A Phase 2/3 Study to Evaluate FP-025 in Patients With Severe to Critical COVID 19

This is a Phase 2/3, randomized, double blind, placebo controlled, multicenter study to evaluate the efficacy and safety of FP-025 in adult patients with severe to critical COVID 19 with associated ARDS.

This is a Phase 2/3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of FP-025 in adult patients with severe to critical COVID-19 with associated ARDS. The patients in each phase (Phase 2 and Phase 3) will be analyzed separately. Each phase will consist of a Screening Visit, Treatment Period, and Follow-Up Period for a total study duration of approximately 60 days.

Phase 2: After eligibility is confirmed, approximately 90 patients will be randomized in a 1:1:1 ratio to receive FP-025 100 mg twice daily (BID), FP-025 300 mg BID, or placebo BID for 28 days. During Phase 2, randomized patients will be stratified by the use of invasive mechanical ventilation at the time of randomization (yes or no). At least one-third of patients should be on invasive mechanical ventilation to ensure that treatment benefits can be assessed for patients at different severity levels.

Patients with Grade 3 to Grade 4 heart failure, Stage 3 or greater chronic obstructive pulmonary disease, persistent asthma, and mild liver disease (ie, Child-Pugh Class A) will not be excluded from the study. The independent Data Monitoring Committee (iDMC) will independently monitor safety of the entire population and in different subgroups and may make recommendations as it deems appropriate. During Phase 2, no limitation in enrollment of subgroups is expected, unless clear safety signals arise in those subgroups during iDMC reviews.

The reason for hospital admission, the standard of care followed for each patient and center, and whether any care decisions were based on resource limitations will be clearly documented for all patients beginning on Day 1 (Visit 2). All patients will be allowed to receive standard of care and/or emergency use authorization (EUA) medications and treatment for COVID-19; however, the study drug should be discontinued for other non-standard of care concomitant medications used with the intent of directly treating COVID-19 unless there is prior Medical Monitor or Sponsor approval for the patient to remain on the study drug. If the use of concomitant medications necessitates study drug discontinuation, the patient should be encouraged to remain in the study and to follow-up for key study visits (Day 28 and Day 60) but will not be required to attend every study visit. If the patient withdraws, he/she should complete the Early Termination Visit.

Standard of care procedures for mechanical ventilation (eg, low tidal volume protective mechanical ventilation) and standard of care procedures for weaning from mechanical ventilation will be followed.

Study drug administration will begin on Day 1 (Visit 2) following randomization. All patients will receive standard of care and/or EUA treatment for COVID-19 in addition to the study drug. Patients will continue study drug treatment BID through Day 27 and take 1 dose on Day 28. If a patient is discharged from the hospital prior to Day 28, he/she will continue treatment as an outpatient at home with his/her assigned treatment (FP-025 100 mg BID, FP-025 300 mg BID, or placebo BID) until Day 28. Dosing instructions will be provided prior to discharge. Although treatment will be identical for inpatients and outpatients, patients discharged from the hospital will follow a different Schedule of Procedures, characterized by telemedicine (or telephone, if sites and/or patients do not have video capability) visits. The End of Treatment (EOT) Visit on Day 28 will be identical for all patients (with the exception of the arterial oxygen partial pressure \[PaO2\]/fractional inspired oxygen \[FiO2\] ratio, performed only in patients on invasive or non-invasive ventilation) and will include a high-resolution, non-contrast CT scan, in addition to other assessments.

After treatment is completed, all patients will undergo 2 follow-up assessments during the Follow-Up Period. The first follow-up will be a telephone visit on Day 45 to assess concomitant medications, adverse events (AEs), and the NIAID 8-point ordinal scale for COVID-19 and hospitalization outcomes score. The second follow-up will be an in-person visit on Day 60 and will include a high-resolution, non-contrast CT scan and pulmonary function tests, in addition to other assessments.

An iDMC will convene to oversee safety and efficacy assessments during and after the Phase 2 study. No formal statistical testing will be conducted. In addition, when all patients in the Phase 2 study have completed the EOT Visit on Day 28, a primary analysis will be conducted by an independent statistician and reviewed by the iDMC. This is the point at which the study was terminated, due to lack of further eligible patients.

Eligibility Criteria:
Inclusion Criteria:

1. Is willing to provide informed consent (or has a legally authorized representative \[LAR\] willing to provide informed consent) and is willing and able (or has an LAR willing and able) to comply with the protocol required therapy, monitoring, and follow-up;
2. Is a male or female aged ≥ 18 years;
3. Has a COVID-19 diagnosis confirmed by a documented, positive severe acute respiratory syndrome (SARS) CoV-2 reverse transcriptase polymerase chain reaction test (or equivalent test) immediately prior to or during the current hospitalization;
4. Is hospitalized with severe to critical COVID 19 within a 72-hour period prior to the Screening Visit and meeting the following characteristics:

   * Diagnosed with ARDS based on the Berlin criteria as follows:

     * Respiratory symptoms developed within 1 week of a known clinical insult or new or worsening respiratory symptoms developed during the past week;
     * Chest radiograph or computed tomography scan shows bilateral opacities not fully explained by pleural effusions, lobar or lung collapse, or pulmonary nodules; and
     * Respiratory failure is not fully explained by cardiac failure or fluid overload; and
   * Requiring at least 1 of the following:

     * Endotracheal intubation and mechanical ventilation;
     * Oxygen delivered by high flow nasal cannula (heated, humidified oxygen delivered via reinforced nasal cannula at flow rates \> 20 L/minute with a fraction of delivered oxygen ≥ 0.5);
     * Non invasive positive pressure ventilation; or
     * Clinical diagnosis of respiratory failure (ie, the clinical need for 1 of the preceding therapies, but preceding therapies are unable to be administered in the setting of resource limitations);
5. If female, is post-menopausal for at least 1 year, surgically sterile (documented by medical record), or a woman of childbearing potential (WCBP) who agrees to use a highly effective method of birth control (ie, method with a failure rate \< 1% per year) from enrollment until 30 days following the last dose of study drug. Highly effective methods of birth control are defined as follows: complete sexual abstinence, intrauterine device, intrauterine hormone-releasing system, progestogen-only hormonal contraception (implant, injectable, or oral), and combined (estrogen and progestogen) contraception (oral, intravaginal, or transdermal);
6. If a WCBP, must have a negative serum human chorionic gonadotropin pregnancy test at the Screening Visit, and must agree to monthly urine pregnancy tests during the study; and
7. If male, must be surgically sterile for at least 1 year prior to the Screening Visit (documented by medical record), or must agree to use a double barrier approach (eg, condoms with spermicide) during sexual intercourse between the Screening Visit and at least 90 days after administration of the last dose of study drug. Male patients must ensure that non pregnant female partners of childbearing potential comply with the contraception requirements in Inclusion Criterion 5.

Exclusion Criteria:

1. Is not expected to survive more than 24 hours;
2. Is on extracorporeal membrane oxygenation (ECMO) at the Screening Visit;
3. Has an underlying clinical condition where, in the opinion of the Investigator, it would be extremely unlikely that the patient would come off ventilation (eg, motor neuron disease, Duchenne muscular dystrophy, or rapidly progressive pulmonary fibrosis);
4. Has a known history of idiopathic pulmonary fibrosis or interstitial lung disease as defined by the American Thoracic Society 2018 guidelines;
5. Has known active tuberculosis (TB), a history of incompletely treated TB, and/or suspected or known extrapulmonary TB;
6. Has Child Pugh Class B or C active liver disease or an alanine aminotransferase or aspartate aminotransferase level \> 4 x the upper limit of normal at the Screening Visit;
7. Has moderate to severe renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2, at the Screening Visit or requires hemodialysis;
8. Has a malignant tumor (excluding a malignant tumor cured with no recurrence in the past 5 years, completely resected basal cell and squamous cell carcinoma of skin, and/or completely resected carcinoma in situ of any type);
9. Has an uncontrolled systemic or local autoimmune or inflammatory disease besides COVID 19;
10. Has evidence of an active concurrent non COVID 19 pneumonia (requiring additional antimicrobial treatment) caused by a known or suspected bacterial pathogen, respiratory syncytial virus (RSV), influenza virus, SARS CoV 1, Middle East respiratory syndrome CoV, aspergillus, mucormycosis causing fungi, or other pulmonary pathogen(s);

    Note: A viral respiratory panel will be administered at the Screening Visit to determine eligibility. At a minimum, the panel will evaluate for RSV, influenza A, and influenza B.
11. Has received any other investigational therapeutic products within 4 weeks or 5 half-lives, whichever is longer, prior to randomization;
12. Has a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection;
13. Has a known serious allergic reaction or hypersensitivity to any components of FP-025;
14. Is pregnant or breastfeeding;
15. Has a history of drug or alcohol abuse within the past 2 years;
16. Is currently on another systemic immunomodulatory therapy that is not considered standard of care treatment for COVID 19 (eg, calcineurin inhibitor, hydroxychloroquine, anti cytokine therapy, or Janus kinase inhibitor); or Note: Corticosteroids, including dexamethasone, in doses used for standard of care treatment for COVID 19 are allowed.

    Note: Corticosteroids that are being used for other indications are also allowed as long as the daily prednisone (or other corticosteroid equivalent) dose is ≤ 10 mg. Inhaled corticosteroids and nasal corticosteroids are also acceptable.

    Note: As therapies for COVID-19 are rapidly evolving, other medications that may be considered standard of care can be considered with prior approval from the Sponsor or Medical Monitor.
17. Has any other condition that, in the opinion of the Investigator, could interfere with (or for which the treatment might interfere with) the conduct of the study or interpretation of the study results or that would place the patient at undue risk by participating in the study.