SARS-CoV-2-Neutralizing Monoclonal COVID-19 Antibody DZIF-10c by Inhalation

A Phase 1/2a Trial of the Inhaled Administration of the SARS-CoV-2-Neutralizing Monoclonal Antibody DZIF-10c in SARS-CoV-2-Infected and -Uninfected Individuals

This is the first-in-human phase 1/2a trial of the inhaled administration of the SARS-CoV-2-neutralizing monoclonal antibody DZIF-10c in healthy volunteers and SARS-CoV-2-infected individuals. It will evaluate the safety, pharmacokinetic profile, immunogenicity, and antiviral activity of DZIF-10c.

Study Overview

• Status: Terminated
• Conditions: SARS-CoV-2 Infection
• Intervention / Treatment: Biological: DZIF-10c; Biological: DZIF-10c; Drug: Placebo; Drug: Placebo

Detailed Description

The phase 1 component of this trial consists of a single-inhalation open-label dose-escalation phase (Groups 1A-1C and Groups 2A-2C). Subsequently, the highest tolerated dose tested will be administered to an expansion cohort of SARS-CoV-2-infected individuals (Group 2D). In this randomized and blinded group, participants will receive DZIF-10c or placebo both by inhalation and intravenous infusion.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Düsseldorf, Germany, 40225
    • University Hospital Düsseldorf
  • Frankfurt am Main, Germany, 60590
    • University Hospital Frankfurt
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg-Eppendorf
  • Munich, Germany, 81377
    • LMU Munich University Hospital
  • Hesse
    • Gießen, Hesse, Germany, 35392
      • University Hospital Giessen and Marburg
  • NRW
    • Cologne, NRW, Germany, 50937
      • University Hospital Cologne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Groups 1A-1C

• Age 18-65.
• SARS-CoV-2-RNA negative naso- or oropharyngeal swab obtained within 3 calendar days before study drug administration by NAAT (e.g., qRT-PCR).
• Non-reactivity of serum antibodies (IgG; and IgA and/or IgM when tested) against SARS-CoV-2 by serological assay at screening.

Groups 2A-2D

• Age 18-70.
• SARS-CoV-2-RNA positive naso- or oropharyngeal swab obtained within 3 calendar days before study drug administration by NAAT (e.g., qRT-PCR).
• Onset of COVID-19 symptoms (e.g., sore throat, cough, fever, chills, fatigue, dys- or anosmia, dys- or ageusia, headache, muscle pain, gastrointestinal symptoms) within 7 days prior to study drug administration or Non-reactivity of serum or plasma antibodies (IgG; and IgA and/or IgM when tested) against SARS-CoV-2 by serological assay at screening.
• Disease severity score 1-4 as defined by the WHO Clinical Progression Scale (WHO, Lancet Inf Dis 2020)

Exclusion Criteria (all groups):

• Known hypersensitivity to any constituent of the investigational medicinal product.
• Hepatitis B infection indicated by detectable HBsAg (Hepatitis B surface antigen) in blood.
• Detectable antibodies against hepatitis C virus in blood unless active hepatitis C is ruled out by negative HCV-RNA.
• HIV infection indicated by detectable HIV antigen and/or HIV antibodies in blood.
• Neutrophil count ≤1,000 cells/µl
• Hemoglobin ≤10 g/dl
• Platelet count ≤100,000 cells/µl
• ALT ≥2.0 x ULN
• AST ≥2.0 x ULN
• Total bilirubin ≥1.5 ULN
• eGFR <60 ml/min/1.73m2
• Pregnancy or lactation.
• Any vaccination within 14 days prior to DZIF-10c administration.
• Receipt of any SARS-CoV-2 vaccine or SARS-CoV-2 monoclonal antibody in the past.
• Diagnosis of bronchial asthma or history of bronchial hyperresponsiveness, COPD, pulmonary fibrosis, or other chronic lung diseases.
• Any chronic or clinically significant medical condition that in the opinion of investigator would jeopardize the safety or rights of the volunteer.
• History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months (a single administration of systemic corticosteroids within ≤6 months and ≥4 weeks of enrollment is acceptable).
• Participation in another clinical trial of an investigational medicinal product within the past 12 weeks or expected participation during this study.
• Dependency on the principal investigator or study staff; or site personnel directly affiliated with this trial.
• Legally incapacitated individuals
• Individuals held in an institution by legal or official order
• If engaging in sexual activity that could result in pregnancy, inability or unwillingness to comply with the requirements for highly effective contraception

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Triple

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1A (uninfected) - low dose; SARS-CoV-2-uninfected volunteers will receive a single dose of DZIF-10c by inhalation	Biological: DZIF-10c; Inhaled administration of the human monoclonal antibody DZIF-10c; Biological: DZIF-10c; Intravenous administration of the human monoclonal antibody DZIF-10c
Experimental: Group 1B (uninfected) - mid dose; SARS-CoV-2-uninfected volunteers will receive a single dose of DZIF-10c by inhalation	Biological: DZIF-10c; Inhaled administration of the human monoclonal antibody DZIF-10c; Biological: DZIF-10c; Intravenous administration of the human monoclonal antibody DZIF-10c
Experimental: Group 1C (uninfected) - high dose; SARS-CoV-2-uninfected volunteers will receive a single dose of DZIF-10c by inhalation	Biological: DZIF-10c; Inhaled administration of the human monoclonal antibody DZIF-10c; Biological: DZIF-10c; Intravenous administration of the human monoclonal antibody DZIF-10c
Experimental: Group 2A (infected) - low dose; SARS-CoV-2-infected volunteers will receive a single dose of DZIF-10c by inhalation	Biological: DZIF-10c; Inhaled administration of the human monoclonal antibody DZIF-10c; Biological: DZIF-10c; Intravenous administration of the human monoclonal antibody DZIF-10c
Experimental: Group 2B (infected) - mid dose; SARS-CoV-2-infected volunteers will receive a single dose of DZIF-10c by inhalation	Biological: DZIF-10c; Inhaled administration of the human monoclonal antibody DZIF-10c; Biological: DZIF-10c; Intravenous administration of the human monoclonal antibody DZIF-10c
Experimental: Group 2C (infected) - high dose; SARS-CoV-2-infected volunteers will receive a single dose of DZIF-10c by inhalation	Biological: DZIF-10c; Inhaled administration of the human monoclonal antibody DZIF-10c; Biological: DZIF-10c; Intravenous administration of the human monoclonal antibody DZIF-10c
Experimental: Group 2D (infected); SARS-CoV-2-infected volunteers will be randomized 1:1:1 to receive DZIF-10c by inhalation and infusion, DZIF-10c by inhalation and placebo by infusion, or placebo by inhalation and infusion	Biological: DZIF-10c; Inhaled administration of the human monoclonal antibody DZIF-10c; Biological: DZIF-10c; Intravenous administration of the human monoclonal antibody DZIF-10c; Drug: Placebo; Inhalation of DZIF-10c diluent as placebo; Drug: Placebo; Intravenous infusion of sterile normal saline (NaCl 0.9%) as placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of Patients With Any AE Within 7 d of Study Drug Administration	Over first 7 days after study drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-Drug Antibody Development	Individuals developing anti-drug antibodies	0, 14, 28, 56, 90 days post dose
Time-weighted SARS-CoV-2 Viral Load Change From Baseline	Time-weighted change of SARS-CoV-2 viral load from baseline in nasopharyngeal swab samples as determined by the SARS-CoV-2 E gene; based on a parametric analysis of covariance model with corresponding baseline viral load, antibody status at baseline, and treatment; determined as the adjusted mean area over the curve (AOC) for samples collected at baseline and 1, 3, 7, 14, 28 days post dose	0, 1, 3, 7, 14, 28 days post dose
MMRM SARS-CoV-2 Viral Load Change From Baseline	Change of SARS-CoV-2 viral load from baseline in nasopharyngeal swab samples as determined by the SARS-CoV-2 E gene; based on Mixed Model for Repeated Measures (MMRM) with fixed effects for antibody status at BL, LOG10 (viral load) at BL and interaction with visit, treatment-by-visit interaction, and random effect for patient; samples collected at baseline and 1, 3, 7, 14, 28 days post dose	0, 1, 3, 7, 14, 28 days post dose
DZIF-10c Area Under the Curve	Area under the Curve based on serum antibody levels; 4 hour post dose collected in groups 1A-1C and 2A-2C, 1 hour post dose in group 2D (timings referring to last adminstered product); 21 day post dose only in groups 1A-1C. Geometric mean values were only calculated for groups in which at least three individuals with detectable serum levels were included.	0, 1, and 4 hours post dose; 1, 3, 7, 14, 21, 28, 56, 90 days post dose

Collaborators and Investigators

• Sponsor: University of Cologne
• Collaborators: Boehringer Ingelheim; ZKS Köln
• Investigators: Principal Investigator: Gerd Fätkenheuer, MD, University of Cologne

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.
• Kreer C, Zehner M, Weber T, Ercanoglu MS, Gieselmann L, Rohde C, Halwe S, Korenkov M, Schommers P, Vanshylla K, Di Cristanziano V, Janicki H, Brinker R, Ashurov A, Krahling V, Kupke A, Cohen-Dvashi H, Koch M, Eckert JM, Lederer S, Pfeifer N, Wolf T, Vehreschild MJGT, Wendtner C, Diskin R, Gruell H, Becker S, Klein F. Longitudinal Isolation of Potent Near-Germline SARS-CoV-2-Neutralizing Antibodies from COVID-19 Patients. Cell. 2020 Sep 17;182(6):1663-1673. doi: 10.1016/j.cell.2020.08.046. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2020
• Primary Completion (Actual): September 23, 2021
• Study Completion (Actual): September 23, 2021

Study Registration Dates

• First Submitted: November 10, 2020
• First Submitted That Met QC Criteria: November 14, 2020
• First Posted (Actual): November 17, 2020

Study Record Updates

• Last Update Posted (Actual): October 3, 2024
• Last Update Submitted That Met QC Criteria: June 19, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Covid-19; Monoclonal Antibody; Inhalation
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: Uni-Koeln-4370

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