A Study to Investigate Intravenous Tocilizumab in Participants With Moderate to Severe COVID-19 Pneumonia (MARIPOSA)

A Phase-II, Open-Label, Randomized, Multicenter Study to Investigate the Pharmacodynamics, Pharmacokinetics, Safety, and Efficacy of 8 mg/kg or 4mg/kg Intravenous Tocilizumab in Patients With Moderate to Severe COVID-19 Pneumonia

This study will assess the pharmacodynamics, pharmacokinetics, safety and efficacy of two different doses of tocilizumab (TCZ) in combination with standard-of-care (SOC) in hospitalized adult participants with moderate to severe COVID-19 pneumonia.

Study Overview

• Status: Completed
• Conditions: COVID-19 Pneumonia
• Intervention / Treatment: Drug: Tociliuzumab

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic - Arizona
  • California
    • Fullerton, California, United States, 92835
      • St. Jude Medical Center
    • Los Angeles, California, United States, 90033
      • LAC + USC Medical Center
    • Los Angeles, California, United States, 90033
      • USC Keck Medical Center of USC
  • Connecticut
    • Norwalk, Connecticut, United States, 06856
      • Norwalk Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
  • Illinois
    • Oak Lawn, Illinois, United States, 60453
      • Advocate Christ Medical Center
    • Park Ridge, Illinois, United States, 60068
      • Advocate Lutheran General Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Nevada
    • Reno, Nevada, United States, 89502
      • Renown Institute for Heart & Vascular Health
  • New Jersey
    • Wayne, New Jersey, United States, 07470
      • St Joseph's Regional Medical Center
  • New York
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center.
    • Jamaica, New York, United States, 11418
      • Jamaica Hospital Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Toledo, Ohio, United States, 43608
      • Mercy St. Vincent Medical Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Health Network
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Health Network (Pittsburg PA)
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Sugar Land, Texas, United States, 77479
      • Houston Methodist Sugar Land Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

• Hospitalization with COVID-19 pneumonia confirmed by a positive polymerase chain reaction (PCR) of any specimen [e.g., respiratory, blood, urine, stool, and other bodily fluids]) and evidence of pneumonia on chest X-ray or computed tomography scan
• For severe patients, SpO2 </= 93% or PaO2/FiO2 < 300 mmHg. If a participant is on supplemental oxygen with SpO2 > 93%, but desaturation </= to 93% on lower supplemental oxygen or ambient air is documented during screening, the inclusion criterion is met
• For moderate patients (those who do not qualify as severe based oxygen requirements), CRP > 2 x upper limit of normal (ULN) is required
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, as defined by the protocol
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined by the protocol

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 SARS-CoV-2)
• Participants who are on a mechanical ventilator > 24 hours or extracorporeal membrane oxygenation (ECMO), in shock, or combination thereof with other organ failure requiring treatment in an ICU
• In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments
• Receipt of oral anti-rejection or immunomodulatory drugs (including TCZ) within the past 3 months
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 10 x ULN detected within 24 hours at screening or at baseline (according to local laboratory reference ranges)
• Absolute neutrophil count (ANC) < 1000/uL at screening and baseline (according to local laboratory reference ranges)
• Platelet count < 50,000/uL at screening and baseline (according to local laboratory reference ranges)
• Pregnancy or breastfeeding, or positive pregnancy test at a predose examination
• Treatment with an investigational drug within 5 drug-elimination half-lives or 30 days (whichever is longer) of randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: TCZ 8 mg/kg; Participants will receive intravenous (IV) tocilizumab (TCZ) at a dose of 8 mg/kg in addition to standard-of-care treatment.	Drug: Tociliuzumab; Participants will receive IV TCZ.
Experimental: TCZ 4 mg/kg; Participants will receive IV tocilizumab (TCZ) at a dose of 4 mg/kg in addition to standard-of-care treatment.	Drug: Tociliuzumab; Participants will receive IV TCZ.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area Under the Curve From Day 0-28 (AUC0-d28) of Tocilizumab)	Days 0-28. Participants received a second dose within 8-24 hours after the initial infusion of TCZ at the discretion of the investigator upon clinically significant demonstration of worsening signs or symptoms.
Maximum Serum Concentration (Cmax) of Tocilizumab	Baseline - Day 60. Participants received a second dose within 8-24 hours after the initial infusion of TCZ at the discretion of the investigator upon clinically significant demonstration of worsening signs or symptoms.
Clearance (CL) of Tocilizumab	Baseline - Day 60. Participants received a second dose within 8-24 hours after the initial infusion of TCZ at the discretion of the investigator upon clinically significant demonstration of worsening signs or symptoms.
Volume of the Central Compartment (Vc) of Tocilizumab	Baseline - Day 60. Participants received a second dose within 8-24 hours after the initial infusion of TCZ at the discretion of the investigator upon clinically significant demonstration of worsening signs or symptoms.
Serum Concentration of C-reactive Protein (CRP) Following Administration of IV TCZ	Baseline - Day 60
Serum Concentration of Ferritin Following Administration of IV TCZ	Baseline - Day 60
Serum Concentration of Soluble Interleukin-6 Receptor (sIL-6R) Following Administration of IV TCZ	Baseline - Day 60
Serum Concentration of Interleukin-6 (IL-6) Following Administration of IV TCZ	Baseline - Day 60

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Any Post-Treatment Infection		Up to Day 60
Pecentage of Participants With Adverse Events	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Up to Day 60
Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) (COVID-19) Viral Load Over Time		Baseline - Day 60
Time to Real-Time Polymerase Chain Reaction (RT-PCR) Virus Negativity	Time to Real-Time Polymerase Chain Reaction (RT-PCR) virus negativity was defined as the number of days from the first dose of study drug to when a negative RT-PCR SARS-CoV-2 assessment result was observed. Results are presented as a cumulative incidence function (CIF) with death as a competing risk.	Up to Day 28

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Kumar PN, Hernandez-Sanchez J, Nagel S, Feng Y, Cai F, Rabin J, Morse CG, Nadig NR, Ashraf O, Gotur DB, McComsey GA, Gafoor K, Perin P, Thornton SC, Stubbings W, Lin CJF, Tsai L. Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial. Open Forum Infect Dis. 2021 Dec 4;9(1):ofab608. doi: 10.1093/ofid/ofab608. eCollection 2022 Jan.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2020
• Primary Completion (Actual): August 12, 2020
• Study Completion (Actual): August 12, 2020

Study Registration Dates

• First Submitted: April 21, 2020
• First Submitted That Met QC Criteria: April 24, 2020
• First Posted (Actual): April 27, 2020

Study Record Updates

• Last Update Posted (Actual): August 31, 2022
• Last Update Submitted That Met QC Criteria: August 26, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• 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: CA42481

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). 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).

Drug and device information, study documents

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