The Long-Covid (LC)-Revitalize clinical study is testing repurposed drug treatments for Long Covid, involving adult participants from Brazil, Canada, Italy, Uganda, the United States, and Zambia. To qualify, participants must have had Covid-19 and experienced Long Covid symptoms for at least three months. The main goal of the study is to determine whether the drug treatments can improve symptoms in five key areas: 1) fatigue, 2) breathing, 3) memory, thinking, and communication, 4) muscle and joint pain, and 5) circulation. A secondary goal is to assess changes in the body, such as reducing inflammation, as well as to confirm the safety and tolerability of the treatments. In the first phase, 348 participants will take either one of two existing medications (upadacitinib or pirfenidone) or a placebo (a pill with no active ingredient) for three months. Although these medications are not yet approved for Long Covid, they are authorized for use in treating other health conditions. This study is adaptive, meaning it may adjust based on early results. In the second phase, the study could continue testing the most effective drug(s) against a placebo with new participants, explore combinations of drugs to see if they improve results, or discontinue the drugs if they prove ineffective or unsafe and test alternative treatments.
Long Covid represents a significant public health challenge, yet effective treatments remain elusive due to the disease's heterogeneity, limited clinical data, and inconsistent methodologies. A previous analysis of clinical and proteomic data from 1,028 subjects diagnosed with Long Covid across three continents (The LC-Optimize Study) suggests that certain repurposed medications may offer potential therapeutic benefits. Drug repurposing is based on the principle that many drugs interact with multiple molecular targets and mechanisms of action, potentially extending their effects beyond their original intended use. This phenomenon arises from the complex nature of biological systems and the interactions between drugs and various cellular components, which our research pipeline is designed to identify. A key advantage of repurposed drugs is that they already have established safety and toxicity profiles, are approved by regulatory authorities, and can therefore expedite clinical trials with sufficient supporting data and justification. This is a Phase III, double-blind, placebo-controlled, multi-arm platform study that will enroll participants from Brazil, Canada, Italy, Uganda, Zambia, and the United States. The first phase of the study will enroll approximately 348 participants globally, all of whom must have previously tested positive for SARS-CoV-2 and have been experiencing Long Covid symptoms for three months or more. A second phase will follow, guided by the results of the first phase and determined through an interim analysis. This phase, which will occur after a protocol amendment, may involve continued testing of one or both repurposed drugs, combination treatments with an additional repurposed drug, or the introduction of a completely new repurposed drug.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
348
Initial dose titration: First week (days 1-7): 1 capsule (267 mg), 3 times daily (801 mg/day) Second week (days 8-14): 2 capsules (534 mg), 3 times daily (1602 mg/day) Maintenance dose: Third week and thereafter (days 15-90): 3 capsules (801 mg), 3 times daily (2403 mg/day)
First week (days 1-7): 1 capsule, 3 times daily Second week (days 8-14): 2 capsules, 3 times daily Third week and thereafter (days 15-90): 3 capsules, 3 times daily
1 capsule (15 mg), once daily for 90 days
1 capsule, once daily for 90 days
Laura Rodriguez Research Institute
San Diego, California, United States
RECRUITINGIni-Fiocruz
Rio de Janeiro, Rio de Janerio, Brazil
NOT_YET_RECRUITINGInstitut de Recherches Cliniques de Montréal (IRCM)
Montreal, Quebec, Canada
RECRUITINGCentre de Recherche du CHUS (CRCHUS)
Sherbrooke, Quebec, Canada
RECRUITINGINMI Lazzaro Spallanzani IRCCS
Roma, Roma, Italy
NOT_YET_RECRUITINGSapienza Università di Roma
Roma, Roma, Italy
NOT_YET_RECRUITINGJoint Clinical Research Centre (JCRC)
Kampala, Kampala, Uganda
NOT_YET_RECRUITINGUniversity Teaching Hospital
Lusaka, Lusaka Province, Zambia
NOT_YET_RECRUITINGSymptom Burden Questionnaire (SBQ) Subscales
The aim of this study is to evaluate the efficacy of two repurposed drugs in reducing symptom severity in participants with Long Covid. The change in symptom score (transformed scale of 0-100) from baseline to both the interim and final analyses will be compared across one of the five validated subscales, relative to the placebo. This study will utilize five validated subscales: 1) Fatigue, 2) Breathing, 3) Memory, Thinking, and Communication, 4) Muscles and Joints, and 5) Circulation. Each subscale is based on a 4-point ordinal scale that assesses frequency, severity, or interference, or it uses a dichotomous yes/no response. The subscale with the highest symptom burden, determined by the highest transformed symptom score (ranging from 0 to 100, with a higher score indicating greater symptom burden) at baseline, will be selected for evaluating treatment effects.
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
General participant reported overall well-being using the Patient Reported Outcome Measurement Information System (PROMIS)-29 questionnaire
To compare symptom burden of participants with Long Covid treated with study drug versus placebo by measuring the change in total scores of the Patient Reported Outcome Measurement Information System (PROMIS)-29 questionnaire. The PROMIS-29 questionnaire consists of 29 items covering an overview of the participant's physical, mental, and social health. Each item is scored on a scale of 1 to 5, with the interpretation of lower scores varying by domain-indicating either better or worse symptom experience.
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
General participant reported overall well-being using the Generalized Anxiety Disorder (GAD)-7 questionnaire
To compare symptom burden of participants with Long Covid treated with study drug versus placebo by measuring the change in total scores of the Generalized Anxiety Disorder (GAD)-7 questionnaire from baseline to the interim and final analyses. The GAD-7 questionnaire consists of 7 items relating to the symptoms of stress and anxiety levels. Each item is scored on a scale of 0-3 with higher scores indicating more severe symptoms. Overall scores can range from 0-21 with scores of 5, 10, and 15 taken as the cut-off points for mild, moderate, and severe anxiety, respectively.
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
General participant reported overall well-being using the Patient Health Questionnaire (PHQ)-9
To compare symptom burden of participants with Long Covid treated with study drug versus placebo by measuring the change in total scores of the Patient Health Questionnaire (PHQ)-9 from baseline to the interim and final analyses. The PHQ-9 questionnaire consists of 9 items related to the symptoms of depression. Each item is scored on a scale of 0-3 with higher scores indicating more severe symptoms. Overall scores can range from 0-27 with scores of 5, 10, 15, and 20 taken as cut off points for mild, moderate, moderately severe, and severe depression, respectively.
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
General participant reported severity of post-exertional malaise (PEM) using the FUNCAP27 questionnaire
To compare symptom burden of participants with Long Covid treated with study drug versus placebo by measuring the change in scores of the Functional Capacity (FUNCAP)27 questionnaire from baseline to the interim and final analyses. The FUNCAP27 questionnaire consists of 27 items related to assessing functional capacity and the consequences of performing activities. Each item is scored on a scale of 0-6, with 0 indicating the participant is unable to complete the activity and 6 indicating the activity is unproblematic and does not affect other activities.
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
Worsening Long Covid Symptoms Measured by SBQ Subscales
To assess whether symptom burden worsens in participants with Long Covid treated with study drugs versus placebo, specifically when symptoms are reported across multiple scales indicated by the total number of participants with increased SBQ subscale scores. The following SBQ subscales will be used during this study: 1) Fatigue, 2) Breathing, 3) Memory, thinking, and communication, 4) Muscles and joints, and 5) Circulation. Each subscale is based on a 4-point ordinal scale that assesses frequency, severity, or interference, or it uses a dichotomous yes/no response. The subscale with the highest symptom burden, determined by the highest transformed symptom score (ranging from 0 to 100, with a higher score indicating greater symptom burden) at baseline, will be selected for evaluating treatment effects.
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
Quantitative measurement of biomarkers specific to relevant inflammatory pathways and to Long Covid identified previously (The LC-Optimize Study)
To measure specific pathophysiological biomarkers of study drugs versus placebo indicated by the normalization of blood biomarkers after treatment in picograms per milliliter (pg/mL).
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
Exercise capacity assessed by the 6-minute walk test (6MWT)
To assess changes in exercise capacity over time of participants with Long Covid treated with study drugs versus placebo. The score is determined by the distance a participant walks in six minutes around the perimeter of a designated circuit.
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
Safety and tolerability of the study drugs in participants with Long Covid
The frequency and severity of adverse events and laboratory abnormalities will be monitored to assess safety and tolerability. A lower incidence and severity will indicate that the drugs are safer and more tolerable.
Time frame: The Phase 1 time frame is from enrollment on Day 1 through to the end of follow-up at Month 6, and the Phase 2 time frame will be determined based on the results of Phase 1.
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