Clazakizumab vs. Placebo - COVID-19 Infection

A Phase 2 Trial to Evaluate the Safety and Tolerability of Clazakizumab® [Anti-Interleukin (IL)-6 Monoclonal] Compared to Placebo for the Treatment of COVID-19 Infection

The purpose of this study is to investigate the effectiveness and safety of treatment with clazakizumab compared to a placebo (inactive substance). We are proposing to try this drug to treat coronavirus disease 2019 (COVID-19) infection. Patients with COVID-19 infection have been shown to have increases in certain inflammatory processes. Clazakizumab is an antibody (immune system protein) that blocks certain inflammatory processes. The treatment plan is to attempt to inhibit or block these inflammatory processes in order to try to limit the damage COVID-19 causes to the lungs.

Study Overview

• Status: Unknown
• Conditions: COVID-19 Infection
• Intervention / Treatment: Drug: Placebo; Drug: Clazakizumab

Detailed Description

The purpose of this randomized, double-blind, placebo-controlled trial is to evaluate the safety and efficacy of clazakizumab vs placebo for the prevention of acute respiratory distress syndrome (ARDS) in patients with COVID-19 and pulmonary manifestations. The study will compare clazakizumab to placebo in a randomized, double-blind fashion followed by an open-label dose of clazakizumab if there is no improvement or a worsening of condition occurs after 24-hours or anytime during the first 14 days after the first dose of clazakizumab or placebo. We hypothesize that clazakizumab will be safely tolerated and will reduce the risk of progression of COVID-19 to acute respiratory distress syndrome.

Primary Objective:

• To evaluate the safety and tolerability of clazakizumab vs placebo for the treatment of patients with COVID-19 disease and signs of pulmonary involvement

Sixty adult patients with COVID-19 and signs of pulmonary involvement at Houston Methodist who are not in need of ventilator support at the time of enrollment.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Darrel Cleere, BSN; Phone Number: 713-441-6232; Email: dwcleere@houstonmethodist.org
• Study Contact Backup: Name: Isioma Agboli, MD; Phone Number: 713-441-6311; Email: iagboli@houstonmethodist.org

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • Houston Methodist Hospital
      • Contact: Darrel Cleere, BSN; Phone Number: 713-441-6232; Email: dwcleere@houstonmethodist.org
      • Contact: Isioma Agboli, MD; Phone Number: 713-441-6311; Email: iagboli@houstonmethodist.org
      • Principal Investigator: Howard J Huang, MD
      • Sub-Investigator: Alex Rogers, PharmD
      • Sub-Investigator: Ahmad Goodarzi, MD
      • Sub-Investigator: Yihad G Youssef, MD
      • Sub-Investigator: Simon Yau, MD
      • Sub-Investigator: Faisal Zahiruddin, MD
      • Sub-Investigator: Linda W Moore, PhD
      • Sub-Investigator: Ahmed O Gaber, MD

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:

1. Age >18 at the time of screening.
2. Participant or legally authorized representative (LAR) must be able to understand and provide informed consent.
3. Hospitalized with coronavirus disease (COVID-19) confirmed by polymerase chain reaction (PCR) assay from any specimen (eg, respiratory, blood, urine, stool, other bodily fluid) within the prior 72 hours.
4. C-reactive protein (CRP) > 3.5 mg/dL

5. Evidence of pulmonary involvement with at least 2 of the following:

   1. oxygen saturation at rest in ambient air with peripheral capillary oxygen saturation (SpO2) ≤ 94%
   2. tachypnea with resting respiration rate > 25 breaths/minute
   3. Partial pressure of oxygen (PaO2)/initial fraction of inspired oxygen (FiO2) ≤ 300 mmHg
   4. Chest imaging (radiograph, CT, or ultrasound) with abnormalities consistent COVID-19 pneumonia

Exclusion Criteria:

1. Previous hypersensitivity or allergic reactions to clazakizumab
2. Lactating or pregnant females
3. Patients with latent tuberculosis (TB) and who are not receiving treatment
4. Patients with active TB
5. Patients with known active inflammatory bowel disease, untreated diverticulitis, or gastrointestinal perforation
6. Requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
7. A significantly abnormal general serum screening lab result defined as a white blood cell (WBC) count < 3.0 X 10^3/mL, a hemoglobin (Hgb) < 8.0 g/dL, a platelet count < 50 X 10^3/mL, an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times upper limit normal
8. Participation in another clinical trial investigating COVID-19-aimed agents
9. Presence of any medical or psychosocial condition, which the investigator believes, would hinder adherence to the study requirements.

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: Clazakizumab; Clazakizumab - 25mg in 50 milliliters (mL) of 0.9% saline, IV infusion over 30 minutes.	Drug: Clazakizumab; Infusion
Placebo Comparator: Placebo; Placebo - 50 mL 0.9% saline, IV infusion over 30 minutes.	Drug: Placebo; Infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary Endpoint	Proportion of participants who experience treatment-related adverse events (TEAE) ≥ Grade 3 (CTCAE v5.0) during the first 24 hours after infusion of clazakizumab or placebo	24 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Requirement for mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO)	Proportion of participants who need mechanical ventilation and/or extracorporeal membrane oxygenation (ECMO) after the first dose of clazakizumab or placebo	14 days
Infusion-related reactions during 24 hours from the time of infusion	Proportion of participants who experience infusion-related reactions during the first 24 hours after infusion of clazakizumab or placebo	24 hours
Patient survival at 28 days	Proportion of participants alive at day 28 after the first dose of clazakizumab or placebo	28 days
Patient survival at 60 days	Proportion of participants alive at day 60 after the first dose of clazakizumab or placebo	60 days
Requirement for open-label clazakizumab	Proportion of participants who require an open-label dose of clazakizumab	14 days
Time in the intensive care unit (ICU)	Number of days in the ICU following the first dose of clazakizumab or placebo	60 days
Time in the hospital	Number of days in the hospital following the first dose of clazakizumab or placebo	60 days
Time to mechanical ventilation	Number of days from first dose of clazakizumab or placebo to requiring mechanical ventilation	60 days
Clinical status improvement assessed by the World Health Organization (WHO) Clinical Progression Scale at day 14	Difference in WHO Clinical Progression Scale between clazakizumab and placebo	14 days
Clinical status improvement assessed by World Health Organization (WHO) Clinical Progression Scale at day 28	Difference in WHO Clinical Progression Scale between clazakizumab and placebo	28 days
Change in Radiologic Assessment of Lung Edema (RALE) at day 14	Difference in mean or median change in radiologic assessment of lung edema (RALE) score at day 14 from baseline between clazakizumab or placebo	14 days
Change in Radiologic Assessment of Lung Edema (RALE) at day 28	Difference in mean or median change in radiologic assessment of lung edema (RALE) score at day 28 from baseline between clazakizumab or placebo	28 days

Collaborators and Investigators

• Sponsor: The Methodist Hospital Research Institute
• Investigators: Principal Investigator: Howard Huang, MD, The Methodist Hospital Research Institute

Publications and helpful links

General Publications

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
• Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020 Jul 1;180(7):934-943. doi: 10.1001/jamainternmed.2020.0994. Erratum In: JAMA Intern Med. 2020 Jul 1;180(7):1031.
• Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.
• Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018 Dec;18(12):773-789. doi: 10.1038/s41577-018-0066-7.
• Tanaka T, Kishimoto T. Targeting interleukin-6: all the way to treat autoimmune and inflammatory diseases. Int J Biol Sci. 2012;8(9):1227-36. doi: 10.7150/ijbs.4666. Epub 2012 Oct 24.
• Uciechowski P, Dempke WCM. Interleukin-6: A Masterplayer in the Cytokine Network. Oncology. 2020;98(3):131-137. doi: 10.1159/000505099. Epub 2020 Jan 20.
• Ruan Q, Yang K, Wang W, Jiang L, Song J. Correction to: Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 Jun;46(6):1294-1297. doi: 10.1007/s00134-020-06028-z.
• Gao Y, Li T, Han M, Li X, Wu D, Xu Y, Zhu Y, Liu Y, Wang X, Wang L. Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol. 2020 Jul;92(7):791-796. doi: 10.1002/jmv.25770. Epub 2020 Apr 10.
• Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, Przepiorka D, Farrell AT, Pazdur R. FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. Oncologist. 2018 Aug;23(8):943-947. doi: 10.1634/theoncologist.2018-0028. Epub 2018 Apr 5.

Study record dates

Study Major Dates

• Study Start (Actual): July 13, 2020
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): July 31, 2021

Study Registration Dates

• First Submitted: July 21, 2020
• First Submitted That Met QC Criteria: July 30, 2020
• First Posted (Actual): July 31, 2020

Study Record Updates

• Last Update Posted (Actual): July 31, 2020
• Last Update Submitted That Met QC Criteria: July 30, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: randomized controlled trial; COVID-19; extracorporeal membrane oxygenation; coronavirus infection; respiratory distress syndrome, adult; respiration, artificial
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Infections; Communicable Diseases
• Other Study ID Numbers: Pro00025969

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