Coronavirus Infections
Conditions
Brief summary
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
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.
Interventions
DRUGOpaganib
Study participants received opaganib 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours (pharmacological and/or supportive).
DRUGPlacebo
Study participants received placebo 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours (pharmacological and/or supportive).
Sponsors
RedHill Biopharma Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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 3. The patient requires supplemental oxygen at baseline 4. 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: 1. not pregnant 2. not breastfeeding 3. not a woman of child-bearing potential (WOCBP, as defined in Section 9.3) 4. 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
1. Any co-morbidity that may add risk to the treatment in the judgement of the investigator. 2. Requiring intubation and mechanical ventilation 3. Patient having a do not intubate or do not resuscitate order 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 judgment, unlikely to survive \>72 hours 7. Pregnant 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) \> 2.5 x upper limit of normal (ULN) 11. Bilirubin \>2.0 x 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. 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. 17. 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. 18. Currently taking warfarin, apixaban, argatroban or rivaroxaban. 19. Current drug or alcohol abuse. 20. Currently participating in a clinical study assessing pharmacological treatments, including anti-viral studies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of the Change in Oxygen Requirement From Baseline | 14 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of Time to the Reduction in Oxygen Requirement. | 14 days | The time required between arms to achieve 50% reduction from baseline in supplemental oxygen based on oxygen flow in L/min. |
| The Percentage of Subjects no Longer Receiving Supplemental Oxygen for at Least 24 Hours by Day 14 | 14 days | The percentage of subjects in each arm no longer requiring supplemental oxygen for at least 24 hours by Day 14. |
| Time to Negative Swabs for SARS-CoV-2 by PCR Post Treatment | 6 weeks | 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. |
| The Percentage of Subjects With at Least Two Consecutive Negative Swabs for SARS-CoV-2 by PCR at Day 14 | 14 days | 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. |
| Evaluation the Proportion of Patients, With at Least One Measurement of Fever at Baseline Who Are Afebrile at Day 14 | From screening phase and every day from day 1 to day 14 of treatment | 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 |
| Evaluation of Mortality 30 Days Post-baseline | 30 days after day 1 of treatment | The mortality in each arm 30 days post-baseline. |
| Intubation and Mechanical Ventilation Requirements | From screening phase and every day from day 1 to day 14 of treatment | The percentage of patients in each arm who require intubation and mechanical ventilation by Day 14 |
| Evaluation of the Time to Intubation and Mechanical Ventilation | From screening phase and every day from day 1 to day 14 of treatment | The time in each arm for the patient to require mechanical ventilation. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety TEAEs | 6 weeks | The number of subjects with treatment-emergent adverse events in each arm of all treatment-emergent adverse events (TEAEs). |
| Safety SAEs | 6 weeks | The number of subjects with serious adverse events (SAEs) in each arm. |
Countries
Israel, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Opaganib Study participants received opaganib 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours (pharmacological and/or supportive). | 23 |
| Placebo Study participants received placebo 2 x 250 mg capsules (500 mg) plus standard of care every 12 hours (pharmacological and/or supportive). | 19 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 3 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Opaganib | Placebo | Total |
|---|---|---|---|
| Age, Customized <70 years | 20 Participants | 15 Participants | 35 Participants |
| Age, Customized >=70 years | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 8 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 11 Participants | 11 Participants | 22 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 18 Participants | 15 Participants | 33 Participants |
| Region of Enrollment United States | 23 participants | 19 participants | 42 participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Male | 16 Participants | 11 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 23 | 3 / 18 |
| other Total, other adverse events | 11 / 23 | 9 / 18 |
| serious Total, serious adverse events | 3 / 23 | 5 / 18 |
Outcome results
Primary
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.
Time frame: 14 days
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Opaganib | Measurement of the Change in Oxygen Requirement From Baseline | -38.8 L/min*day |
| Placebo | Measurement of the Change in Oxygen Requirement From Baseline | -33.0 L/min*day |
Secondary
Evaluation of Mortality 30 Days Post-baseline
The mortality in each arm 30 days post-baseline.
Time frame: 30 days after day 1 of treatment
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Opaganib | Evaluation of Mortality 30 Days Post-baseline | 3 Participants |
| Placebo | Evaluation of Mortality 30 Days Post-baseline | 2 Participants |
Secondary
Evaluation of the Time to Intubation and Mechanical Ventilation
The time in each arm for the patient to require mechanical ventilation.
Time frame: From screening phase and every day from day 1 to day 14 of treatment
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Opaganib | Evaluation of the Time to Intubation and Mechanical Ventilation | NA Days |
| Placebo | Evaluation of the Time to Intubation and Mechanical Ventilation | NA Days |
Secondary
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
Time frame: From screening phase and every day from day 1 to day 14 of treatment
Population: Patients in the Modified ITT (mITT) population (randomized and treated with at least one dose of study medication) with at least one measurement of fever at baseline.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Opaganib | Evaluation the Proportion of Patients, With at Least One Measurement of Fever at Baseline Who Are Afebrile at Day 14 | 3 Participants |
| Placebo | Evaluation the Proportion of Patients, With at Least One Measurement of Fever at Baseline Who Are Afebrile at Day 14 | 0 Participants |
Secondary
Intubation and Mechanical Ventilation Requirements
The percentage of patients in each arm who require intubation and mechanical ventilation by Day 14
Time frame: From screening phase and every day from day 1 to day 14 of treatment
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Opaganib | Intubation and Mechanical Ventilation Requirements | 2 Participants |
| Placebo | Intubation and Mechanical Ventilation Requirements | 2 Participants |
Secondary
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.
Time frame: 14 days
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication). However, one subject who did not have supplemental oxygen requirement at randomization was excluded from this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Opaganib | Measurement of Time to the Reduction in Oxygen Requirement. | 5.00 Days |
| Placebo | Measurement of Time to the Reduction in Oxygen Requirement. | 8.00 Days |
Secondary
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.
Time frame: 14 days
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Opaganib | The Percentage of Subjects no Longer Receiving Supplemental Oxygen for at Least 24 Hours by Day 14 | 11 Participants |
| Placebo | The Percentage of Subjects no Longer Receiving Supplemental Oxygen for at Least 24 Hours by Day 14 | 4 Participants |
Secondary
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.
Time frame: 14 days
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication). However, as most subjects had been discharged by Day 7 and as the study was not designed to be performed on an outpatient basis, data was not available from enough subjects to perform these analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Opaganib | The Percentage of Subjects With at Least Two Consecutive Negative Swabs for SARS-CoV-2 by PCR at Day 14 | NA Participants |
| Placebo | The Percentage of Subjects With at Least Two Consecutive Negative Swabs for SARS-CoV-2 by PCR at Day 14 | NA Participants |
Secondary
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.
Time frame: 6 weeks
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication). However, as most subjects had been discharged by Day 7 and as the study was not designed to be performed on an outpatient basis, data was not available from enough subjects to perform these analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Opaganib | Time to Negative Swabs for SARS-CoV-2 by PCR Post Treatment | NA Days |
| Placebo | Time to Negative Swabs for SARS-CoV-2 by PCR Post Treatment | NA Days |
Post Hoc
Measurement of the Relative Benefit for Each Treatment Are as Derived From Oxygen Requirements
The relative benefit for each treatment group derived from total oxygen requirement \[area under the curve (AUC)\] for each arm using daily supplemental oxygen flow (L/min) over 14 days based on the daily percent change (reduction or increase) from baseline adjusted for each subject. As the maximal possible AUC benefit of -1250% is achieved if reduction to zero (100% reduction) occurred the day after baseline and was maintained through Day 14, the relative benefit derived for each group was calculated.
Time frame: 14 days
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication). However, one subject who did not have supplemental oxygen requirement at randomization was excluded from this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Opaganib | Measurement of the Relative Benefit for Each Treatment Are as Derived From Oxygen Requirements | 61.6 Percentage of relative benefit |
| Placebo | Measurement of the Relative Benefit for Each Treatment Are as Derived From Oxygen Requirements | 46.7 Percentage of relative benefit |
Post Hoc
Percent Change in Measurement of the Daily Oxygen Requirement
The changes in supplemental oxygen requirement \[oxygen flow (L/min)\] were calculated as percent change from baseline to account for the variability of baseline values, up to Day 14. Percentage from baseline area under the (AUC) is calculated by dividing the baseline adjusted AUC with the baseline. The median AUC absolute change from baseline (L/min) for each treatment arm is presented.
Time frame: 14 days
Population: Modified ITT (mITT) population (randomized and treated with at least one dose of study medication). However, one subject who did not have supplemental oxygen requirement at randomization was excluded from this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Opaganib | Percent Change in Measurement of the Daily Oxygen Requirement | -770.0 Percentage of change from baseline*day |
| Placebo | Percent Change in Measurement of the Daily Oxygen Requirement | -583.6 Percentage of change from baseline*day |
Other Pre-specified
Safety SAEs
The number of subjects with serious adverse events (SAEs) in each arm.
Time frame: 6 weeks
Population: Safety population includes all subjects randomized and treated with at least one dose of study medication. One subject randomized to receive placebo, was mistakenly given 2 doses of opaganib and is therefore included twice.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Opaganib | Safety SAEs | 3 Participants |
| Placebo | Safety SAEs | 5 Participants |
Other Pre-specified
Safety TEAEs
The number of subjects with treatment-emergent adverse events in each arm of all treatment-emergent adverse events (TEAEs).
Time frame: 6 weeks
Population: Safety population includes all subjects randomized and treated with at least one dose of study medication. One subject randomized to receive placebo, was mistakenly given 2 doses of opaganib and is therefore included twice.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Opaganib | Safety TEAEs | 11 Participants |
| Placebo | Safety TEAEs | 9 Participants |