Piclidenoson for Treatment of COVID-19

• ClinicalTrials.gov Identifier: NCT04333472
• Recruitment Status: Completed
• First Posted: April 3, 2020
• Last Update Posted: April 22, 2022
• Sponsor: Can-Fite BioPharma
• Collaborator: Rabin Medical Center
• Information provided by (Responsible Party): Can-Fite BioPharma

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
COVID-19; Coronavirus Infection	Drug: Piclidenoson; Drug: Placebo	Phase 2

Detailed Description:

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 6 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Piclidenoson for Treatment of COVID-19 - A Randomized, Double-Blind, Placebo-Controlled Trial
• Actual Study Start Date: January 6, 2021
• Actual Primary Completion Date: March 6, 2022
• Actual Study Completion Date: April 21, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Piclidenoson; Piclidenoson 2 mg every 12 hours orally added to standard of care	Drug: Piclidenoson; Piclidenoson 2 mg orally every 12 hours for up to 28 days; Other Name: CF101
Placebo Comparator: Placebo; Placebo every 12 hours orally added to standard of care	Drug: Placebo; Placebo orally every 12 hours for up to 28 days

Outcome Measures

Primary Outcome Measures :

1. Proportion of subjects alive and free of respiratory failure [ Time Frame: 29 days ]
   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
2. Proportion of subjects discharged home alive [ Time Frame: 29 days ]
   Proportion of subjects alive and discharged to home without need for supplemental oxygen at Day 29
3. Treatment-emergent adverse events (AEs) [ Time Frame: 29 days ]
   Proportion of patients experiencing AEs

Secondary Outcome Measures :

1. Clinical status [ Time Frame: 29 days ]

   • Clinical status at Day 29 on NIAID 8-point ordinal scale (NIH 2020):

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

1. Hospitalized subjects 18 to 85 years of age, inclusive
2. Able and willing to sign informed consent
3. Molecular (RT-PCR) diagnosis of SARS-CoV-2 infection

4. 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
5. 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

6. 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.

   1. 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.
   2. For males: Surgical sterilization (vasectomy at least 1 month before screening) or double barrier methods.

Exclusion Criteria

1. 1. "Critical" Illness, per NIH COVID-19 Treatment Guidelines, including any of the following:

   • Respiratory failure; or
   • Septic shock; or
   • Multiple organ dysfunction
2. Subjects who require mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
3. Participation in another clinical trial concurrently
4. Concurrent treatment with immunomodulators or anti-rejection drugs
5. Nursing women, pregnant women, women of childbearing potential who do not want adequate contraception

6. 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

7. 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)

Contacts and Locations

Locations

Bulgaria

II Multiprofile Hospital for Active Treatment - Sofia EAD

Sofia, Bulgaria

IV Multiprofile Hospital for Active Treatment - Sofia EAD

Sofia, Bulgaria

Israel

Hadassah Medical Center

Jerusalem, Israel

Shaare Zedek Medical Center

Jerusalem, Israel

Romania

Clinical Hospital for Infectious Diseases "St. Parascheva" Iasi

Iaşi, Romania

"Sfantul Ioan cel Nou" County Emergency Hospital Suceava

Suceava, Romania

Sponsors and Collaborators

Can-Fite BioPharma

Rabin Medical Center

Investigators

• Study Director: Zivit Harpaz; Can-Fite BioPharma Ltd

More Information

Additional Information:

Sponsor website 

Publications:

Fishman P, Cohen S. The A3 adenosine receptor (A3AR): therapeutic target and predictive biological marker in rheumatoid arthritis. Clin Rheumatol. 2016 Sep;35(9):2359-62. doi: 10.1007/s10067-016-3202-4. Epub 2016 Feb 17.

Cohen S, Fishman P. Targeting the A3 adenosine receptor to treat cytokine release syndrome in cancer immunotherapy. Drug Des Devel Ther. 2019 Jan 30;13:491-497. doi: 10.2147/DDDT.S195294. eCollection 2019.

• Responsible Party: Can-Fite BioPharma
• ClinicalTrials.gov Identifier: NCT04333472
• Other Study ID Numbers: CF101-241COVID-19
• First Posted: April 3, 2020
• Last Update Posted: April 22, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: To be determined
• Supporting Materials: Study Protocol; Clinical Study Report (CSR)
• Time Frame: January 2021, indefinitely
• Access Criteria: To be determined

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Can-Fite BioPharma:

Piclidenoson; CF101; SARS-CoV-2

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases