COVID-19 - Administration of the SARS-CoV-2-Neutralizing Monoclonal Antibody DZIF-10c (Inhalation)

• ClinicalTrials.gov Identifier: NCT04631705
• Recruitment Status: Not yet recruiting
• First Posted: November 17, 2020
• Last Update Posted: November 17, 2020
• Sponsor: University of Cologne
• Collaborators: The Clinical Trials Centre Cologne; Boehringer Ingelheim
• Information provided by (Responsible Party): Gerd Fätkenheuer, University of Cologne

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
SARS-CoV Infection	Biological: human monoclonal antibody DZIF-10c (Group 1A-2D); Other: Placebo (NaCl 0.9%) (Group 2D)	Phase 1; Phase 2

Detailed Description:

This trial is a phase 1/2a first-in-human clinical trial to evaluate the safety , pharmacokinetics, and antiviral activity of the monoclonal SARS-CoV-2-neutralizing antibody DZIF-10c administered by inhalation. This study includes both SARS-CoV-2-uninfected individuals (Groups 1A-1C) and SARS-CoV-2-infected individuals (Groups 2C-2D). Following a single-inhalation open-label dose-escalation phase (Groups 1A-1C and Group 2C, phase I component), the highest tested and tolerated dose will be administered to an expansion cohort of SARS-CoV-2-infected individuals in a randomized double-blind placebo-controlled manner (Group 2D).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

This study includes a total of 5 trial groups (up to 6 in case of an additional dose group).

1A-1D+2C=Dose-escalation phase open label. 2D double blind placebo controlled randomized extension cohort

• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Estimated Study Start Date: November 23, 2020
• Estimated Primary Completion Date: June 30, 2021
• Estimated Study Completion Date: June 30, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: SARS-CoV-2-uninfected and -infected individuals (Group 1A-1B-1C-(1D)-2C) open label; Experimental: SARS-CoV-2-uninfected and -infected individuals (Group 1A-1B-1C-(1D)-2C) open label During the dose escalation phase, SARS-CoV-2-uninfected (Groups 1A-C) and SARS-CoV-2-infected individuals (Group 2C) will receive a single inhalation of DZIF-10c at the specified dose on day 0. Group 1A (n=3-6): 2.5 mg/kg of DZIF-10c p.o. Group 1B (n=3-6): 10 mg/kg of DZIF-10c p.o. Group 1C (n=6): 40 mg/kg of DZIF-10c p.o. Should the dose escalation phase in Group 1C be completed without dose-limiting toxicities, an additional three participants of healthy volunteers will be enrolled to receive a single 40 mg/kg inhalation of DZIF-10c Group 2C (n=3-6): 40 mg/kg of DZIF-10c p.o. Should a maximum tolerated dose be defined during the dose escalation phase in healthy volunteers, participants in group 2C or group 2D will receive DZIF-10c at this maximum tolerated dose.	Biological: human monoclonal antibody DZIF-10c (Group 1A-2D); inhaled administration of the human monoclonal antibody DZIF-10c
Placebo Comparator: SARS-CoV-2-infected individuals (Group 2D) Placebo double blind randomized; Group 2D (n=13): sterile normal saline (NaCl 0.9%) Should a maximum tolerated dose be defined during the dose escalation phase in healthy volunteers, participants in group 2C or group 2D will receive DZIF-10c at this maximum tolerated dose.	Other: Placebo (NaCl 0.9%) (Group 2D); inhaled administration of sterile normal saline (NaCl 0.9%)

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 3 Month ]
   Primary target variables are (S)AEs and Adverse Events of Special Interest (AESIs)
2. Incidence of Reactogenicity Adverse Events [Safety and Tolerability] [ Time Frame: 1. Week ]
   Reactogenicity Events occurring during the first week after study drug administration will be separately summarized based on their relationship to the study drug.

Secondary Outcome Measures :

1. Pharmacokinetic parameter AUC0-672 [ Time Frame: 0 to 672 hours ]
   AUC0-672 (the area under the concentration-time curve of DZIF-10c in serum over the time interval from 0 to 672 hours (Day 28))
2. Pharmacokinetic parameter tmax [ Time Frame: 0 to 504 hours ]
   AUC0-504 (the area under the concentration-time curve of DZIF-10c in serum over the time interval from 0 to 504 hours) in healthy volunteers
3. Pharmacokinetic parameter AUC0-inf [ Time Frame: 0 to 504 hours ]
   AUC0-504 (the area under the concentration-time curve of DZIF-10c in serum over the time interval from 0 to 504 hours) in healthy volunteers
4. Pharmacokinetic parameter Cmax [ Time Frame: 3 Month ]
   Cmax (maximum measured concentration of DZIF-10c in serum)
5. Pharmacokinetic parameter t1/2 [ Time Frame: 3 Month ]
   t1/2 (the terminal elimination half-life of DZIF-10c in serum)
6. Pharmacokinetic parameter CL [ Time Frame: 3 Month ]
   CL (total clearance of DZIF-10c in serum following i.v. administration)
7. Pharmacokinetic parameter Vss [ Time Frame: 3 Month ]
   Vss (volume of distribution at steady state following i.v. administration)
8. Pharmacokinetic parameter Vz [ Time Frame: 3 Month ]
   Vz (volume of distribution during the terminal phase following i.v. administration)
9. Anti-Drug Antibodies [ Time Frame: 3 Month ]
   The frequency of participants with antibodies and magnitude of antibodies targeting DZIF-10c will be calculated and described in tables.
10. Viral Shedding nasopharyngeal [ Time Frame: Day 0-28 ]
    Viral Shedding Determined by qRT-PCR in nasopharyngeal swabs
11. Viral Shedding oropharyngeal [ Time Frame: Day 0-28 ]
    Viral Shedding Determined by qRT-PCR in oropharyngeal swabs
12. Viral Shedding Determined by the Isolation of Infectious Virus [ Time Frame: Day 0-3 ]
    Frequency of viral shedding by as determined by successful isolation of infectious virus in virus isolation assays will be analysed by visit at baseline and at days 1 and 3 (Groups 2C-2D).
13. Viral Replication Determined by Subgenomic SARS-CoV-2 mRNA [ Time Frame: 3 Month ]
    Levels of subgenomic SARS-CoV-2 mRNA will be determined swab samples by qRT-PCR (Groups 2C-2D).
14. Frequency of COVID-19-related hospitalizations and medically-attended contacts [ Time Frame: 3 Month ]
    The frequency of unplanned hospitalizations and medically-attended contacts deemed to be related to COVID-19 by the Investigator will be described (Groups 2C-2D).
15. Duration of COVID-19 symptoms [ Time Frame: 3 Month ]
    The duration of COVID-19-related symptoms will be described based on participants's self-assessment documented on patient diaries.
16. Activity and Frequency of SARS-CoV-2-reactive immune responses [ Time Frame: 3 Month ]
    SARS-CoV-2-reactive B cells and T cells are evaluated as number of participants with reactive cells and as activity of reactive cells. This analysis only takes place in SARS-CoV-2-infected individuals (2C, 2D).

Eligibility Criteria

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

Criteria

Inclusion Criteria:

Groups 1A-1C

• Age 18-65
• SARS-CoV-2-RNA negative in naso- or oropharyngeal swab obtained within 72 hours before study drug administration by qRT-PCR.
• Non-reactivity of serum antibodies (IgG, and IgA and/or IgM when tested) against SARS-CoV-2 by serological assay

Groups 2C-2D

• Age 18-70
• SARS-CoV-2-RNA positive in naso- or oropharyngeal swab obtained within 72 hours before study drug administration by qRT-PCR.
• Non-reactivity of serum antibodies (IgM and IgG or IgA and IgG) against SARS-CoV- 2 by serological assay
• Disease severity 1-3 as defined by WHO R&D Blueprint Ordinal Scale (February 18, 2020)

Exclusion Criteria:

• 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.
• Blood laboratory parameter abnormalities as listed below
• 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.
• 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.
• Any kind of dependency on the principal investigator or employment by the sponsor or principal investigator
• 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

Contacts and Locations

Contacts

Contact: Florian Klein, Univ.Prof.; 022147885801; florian.klein@uk-koeln.de

Contact: Henning Gruell, Dr. med.; 022147896973; henning.gruell@uk-koeln.de

Sponsors and Collaborators

University of Cologne

The Clinical Trials Centre Cologne

Boehringer Ingelheim

More Information

• Responsible Party: Gerd Fätkenheuer, Coordinating Investigator, University of Cologne
• ClinicalTrials.gov Identifier: NCT04631705
• Other Study ID Numbers: Uni-Koeln-4370
• First Posted: November 17, 2020
• Last Update Posted: November 17, 2020
• Last Verified: November 2020

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

Keywords provided by Gerd Fätkenheuer, University of Cologne:

SARS-CoV-2; Covid19; Antibody; Inhalation

Additional relevant MeSH terms:

Coronavirus Infections; Severe Acute Respiratory Syndrome; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Antibodies; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs