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

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; Lung Infection
• Intervention / Treatment: Drug: Opaganib; Drug: Placebo

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: Interventional
• Enrollment (Actual): 475
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Belo Horizonte, Brazil
    • ABC-201 Site 408
  • Belo Horizonte, Brazil
    • ABC-201 Site 411
  • Joinville, Brazil
    • ABC-201 Site 405
  • Paraná, Brazil
    • ABC-201 Site 404
  • Passo Fundo, Brazil
    • ABC-201 Site 410
  • Porto Alegre, Brazil
    • ABC-201 Site 409
  • Sao Paulo, Brazil
    • ABC-201 Site 401
  • São Bernardo Do Campo, Brazil
    • ABC-201 Site 402
  • São Paulo, Brazil
    • ABC-201 Site 403
  • Tubarão, Brazil
    • ABC-201 Site 407
• Colombia
  • Bogotá, Colombia
    • ABC-201 Site 603
  • Cundinamarca, Colombia
    • ABC-201 Site 605
  • Medellín, Colombia
    • ABC-201 Site 602
  • Santiago de Cali, Colombia
    • ABC-201 Site 601
  • Antioquia
    • Medellín, Antioquia, Colombia
      • ABC-201 Site 604
• Israel
  • Ashdod, Israel
    • ABC-201 Site 702
  • Holon, Israel
    • ABC-201 Site 704
  • Jerusalem, Israel
    • ABC-201 Site 701
  • Kfar Saba, Israel
    • ABC-201,Site 709
  • Nahariya, Israel
    • ABC-201 Site 705
  • Nazareth, Israel
    • ABC-201 Site 706
  • Safed, Israel
    • ABC-201 Site 703
  • Ashketon
    • Ashkelon, Ashketon, Israel
      • ABC-201 Site 708
• Italy
  • Alessandria, Italy
    • ABC-201 Site 203
  • Lecco, Italy
    • ABC-201 Site 201
  • Milano, Italy
    • ABC-201 Site 202
  • Torino, Italy
    • ABC-201 Site 204
• Mexico
  • Mexico City, Mexico
    • ABC-201 Site 501
  • Sinaloa, Mexico
    • ABC-201 Site 503
• Peru
  • Lima, Peru
    • ABC-201 Site 655
• Poland
  • Bolesławiec, Poland
    • ABC-201 Site 303
  • Katowice, Poland
    • ABC-201 Site 306
  • Koszalin, Poland
    • ABC-201 Site 304
  • Lublin, Poland
    • ABC-201 Site 307
  • Ostróda, Poland
    • ABC-201 Site 302
  • Racibórz, Poland
    • ABC-201 Site 301
  • Wrocław, Poland
    • ABC-201 Site 305
  • Łódź, Poland
    • ABC-201 Site 308
• Russian Federation
  • Barnaul, Russian Federation
    • ABC-201 Site 110
  • Kirovsk, Russian Federation
    • ABC-201 Site 122
  • Moscow, Russian Federation
    • ABC-201 Site 101
  • Moscow, Russian Federation
    • ABC-201 Site 132
  • Murmansk, Russian Federation
    • ABC-201 Site 120
  • Ryazan, Russian Federation
    • ABC-201 Site 103
  • Ryazan, Russian Federation
    • ABC-201 Site 114
  • Saint Petersburg, Russian Federation
    • ABC-201 Site 129
  • Saratov, Russian Federation
    • ABC-201 Site 108
  • Smolensk, Russian Federation
    • ABC-201 Site 102
  • St Petersburg, Russian Federation
    • ABC-201 Site 109
  • St Petersburg, Russian Federation
    • ABC-201 Site 111
  • Tver, Russian Federation
    • ABC-201 Site 104
  • Volgograd, Russian Federation
    • ABC-201 Site 118
  • Yaroslavl, Russian Federation
    • ABC-201 Site 112
• United Kingdom
  • Antrim, United Kingdom
    • ABC-201 Site 253
  • Gillingham, United Kingdom
    • ABC-201 Site 251
  • Taunton, United Kingdom
    • ABC-201 Site 252
• United States
  • Michigan
    • Detroit, Michigan, United States, 00000
      • ABC-201 Site 901

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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
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.	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).

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	To compare the number of participants with treatment emergent adverse events (TEAEs) in patients with severe COVID-19 pneumonia between participants taking opaganib and participants taking placebo	From first dose until 4 weeks follow-up after the end of treatment

Collaborators and Investigators

• Sponsor: RedHill Biopharma Limited
• Investigators: Study Director: Mark L Levitt, MD, RedHill Biopharma Limited

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2020
• Primary Completion (Actual): July 18, 2021
• Study Completion (Actual): July 18, 2021

Study Registration Dates

• First Submitted: July 9, 2020
• First Submitted That Met QC Criteria: July 9, 2020
• First Posted (Actual): July 13, 2020

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: September 25, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Therapeutic Use
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Lung Diseases; COVID-19; Pneumonia
• Other Study ID Numbers: ABC-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No