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NCT Number: NCT07400848

Clinical Laboratory Evaluation, Assessment of Symptoms and Recovery in Patients With Post-COVID-19-Vaccination Syndrome

Some people report persistent health problems after receiving the COVID-19 vaccine. These symptoms persist well beyond typical short-term vaccine side effects and are not attributable to any other known medical conditions. This condition is known as Post-Acute COVID-19 Vaccination Syndrome (PACVS). Symptoms can persist for months and affect several organ systems, causing issues such as fatigue, heart-related problems, neurological difficulties, and decreases in both physical ability and mental performance. PACVS shows similarities to Post-Acute COVID-19 syndrome (PACS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

The biological processes that cause PACVS are still not fully understood. Recent research indicates that endothelial dysfunction, abnormalities in blood coagulation, and persistent inflammatory responses may contribute significantly to this process. However, it remains unclear how symptoms develop over time, which biological markers are associated with disease severity, and how these findings could support diagnosis and future treatment strategies.

The CLEAR study is an observational research project designed to address these knowledge gaps by systematically documenting symptoms over time and investigating potential biological correlates in individuals affected by PACVS. The study consists of three complementary subprojects.

The PROGRESS subproject aims to assess symptom burden, disease course, and patient-reported treatment experiences over an eight-month period using standardized questionnaires completed by participants.

The ENDOCLOT subproject investigates whether individuals with PACVS show objective signs of endothelial dysfunction, abnormalities in blood clotting, and markers of systemic inflammation. Endothelial function will be evaluated through non-invasive vascular reactivity tests (EndoPAT), microscopic examination of blood cells, standardized platelet function assessments, and standard laboratory diagnostics. It further explores the correlation between these biological parameters and clinical symptom trajectories identified in PROGRESS.

The REAL subproject examines the role of endothelial activation and the release of inflammatory signaling molecules (cytokines) in the development and persistence of PACVS.

The main hypothesis of the CLEAR study is that PACVS is associated with measurable endothelial dysfunction, inflammatory activation, and coagulation abnormalities, and that these biological changes are related to symptom severity and persistence over time. By combining longitudinal symptom assessment with biological measurements, this study aims to improve understanding of PACVS and support the development of better diagnostic and therapeutic approaches in the future.

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Key information

Conditions

Post-Acute COVID-19 Vaccination Syndrome Chronic Disease Disease Attributes Encephalomyelitis Fatigue Syndrome, Chronic Inflammation Muscular Diseases Musculoskeletal Diseases Nervous System Diseases Neuroinflammatory Diseases Neuromuscular Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Postviral Fatigue

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Institute of Sport Science, University of Bern

Bern, 3012, Switzerland

Location status: Recruiting

Location contact

Michaela Fux, PD Dr. phil. nat.

CONTACT

[email protected]

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

General Criteria (apply to all study parts: PROGRESS, ENDOCLOT, REAL, patients and matched healthy controls)

Inclusion criteria

  • Age ≥ 18 years
  • Sufficient knowledge of German to complete study-related questionnaires and procedures

Exclusion criteria

  • Severe cognitive, physical impairment or psychiatric conditions impeding participation
  • Active oncological disease or immunosuppressive
  • Known pregnancy at the time of enrolment

PROGRESS (patients only)

Inclusion criteria

  • Coded participation with online consent confirmation
  • Self-reported onset of persistent symptoms temporally associated with a COVID-19 vaccination
  • Willingness and ability to participate in the 8-month follow-up period

Exclusion criteria

  • No specific exclusion criteria for this part

ENDOCLOT and REAL (patients and matched healthy controls)

Inclusion criteria

  • Signed informed consent form
  • For patients:
  • Receipt of at least one COVID-19 vaccination
  • Onset of new, otherwise unexplained symptoms within 0-14 days after vaccination
  • Persistence of symptoms for at least 6 months following vaccination
  • Selection is based on a diagnosis of ME/CFS according to the Canadian Consensus Criteria (CCC) and PEM.
  • For controls: History of COVID-19 vaccination without persistent adverse effects; age (+/- 10 years), and sex match to a corresponding case

Exclusion criteria

(patients and matched healthy controls)

  • Clinically suspected or laboratory confirmed SARS-CoV-2 infection after vaccination or temporally related to symptom onset.
  • Concurrent pre-existing Long COVID symptoms, obtained from the patient´s history
  • Any self-reported or uncertain history of an acute infectious event (including mild or subclinical infections) in temporal proximity to COVID-19 vaccination
  • Known pre-existing medical conditions or ongoing medications that could plausibly explain the reported symptoms (e.g., preexisting ME/CFS, POTS, fibromyalgia, small-fiberneuropathy, autoimmune disease with systemic involvement or other chronic multisystemic dysautonomia syndromes)
  • Use of long-term, high-dose anti-inflammatory

Treatment and study plan

Blood sampling and analysis

Diagnostic Test

Blood sampling to analyze:

  • Routine laboratory diagnostics including complete blood count, coagulation and inflammation markers (e.g., fibrinogen, von Willebrand Factor, D-dimer, Factor VIII, hsCRP, Troponin-T, NT-proBNP
  • Platelet function analysis using the Multiplate Analyzer (ADPtest, ASPItest, TRAPtest)
  • Blood morphology assessment using real-time confocal microscopy
  • Endothelial activation (Syndecan-1, ICAM-1, PAI-1/tPA complex, Heparan sulfate)
  • Complement activation (sC5b-9)

The continuous Reactive Hyperemia Index (InRHI) measured by EndoPAT

Other

To assess endothelial function, participants undergo a non-invasive measurement using the EndoPAT device. This system evaluates vascular reactivity by continuously recording the peripheral arterial tone (PAT) signal via pneumatic finger probes placed on both index fingers. The total duration of the measurement is approximately 17 minutes. During the first 6 minutes, the baseline vascular tone is recorded at rest. This is followed by a 5-minute arterial occlusion phase, during which a blood pressure cuff on one arm (typically the non-dominant arm) is inflated to suprasystolic pressure to temporarily interrupt arterial blood flow. After the cuff is released, the reactive hyperemia response is recorded for an additional 6 minutes to assess endothelial-dependent vasodilation. The procedure is painless and well-tolerated. Participants may experience a mild tingling sensation in the occluded arm during the occlusion phase. No adverse effects are expected.

Primary outcomes

  1. Self-reported health status (EQ-VAS)

    Time frame: From enrollment to baseline assessment (T0)

    Self-reported overall health status measured using the EuroQoL Visual Analogue Scale (EQ-VAS), ranging from 0 to 100, with higher scores indicating better perceived health status.

  2. Health-related quality of life (EQ-5D-5L index score)

    Time frame: From enrollment to baseline assessment T0

    Health-related quality of life assessed using the EuroQoL EQ-5D-5L index score, typically ranging from values below 0 (health states worse than death) to 1, with higher scores indicating better health-related quality of life.

  3. Reactive Hyperemia Index (lnRHI)

    Time frame: From enrollment to the day of examination, estimated to occur within 14 days after enrollment.

    Continuous Reactive Hyperemia Index measured using EndoPAT; noting that values ≤0.51 indicating dysfunction

Secondary outcomes

  1. Change in self-reported health status (EQ-VAS)

    Time frame: During follow-up at approximately 4 months (±2 weeks, T1) and 8 months (±2 weeks; T2) after enrollment.

    Self-reported health status measured using the EQ-VAS, ranging from 0 to 100, with higher scores indicating better perceived health status.

  2. Change in health-related quality of life (EQ-5D-5L index score)

    Time frame: During follow-up at approximately 4 months (±2 weeks, T1) and 8 months (±2 weeks, T2) after enrollment.

    Health-related quality of life measured using the EQ-5D-5L index score; higher scores indicate better quality of life.

  3. Functional impairment (Bell Disability Scale)

    Time frame: From enrollment to baseline assessment (T0), and during follow-up at approximately 4 months (±2 weeks, T1) and 8 months (±2 weeks, T2) after enrollment.

    Functional impairment assessed using the Bell Disability Scale, ranging from 0 to 100, with lower scores indicating greater disability.

  4. ME/CFS symptom severity (Canadian Consensus Criteria)

    Time frame: From enrollment to baseline assessment (T0), and during follow-up at approximately 4 months (±2 weeks, T1) and 8 months (±2 weeks, T2) after enrollment.

    Assessment of ME/CFS symptom severity, including fatigue, post-exertional malaise, unrefreshing sleep, pain, cognitive/neurological impairments, and autonomic, neuroendocrine, or immune manifestations. Symptoms are rated on a standardized scale, with higher scores indicating greater symptom severity and functional impairment.

  5. Presence of post-exertional malaise (PEM)

    Time frame: From enrollment to baseline assessment (T0), and during follow-up at approximately 4 months (±2 weeks, T1) and 8 months (±2 weeks, T2) after enrollment.

    Presence of post-exertional malaise assessed using a standardized PEM screening instrument (binary outcome: present/absent whereby at least one of the answer is indicated with a frequency and severity of ≥ 2. )

  6. Functional capacity (FUNCAP55)

    Time frame: From enrollment to baseline assessment (T0), and during follow-up at approximately 4 months (±2 weeks, T1) and 8 months (±2 weeks, T2) after enrollment.

    Functional capacity assessed using the FUNCAP55 screening instrument; higher scores indicate better functional capacity.

  7. Reported treatments and medications

    Time frame: From enrollment to baseline assessment (T0), and during follow-up at approximately 4 months (±2 weeks, T1) and 8 months (±2 weeks, T2) after enrollment.

    Self-reported past and current treatments and medications used by participants.

  8. Self-reported treatment effects and side effects

    Time frame: From enrollment to baseline assessment (T0), and during follow-up at approximately 4 months (±2 weeks, T1) and 8 months (±2 weeks, T2) after enrollment.

    Participant-reported perceived treatment effects and adverse effects.

  9. Platelet reactivity (ADPtest AUC)

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Platelet aggregation measured using Multiplate analyzer (ADPtest), reported as area under the curve (AUC); higher values indicate increased platelet reactivity.

  10. Platelet reactivity (ASPItest AUC)

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Platelet aggregation measured using Multiplate analyzer (ASPItest), reported as area under the curve (AUC); higher values indicate increased platelet reactivity.

  11. Platelet reactivity (TRAPtest AUC)

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Platelet aggregation measured using Multiplate analyzer (TRAPtest), reported as area under the curve (AUC); higher values indicate increased platelet reactivity.

  12. High-sensitivity C-reactive protein (hs-CRP) level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Serum hs-CRP concentration; higher levels indicate increased systemic inflammation

  13. Fibrinogen level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma fibrinogen concentration; higher levels indicate increased coagulation activity

  14. D-dimer level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma D-dimer concentration; higher levels indicate increased fibrin turnover

  15. von Willebrand factor level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma von Willebrand factor concentration; higher levels indicate endothelial activation.

  16. Factor VIII activity

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma Factor VIII activity; higher activity indicates increased coagulation potential.

  17. Troponin T (high sensitivity)

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    High-sensitivity cardiac troponin T concentration; higher levels indicate myocardial injury.

  18. NT-proBNP level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma NT-proBNP concentration; higher levels indicate cardiac strain.

  19. Blood cell morphology

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Microscopic assessment of leukocyte count and platelet and erythrocyte morphology.

  20. Syndecan-1 level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma Syndecan-1 concentration; higher levels indicate increased endothelial activation.

  21. ICAM-1 level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma ICAM-1 concentration; higher levels indicate endothelial activation.

  22. PAI-1/tPA complex level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma PAI-1/tPA complex concentration; higher levels indicate impaired fibrinolysis.

  23. Heparan sulfate level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma heparan sulfate concentration; higher levels indicate glycocalyx degradation.

  24. Terminal complement complex (sC5b-9) level

    Time frame: From enrollment to the day of blood sampling, estimated to occur within 14 days after enrollment.

    Plasma sC5b-9 concentration; higher levels indicate complement activation.

Study contacts

Contact information is provided by the study sponsor or research team.

Michaela Fux, PD Dr. phil. nat.

CONTACT

[email protected]

+41 79 342 67 30

Mirko Schmidt, Prof. Dr.

CONTACT

[email protected]

+41 79 342 67 30

Sponsors and collaborators

Lead sponsor

University of Bern

Other

Collaborators

  • Medical University Innsbruck
  • Post-Vakzin-Syndrom Schweiz
  • private practice Cell-Re-Active-Training in Bern

Registry information

Acronym: CLEAR

Important dates

Study start
2026
Primary completion
2026
Study completion
2026
First posted
Feb 10, 2026
Registry last updated
May 5, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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