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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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SARS-CoV-2 Infection

Intervention / Treatment
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* Biological: DZIF-10c
* Biological: DZIF-10c
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This study consists of an open-label dose escalation phase in both healthy volunteers (Groups 1A-1C) and SARS-CoV-2-infected participants (Groups 2A-2C). After completion of the dose escalation phase, SARS-CoV-2-infected individuals will be enrolled into a randomized placebo-controlled expansion cohort (Group 2D).
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Adverse Events after a single DZIF-10c inhalation [Safety and Tolerability] | Primary target variables are (S)AEs and Adverse Events of Special Interest (AESIs) | 3 months | 
| Rate of Adverse Events after a single combined DZIF-10c inhalation and infusion [Safety and Tolerability] | Primary target variables are (S)AEs and Adverse Events of Special Interest (AESIs) | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameter AUC0-672 | 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)) after inhaled and combined inhaled and intravenous application | 0 to 672 hours | 
| Development of anti-drug antibodies | Frequency of the development of anti-drug antibodies targeting DZIF-10c determined by immunoassay | 3 months | 
| Development of anti-drug antibodies | Titer of anti-drug antibodies targeting DZIF-10c determined by immunoassay | 3 months | 
| Change in viral load in nasopharyngeal swabs after DZIF-10c administration | Change in SARS-CoV-2 RNA from baseline in nasopharyngeal swabs as determined by qRT-pCR | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, Covid-19, Monoclonal Antibody, Inhalation