)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Universitair Ziekenhuis Brussel

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Vrije Universiteit Brussel, Jette, Belgium

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Elisabeth De Waele, MD, PhD, Universitair Ziekenhuis Brussel

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 20, 2025

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 3, 2025

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 3, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 3, 2025

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 16, 2025

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 17, 2025

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 8, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 7, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant 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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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