Evaluating Immunomodulatory Interventions in Post-Acute Sequelae of SARS-CoV-2 InfEction (RISE)

A Randomized Controlled Basket Study for Evaluating Immunomodulatory Interventions in Post-Acute Sequelae of SARS-CoV-2 InfEction (RISE)

This study is a prospective, randomized controlled, basket trial. Patients diagnosed with Post-Acute Sequelae of SARS-CoV-2 Infection who meet the inclusion and exclusion criteria are recruited and divided into three symptom clusters: Inflammatory Cardiac involvement symptoms cluster, cough symptoms cluster and fatigue symptoms cluster. Each symptom cluster is randomly divided into an experimental group and a control group, Patients who do not accept treatment can be included in the observational cohort. Subjects in the experimental group receive immunomodulatory interventions plus conventional treatment, while subjects in the control group receive conventional treatment only. Subjects in each symptom cluster undergo clinical medical record data collection, laboratory tests, and imaging examinations at specified time points, as well as records of adverse events.

Study Overview

• Status: Not yet recruiting
• Conditions: Post-acute Sequelae of SARS-COV-2 Infection
• Intervention / Treatment: Drug: Prednisone; Drug: Vitamin C combined with Coenzyme Q10 oral treatment; Drug: Budesonide/Formoterol; Drug: Montelukast tablets oral treatment

• Study Type: Interventional
• Enrollment (Estimated): 632
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital of Fudan University
      • Contact: Wenhong Zhang, PhD, MD; Phone Number: 8123 +86 21 52889999; Email: zhangwenhong@fudan.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 1. Age ≥18 years;
• 2. Post-infection with SARS-CoV-2 for more than 3 months and meets the World Health Organization (WHO) definition of Long COVID;
• 3. Symptom criteria: Meet the inclusion and exclusion criteria for each symptom cluster;
• 4. Fertile female subjects are not breastfeeding or pregnant at the time of enrollment (negative urine pregnancy test);
• 5. Willing and able to provide informed consent, complete surveys, clinical assessments, and all necessary follow-up visits;

Symptom Cluster Inclusion Criteria:

• Inflammatory Cardiac Involvement Symptom Cluster
• 1) Age: 18-75 years old;
• 2) Presence of cardiac symptoms at the time of enrollment (e.g., Chest tightness after physical activity, chest pain, difficulty breathing, palpitations, fatigue, etc.);
• 3) CMR shows the following abnormal findings based on any of the following criteria:
• a) Native T1 increase ≥ 1130 milliseconds at 3.0 T (or an increase of 1030 milliseconds at 1.5 T) and/or;
• b) Native T2 ≥ 39.5 milliseconds at 3.0 T (or 49.5 milliseconds at 1.5 T) and/or;
• c) Presence of non-ischemic myocardial and pericardial late gadolinium enhancement and/or;
• d) Left ventricular ejection fraction ≥ 40% and ≤50%.
• Cough Symptom Cluster
• 1) Clinical assessment of cough according to ACCP guidelines indicates no cough caused by other diseases such as COPD, asthma, chronic bronchitis, gastroesophageal reflux, bronchiectasis, etc.;
• 2) Chest X-ray or CT scan shows no abnormalities that could lead to cough or other serious lung diseases;
• 3) FENO ≥25 ppb, or the proportion of eosinophils in sputum cytology ≥2.5%; or the blood eosinophil count >0.3×10⁹/L.
• Fatigue Symptom Cluster
• 1) Fatigue Severity Scale (FSS) average score ≥ 4;
• 2) Any inflammatory marker (CRP, ESR, PCT, ferritin, IL-6, TNFα) is above the upper limit of normal.

Exclusion Criteria:

• 1. Known SARS-CoV-2 infection within 3 months prior to the date of informed consent signature;
• 2. Systemic fungal infection and active infections that cannot be controlled by anti-infective agents;
• 3. Current or recent (within the last 10 weeks) use of glucocorticoids, other immunosuppressants, or biologic agents;
• 4. Known allergy/sensitivity or any hypersensitivity reaction to the study intervention or control components;
• 5. Known contraindications to the study intervention;
• 6. Any persistent central nervous system disorders, psychiatric illnesses, chronic respiratory or cardiac diseases, Underlying diseases (poorly controlled diabetes, poorly controlled hypertension, peripheral edema, cataracts or glaucoma, peptic ulcer disease, femoral head necrosis, low bone density, or osteoporosis);
• 7. For female participants: pregnant or breastfeeding at screening, or expecting to become pregnant during the study period; women of childbearing age who are unwilling to use effective contraceptive measures (defined as PEARL index <1, such as birth control pills, intrauterine devices);
• 8. Known alcohol, drug, or chemical abuse;
• 9. Currently participating in another clinical trial;
• 10. Deemed ineligible to participate in this study by the investigator's assessment.

Symptom Cluster Exclusion Criteria:

• Inflammatory Cardiac Involvement Symptom Cluster
• 1) Past medical history or cardiac magnetic resonance (CMR) evidence indicating significant cardiac disease, including:
• a) Known left ventricular ejection fraction (LVEF) <40% indicating cardiac dysfunction;
• b) Congestive heart failure (New York Heart Association Class III-IV);
• c) Ongoing treatment for heart failure (including HFrEF and HFpEF);
• d) Confirmed ischemic heart disease, peripheral artery disease, and/or cerebrovascular disease;
• e) Persistent or permanent atrial fibrillation or significant arrhythmias;
• f) Congenital or clinically relevant valvular heart disease (moderate or severe);
• g) Specific cardio myopathies (hypertrophic, hypertensive heart disease, amyloidosis, previous myocarditis, non-ischemic dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, non-compacted cardiomyopathy, etc.);
• 2) Contraindications for contrast-enhanced cardiac magnetic resonance (CMR) imaging, such as: use of implanted devices not compatible with MRI; known allergy to gadolinium-based contrast agents (CBGA);
• 3) Patients with structural heart disease or incidental arrhythmias detected on cardiac magnetic resonance imaging will be advised to consult their physicians.
• Cough Symptom Cluster
• 1) Current smoker or having quit smoking for less than 6 months;
• 2) Intolerance to pulmonary function testing and/or FeNO;
• 3) Chest CT showing acute pulmonary infection-related diseases;
• 4) Forced expiratory volume in 1 second (FEV1) / Forced vital capacity (FVC) ratio less than 60%;
• 5) Currently taking or having used angiotensin-converting enzyme inhibitors (ACEI) within the past 3 months of screening;
• 6) Received any relevant traditional Chinese or Western medical treatment within the last month.
• Fatigue Symptom Cluster
• 1) Received any relevant traditional Chinese or Western medical treatment within the last month, taking sedatives, hypnotics, melatonin, or antidepressants;
• 2) Known previous diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome unrelated to SARS-CoV-2 infection;
• 3) Known previous autonomic dysfunction unrelated to SARS-CoV-2 infection;
• 4) Fatigue caused by metabolism-related diseases (such as hyperthyroidism or hypothyroidism, malnutrition) that developed following SARS-CoV-2 infection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inflammatory Cardiac Involvement symptom cluster - immunomodulatory intervention	Drug: Prednisone; Total 4 weeks of treatment; Drug: Vitamin C combined with Coenzyme Q10 oral treatment; Total 4 weeks of treatment
Active Comparator: Inflammatory Cardiac Involvement symptom cluster	Drug: Vitamin C combined with Coenzyme Q10 oral treatment; Total 4 weeks of treatment
Experimental: Cough symptom cluster - immunomodulatory intervention	Drug: Budesonide/Formoterol; Total 8 weeks of treatment; Drug: Montelukast tablets oral treatment; Total 8 weeks of treatment
Active Comparator: Cough symptom cluster	Drug: Montelukast tablets oral treatment; Total 8 weeks of treatment
Experimental: Fatigue symptom cluster - immunomodulatory intervention	Drug: Prednisone; Total 4 weeks of treatment; Drug: Vitamin C combined with Coenzyme Q10 oral treatment; Total 4 weeks of treatment
Active Comparator: Fatigue symptom cluster	Drug: Vitamin C combined with Coenzyme Q10 oral treatment; Total 4 weeks of treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory Cardiac Involvement symptom cluster: cardiac magnetic resonance (CMR) indicators	Assessing the difference in changes in cardiac magnetic resonance (CMR) indicators [left ventricular ejection fraction, late gadolinium enhancement (LGE), and T1 and T2 mapping values (in milliseconds)] from baseline between the experimental and control groups.	4 weeks
Cough symptom cluster: Leicester Cough Questionnaire (LCQ) scale scores	Assessing the difference in changes in the Leicester Cough Questionnaire (LCQ) scale scores from baseline. The total score range of the LCQ is from 3 to 21 points, with higher scores indicating a lesser impact of cough on the patient's life.	8 weeks
Fatigue symptom cluster: Fatigue Severity Scale (FSS) scale scores	Assessing the difference in changes in the Fatigue Severity Scale (FSS) scale scores from baseline. The total score range of the FSS is from 9 to 63 points, with higher scores indicating a greater severity of fatigue.	4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammatory Cardiac Involvement symptom cluster: other relevant cardiac magnetic resonance (CMR) indicators	Assessing the changes in in other relevant cardiac magnetic resonance (CMR) indicators from baseline.	4 weeks
Inflammatory Cardiac Involvement symptom cluster: VO2max	Assessing the changes in VO2max in cardiopulmonary exercise testing.	At baseline, 4 weeks
Inflammatory Cardiac Involvement symptom cluster: Kansas City Cardiomyopathy Questionnaire (KCCQ) scores	Assessing the changes in the KCCQ scores between the experimental and control groups. The total score range of the KCCQ is from 0 to 100, with lower scores indicating poorer quality of life for heart failure patients.	At baseline, 4, 8, 12, and 24 weeks
Inflammatory Cardiac Involvement symptom cluster: Change in cTNT Levels	Measures the change in cardiac troponin T (cTNT) levels	At baseline, 4, 8, 12 and 24 weeks
Inflammatory Cardiac Involvement symptom cluster: the proportion of patients experiencing heart failure and major adverse cardiac events (MACE)	From baseline to week 52, assessing the proportion of patients experiencing heart failure and MACE between the experimental and control groups.	From baseline to 52 weeks
EuroQoL 5-Dimension 5-Level (EQ-5D-5L) questionnaire scores	Assessing the changes in the EQ-5D-5L questionnaire scores between the experimental and control groups. The EQ-5D-5L is a widely used generic measure of health status consisting of two parts. The first part (the descriptive system) provides a descriptive profile that can be used to generate a health state profile. Each health state can be assigned a summary index score. Health state index scores generally range from less than 0 (where 0 is the value of a health state equivalent to dead; negative values representing values as worse than dead) to 1 (the value of full health), with higher scores indicating higher health utility. The second part of the questionnaire consists of a visual analogue scale (VAS) on which the patient rates his/her perceived health from 0 (the worst imaginable health) to 100 (the best imaginable health).	At baseline, 4, 8, 12 and 24 weeks
Pittsburgh Sleep Quality Index (PSQI) scores	Assessing the changes in the PSQI scores between the experimental and control groups. The total score range of the PSQI is from 0 to 21, with higher scores indicating poorer sleep quality.	At baseline 4, 8, 12, and 24 weeks
Generalized Anxiety Disorder-7 (GAD-7)	Assessing the changes in the GAD-7 scores between the experimental and control groups. The total score range of the GAD-7 is from 0 to 21, with higher scores indicating more severe anxiety.	At baseline, 4, 8, 12 and 24 weeks
Patient Health Questionnaire-9 (PHQ-9) depression symptom cluster scores	Assessing the changes in the PHQ-9 cores between the experimental and control groups. The total score range of the PHQ-9 is from 0 to 27, with higher scores indicating more severe depression.	At baseline, 4, 8, 12 and 24 weeks
Cough symptom cluster: Visual Analogue Scale (VAS)	Assessing the change in the severity of cough as measured by the VAS between the experimental and control groups . The total score range of the VAS is from 0 to 100, with higher scores indicating more severe coughing in the patient.	At baseline 4, 8 and 12 weeks
Cough symptom cluster: pulmonary function and fractional exhaled nitric oxide (FeNO) levels	Assessing the changes in pulmonary function and FeNO levels between the experimental and control groups.	At baseline and 8 weeks
Fatigue symptom cluster: Visual Analogue Scale (VAS)	The total score range of the VAS is from 0 to 100, with higher scores indicating more severe fatigue in the patient.	At baseline, 4, 8, and 12 weeks
Change in proBNP Levels	Measures the change in N-terminal pro-brain natriuretic peptide (proBNP) levels, which are associated with heart failure.	Baseline, 4, 8, 12, 24 weeks
Change in Angiotensin II Levels	Measures the change in angiotensin II levels	Baseline, 4, 8, 12, 24 weeks
Change in Ferritin Levels	Measures the change in ferritin levels	Baseline, 4, 8, 12, 24 weeks
Change in IL-6 Levels	Measures the change in interleukin-6 (IL-6) levels	Baseline, 4, 8, 12, 24 weeks
Change in hsCRP Levels	Measures the change in high-sensitivity C-reactive protein (hsCRP) levels	Baseline, 4, 8, 12, 24 weeks

Collaborators and Investigators

• Sponsor: Huashan Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2025
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2027

Study Registration Dates

• First Submitted: September 12, 2024
• First Submitted That Met QC Criteria: September 12, 2024
• First Posted (Actual): September 19, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 5, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Long COVID; Post-acute Sequelae of SARS-COV-2 Infection; Immunomodulatory Interventions
• Additional Relevant MeSH Terms: Post-Infectious Disorders; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; Post-Acute COVID-19 Syndrome; Infections; Communicable Diseases; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Autonomic Agents; Peripheral Nervous System Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neurotransmitter Agents; Micronutrients; Hormone Antagonists; Adrenergic Agonists; Adrenergic Agents; Respiratory System Agents; Vitamins; Anti-Asthmatic Agents; Bronchodilator Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP1A2 Inducers; Leukotriene Antagonists; Formoterol Fumarate; Prednisone; Budesonide; Ubiquinone; Coenzyme Q10; Montelukast
• Other Study ID Numbers: RISE

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