Piclidenoson for Treatment of COVID-19

Study Overview
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Brief Summary
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Patients with documented moderate COVID-19 infection will be randomized 1:1 to receive piclidenoson 2 mg Q12H orally with standard supportive care (SSC - intervention arm) or placebo orally with SSC (control arm) for up to 28 days.

Detailed Description
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This is a randomized, double-blind, placebo-controlled, pilot trial of piclidenoson 2 mg Q12H added to SSC, compared to placebo plus SSC, in a population of hospitalized subjects with Moderate or Severe COVID-19 per U.S. National Institutes of Health (NIH) Coronavirus Disease 2019 (COVID-19) Treatment Guidelines (2020). Subjects will be randomized according to a 1:1 ratio to one of the trial arms, and treated for up to 28 days, at the discretion of the Investigator. Piclidenoson 2 mg and placebo are supplied as matching tablets for oral administration. Following initial diagnosis of COVID-19, and after having provided informed consent, subjects will be randomized according to 1:1 ratio to one of the trial arms on Day 0. SSC will be implemented and documented for all subjects, and maintained throughout the treatment period. Vital signs (temperature, blood pressure, pulse rate per minute, respiratory rate per minute, oxygen saturation (SpO2), and PaO2/FiO2) of subjects will be monitored twice daily according to SSC. Parameters of clinical, respiratory, and vital status will be collected daily. Viral shedding will be assessed on a regular basis. Samples for pharmacokinetic (PK) analysis will be collected on Day 4. Efficacy of piclidenoson will be assessed by clinical, respiratory, and virologic parameters. Safety and tolerability of piclidenoson will be assessed by adverse event (AE) monitoring, vital signs assessment, electrocardiograms (ECGs), and clinical laboratory tests (complete blood count (CBC) and extended chemistry panel). Adverse events will be graded by the Common Terminology Criteria for Adverse Events (CTCAE v5.0).

Official Title
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Piclidenoson for Treatment of COVID-19 - A Randomized, Double-Blind, Placebo-Controlled Trial

Conditions
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COVID-19, Coronavirus Infection

Intervention / Treatment
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* Drug: Piclidenoson
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Hospitalized subjects 18 to 85 years of age, inclusive Able and willing to sign informed consent Molecular (RT-PCR) diagnosis of SARS-CoV-2 infection Moderate or Severe illness per NIH COVID-19 Treatment Guidelines: Moderate Illness: Symptoms such as cough, fever, sore throat, malaise, myalgias, headache; and Evidence of lower respiratory tract disease by clinical assessment and/or imaging; and SpO2 >93% on room air at sea level Severe Illness, including any of the following: Respiratory rate >30 breaths/minute; or SpO2 ≤93% on room air at sea level; or Ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300; or Lung infiltrates >50% of pulmonary volume on imaging Female subjects must have a negative serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of investigational product Female subjects of childbearing potential and male subjects with partners of childbearing potential must agree to use adequate methods of contraception during the study and through 90 days after the last dose of study medication. Female subjects of childbearing potential are all those except subjects who are surgically sterile, who have medically documented ovarian failure, or who are at least 1 year postmenopausal. For females: 2 of the following contraceptive methods, with at least 1 being a barrier method: Hormonal contraceptives for at least 27 days before dosing Intrauterine device (IUD) in place at least 27 days before dosing Double-barrier methods (use of condom [male partner] with either diaphragm with spermicide or cervical cap with spermicide) from screening Surgical sterilization of the partner (vasectomy at least 1 month before screening) Female subjects must have a negative urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of investigational product. For males: Surgical sterilization (vasectomy at least 1 month before screening) or double barrier methods. Exclusion Criteria 1. Critical Illness, per NIH COVID-19 Treatment Guidelines, including any of the following: Respiratory failure; or Septic shock; or Multiple organ dysfunction Subjects who require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) Participation in another clinical trial concurrently Concurrent treatment with immunomodulators or anti-rejection drugs Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception History of any of the following diseases or conditions: Advanced or decompensated liver disease (including presence or history of bleeding varices, ascites, encephalopathy, or hepato-renal syndrome) Inability to swallow tablets, or gastrointestinal disease which could interfere with the absorption of piclidenoson Any malignancy within 5 years before screening; exceptions are superficial dermatologic malignancies (e.g., squamous cell or basal cell skin cancer treated with curative intent) Cardiomyopathy, significant ischemic cardiac or cerebrovascular disease (including history of angina, myocardial infarction, or interventional procedure for coronary artery disease), or cardiac rhythm disorder QTcF interval on an average of triplicate ECGs >450 milliseconds (msec) for males or >470 msec for females (except when QT prolongation is associated with right or left bundle branch block, in which case enrollment is allowed) Any condition which increases proarrhythmic risk, including hypokalemia, hypomagnesemia, congenital Long QT Syndrome Ongoing or planned use of a concomitant medication that is on the CredibleMeds list of drugs known to cause Torsades de Pointes unless the subject can be screened and monitored under the guidelines proposed by Giudicessi (2020) Pancreatitis Severe or uncontrolled psychiatric disorder, e.g., depression, manic condition, psychosis, acute and/or chronic cognitive dysfunction, suicidal behavior, and relapse of substance abuse Active seizure disorder defined by either an untreated seizure disorder or continued seizure activity within the preceding year despite treatment with anti-seizure medication Bone marrow or solid organ transplantation Any serious condition that, in the opinion of the investigator, would preclude evaluation of response or make it unlikely that the contemplated course of therapy and follow-up could be completed Any of the following abnormal laboratory tests: Platelet count <90,000 cells/mm3 Absolute neutrophil count (ANC) <1,500 cells/mm3 Estimated creatinine clearance (CrCl) <50 mL/min by Cockroft-Gault formulation Bilirubin level ≥2.5 mg/dL unless due to Gilbert's syndrome AST or ALT level ≥3X the upper limit of normal Serum albumin level <3.0 g/dL International normalized ratio (INR) ≥1.5 (except subjects maintained on anticoagulant medications)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Piclidenoson<br>Piclidenoson 2 mg every 12 hours orally added to standard of care | Drug: Piclidenoson<br>* Piclidenoson 2 mg orally every 12 hours for up to 28 days<br>* Other names: CF101;|
| Placebo Comparator: Placebo<br>Placebo every 12 hours orally added to standard of care | Drug: Placebo<br>* Placebo orally every 12 hours for up to 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects alive and free of respiratory failure | Proportion of subjects alive and free of respiratory failure (defined as need for non-invasive or invasive mechanical ventilation, high-flow oxygen, or extracorporeal membrane oxygenation) at Day 29 | 29 days | 
| Proportion of subjects discharged home alive | Proportion of subjects alive and discharged to home without need for supplemental oxygen at Day 29 | 29 days | 
| Treatment-emergent adverse events (AEs) | Proportion of patients experiencing AEs | 29 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical status | • Clinical status at Day 29 on NIAID 8-point ordinal scale (NIH 2020): Not hospitalized, no limitations Not hospitalized, with limitations Hospitalized, no active medical problems Hospitalized, not on oxygen Hospitalized, on oxygen Hospitalized, on high-flow oxygen or noninvasive mechanical ventilation Hospitalized, on mechanical ventilation or ECMO Death | 29 days | 
| Time to improvement | Time (days) to improvement of 2 points on 7-point ordinal clinical scale | 29 days | 
| Incidence of mechanical ventilation | Proportion of patients who require mechanical ventilation | 29 days | 
| Ventilator-free days | Ventilator-free days to Day 29 | 29 days | 
| Incidence of Intensive Care Unit (ICU) admission | Proportion of patients who require ICU admission | 29 days | 
| Duration of ICU stay | Duration (days) of ICU stay | 29 days | 
| Time to hospital discharge | Time (days) to hospital discharge | 29 days | 
| Duration of need for supplemental oxygen | Duration (days) of need for supplemental oxygen | 29 days | 
| Time to virus negativity | Time (days) to virus negativity by RT-PCR, defined as absence of SARS CoV 2 on 2 consecutive days of sampling | 29 days | 
| SARS-CoV-2 viral load | SARS-CoV-2 viral load (number of copies) by quantitative RT-PCR | 29 days | 
| AEs leading to withdrawal | Proportion of patients experiencing AEs leading to early discontinuation of trial treatment | 29 days | 
| Treatment-emergent serious AEs (SAEs) | Proportion of patients experiencing SAEs | 29 days | 
| Treatment-emergent abnormalities in clinical laboratory parameters or electrocardiograms (ECGs) | Proportion of patients experiencing treatment-emergent changes in clinical laboratory parameters or ECGs | 29 days | 
| Incidence of meeting safety-related stopping rules | Proportion of patients who meet study safety-related stopping rules | 29 days | 
| Pharmacokinetics of piclidenoson in this patient population | Plasma concentrations over time of piclidenoson | 5 days | 
| Serum cytokine levels | Change from baseline in serum concentrations of cytokines | 29 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Piclidenoson, CF101, SARS-CoV-2