Clazakizumab vs. Placebo - COVID-19 Infection

• ClinicalTrials.gov Identifier: NCT04494724
• Recruitment Status: Unknown
• First Posted: July 31, 2020
• Last Update Posted: July 31, 2020
• Sponsor: The Methodist Hospital Research Institute
• Information provided by (Responsible Party): The Methodist Hospital Research Institute

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
COVID-19 Infection	Drug: Clazakizumab; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This single-site, phase 2 randomized, double-blind, placebo-controlled trial is designed to administer a single dose of clazakizumab or placebo on day 0. If, after 24 hours or up to 14 days from the first infusion, the participant's condition worsens or does not improve, the investigator may elect to provide a single, open-label dose of clazakizumab regardless of the initial group assignment. All except the investigational pharmacist will remain blinded as to the initial group assignment until data lock.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Blinded to all except investigational pharmacy. Only the optional second infusion, if determined necessary to administer, will be open-label. The patient and study team will remain blinded until data lock at the end of the study.
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: July 13, 2020
• Estimated Primary Completion Date: December 31, 2020
• Estimated Study Completion Date: July 31, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Primary Endpoint [ Time Frame: 24 hours ]
   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

Secondary Outcome Measures :

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

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:

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.

Contacts and Locations

Contacts

Contact: Isioma Agboli, MD; 713-441-6311; iagboli@houstonmethodist.org

Contact: Darrel Cleere, BSN; 713-441-6232; dwcleere@houstonmethodist.org

Locations

United States, Texas

Houston Methodist Hospital; Recruiting

Houston, Texas, United States, 77030

Contact: Isioma Agboli, MD 713-441-6311 iagboli@houstonmethodist.org

Contact: Darrel Cleere, BSN 713-441-6232 dwcleere@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

Sponsors and Collaborators

The Methodist Hospital Research Institute

Investigators

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

More Information

Publications of Results:

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. Review.

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. Review.

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. Review.

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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:CD013825. doi: 10.1002/14651858.CD013825.pub2. Review.

• Responsible Party: The Methodist Hospital Research Institute
• ClinicalTrials.gov Identifier: NCT04494724
• Other Study ID Numbers: Pro00025969
• First Posted: July 31, 2020
• Last Update Posted: July 31, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by The Methodist Hospital Research Institute:

COVID-19; coronavirus infection; respiration, artificial; extracorporeal membrane oxygenation; randomized controlled trial; respiratory distress syndrome, adult

Additional relevant MeSH terms:

Infections; Communicable Diseases; COVID-19; Disease Attributes; Pathologic Processes; Respiratory Tract Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases