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A Randomized Placebo-controlled Safety and Dose-finding Study for the Use of the IL-6 Inhibitor Clazakizumab in Patients With Life-threatening COVID-19 Infection

Primary Purpose

COVID-19

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Clazakizumab 25 mg

Clazakizumab 12.5 mg

Placebo

About this trial

This is an interventional treatment trial for COVID-19

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

In order to be eligible to participate in this study, the patients must meet all of the following criteria:

At least 18 years of age
Confirmed COVID-19 disease (by Cobas SARS-CoV-2 real time RT-PCR using nasopharyngeal swab sample, or equivalent test available to be performed by the NYU Langone clinical laboratory). Effort will be made to have the confirmatory test result <72 hours prior to enrollment however given overall clinical demand this may not be feasible in all cases.
Respiratory failure manifesting as: Acute Respiratory Distress Syndrome (defined by a P/F ratio of <200), OR SpO2 < 90% on 4L (actual or expected given higher O2 requirement) OR increasing O2 requirements over 24 hours, PLUS 2 or more of the following predictors for severe disease:
CRP > 35 mg/L Ferritin > 500 ng/mL D-dimer > 1000 mg/mL Neutrophil-Lymphocyte Ratio > 4 LDH > 200 U/L Increase in troponin in patient w/out known cardiac disease
Has a consent designee willing to provide informed consent on behalf of the patient (this assumes that a mechanically ventilated patients lacks capacity to consent on his/her own behalf. Should it be deemed that the patient has capacity to consent, consent may be obtained from the patient.)
Women of childbearing potential must be willing and able to use at least one highly effective contraceptive method for a period of 5 months following the study drug administration. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly such as:
1. combined (estrogen and progestogen containing) hormonal contraception combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, or transdermal)
2. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
3. intrauterine device (IUD)
4. intrauterine hormone-releasing system (IUS)
5. vasectomized partner
6. bilateral tubal occlusion
7. true abstinence. when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence, such as calendar, ovulation, symptothermal, postovulation methods, and withdrawal are not acceptable methods of contraception.
Men must be willing to use a double-barrier contraception from enrollment until at 5 months after the last dose of study drug, if not abstinent.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

Evidence of irreversible injury deemed non-survivable even if the pulmonary failure recovers (for example severe anoxic brain injury)
Known active inflammatory bowel disease
Known active, untreated diverticulitis
Known untreated bacteremia
Pregnancy. (The protocol will exclude pregnant subjects given the lack of overall data on use of clazakizumab in pregnancy however the study team would consider a protocol revision should more than 3 potential pregnant study subjects be excluded on this basis).
Known hypersensitivity to the clazakizumab

Sites / Locations

Mayo Clinic
The Johns Hopkins Hospital
New York University School of Medicine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Arm Label

Clazakizumab 25 mg

Clazakizumab 12.5 mg

Placebo

Arm Description

Outcomes

Primary Outcome Measures

Ventilator Free Survival

Ventilator Free Survival is defined as the total number of patients who were alive and ventilator free at 28 days.

Number of Serious Adverse Events Associated With High and Low Dose of Clazakizumab

Secondary Outcome Measures

Overall Patient Survival

Overall Patient Survival is defined as the total number of patients per group who were alive at 28 days

Overall Patient Survival

Overall patient survival is defined as total number of patients per group who were alive at 60 days.

Number of Participants With Change in Clinical Status

Change in clinical status defined by an improvement in status by at least 2 score points on WHO 11-point ordinal scale, where 0 = uninfected; no viral RNA detected, 1 = asymptomatic; viral RNA detected, 2 = symptomatic; independent, 3 = symptomatic; assistance needed, 4 = hospitalized; no oxygen therapy, 5 = hospitalized; oxygen by mask or nasal prongs, 6 = hospitalized; oxygen by NIV or high flow, 7 = intubation and mechanical ventilation, pO2/FiO2 >/= 150 or SpO2/FiO2 >/= 200, 8 = mechanical ventilation pO2/FiO2 < 150 (SpO2/FiO2 < 200) or vasopressors, 9 = mechanical ventilation pO2/FiO2 < 150 and vasopressors, dialysis, or ECMO, and 10 = Dead

Number of Participants With a Change in Clinical Status

Number of Clazakizumab-expected Adverse Events

Full Information

NCT ID

NCT04343989

First Posted

April 9, 2020

Last Updated

June 10, 2022

Sponsor

NYU Langone Health

1. Study Identification

Unique Protocol Identification Number

NCT04343989

Brief Title

A Randomized Placebo-controlled Safety and Dose-finding Study for the Use of the IL-6 Inhibitor Clazakizumab in Patients With Life-threatening COVID-19 Infection

Official Title

A Randomized Placebo-controlled Safety and Dose-finding Study for the Use of the IL-6 Inhibitor Clazakizumab in Patients With Life-threatening COVID-19 Infection

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Completed

Study Start Date

March 31, 2020 (Actual)

Primary Completion Date

February 3, 2021 (Actual)

Study Completion Date

March 12, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

NYU Langone Health

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

In this study invetigators propose to administer clazakizumab to patients with life-threatening COVID-19 infection manifest by pulmonary failure and a clinical picture consistent with a cytokine storm syndrome. This is a double-blinded randomized multi-center trial designed as a phase II dose-finding three arm trial with seamless adaptive transition to a phase III efficacy trial. For phase II, patients were randomized 1:1:1 ratio to three study arms and received clazakizumab at a dose of 12.5 mg, 25 mg or placebo. Based on interim analysis, the low dose arm was dropped and the phase III portion of the study continued to enroll patients randomized 1:1 to high dose clazakizumab or placebo. Based on interim analysis, the remaining 10 subjects at NYU will be randomly assigned to a 1:1 ratio to two arms that will receive clazakizumab at a dose of 25 mg or placebo. The NYU site will serve as the central data management site for other centers who undertake this protocol. Other sites will enroll patients based on the two arm 1:1 randomization. 60 patients at outside sites are expected to enroll.

Detailed Description

The limited understanding of the clinical behavior of patients infected with SARS-CoV-2 (the viral organism responsible for COVID-19 disease) is evolving on a daily basis. Reports from China indicate that a subset of patients with the worst clinical outcomes may manifest cytokine storm syndrome. Hypotheses that excess cytokines may trigger a secondary hemophagocytic lymphhistiocytosis (sHLH) have been proposed. Indeed, cytokine profiles consistent with this picture were observed in Chinese patients with severe pulmonary involvement. Specifically, elevated ferritin and interleukin-6 (IL-6) were associated with fatalities among the infected patients. A role for targeted anti-inflammatory and anti-cytokine therapies in the treatment of pulmonary hyperinflammation has been proposed. Clazakizumab is a genetically engineered humanized IgG1 monoclonal antibody (mAb) that binds with high affinity to human IL-6. This investigational agent is currently being studied as a treatment for chronic active antibody mediated rejection of renal allografts. In this study investigators propose to administer clazakizumab to patients with life-threatening pulmonary failure secondary to COVID-19 disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

COVID-19

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

This is a randomized, double-blind, placebo-controlled, adaptive seamless Phase II/III design (ASD). We propose the administration of an investigational drug in patients with high predicted short-term mortality secondary to COVID-19 disease. 80 patients were randomly assigned in a 1:1:1 ratio to three study arms that will receive clazakizumab at a dose of 12.5 mg, 25 mg or placebo. Interim analyses occurred every 7 days since the enrollment of the first 30 patients. Based on week 4 interim analysis the DSMB has recommendation discontinuing the low-dose 12.5 mg of clazakizumab arm. The DSMB has advised continuing enrollment in the placebo and high-dose 25mg of clazakizumab arms in a 1:1 randomization.

Masking

ParticipantInvestigator

Masking Description

This study is double-blind and therefore neither the Investigator, the subject, the Sponsor and its representatives, nor other designated study site personnel involved in running of the study will be aware of the identification of the investigational drug administered to each subject.

Allocation

Randomized

Enrollment

178 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Clazakizumab 25 mg

Arm Type

Experimental

Arm Title

Clazakizumab 12.5 mg

Arm Type

Experimental

Arm Title

Placebo

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

Clazakizumab 25 mg

Intervention Description

The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Clazakizumab 25 mg arm. The route of administration will be intravenous. Each dose will be administered as an infusion that is run over 30 minutes. Serum CRP will be evaluated at baseline and on days 1 and 2 following clazakizumab administration. If the CRP does not decrease by 50% within 36-48 hours after the first dose, a second dose of 25 mg clazakizumab will be given no later than day 3.

Intervention Type

Drug

Intervention Name(s)

Clazakizumab 12.5 mg

Intervention Description

The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Clazakizumab 12.5 mg arm. The route of administration will be intravenous. Each dose will be administered as an infusion that is run over 30 minutes. Serum CRP will be evaluated at baseline and on days 1 and 2 following clazakizumab administration. If the CRP does not decrease by 50% within 36-48 hours after the first dose, a second dose of 12.5 mg clazakizumab will be given no later than day 3.

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

The first dose will be administered as soon as possible after the patient is enrolled and randomized into the Placebo arm. The route of administration will be intravenous. Each dose will be administered as an infusion that is run over 30 minutes. Serum CRP will be evaluated at baseline and on days 1 and 2 following clazakizumab administration. If the CRP does not decrease by 50% within 36-48 hours after the first dose, a second dose of placebo will be given no later than day 3.

Primary Outcome Measure Information:

Title

Ventilator Free Survival

Description

Ventilator Free Survival is defined as the total number of patients who were alive and ventilator free at 28 days.

Time Frame

28 days

Title

Number of Serious Adverse Events Associated With High and Low Dose of Clazakizumab

Time Frame

60 days

Secondary Outcome Measure Information:

Title

Overall Patient Survival

Description

Overall Patient Survival is defined as the total number of patients per group who were alive at 28 days

Time Frame

28 days

Title

Overall Patient Survival

Description

Overall patient survival is defined as total number of patients per group who were alive at 60 days.

Time Frame

60 days

Title

Number of Participants With Change in Clinical Status

Description

Time Frame

28 days

Title

Number of Participants With a Change in Clinical Status

Description

Time Frame

60 days

Title

Number of Clazakizumab-expected Adverse Events

Time Frame

60 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: In order to be eligible to participate in this study, the patients must meet all of the following criteria: At least 18 years of age Confirmed COVID-19 disease (by Cobas SARS-CoV-2 real time RT-PCR using nasopharyngeal swab sample, or equivalent test available to be performed by the NYU Langone clinical laboratory). Effort will be made to have the confirmatory test result <72 hours prior to enrollment however given overall clinical demand this may not be feasible in all cases. Respiratory failure manifesting as: Acute Respiratory Distress Syndrome (defined by a P/F ratio of <200), OR SpO2 < 90% on 4L (actual or expected given higher O2 requirement) OR increasing O2 requirements over 24 hours, PLUS 2 or more of the following predictors for severe disease: CRP > 35 mg/L Ferritin > 500 ng/mL D-dimer > 1000 mg/mL Neutrophil-Lymphocyte Ratio > 4 LDH > 200 U/L Increase in troponin in patient w/out known cardiac disease Has a consent designee willing to provide informed consent on behalf of the patient (this assumes that a mechanically ventilated patients lacks capacity to consent on his/her own behalf. Should it be deemed that the patient has capacity to consent, consent may be obtained from the patient.) Women of childbearing potential must be willing and able to use at least one highly effective contraceptive method for a period of 5 months following the study drug administration. In the context of this study, an effective method is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly such as: combined (estrogen and progestogen containing) hormonal contraception combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, or transdermal) progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) intrauterine device (IUD) intrauterine hormone-releasing system (IUS) vasectomized partner bilateral tubal occlusion true abstinence. when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence, such as calendar, ovulation, symptothermal, postovulation methods, and withdrawal are not acceptable methods of contraception. Men must be willing to use a double-barrier contraception from enrollment until at 5 months after the last dose of study drug, if not abstinent. Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Evidence of irreversible injury deemed non-survivable even if the pulmonary failure recovers (for example severe anoxic brain injury) Known active inflammatory bowel disease Known active, untreated diverticulitis Known untreated bacteremia Pregnancy. (The protocol will exclude pregnant subjects given the lack of overall data on use of clazakizumab in pregnancy however the study team would consider a protocol revision should more than 3 potential pregnant study subjects be excluded on this basis). Known hypersensitivity to the clazakizumab

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bonnie Lonze, MD

Organizational Affiliation

NYU Langone Health

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

85054

Country

United States

Facility Name

The Johns Hopkins Hospital

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21205

Country

United States

Facility Name

New York University School of Medicine

City

New York

State/Province

New York

ZIP/Postal Code

10016

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

The de-identified participant data from the final research dataset used in the published manuscript will be shared upon reasonable request beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research provided the investigator who proposes to use the data executes a data use agreement with NYU Langone Health. Requests may be directed to: [contact information for PI or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

IPD Sharing Time Frame

Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.

IPD Sharing Access Criteria

Upon reasonable request by an investigator who proposes to use the data.

Citations:

PubMed Identifier

35583232

Citation

Lonze BE, Spiegler P, Wesson RN, Alachkar N, Petkova E, Weldon EP, Dieter RA, Li Y, Quinn M, Mattoo A, Soomro I, Cohen SM, Leung S, Deterville CL, Landrum BM, Ali MI, Cohen DJ, Singer AL, Sen A, Chong E, Hochman JS, Troxel AB, Montgomery RA. A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation. Crit Care Med. 2022 Sep 1;50(9):1348-1359. doi: 10.1097/CCM.0000000000005591. Epub 2022 May 17.

Results Reference

derived

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A Randomized Placebo-controlled Safety and Dose-finding Study for the Use of the IL-6 Inhibitor Clazakizumab in Patients With Life-threatening COVID-19 Infection

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