A Study of Opaganib in Coronavirus Disease 2019 Pneumonia

Study Overview
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Brief Summary
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This proof of concept study will take place in the US and other countries in approximately 15 clinical sites and will enroll about 40 hospitalized patients diagnosed with COVID-19 infection who have developed pneumonia and require supplemental oxygen. 20 patients will receive opaganib in addition to standard of care twice each day for 14 days. 20 will receive matching placebo in addition to standard of care unless the patient has been discharged from the hospital without requiring supplemental oxygen, in which case study drug will only be administered for 10 days. All participants will be followed up for 4 weeks after their last dose of study drug.

Detailed Description
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Opaganib, a sphingosine kinase-2 (SphK2) inhibitor, has been broadly tested in Phase I/II studies. Extensive nonclinical data indicates both anti-viral and anti-inflammatory activity via selective SphK2 inhibition which may prove beneficial for treating COVID-19 infection and resulting pneumonia. This proof of concept study will take place in the US and other countries and will enroll about 40 hospitalized patients diagnosed with COVID-19 infection who have developed pneumonia and require supplemental oxygen. Half of the patients, i.e. 20 patients, will receive opaganib in addition to standard of care for 14 days. The other 20 will receive matching placebo (capsules that do not contain the medication) in addition to standard of care. Study drug will be administered every day for 14 days, twice each day, unless the patient has been discharged from the hospital without requiring supplemental oxygen, in which case study drug will only be administered for 10 days. All participants will be followed up for 4 weeks after their last dose of study drug.

Official Title
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Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia: a Randomized, Double-blind, Placebo-Controlled Phase 2a Study, in Adult Subjects Hospitalized With SARS-CoV-2 Positive Pneumonia

Conditions
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Coronavirus Infections

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 The patient requires supplemental oxygen at baseline The patient, guardian or legal representative has signed a written IRB-approved informed consent. 5) Male participants with female partners of child-bearing potential agree to one of the following methods of contraception during the treatment period and for at least 1 month after the last dose of study drug: Abstinence from penile-vaginal intercourse and agree to remain abstinent. Male condom, with female partner using a highly effective contraceptive method. (For further details regarding highly effective contraceptive methods please see section 9.3.) In addition, male participants must refrain from donating sperm for the duration of the study and for 1 months after last dose of study drug. Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration for at least 1 months after the last dose of study drug Female participants: A female participant is eligible to participate if she is: not pregnant not breastfeeding not a woman of child-bearing potential (WOCBP, as defined in Section 9.3) a WOCBP who agrees to use a highly effective method of contraception consistently and correctly during the treatment period and for at least 1 months after the last dose of study drug (please see further details on Section 9.3). Exclusion Criteria: Any co-morbidity that may add risk to the treatment in the judgement of the investigator. Requiring intubation and mechanical ventilation Patient having a do not intubate or do not resuscitate order 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 judgment, unlikely to survive >72 hours Pregnant 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) > 2.5 x upper limit of normal (ULN) Bilirubin >2.0 x 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 Currently taking medications that are sensitive CYP3A4, CYP1A2, CYP2C9, or CYP2C19 or CYP2D6 substrates and have a narrow therapeutic index. These should be decided in discussion with the Medical Monitor on a case-by-case basis. Currently taking medications that are strong inducers or inhibitors of CYP2D6 and CYP3A4. These should be decided in discussion with the Medical Monitor on a case-by-case basis. Currently taking warfarin, apixaban, argatroban or rivaroxaban. Current drug or alcohol abuse. Currently participating in a clinical study assessing pharmacological treatments, including anti-viral studies.

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 |
| --- | --- |
| Active Comparator: opaganib<br>Study participants will receive opaganib 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours | Drug: Opaganib<br>* Study participants received opaganib 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours (pharmacological and/or supportive).<br>* Other names: ABC294640;|
| Placebo Comparator: placebo<br>Study participants will receive placebo 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours | Drug: Placebo<br>* Study participants received placebo 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours (pharmacological and/or supportive).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of the Change in Oxygen Requirement From Baseline | Maximal oxygen flow (L/min) was recorded daily for the 14 days of treatment for each participant. Participant individual area under the curve (AUC) was calculated based on the trapezoidal rule, after subtracting the baseline oxygen requirement at each day. The median AUC absolute change from baseline (L/min) for each treatment arm is presented. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of Time to the Reduction in Oxygen Requirement. | The time required between arms to achieve 50% reduction from baseline in supplemental oxygen based on oxygen flow in L/min. | 14 days | 
| The Percentage of Subjects no Longer Receiving Supplemental Oxygen for at Least 24 Hours by Day 14 | The percentage of subjects in each arm no longer requiring supplemental oxygen for at least 24 hours by Day 14. | 14 days | 
| Time to Negative Swabs for SARS-CoV-2 by PCR Post Treatment | The time in each arm to two consecutive negative swabs for SARS-CoV-2 by PCR nasopharyngeal or oropharyngeal swab, at least 24 hrs. apart. | 6 weeks | 
| The Percentage of Subjects With at Least Two Consecutive Negative Swabs for SARS-CoV-2 by PCR at Day 14 | The percentage of subjects in each arm to achieve two consecutive negative PCR nasopharyngeal or oropharyngeal swabs for SARS-CoV-2 at Day 14, at least 24 hrs. apart. | 14 days | 
| Intubation and Mechanical Ventilation Requirements | The percentage of patients in each arm who require intubation and mechanical ventilation by Day 14 | From screening phase and every day from day 1 to day 14 of treatment | 
| Evaluation of the Time to Intubation and Mechanical Ventilation | The time in each arm for the patient to require mechanical ventilation. | From screening phase and every day from day 1 to day 14 of treatment | 
| Evaluation the Proportion of Patients, With at Least One Measurement of Fever at Baseline Who Are Afebrile at Day 14 | The proportion of patients in each arm, 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 | From screening phase and every day from day 1 to day 14 of treatment | 
| Evaluation of Mortality 30 Days Post-baseline | The mortality in each arm 30 days post-baseline. | 30 days after day 1 of treatment |