The Long-Covid (LC)-Revitalize clinical study is testing repurposed drug treatments forLong Covid, involving adult participants from Brazil, Canada, Italy, Uganda, Zambia, andthe United States. To qualify, participants must have had Covid-19 and experienced LongCovid symptoms for at least three months. The main goal of the study is to determinewhether 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 reducinginflammation, as well as to confirm the safety and tolerability of the treatments. In thefirst phase, 348 participants will take either one of two existing medications(upadacitinib or pirfenidone) or a placebo (a pill with no active ingredient) for threemonths. Although these medications are not yet approved for Long Covid, they areauthorized for use in treating other health conditions. This study is adaptive, meaningit may adjust based on early results. In the second phase, the study could continuetesting the most effective drug(s) against a placebo with new participants, explorecombinations of drugs to see if they improve results, or discontinue the drugs if theyprove 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.
Drug: Pirfenidone
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)
Other Name: Esbrit
Drug: Placebo for pirfenidone
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
Drug: Upadacitinib
1 capsule (15 mg), once daily for 90 days
Other Name: Rinvoq
Drug: Placebo for upadacitinib
1 capsule, once daily for 90 days
Inclusion Criteria:
Eligible participants must meet all the following inclusion criteria:
1. Adults ≥ 18 years of age and ≤ 65 years of age
2. Previous Covid-19 (SARS-CoV-2) infection, positive on either nasopharyngeal PCR or
antigen testing (positive plasma N-Capsid antibodies as an alternative), with Long
Covid one year from presumed Covid-19 diagnosis.
3. Persistent or new symptoms diagnosed as "Long Covid" as defined by the World Health
Organization; "the continuation or development of new symptoms 3 months after the
initial SARS-CoV-2 infection (Covid-19), with these symptoms lasting for at least 2
months with no other explanation". This diagnosis may come from a healthcare
professional experienced in Long Covid diagnosis, or the site investigator. These
symptoms must be present for more days than not and must not have been present prior
to the onset of SARS-CoV-2 (Covid-19) infection.
4. Participants should be experiencing at least one of the following self-reported
symptoms or symptom clusters. Participant has self-reported issues with:
1. Fatigue
2. Breathing
3. Circulation
4. Memory, thinking, and/or communication
5. Muscles and/or joints
These five symptoms or symptom clusters were selected based on unpublished data from
the National Institutes for Health and Care Research (NIHR, United Kingdom) and
their alignment with five validated SBQ scales. The selection was driven by their
prevalence and their significant impact on quality of life as reported in symptom
assessments.
5. Participant has the ability and is willing to follow study procedures throughout the
study
6. Participant can provide informed consent
Exclusion Criteria:
Participants who have any one or more of the following criteria at the time of enrollment
will be excluded:
1. Participants who do not meet the criteria outlined above
2. Participants who are unable to provide their informed consent
3. Participants who are pregnant, lactating, or plan to become pregnant during the time
of the study
4. Persons of childbearing potential who are unwilling or unable to abstain from sex or
to use at least one acceptable method of contraception from the time of screening
through at least 30 days after the end of the study intervention period. Acceptable
methods include barrier contraceptives (e.g., condoms or diaphragm) with spermicide,
intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive pills, and
surgical sterilization. Participants unwilling to be counseled about the risks
related to pregnancy or breastfeeding will also be excluded.
5. Male participants must take precautions to avoid impregnating a female while
participating in this study. If a male participant's partner can become pregnant,
she must use an effective and reliable form of birth control, as listed above,
during the study and for 30 days after the male participant's last dose of the
investigational product. Additionally, male participants must agree to use a latex
condom during sexual activity with partners who could become pregnant.
6. eGFR <30 mL/min/1.73m2
7. Moderate to severe liver dysfunction, defined as Bilirubin > 1.5 x ULN or AST or ALT
> 2 x ULN
8. Hemoglobin (Hbg) < 8.0 g/dL
9. Absolute neutrophil count (ANC) below 1,000 cells/mm³, confirmed with repeat testing
10. Absolute lymphocyte count (ALC) below 500 cells/mm³
11. Alkaline phosphatase (ALP) levels equal to or greater than three times the upper
limit of normal (ULN)
12. Creatine phosphokinase (CPK) levels equal to or greater than three times the ULN
13. Platelet count below 100,000 cells/mm³, confirmed with repeat testing
14. Platelet count above 500,000 cells/mm³, confirmed with repeat testing
15. Total fasting cholesterol levels of 280 mg/dL or higher, confirmed with repeat
testing
16. Fasting low-density lipoprotein (LDL) levels of 180 mg/dL or higher, confirmed with
repeat testing
17. A personal or family history of long QT syndrome or an electrocardiogram (ECG)
during screening showing a corrected QT interval (QTc) of 500 milliseconds or
greater, calculated using Fridericia's formula
18. Participants with HIV diagnosis
19. Participants with active hepatitis B or C diagnosis. Note: treated or cleared
hepatitis C is not exclusionary.
20. Active herpes zoster infection (visible skin lesions) within 3 months prior to
screening, or any history of disseminated or complicated herpes zoster or herpes
simplex infection (e.g., VZV encephalitis)
21. Participants with active or latent tuberculosis
22. Immunocompromised status, as determined by the investigator, that places the
participant at an unacceptable risk for study participation
23. Active malignancy or lymphoproliferative disorder that has not been in remission for
at least five years. Localized non-melanoma skin cancers that have been definitively
treated are not exclusionary.
24. Positive SARS-CoV-2 test in the last 30 days or symptomatic with Covid-19 like
illness
25. Previous admission to an intensive care unit (ICU) for the treatment of acute
COVID-19 infection
26. Any history of deep venous thrombosis, pulmonary embolism, unstable angina, atrial
fibrillation, ventricular fibrillation, or myocardial infarction or stroke
27. History of sepsis or a significant viral, bacterial, fungal, or parasitic infection
within 30 days prior to enrollment, as determined by the investigator.
28. Use of one or more of the study drugs within 30 days prior to enrollment for the
original indication or other purposes
29. Known allergic reactions to the components of the study drugs
30. Any prior exposure to JAK inhibitors
31. Taking any of the listed medications on the prohibited medications list in Appendix
A
32. Intake or planned consumption of any of the following: Taurine, Curcumin, CoQ10,
Creatine, Resveratrol, Fisetin, Nicotinamide mononucleotide (NMN), Nicotinamide
adenine dinucleotide (NAD+), Quercetin, Glycine, Spermidine, Arginine
alpha-ketoglutarate, Ergothioneine, Alpha Lipoic Acid, Carnitine, Benfotiamine,
Carnosine, Crocin, N-acetylcysteine
33. Covid vaccinations are prohibited within 30 days prior to enrollment
34. Live vaccine within the 30 days before enrollment or plan to receive live vaccines
during the study period
35. Other vaccines, including influenza vaccine, are prohibited within 14 days of
enrollment
36. Major surgery within 30 days prior to enrollment or plans for major surgery during
the study
37. Any other co-existing medical condition or concomitant medication/therapy that might
in the judgment of the study investigators, potentially impact the participant's
safety or ability to adhere to the study protocol or interfere with the meaning of
the clinical and research measurements as judged by the study investigators
38. Participation in any clinical study within the last 30 days prior to enrollment
39. Participants who participated in Phase One of this study (LC-Revitalize) are not
eligible to participate in Phase Two
40. Currently hospitalized and/or incarcerated
Not Provided
Stephanie Perkin
1-519-685-8500 - 55051
stephanie.perkin@lhsc.on.ca
Douglas D Fraser, MD, PhD, FRCPC, Principal Investigator
Western University