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

NCT04343989 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 20-00392
• Study Type: interventional
• Target: 178
• Locations: 1 country
• Sites: 3

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.

Conditions

COVID-19

Outcome Measures

Primary Outcomes (2)

• Ventilator Free Survival

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

  28 days

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

  60 days

Secondary Outcomes (5)

• Overall Patient Survival

  28 days

• Overall Patient Survival

  60 days

• Number of Participants With Change in Clinical Status

  28 days

• Number of Participants With a Change in Clinical Status

  60 days

• Number of Clazakizumab-expected Adverse Events

  60 days

Study Arms (3)

Clazakizumab 25 mg

EXPERIMENTAL

Drug: Clazakizumab 25 mg

Clazakizumab 12.5 mg

EXPERIMENTAL

Drug: Clazakizumab 12.5 mg

Placebo

PLACEBO COMPARATOR

Other: Placebo

Interventions

Clazakizumab 25 mg DRUG

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.

Clazakizumab 25 mg

Clazakizumab 12.5 mg DRUG

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.

Clazakizumab 12.5 mg

Placebo OTHER

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.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• NYU Langone Health: lead

Study Sites (3)

Mayo Clinic

Phoenix, Arizona, 85054, United States

Location

The Johns Hopkins Hospital

Baltimore, Maryland, 21205, United States

Location

New York University School of Medicine

New York, New York, 10016, United States

Location

Related Publications (1)

• 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.

  PMID: 35583232 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

clazakizumab

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Bonnie Lonze, MD, PhD
• Organization: NYU Langone Health

bonnie.lonze@nyulangone.org

212-263-3865

Study Officials

• Bonnie Lonze, MD

  NYU Langone Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 9, 2020
• First Posted: April 14, 2020
• Study Start: March 31, 2020
• Primary Completion: February 3, 2021
• Study Completion: March 12, 2021
• Last Updated: June 14, 2022
• Results First Posted: February 15, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• 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.
• Access Criteria: Upon reasonable request by an investigator who proposes to use the data.

Locations

US (3)