A Multi-Center, Individually-Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Superiority Trial to Evaluate the Efficacy of the Combination of Maraviroc and Atorvastatin for the Treatment of Subjects With Long COVID

A Multi-Center, Individually-Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Superiority Trial to Evaluate the Efficacy of the Combination of Maraviroc and Atorvastatin for the Treatment of Subjects With Long COVID

The IMPACT Long Covid Treatment clinical study (IMPACT-LC) is testing two repurposed and previously approved drugs, Maraviroc and Atorvastatin, for the treatment of non-hospitalized subjects with Long COVID. The main goals of the clinical study are to determine if this combination drug therapy can improve neurocognitive and physical functions in Long Covid patients, such as fatigue severity, heart rate, blood pressure, digestion, breathing, dizziness, and cognitive function. A secondary goal is to determine if biomarker levels, measured by a diagnostic test, can improve during treatment. To qualify for the trial, a subject must be an adult ≥ 18 and ≤ 65 years of age and meets the WHO-defined post-COVID-19 condition and has one or more new-onset Long Covid symptom that persist ≥ 3 months after the diagnosis of acute COVID-19 infection. A total of 252 participants will take either two daily doses of two existing medications (Maraviroc and Atorvastatin together as separate tablets) or a placebo (pills with no active ingredient) for 16 weeks. Although these medications are not yet approved for Long Covid, they are FDA-approved for use in treating other health conditions.

Inclusion Criterial

1. ≥ 18 and ≤ 65 years of age at the time of consent
2. Meets WHO-defined post-COVID-19 condition (WHO definition: 'Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time).
3. One or more new onset symptoms that persisted for greater than 6 months after the diagnosis of acute COVID-19 infection. These symptoms include: cognitive impairment (brain fog), migraines, post-exertional malaise (PEM), myalgias, arthralgias, severe fatigue, tachyarrhythmias, postural orthostatic tachycardia syndrome (POTS), and shortness of breath. The previous COVID-19 infection should be documented in the form of a positive PCR laboratory test and/or medical records from a healthcare provider. The Long-COVID diagnosis should be documented in the medical records by a healthcare provider.
4. Negative Lyme screen, as measured by the AcuDart test.
5. Epstein-Barr Virus (EBV) DNA negative (centrally assessed).
6. A long hauler index (LHI) of >0.71
7. A PROMIS Fatigue 10a T-score score > 55
8. Participants of childbearing potential should be surgically sterilized or post-menopausal or must agree to take effective contraceptive measures during the study period. Adequate methods of birth control include: condoms, male or female, with or without a spermicide; diaphragm or cervical cap with spermicide; intrauterine device; any of the methods that require a prescription (such as contraceptive pills or path) or a male partner who has previously undergone vasectomy.
9. Participant is willing and able to participate in the study and comply with all study requirements.
10. Participant provided signed and dated IRB approved informed consent prior to initiation of any study procedures.
11. Participant is able to read and understand English.

Exclusion Criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Participation in another therapeutic clinical trial in the past 2 months.

2. History of allergy or anaphylaxis or allergic reaction to any component of atorvastatin and/or maraviroc.

3. Uncontrolled hypothyroidism as defined as thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) values outside the local laboratory reference range at screening, or a change in thyroid hormone replacement dose within 6 weeks prior to screening.

4. Pre-COVID history of autoimmune conditions, migraines, neuropathy, inflammatory bowel disease (IBD), obsessive-compulsive disorder (OCD), or fatigue duration for ≥5 years, EBV infection, Lyme disease, fibromyalgia, arthritis, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD G3a or greater), chronic heart failure (CHF), arrhythmias, bleeding disorders, and anticoagulation therapy.

5. Presence of other conditions or differential diagnosis that better explains the symptoms of the patient than the suspected long COVID, in the opinion of the investigator.

6. Hepatic impairment, defined as Child-Pugh Score 7-9 (Class B) or greater.

7. Active/acute infectious diseases like tuberculosis, human immunodeficiency virus infection (HIV), cytomegalovirus (CMV), (vector based) Lyme, EBV, hepatitis B virus (HBV), hepatitis C virus (HCV).

8. Ongoing immunosuppressive therapy, such as cyclosporine A (CsA).

9. Use of statins within 6 months of randomization.

10. Concomitant use of cyclosporine, gemfibrozil, tipranavir plus ritonavir, or glecaprevir plus pibrentasvir, or lipid-modifying doses (>1 gram/day) of niacin.

11. AST:ALT ratio>1.5

12. Elevations in IL-8 (>21 (pg/ml) and or IL-13 (>6.1 pg/ml) (centrally assessed with IncellKINE panel).

13. Pregnant or breastfeeding

14. History of substance use disorder (including alcohol use disorder or cannabis use disorder per DSM-5 criteria) within 3 months of enrollment, OR current hazardous alcohol use as defined by:

    • Self-reported consumption >14 drinks/week (males) or >7 drinks/week (females), OR
    • Binge drinking (≥5 drinks on one occasion for males, ≥4 for females) ≥1 time per week, OR
    • Clinical judgment that alcohol use would interfere with study compliance or safety

15. Subjects with risk factors for myocardial ischemia/infarction, including but not limited to those with a prior history of MI, stroke, unstable angina,

16. Any significant disease or disorder, which, in the opinion of the Investigator, may either put the participants at risk

17. Azole antifungals (ketoconazole or itraconazole are not allowed) or macrolide antibiotics (clarithromycin is not allowed)

18. History of use of maraviroc and/or atorvastatin for the off-label treatment of Long COVID.

    Prohibited concomitant medications

19. Any statins within 6 months of randomization and between randomization and the participant's scheduled final visit

20. Other systemically administered drugs with significant immunosuppressive activity, such as azathioprine, tacrolimus, cyclosporine, methotrexate, or cytotoxic chemotherapy between randomization and the participant's scheduled final visit

21. Potent CYP3A inhibitors (with or without a potent CYP3A inducer) including:

    1. clarithromycin
    2. cobicistat
    3. elvitegravir/ritonavir
    4. itraconazole
    5. ketoconazole
    6. nefazodone
    7. protease inhibitors (except tipranavir/ritonavir)
    8. telithromycin

22. Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis:

    1. cyclosporine or gemfibrozil
    2. tipranavir plus ritonavir or glecaprevir plus pibrentasvir
    3. niacin (≥1 gram/day niacin)