SARS-CoV-2 Specific Monoclonal Antibody for Post-COVID-19 Conditions (Long COVID)

Effectiveness of Treating Post-COVID-19 Conditions (Long COVID) With the SARS-CoV-2 Specific Monoclonal Antibody, Sipavibart

This placebo-controlled, randomized, blinded, two-arm phase II study will test the safety and potential efficacy of the targeted mAb, Sipavibart (formerly AZD3152) in patients with Long COVID.

Acute COVID-19 infection can present differently among infected patients, with the infection ranging in symptom presentation from asymptomatic and mild symptomatology to severe illness. Common symptoms tied to a COVID-19 infection include fever, chills, cough, respiratory ailments (shortness of breath or difficulty breathing), fatigue, muscle and/or joint pain, headache, loss of taste or smell, sore throat, congestion, and/or gastrointestinal (GI) disturbances (nausea, vomiting, and/or diarrhea). In some patients, these symptoms are short-lived and span the length of the acute infection, while in many patients the symptoms can linger for an extended period. Early indications point to inflammation playing a key role in acute COVID-19 illness and severity, and may play a role in prolonged Long COVID(LC) symptom intolerance and long-term sequelae. Researchers have demonstrated the involvement of persistent inflammation, poor antiviral responses, and evidence of chronic viral reactivation.

More recently, studies have demonstrated that mAb targeting the spike (S) protein of the SARS-CoV-2 may not only be effective in treating acute COVID-19 infection, especially variants prior to Omicron (alpha, beta, and delta), but also may play a role in addressing Long COVID. This implies that mAb infusions likely target SARS-CoV-2, decreasing activity, and potentially addressing disease pathogenesis tied to its activation, shutting down negative implications of inflammation tied to viral activation. This study will employ a two-arm randomized design to evaluate the efficacy of the drug Sipavibart in individuals experiencing LC symptoms. Participants will undergo six months of follow up after receiving either one dose of Sipavibart or one dose of placebo. After completion of the 6-month follow up, an open-label extension phase will be added at month 6 (week 24), where subjects who continue to experience symptoms of long COVID (regardless of the blinded treatment assignment) could be eligible to receive one dose of Sipavibart in an open-label fashion.

Inclusion Criteria:

An individual is eligible for inclusion if all of the following apply:

1. 18 to 70 years old,

2. Inciting event: Acute COVID documented by testing (PCR or antigen testing in a clinical setting).

3. Onset of COVID symptoms occurring on or prior to August 31st, 2023; and persistence of symptomatic expression of Long COVID (defined #6 below) for more than 3 months after COVID diagnosis.

4. Current symptomatic expression meets the case definition of ME/CFS.

5. PROMIS 29 score at screening of moderate to severe (≥60).

6. Meets National Academy of Sciences (NAS) criteria for Long COVID with the following provisions:

   1. Allowance for normal illnesses of aging, such as hypertension and diabetes, if the conditions are treated and are in demonstrable stable and acceptable ranges at the time of screening and assessment. Specifically, blood pressures < 150 systolic and 90 diastolic mmHg are required.
   2. Allowance of stable comorbid conditions common in post viral illness, such as fibromyalgia, irritable bowel, interstitial cystitis, dysautonomia that have not required hospitalization in the two years prior to recruitment.

7. Able to provide written consent to study. Agrees to participate in follow-up visits.

Subject Exclusion Criteria

An individual is ineligible to participate if any of the following apply:

1. Known active acute SARS-CoV-2 infection ≤ 4 weeks from consent.

2. Known severe anemia, defined as < 8 g/dL.

3. Known stroke that resulted in cognitive impairment within 3 months of enrollment.

4. Self-report of current treated or untreated major depression with psychotic or melancholic features, schizophrenia, bipolar disorder, delusional disorders, dementias of any type, or a history of CNS disorders that may affect cognitive function (i.e., epilepsy, stroke, brain tumor, multiple sclerosis, Parkinson's Disease, Alzheimer's disease), or substance abuse during the last two years, excluding cannabis products.

5. Allergy to any ingredient of the study drug (self-report)

   1. Sipavibart is supplied as 150 mg/mL of active ingredient in 20 mM L-histidine/L-histidine hydrochloride, 220 mM L-arginine hydrochloride, and 0.04% (w/v) polysorbate 80, at pH 6.0.
   2. Hypersensitivity to other humanized mAbs.

6. Current heavy alcohol or tobacco use (self-report). Alcohol consumption not to exceed approximately 15 drinks per week (with a drink defined as 12 oz beer, 5 oz wine, or 1.5 oz distilled spirits) and tobacco use not to exceed 20 cigarettes (or equivalent) per day during the last month.

7. Active chronic infections such as HIV, Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV), indicated by self-report, and abnormal liver function tests (>3x upper limit of normal) or evidence in the health record of chronic active hepatitis or human immunodeficiency virus (HIV).

8. Renal disease (self-report; laboratory results: renal insufficiency with serum creatinine > 2.0 mg/dL or eGFR < 44; or currently on renal dialysis)

9. Liver disease (self-report or laboratory results: hepatic insufficiency (bilirubin >2.5mg/dL or transaminases > 3X the upper limits of normal)

10. Uncontrolled diabetes, evidenced by combination of morning blood glucose and previous diagnosis of diabetes, AIC>7

11. Diagnosed with congestive heart failure or significant arrythmia (ventricular tachycardia with a rapid rate at rest (> 100 bpm), persistent atrial fibrillation, or second- or third-degree heart block)

12. Pre-existing sustained severe hypertension (BP >180/110 mmHg in the sitting position)

13. Any of the following within 4 weeks of consent (Self-reported/medical record):

    1. an acute myocardial infarction or unstable angina
    2. uncontrolled arrhythmias causing symptoms or hemodynamic compromise
    3. acute myocarditis or pericarditis, uncontrolled acutely decompensated heart failure (acute pulmonary edema)
    4. acute pulmonary embolism
    5. suspected dissecting aneurysm
    6. severe hypoxemia at rest
    7. any acute or chronic disorder that may affect exercise performance, or
    8. if they are aggravated by exercise (e.g., infection, thyrotoxicosis, unable to cooperate)

14. Diagnosed bleeding disorders or use of blood-thinning medications.

15. Current or previous receipt of any COVID antiviral medication within 30 days prior to screening (self reported)

16. Currently have exclusionary diagnoses that could reasonably explain the symptoms of their fatiguing illness and their severity, using the exclusion criteria best described in the Ambiguities in case definition paper for CFS, as described in detail in [13] which clarifies exclusionary conditions. These exclusionary diagnoses that are not otherwise listed above comprise:

    1. Organ failure

    2. Chronic inflammatory diseases

    3. Major neurologic diseases that could cause fatigue or neurologic deficits

    4. Diseases requiring systemic treatment (i.e., transplantation, chemotherapy, radiation)

    5. Major endocrine diseases

    6. Untreated primary sleep disorders

    7. BMI > 40 kg/m2

    8. Temporary conditions discovered at screening, such as

       • Temporary effects of medications
       • Temporary sleep deprivation
       • Untreated hypothyroidism, hypothyroidism that has been inadequately controlled during the last 3 months, or free T4 level not within normal limits
       • Active infection (for COVID-19 infection and other infections, participants may be rescreened six weeks after resolution of infection)

17. Known diagnosis of chronic Lyme disease with persistent symptoms, sequelae, or related therapy.

18. Any marijuana illicit drug use within 30 days of informed consent

19. Inability to discontinue symptomatic medications for the identified time periods

20. Moderate or severe immunocompromised patients, such as those described in the NIH COVID-Treatment Guidelines

21. Are scheduled for a surgery during the period of study participation, had minor surgery within three months prior to screening, or had major surgery within 6 months prior to screening

22. Participating in any interventional (including social-behavioral therapy) clinical trial of an investigational therapy within 6 weeks prior to consent, or planning to participate in another interventional clinical trial of an investigational therapy during the course of this study

23. COVID Vaccination within 90 days prior to entry and for the duration of the study

24. Pregnancy is excluded. Women of childbearing age will be given a pregnancy test.