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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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COVID-19, Lung Infection

Intervention / Treatment
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* Drug: Opaganib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult male or female ≥18 to ≤80 years of age 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 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 Patient agrees to use appropriate methods of contraception during the study and 3 months after the last dose of study drug The patient or legal representative has signed a written informed consent approved by the IRB/Ethics Committee Exclusion Criteria: 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 Requiring intubation and mechanical ventilation at baseline Patient has a 'Do Not Intubate' and/or 'Do Not Resuscitate' order in place Oxygen saturation >95% on room air Any preexisting respiratory condition that requires intermittent or continuous ambulatory oxygen prior to hospitalization Patient is, in the investigator's clinical judgement, unlikely to survive >72 hours Pregnant (positive serum or urine test within 3 days prior to randomization) or nursing women . Unwillingness or inability to comply with procedures required in this protocol. Corrected QT (QTc) interval on electrocardiogram (ECG) >470 ms for females or >450 ms for males, calculated using Friedericia's formula (QTcF) AST (SGOT) or ALT (SGPT) > 2.0 x upper limit of normal (ULN) Total bilirubin >1.5x ULN (except where bilirubin increase is due to Gilbert's Syndrome) Serum creatinine >2.0 X ULN Absolute neutrophil count <1000 cells/mm3 Platelet count <75,000/mm3 Hemoglobin <8.0 g/dL 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 Moderate or strong inhibitors of CYP1A2, CYP3A4, CYP2D6 or P-gP or moderate to strong inducers of CYP3A4 and CYP1A2 are prohibited Currently taking warfarin, apixaban, argatroban or rivaroxaban due to drug-drug interaction based on CYP450 metabolism Current drug or alcohol abuse Currently participating in a clinical study assessing pharmacological treatments, including anti-viral studies 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Opaganib<br>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. | Drug: Opaganib<br>* 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).<br>* Other names: ABC294640;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* 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).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Supplemental Oxygen Requirement | 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. | 14 days maintained up to 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With ≥ 2 Category Improvement on the World Health Organization (WHO) Ordinal Scale for Clinical Improvement by Day 14 Maintained to Day 42 | Compare ≥2 category improvement on the WHO Ordinal Scale for Clinical Improvement from 0(uninfected) to 8(death) for subjects taking opaganib and those on placebo, lower scores indicate improvement. Success was defined as subject who reached improvement of at least two points on the WHO Ordinal Scale by Day 14, maintained by the end of study visit, and failure otherwise. | 14 days maintained up to 42 days | 
| Number of Subjects With 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 | Compare scores of subjects taking opaganib and those on placebo, lower scores indicate improvement to determine 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 0 (uninfected) to 8 (death) | 14 days maintained up to 42 days | 
| Number of Participants With Low Oxygen Flow Via Nasal Cannula | 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. | 14 days maintained up to 42 days | 
| Time to Discharge From Hospital Measured at 14 Days | Time to subject discharge from hospital | 14 days | 
| Patients Requiring Intubation and Mechanical Ventilation by Day 42 | To compare the proportion of patients requiring intubation and mechanical ventilation between subjects taking opaganib and those on placebo. | 42 days | 
| Number of Patients With Two Consecutive Negative Swabs for SARS-CoV-2 at Day 14 | To compare the number of patients with two consecutive negative swabs for SARS-CoV-2 by PCR at Day 14 between subjects taking opaganib and those on placebo. | 14 days | 
| Patients With Negative Swabs for SARS-CoV-2 at Day 14 | 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. | 14 days | 
| Mortality Due to Any Cause | To compare mortality 28 days post-baseline between subjects taking opaganib and those taking placebo | 28 days | 
| Mortality Due to Any Cause | To compare mortality 42 days post-baseline between subjects taking opaganib and those taking placebo | 42 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Therapeutic Use