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Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia

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ClinicalTrials.gov Identifier: NCT04467840
Recruitment Status : Completed
First Posted : July 13, 2020
Last Update Posted : July 20, 2021
Sponsor:
Information provided by (Responsible Party):
RedHill Biopharma Limited

Tracking Information
First Submitted Date  ICMJE July 9, 2020
First Posted Date  ICMJE July 13, 2020
Last Update Posted Date July 20, 2021
Actual Study Start Date  ICMJE August 21, 2020
Actual Primary Completion Date July 18, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 11, 2021)
Supplemental oxygen requirement [ Time Frame: 14 days ]
To compare the proportion of patients no longer requiring supplemental oxygen for at least 24 hours by Day 14 between subjects taking opaganib and those on placebo.
Original Primary Outcome Measures  ICMJE
 (submitted: July 9, 2020)
Intubation and mechanical ventilation [ Time Frame: 14 days ]
To compare the proportion of patients requiring intubation and mechanical ventilation by Day 14 between subjects taking opaganib and those on placebo.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2021)
  • WHO Ordinal Scale for Clinical Improvement with a scale ranging from 8 down to 0 [ Time Frame: 14 days ]
    Compare ≥2 category improvement on the WHO Ordinal Scale for subjects taking opaganib and those on placebo, lower scores indicate improvement.
  • Time to recovery as defined by improvement to a score of 3 or less on the WHO Ordinal Scale for Clinical Improvement with a scale ranging from 8 down to 0 [ Time Frame: 14 days ]
    Compare scores of subjects taking opaganib and those on placebo, lower scores indicate improvement.
  • Time to low oxygen flow via nasal cannula [ Time Frame: 14 days ]
    To compare the time to low oxygen flow via nasal cannula e.g. from high oxygen flow via nasal cannula or CPAP, if high oxygen flow is not an available option between subjects taking opaganib and those on placebo.
  • Time to discharge from hospital [ Time Frame: 14 days ]
    To compare the time to low oxygen flow via nasal cannula e.g. from high oxygen flow via nasal cannula or CPAP, if high oxygen flow is not an available option between subjects taking opaganib and those on placebo.
  • Requiring intubation and mechanical ventilation by Day 42 [ Time Frame: 42 days ]
    To compare the proportion of patients requiring intubation and mechanical ventilation between subjects taking opaganib and those on placebo.
  • Time to two consecutive negative swabs for SARS-CoV-2 at day 14 [ Time Frame: 14 days ]
    To compare the the time to two consecutive negative swabs for SARS-CoV-2 by PCR at Day 14 between subjects taking opaganib and those on placebo.
  • Negative swabs for SARS-CoV-2 at day 14 [ Time Frame: 14 days ]
    To compare the proportion of patients with two consecutive negative swabs for SARS-CoV-2 by PCR at Day 14 between subjects taking opaganib and those on placebo.
  • Fever [ Time Frame: 14 days ]
    To compare the proportion of patients, with at least one measurement of fever at baseline (defined as temperature >38.0 C [100.4 F]), who are afebrile (defined as temperature <37.2C [99 F]) at Day 14 between subjects taking opaganib and those on placebo.
  • Mortality [ Time Frame: 28 and 42 days ]
    To compare mortality 28 and 42 days post-baseline between subjects taking opaganib and those taking placebo
Original Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2020)
  • WHO Ordinal Scale for Clinical Improvement [ Time Frame: 14 days ]
    To compare the change on the WHO Ordinal Scale for Clinical Improvement between subjects taking opaganib and those on placebo.
  • Time to intubation and mechanical ventilation [ Time Frame: 14 days ]
    To compare the time to intubation and mechanical ventilation between subjects taking opaganib and those on placebo.
  • Time to low oxygen flow via nasal cannula [ Time Frame: 14 days ]
    To compare the time to low oxygen flow via nasal cannula e.g. from high oxygen flow via nasal cannula or CPAP, if high oxygen flow is not an available option between subjects taking opaganib and those on placebo.
  • Supplemental oxygen requirement [ Time Frame: 14 days ]
    To compare the proportion of patients no longer requiring supplemental oxygen for at least 24 hours by Day 14 between subjects taking opaganib and those on placebo.
  • Total daily oxygen requirement [ Time Frame: 14 days ]
    To compare the total oxygen requirement (area under the curve) using daily supplemental oxygen flow (L/min) over 14 days (Day 1 to Day 14) between subjects taking opaganib and those on placebo.
  • Time to negative swabs for SARS-CoV-2 [ Time Frame: 14 days ]
    To compare the time to two consecutive negative swabs for SARS-CoV-2 by PCR between subjects taking opaganib and those on placebo.
  • Negative swabs for SARS-CoV-2 at day 14 [ Time Frame: 14 days ]
    To compare the proportion of patients with two consecutive negative swabs for SARS-CoV-2 by PCR at Day 14 between subjects taking opaganib and those on placebo.
  • Fever [ Time Frame: 14 days ]
    To compare the proportion of patients, with at least one measurement of fever at baseline (defined as temperature >38.0 C [100.4 F]), who are afebrile (defined as temperature <37.2C [99 F]) at Day 14 between subjects taking opaganib and those on placebo.
  • Mortality [ Time Frame: 30 days post baseline ]
    To compare mortality 30 days post-baseline between subjects taking opaganib and those taking placebo
Current Other Pre-specified Outcome Measures
 (submitted: June 7, 2021)
Adverse events [ Time Frame: Up to 14 days and at the end of the 4 weeks follow-up after the end of treatment ]
To compare the number of adverse events in patients with severe COVID-19 pneumonia between subjects taking opaganib and subjects taking placebo
Original Other Pre-specified Outcome Measures
 (submitted: July 9, 2020)
  • Safety and tolerability [ Time Frame: Up to 14 days and at the end of the 4 weeks follow-up after the end of treatment ]
    To compare the number of adverse events in patients with severe COVID-19 pneumonia between subjects taking opaganib and subjects taking placebo
  • Inflammatory markers - D-dimer [ Time Frame: 14 days ]
    To compare the change in the systemic marker of inflammation, D-dimer, over the treatment period between subjects taking opaganib and those on placebo.
  • Inflammatory markers - cardiac troponin [ Time Frame: 14 days ]
    To compare the change in the systemic marker of inflammation, cardiac troponin, over the treatment period between subjects taking opaganib and those on placebo.
  • Inflammatory markers - C-reactive protein [ Time Frame: 14 days ]
    To compare the change in the systemic marker of inflammation, C-reactive protein [CRP], over the treatment period between subjects taking opaganib and those on placebo.
  • Inflammatory markers - lactate dehydrogenase [ Time Frame: 14 days ]
    To compare the change in the systemic marker of inflammation lactate dehydrogenase [LDH] over the treatment period between subjects taking opaganib and those on placebo.
  • Inflammatory markers - ferritin [ Time Frame: 14 days ]
    o compare the change in the systemic marker of inflammation ferritin over the treatment period between subjects taking opaganib and those on placebo.
 
Descriptive Information
Brief Title  ICMJE Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia
Official Title  ICMJE Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a Randomized, Double-blind, Placebo-Controlled Phase 2/3 Study, in Adult Subjects Hospitalized With Severe SARS-CoV-2 Positive Pneumonia
Brief Summary A phase 2/3 multi-center randomized, double-blind, parallel arm, placebo- controlled study in Adult Subjects Hospitalized with Severe SARS-CoV-2 Positive Pneumonia to determine the potential of opaganib to improve and/or stabilize the clinical status of the patient.
Detailed Description

This is a phase 2/3 multi-center randomized, double-blind, parallel arm, placebo- controlled study with an adaptive design that will utilize a futility assessment. The study is planned be performed worldwide in up to approximately 80 clinical sites.

After informed consent is obtained, patients will enter a screening phase for no more than 3 days, to determine eligibility. Approximately 464 eligible patients will be randomized and receive either opaganib added to standard of care, or matching placebo added to standard of care, in a randomization ratio of 1:1. Treatment assignments will remain blinded to the patient, investigator and hospital staff, as well as the sponsor. As the approval and/or guidance for treating COVID-19 are evolving, for this protocol, standard of care will be defined by the recommended schemes of treatment according to the severity of the disease, taking into consideration regulatory approvals in one or more regions.

Study participants will receive either opaganib 2 x 250 mg capsules (500 mg) every 12 hours, or matching placebo, in addition to standard of care (pharmacological as defined above and/or supportive) at any given institution. Study drug will be administered every day for 14 days (Day 1 to Day 14). All participants will be followed up for 28 days after their last dose of study drug, which may occur at Day 14 or after premature study drug discontinuation, based upon patient or physician determination.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • COVID-19
  • Lung Infection
Intervention  ICMJE
  • Drug: Opaganib
    Study participants will receive either opaganib 2 x 250 mg capsules (500 mg) every 12 hours, or matching placebo, in addition to standard of care (pharmacological as defined above and/or supportive) at any given institution. Study drug will be administered every day for 14 days (Day 1 to Day 14).
    Other Names:
    • Yeliva
    • ABC294640
  • Drug: Placebo
    Study participants will receive either opaganib 2 x 250 mg capsules (500 mg) every 12 hours, or matching placebo, in addition to standard of care (pharmacological as defined above and/or supportive) at any given institution. Study drug will be administered every day for 14 days (Day 1 to Day 14).
Study Arms  ICMJE
  • Experimental: Opaganib
    In addition to standard of care, opaganib will be administered orally with 2 x 250 mg capsules (500 mg) every 12 hours. When required this may be made into a suspension form and may be administered by nasogastric tube.
    Intervention: Drug: Opaganib
  • Placebo Comparator: Placebo
    In addition to standard of care, a matching placebo will be administered orally with 2 x 250 mg capsules (500 mg) every 12 hours. Where required this may be made into a suspension form and may be administered by nasogastric tube.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 19, 2021)
475
Original Estimated Enrollment  ICMJE
 (submitted: July 9, 2020)
270
Actual Study Completion Date  ICMJE July 18, 2021
Actual Primary Completion Date July 18, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Adult male or female ≥18 to ≤80 years of age
  2. Proven COVID-19 infection per RT-PCR assay of a pharyngeal sample (nasopharyngeal or oropharyngeal) AND pneumonia defined as radiographic opacities on chest X-ray or CT scan. that diagnosed COVID-19 pneumonia. Pharyngeal samples collected either at screening or within 7-days prior to screening for the same ongoing COVID-19 pneumonia illness are acceptable
  3. The patient requires, at baseline, high flow supplemental oxygen or positive pressure ventilation or is receiving oxygen via face mask, such as a non-rebreather or reservoir mask, capable of delivering high concentrations of oxygen
  4. Patient agrees to use appropriate methods of contraception during the study and 3 months after the last dose of study drug
  5. The patient or legal representative has signed a written informed consent approved by the IRB/Ethics Committee

Exclusion Criteria:

  1. Any co-morbidity that may add risk to the treatment in the judgment of the investigator, particularly patients with known cardiac conditions, and serious neuropsychiatric conditions such as psychosis or major depression
  2. Requiring intubation and mechanical ventilation at baseline
  3. Patient has a 'Do Not Intubate' and/or 'Do Not Resuscitate' order in place
  4. Oxygen saturation >95% on room air
  5. Any preexisting respiratory condition that requires intermittent or continuous ambulatory oxygen prior to hospitalization
  6. Patient is, in the investigator's clinical judgement, unlikely to survive >72 hours
  7. Pregnant (positive serum or urine test within 3 days prior to randomization) or nursing women .
  8. Unwillingness or inability to comply with procedures required in this protocol.
  9. Corrected QT (QTc) interval on electrocardiogram (ECG) >470 ms for females or >450 ms for males, calculated using Friedericia's formula (QTcF)
  10. AST (SGOT) or ALT (SGPT) > 2.0 x upper limit of normal (ULN)
  11. Total bilirubin >1.5x ULN (except where bilirubin increase is due to Gilbert's Syndrome)
  12. Serum creatinine >2.0 X ULN
  13. Absolute neutrophil count <1000 cells/mm3
  14. Platelet count <75,000/mm3
  15. Hemoglobin <8.0 g/dL
  16. Medications that are sensitive substrates, or substrates with a narrow therapeutic range, for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 CYP2D6 , CYP3A4, P-gP, BCRP and OATP1B1 should be avoided with opaganib
  17. Moderate or strong inhibitors of CYP1A2, CYP3A4, CYP2D6 or P-gP or moderate to strong inducers of CYP3A4 and CYP1A2 are prohibited
  18. Currently taking warfarin, apixaban, argatroban or rivaroxaban due to drug-drug interaction based on CYP450 metabolism
  19. Current drug or alcohol abuse
  20. Currently participating in a clinical study assessing pharmacological treatments, including anti-viral studies
  21. Treatment with any medication that causes QT prolongation within seven days, or 5 half-lives, whichever is longest, prior to initiation of study drug, or intention to use them throughout the study, including but not limited to: amiodarone, amitriptyline, citalopram dose greater than 20 mg/day, dihydroergotamine, disopyramide, dofetilide, dronedarone, ergotamine, ibutilde, ondansetron or other 5-HT3 receptor antagonists, pimozide, procainamide, quinidine, quinine, quinolone, ranolazine, risperidone, sotaloland tolteridine. Investigators are directed to the following up-to-date web site listing QT prolonging drugs: https://www.crediblemeds.org/index.php/drugsearch
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil,   Colombia,   Israel,   Italy,   Mexico,   Peru,   Poland,   Russian Federation,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04467840
Other Study ID Numbers  ICMJE ABC-201
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party RedHill Biopharma Limited
Study Sponsor  ICMJE RedHill Biopharma Limited
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Mark L Levitt, MD RedHill Biopharma Limited
PRS Account RedHill Biopharma Limited
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP