A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia (COVACTA)

• ClinicalTrials.gov Identifier: NCT04320615
• Recruitment Status: Completed
• First Posted: March 25, 2020
• Results First Posted: June 30, 2021
• Last Update Posted: June 30, 2021
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: March 23, 2020
• First Posted Date: March 25, 2020
• Results First Submitted Date: June 23, 2021
• Results First Posted Date: June 30, 2021
• Last Update Posted Date: June 30, 2021
• Actual Study Start Date: April 3, 2020
• Actual Primary Completion Date: June 24, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 23, 2021)

Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 28 (Week 4) [ Time Frame: Day 28 ]

Clinical status was assessed using a 7-category ordinal scale:

1. - Discharged (or "ready for discharge")
2. - Non- intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
3. - Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
4. - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
5. - ICU, requiring intubation and mechanical ventilation
6. - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support
7. - Death

• Original Primary Outcome Measures (submitted: March 23, 2020): Clinical Status Assessed Using a 7-Category Ordinal Scale [ Time Frame: Day 28 ]

Current Secondary Outcome Measures (submitted: June 23, 2021)

• Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of </= 2 Maintained for 24 Hours [ Time Frame: Up to Day 28 ]
  Defined as time from first dose of study drug to at least two NEWS2 assessments with a score of <=2 covering a span of at least 21.5 hours, with a maximum of 26.5 hours between the first and last of these assessments and no assessments with a score >2 in between. If one of the components of the NEWS2 score was missing at a particular time point, then the NEWS2 score was not calculated. Participants who died were censored at Day 28.
• Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status [ Time Frame: Up to Day 28 ]
  Time to improvement for this outcome measure was defined as the days from the first dose of study drug to when at least a 2-category improvement in clinical status (based on a 7-category ordinal scale) is observed. Participants who died were censored at Day 28.
• Time to Hospital Discharge or "Ready for Discharge" [ Time Frame: Up to Day 28 ]
  Time to Hospital Discharge was defined as the time from the first dose of study drug to hospital discharge or "ready for discharge" (normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or </=2L supplemental oxygen) Participants who died were censored at Day 28.
• Incidence of Mechanical Ventilation by Day 28 [ Time Frame: Up to Day 28 ]
  Participants who died by Day 28 were assumed to have required mechanical ventilation.
• Ventilator-Free Days to Day 28 [ Time Frame: Up to Day 28 ]
  Participants who died by Day 28 were assigned 0 ventilator-free days.
• Incidence of Intensive Care Unit (ICU) Stay by Day 28 (Week 4) [ Time Frame: Up to Day 28 ]
  Participants who died by Day 28 were assumed to have required an ICU stay.
• Duration of ICU Stay to Day 28 (Week 4) [ Time Frame: Up to Day 28 ]
  Participants who died by Day 28 were assigned a duration from the first dose of study drug to Day 28 at hour 23:59:59.
• Clinical Status Assessed Using a 7-Category Ordinal Scale at Day 14 [ Time Frame: Day 14 ]
  Clinical status was assessed using a 7-category ordinal scale:

  1. - Discharged (or "ready for discharge")
  2. - Non- intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
  3. - Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
  4. - ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
  5. - ICU, requiring intubation and mechanical ventilation
  6. - ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support
  7. - Death
• Time to Clinical Failure to Day 28 (Week 4) [ Time Frame: Up to Day 28 ]
  Time to clinical failure was defined as the number of days from the first dose of study drug to the first occurrence on study of death, mechanical ventilation, ICU admission, or study withdrawal prior to discharge, whichever occurs first.
• Mortality Rate at Day 28 (Week 4) [ Time Frame: Day 28 ]
• Time to Recovery to Day 28 (Week 4) [ Time Frame: Up to Day 28 ]
  Time to recovery was defined as the number of days from the first dose of study drug to hospital discharge or "ready for discharge" (normal body temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen) or non-ICU hospital ward or "ready for hospital ward" not requiring supplemental oxygen. Participants who died were censored at Day 28.
• Duration of Supplemental Oxygen to Day 28 (Week 4) [ Time Frame: Up to Day 28 ]
  Participants who died by Day 28 were assigned a duration of 28 days of supplemental oxygen.

Original Secondary Outcome Measures (submitted: March 23, 2020)

• Time to Clinical Improvement (TTCI), Defined as a National Early Warning Score 2 (NEWS2) of </= 2 Maintained for 24 Hours [ Time Frame: Up to 60 days ]
• Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-Category Ordinal Scale of Clinical Status [ Time Frame: Up to 60 days ]
• Incidence of Mechanical Ventilation [ Time Frame: Up to 60 days ]
• Ventilator-Free Days to Day 28 [ Time Frame: Up to Day 28 ]
• Organ Failure-Free Days to Day 28 [ Time Frame: Up to Day 28 ]
• Incidence of Intensive Care Unit (ICU) Stay [ Time Frame: Up to 60 days ]
• Duration of ICU Stay [ Time Frame: Up to 60 days ]
• Time to Clinical Failure [ Time Frame: From first dose to time of death, mechanical ventilation, ICU admission, or study withdrawal (whichever occurs first, for up to 60 days) ]
• Mortality Rate [ Time Frame: Days 7, 14, 21, 28, and 60 ]
• Time to Hospital Discharge [ Time Frame: Up to 60 days ]
• Duration of Time on Supplemental Oxygen [ Time Frame: Up to 60 days ]
• Percentage of Participants with Adverse Events [ Time Frame: Up to 60 days ]
• COVID-19 (SARS-CoV-2) Viral Load Over Time [ Time Frame: Up to 60 days ]
• Time to Reverse-Transcriptase Polymerase Chain Reaction (RT-PCR) Virus Negativity [ Time Frame: Up to 60 days ]
• Proportion of Participants with Post-Treatment Infection [ Time Frame: Up to 60 days ]
• Serum Concentration of IL-6 [ Time Frame: Up to 60 days ]
• Serum Concentration of sIL-6R [ Time Frame: Up to 60 days ]
• Serum Concentration of Ferritin [ Time Frame: Up to 60 days ]
• Serum Concentration of C-Reactive Protein (CRP) [ Time Frame: Up to 60 days ]
• Serum Concentration of TCZ [ Time Frame: Up to 60 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Safety and Efficacy of Tocilizumab in Patients With Severe COVID-19 Pneumonia
• Brief Summary: This study will evaluate the efficacy, safety, pharmacodynamics, and pharmacokinetics of tocilizumab (TCZ) compared with a matching placebo in combination with standard of care (SOC) in hospitalized patients with severe COVID-19 pneumonia.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: COVID-19 Pneumonia

Intervention

• Drug: Tocilizumab (TCZ)
  Participants will receive 1 dose of IV TCZ. 1 additional dose may be given if clinical symptoms worsen or show no improvement.
• Drug: Placebo
  Participants will receive 1 dose of IV placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.

Study Arms

• Experimental: Tocilizumab (TCZ) Arm
  Participants will receive 1 intravenous (IV) infusion of TCZ, dosed at 8 mg/kg, up to a maximum dose 800 mg. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.
  Intervention: Drug: Tocilizumab (TCZ)
• Placebo Comparator: Placebo Arm
  Participants will receive 1 IV infusion of placebo matched to TCZ. Up to 1 additional dose may be given if clinical symptoms worsen or show no improvement.
  Intervention: Drug: Placebo

Publications *

• Rosas IO, Brau N, Waters M, Go RC, Malhotra A, Hunter BD, Bhagani S, Skiest D, Savic S, Douglas IS, Garcia-Diaz J, Aziz MS, Cooper N, Youngstein T, Sorbo LD, Zerda DJ, Ustianowski A, Gracian AC, Blyth KG, Carratala J, Francois B, Benfield T, Haslem D, Bonfanti P, van der Leest CH, Rohatgi N, Wiese L, Luyt CE, Bauer RN, Cai F, Lee IT, Matharu B, Metcalf L, Wildum S, Graham E, Tsai L, Bao M. Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA). EClinicalMedicine. 2022 May;47:101409. doi: 10.1016/j.eclinm.2022.101409. Epub 2022 Apr 21.
• Tom J, Bao M, Tsai L, Qamra A, Summers D, Carrasco-Triguero M, McBride J, Rosenberger CM, Lin CJF, Stubbings W, Blyth KG, Carratala J, Francois B, Benfield T, Haslem D, Bonfanti P, van der Leest CH, Rohatgi N, Wiese L, Luyt CE, Kheradmand F, Rosas IO, Cai F. Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial. Crit Care Med. 2022 Mar 1;50(3):398-409. doi: 10.1097/CCM.0000000000005229. Erratum In: Crit Care Med. 2023 Aug 1;51(8):e177.
• Rosas IO, Brau N, Waters M, Go RC, Hunter BD, Bhagani S, Skiest D, Aziz MS, Cooper N, Douglas IS, Savic S, Youngstein T, Del Sorbo L, Cubillo Gracian A, De La Zerda DJ, Ustianowski A, Bao M, Dimonaco S, Graham E, Matharu B, Spotswood H, Tsai L, Malhotra A. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021 Apr 22;384(16):1503-1516. doi: 10.1056/NEJMoa2028700. Epub 2021 Feb 25.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 23, 2021): 452
• Original Estimated Enrollment (submitted: March 23, 2020): 330
• Actual Study Completion Date: July 28, 2020
• Actual Primary Completion Date: June 24, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Hospitalized with COVID-19 pneumonia confirmed per WHO criteria (including a positive PCR of any specimen; e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan
• SPO2 </=93% or PaO2/FiO2 <300 mmHg

Exclusion Criteria:

• Known severe allergic reactions to TCZ or other monoclonal antibodies
• Active tuberculosis (TB) infection
• Suspected active bacterial, fungal, viral, or other infection (besides COVID-19)
• In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments
• Have received oral anti-rejection or immunomodulatory drugs (including TCZ) with the past 3 months
• Participating in other drug clinical trials (participation in COVID-19 anti-viral trials may be permitted if approved by Medical Monitor)
• Pregnant or breastfeeding, or positive pregnancy test in a pre-dose examination
• Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization (investigational COVID-19 antivirals may be permitted if approved by Medial Monitor)
• Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 10 x upper limit of normal (ULN) detected within 24 hours at screening (per local lab)
• Absolute neutrophil count (ANC) < 1000/mL at screening (per local lab)
• Platelet count < 50,000/mL at screening (per local lab)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Denmark, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04320615
• Other Study ID Numbers: WA42380; 2020-001154-22 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes

Plan Description

Qualified researchers may request access to individual patient level data through the clinical study data request platform https://vivli.org.

Further details on Roche's criteria for eligible studies are available here: https://vivli.org.

For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm

• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: June 2021