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

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

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).

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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

Resource links provided by the National Library of Medicine


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%)




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).



Information from the National Library of Medicine

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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04631705


Contacts
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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
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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    Key Record Dates
Last Update Posted: November 17, 2020
Last Verified: November 2020

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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:
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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