Clinical trial NCT04467840: Opaganib, a Sphingosine Kinase-2 (SK2) Inhibitor in COVID-19 Pneumonia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: COVID-19
Lung Infection
Keywords: Therapeutic Use
Lead sponsor: RedHill Biopharma Limited
Sponsor class: INDUSTRY
First posted: 2020-07-13
Enrollment: 475
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Supplemental Oxygen Requirement
timeFrame: 14 days maintained up to 42 days
Secondary outcomes:
measure: 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
timeFrame: 14 days maintained up to 42 days
measure: 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
timeFrame: 14 days maintained up to 42 days
measure: Number of Participants With Low Oxygen Flow Via Nasal Cannula
timeFrame: 14 days maintained up to 42 days
measure: Time to Discharge From Hospital Measured at 14 Days
timeFrame: 14 days
measure: Patients Requiring Intubation and Mechanical Ventilation by Day 42
timeFrame: 42 days
measure: Number of Patients With Two Consecutive Negative Swabs for SARS-CoV-2 at Day 14
timeFrame: 14 days
measure: Patients With Negative Swabs for SARS-CoV-2 at Day 14
timeFrame: 14 days
measure: Mortality Due to Any Cause
timeFrame: 28 days
measure: Mortality Due to Any Cause
timeFrame: 42 days
Other outcomes:
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From first dose until 4 weeks follow-up after the end of treatment
Locations:
city: Detroit
country: United States
facility: ABC-201 Site 901
state: Michigan
city: Belo Horizonte
country: Brazil
facility: ABC-201 Site 408
city: Belo Horizonte
country: Brazil
facility: ABC-201 Site 411
city: Joinville
country: Brazil
facility: ABC-201 Site 405
city: Paraná
country: Brazil
facility: ABC-201 Site 404
city: Passo Fundo
country: Brazil
facility: ABC-201 Site 410
city: Porto Alegre
country: Brazil
facility: ABC-201 Site 409
city: Sao Paulo
country: Brazil
facility: ABC-201 Site 401
city: São Bernardo Do Campo
country: Brazil
facility: ABC-201 Site 402
city: São Paulo
country: Brazil
facility: ABC-201 Site 403
city: Tubarão
country: Brazil
facility: ABC-201 Site 407
city: Medellín
country: Colombia
facility: ABC-201 Site 604
state: Antioquia
city: Bogotá
country: Colombia
facility: ABC-201 Site 603
city: Cundinamarca
country: Colombia
facility: ABC-201 Site 605
city: Medellín
country: Colombia
facility: ABC-201 Site 602
city: Santiago de Cali
country: Colombia
facility: ABC-201 Site 601
city: Ashkelon
country: Israel
facility: ABC-201 Site 708
state: Ashketon
city: Ashdod
country: Israel
facility: ABC-201 Site 702
city: Holon
country: Israel
facility: ABC-201 Site 704
city: Jerusalem
country: Israel
facility: ABC-201 Site 701
city: Kfar Saba
country: Israel
facility: ABC-201,Site 709
city: Nahariya
country: Israel
facility: ABC-201 Site 705
city: Nazareth
country: Israel
facility: ABC-201 Site 706
city: Safed
country: Israel
facility: ABC-201 Site 703
city: Alessandria
country: Italy
facility: ABC-201 Site 203
city: Lecco
country: Italy
facility: ABC-201 Site 201
city: Milano
country: Italy
facility: ABC-201 Site 202
city: Torino
country: Italy
facility: ABC-201 Site 204
city: Mexico City
country: Mexico
facility: ABC-201 Site 501
city: Sinaloa
country: Mexico
facility: ABC-201 Site 503
city: Lima
country: Peru
facility: ABC-201 Site 655
city: Bolesławiec
country: Poland
facility: ABC-201 Site 303
city: Katowice
country: Poland
facility: ABC-201 Site 306
city: Koszalin
country: Poland
facility: ABC-201 Site 304
city: Lublin
country: Poland
facility: ABC-201 Site 307
city: Ostróda
country: Poland
facility: ABC-201 Site 302
city: Racibórz
country: Poland
facility: ABC-201 Site 301
city: Wrocław
country: Poland
facility: ABC-201 Site 305
city: Łódź
country: Poland
facility: ABC-201 Site 308
city: Barnaul
country: Russian Federation
facility: ABC-201 Site 110
city: Kirovsk
country: Russian Federation
facility: ABC-201 Site 122
city: Moscow
country: Russian Federation
facility: ABC-201 Site 101
city: Moscow
country: Russian Federation
facility: ABC-201 Site 132
city: Murmansk
country: Russian Federation
facility: ABC-201 Site 120
city: Ryazan
country: Russian Federation
facility: ABC-201 Site 103
city: Ryazan
country: Russian Federation
facility: ABC-201 Site 114
city: Saint Petersburg
country: Russian Federation
facility: ABC-201 Site 129
city: Saratov
country: Russian Federation
facility: ABC-201 Site 108
city: Smolensk
country: Russian Federation
facility: ABC-201 Site 102
city: St Petersburg
country: Russian Federation
facility: ABC-201 Site 109
city: St Petersburg
country: Russian Federation
facility: ABC-201 Site 111
city: Tver
country: Russian Federation
facility: ABC-201 Site 104
city: Volgograd
country: Russian Federation
facility: ABC-201 Site 118
city: Yaroslavl
country: Russian Federation
facility: ABC-201 Site 112
city: Antrim
country: United Kingdom
facility: ABC-201 Site 253
city: Gillingham
country: United Kingdom
facility: ABC-201 Site 251
city: Taunton
country: United Kingdom
facility: ABC-201 Site 252
Study officials:
affiliation: RedHill Biopharma Limited
name: Mark L Levitt, MD
role: STUDY_DIRECTOR
References: