Treatment of Moderate to Severe Coronavirus Disease (COVID-19) in Hospitalized Patients

• ClinicalTrials.gov Identifier: NCT04321993
• Recruitment Status: Active, not recruiting
• First Posted: March 26, 2020
• Last Update Posted: March 15, 2023
• Sponsor: Lisa Barrett
• Collaborators: Nova Scotia Health Authority; Dalhousie University
• Information provided by (Responsible Party): Lisa Barrett, Nova Scotia Health Authority

Study Description

Brief Summary:

Investigational medications adjunct to clinical standard of care treatment will be assessed to evaluate safety and effectiveness as an anti-COVID-19 treatment. All hospitalized persons with moderate to severe COVID-19 disease that meet eligibility criteria will be offered participation.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Baricitinib (janus kinase inhibitor); Drug: Remdesivir (antiviral) + barictinib (janus kinase inhibitor); Drug: Remdesivir (antiviral); Drug: Tocilizumab (interleukin 6 inhibitor)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 363 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Treatment of Moderate to Severe Coronavirus Disease (COVID-19) in Hospitalized Patients
• Actual Study Start Date: April 17, 2020
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: September 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Baricitinib; Moderate and severe, not critical disease	Drug: Baricitinib (janus kinase inhibitor); Baricitinib will be administered as 4 mg po daily for 14 days or until hospital discharge, whichever is sooner.
Experimental: Remdesivir; Moderate and severe, not critical disease	Drug: Remdesivir (antiviral); Remdesivir will be administered as a loading dose of 200 mg IV over one hour on day 1 followed by 100 mg IV daily over one hour on days 2-5 (with a possibility to extend to up to 10 days total).
Experimental: Remdesivir + baricitinib; Moderate and severe, not critical disease	Drug: Remdesivir (antiviral) + barictinib (janus kinase inhibitor); Remdesivir will be administered as a loading dose of 200 mg IV over one hour on day 1 followed by 100 mg IV daily over one hour on days 2-5 (with a possibility to extend to up to 10 days total). Baricitinib will be administered as 4 mg po daily for 14 days or until hospital discharge, whichever is sooner.
Experimental: Tocilizumab; Severe, critical disease	Drug: Tocilizumab (interleukin 6 inhibitor); Tocilizumab will be administered as a single IV infusion over one hour. Dosage will be 8 mg/kg total bodyweight up to a maximum of 800 mg.
No Intervention: Clinical standard of care; Moderate and severe, not critical disease AND severe, critical disease as applicable

Outcome Measures

Primary Outcome Measures :

1. Clinical status of subject at day 15 (on a 7 point ordinal scale). [ Time Frame: Up to 15 days ]
   1. Not hospitalized, no limitations on activities
   2. Not hospitalized, limitation on activities;
   3. Hospitalized, not requiring supplemental oxygen;
   4. Hospitalized, requiring supplemental oxygen;
   5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
   6. Hospitalized, on invasive mechanical ventilation or ECMO;
   7. Death.

Secondary Outcome Measures :

1. Status on an ordinal scale assessed daily while hospitalized and on days 15 and 29 and 180. [ Time Frame: Up to 180 days ]
   1. Not hospitalized, no limitations on activities
   2. Not hospitalized, limitation on activities;
   3. Hospitalized, not requiring supplemental oxygen;
   4. Hospitalized, requiring supplemental oxygen;
   5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
   6. Hospitalized, on invasive mechanical ventilation or ECMO;
   7. Death.
2. Length of time to clinical improvement [ Time Frame: Up to 29 days ]
   Time to clinical improvement is defined as the time to normalization of respiratory rate, fever, and oxygen saturation, and alleviation of cough within 72 hours.
3. Number of participants with normal pulmonary function and normal O2 saturation on days 11, 15 and 29 [ Time Frame: Up to 29 days ]
4. Number of participants that developed Acute Respiratory Distress Syndrome (ARDS) after treatment [ Time Frame: Up to 24 weeks ]
5. Length of time to clinical progression [ Time Frame: Up to 29 days ]
   Time to clinical progression, defined as the time to death, mechanical ventilation, or ICU admission
6. Cause of death (if applicable) [ Time Frame: Up to 24 weeks ]
7. Sequential Organ Failure Assessment (SOFA) score, daily while hospitalized and on days 15 and 29. (Initial, highest, deltas and mean) [ Time Frame: Up to 29 days ]
8. Length of time to normalization of fever [ Time Frame: Up to 29 days ]
   Fever normalization as defined by: Temperature < 36.6 °C armpit, < 37.2 °C oral, or < 37.8 °C rectal sustained for minimum 24 hours
9. Length of time to normalization of oxygen saturation [ Time Frame: Up to 29 days ]
   Oxygen normalization as defined by: peripheral capillary oxygen saturation (Sp02) > 94% sustained minimum 24 hours.
10. Duration of supplemental oxygen (if applicable) [ Time Frame: Up to 29 days ]
11. Duration of mechanical ventilation (if applicable) [ Time Frame: Up to 29 days ]
12. Duration of hospitalization [ Time Frame: Up to 29 days ]
13. Adverse events [ Time Frame: Up to 180 days ]

Other Outcome Measures:

1. Global and SARS-CoV-2-specific immune responses before, during and after intervention and in standard of care treatment arm [ Time Frame: Up to 180 days ]
2. Percent of subjects with SARS-CoV-2 detectable in blood at days 3, 5, 8, 11, 15, 29 and 180. [ Time Frame: Up to 180 days ]
3. Quantitative SARS-CoV-2 viral load in blood at days 3, 5, 8, and 11, 15, 29, and 180. [ Time Frame: Up to 180 days ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 18 years or older
• Moderate to severe COVID-19 associated disease as defined by the WHO
• Willing and able to provide informed consent prior to performing study procedures
• Has laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial or public health assay
• Illness of any duration, and at least one of the following: Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), or Clinical assessment (evidence of rales/crackles on exam) AND SpO2 ≤ 94% on room air, or Require mechanical ventilation and/or supplemental oxygen.
• Normal potassium, magnesium, and calcium levels pre-therapy when used in agents at risk of QT prolongation

Patients will be further distinguished based on their disease severity into one of two categories:

• Moderate and severe, not critical disease: patients with SpO2 ≤ 94% on room air, and those who require supplemental oxygen
• Severe, critical disease: patients with critical illness requiring ICU-level care including requiring mechanical ventilation or ECMO, and/or end organ dysfunction as seen in sepsis/septic shock.

Exclusion Criteria:

• Concurrent treatment with other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 is prohibited < 24 hours prior to study medication initiation
• Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 X upper limit of normal (ULN)
• Consideration by the investigator, for any reason, that the subject is an unsuitable candidate to receive study treatment Medication specific Exclusion

Baricitinib:

1. Contraindicated for patients with known hypersensitivity to baricitinib or to any of the excipients.
2. Prior untreated latent tuberculosis
3. Any individuals with TB risk factors will not be enrolled in the baricitinib arm of the study.
4. Presence of active viral hepatitis C or B
5. People with a clinical history of invasive or active fungal infection
6. People with a clinical history of active CMV disease in the last year
7. Patients who are pregnant or breastfeeding
8. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR <15)

Tocilizumab:

1. Known hypersensitivity to tocilizumab or any of its components
2. Prior untreated latent tuberculosis
3. Any individuals with TB risk factors will not be enrolled in the tocilizumab arm of the study.
4. Presence of active viral hepatitis C or B
5. People with a clinical history of invasive or active fungal infection
6. People with a clinical history of active CMV disease in the last year
7. CRP<75 mg/L
8. SpO2 ≥ 92% on room air

Remdesivir:

1. Known hypersensitivity to remdesivir or any of its components
2. Weight below 40 kg
3. SpO2 ≥ 94% on room air
4. Stage 4 severe chronic kidney disease or requiring dialysis (i.e. eGFR <30)

Contacts and Locations

Locations

Canada, Nova Scotia

Nova Scotia Health Authority

Halifax, Nova Scotia, Canada, B3H 1V7

Sponsors and Collaborators

Lisa Barrett

Nova Scotia Health Authority

Dalhousie University

More Information

• Responsible Party: Lisa Barrett, Clinician Scientist, Nova Scotia Health Authority
• ClinicalTrials.gov Identifier: NCT04321993
• Other Study ID Numbers: SAIL-004
• First Posted: March 26, 2020
• Last Update Posted: March 15, 2023
• Last Verified: March 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lisa Barrett, Nova Scotia Health Authority:

COVID; coronavirus; SARS-CoV-2

Additional relevant MeSH terms:

COVID-19; Coronavirus Infections; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Antiviral Agents; Remdesivir; Janus Kinase Inhibitors; Anti-Infective Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Protein Kinase Inhibitors; Enzyme Inhibitors