SARS-CoV-2 Infection
Conditions
Keywords
SARS-CoV-2, Covid-19, Monoclonal Antibody, Inhalation
Brief summary
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
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.
Interventions
BIOLOGICALDZIF-10c
Inhaled administration of the human monoclonal antibody DZIF-10c
DRUGPlacebo
Inhalation of DZIF-10c diluent as placebo
Sponsors
ZKS Köln
Boehringer Ingelheim
University of Cologne
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention 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).
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| DZIF-10c Area Under the Curve | 0, 1, and 4 hours post dose; 1, 3, 7, 14, 21, 28, 56, 90 days post dose | 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. |
| Anti-Drug Antibody Development | 0, 14, 28, 56, 90 days post dose | Individuals developing anti-drug antibodies |
| Time-weighted SARS-CoV-2 Viral Load Change From Baseline | 0, 1, 3, 7, 14, 28 days post dose | 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 |
| MMRM SARS-CoV-2 Viral Load Change From Baseline | 0, 1, 3, 7, 14, 28 days post dose | 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 |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1A: Healthy, 50 mg Inh. Open label, SARS-CoV-2 negative, DZIF-10c dose administered by inhalation | 3 |
| 1B: Healthy, 100 mg Inh. Open label, SARS-CoV-2 negative, DZIF-10c dose administered by inhalation | 3 |
| 1C: Healthy, 250 mg Inh. Open label, SARS-CoV-2 negative, DZIF-10c dose administered by inhalation | 3 |
| 2A: Infected, 50 mg Inh. Open label, SARS-CoV-2-infected, DZIF-10c dose administered by inhalation | 3 |
| 2B: Infected, 100 mg Inh. Open label, SARS-CoV-2-infected, DZIF-10c dose administered by inhalation | 3 |
| 2C: Infected, 250 mg Inh. Open label, SARS-CoV-2-infected, DZIF-10c dose administered by inhalation | 3 |
| 2D: Infected, Placebo Inh., Placebo i.v. Double blind and randomized, SARS-CoV-2-infected, placebo by inhalation, placebo by i.v. infusion | 10 |
| 2D: Infected, 250 mg Inh., Placebo i.v. Double blind and randomized, SARS-CoV-2-infected, DZIF-10c by inhalation, placebo by i.v. infusion | 8 |
| 2D: Infected, 250 mg Inh., 40 mg/kg i.v. Double blind and randomized, SARS-CoV-2-infected, DZIF-10c by inhalation, DZIF-10c by i.v. infusion | 9 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | 1A: Healthy, 50 mg Inh. | 1B: Healthy, 100 mg Inh. | 1C: Healthy, 250 mg Inh. | 2A: Infected, 50 mg Inh. | 2B: Infected, 100 mg Inh. | 2C: Infected, 250 mg Inh. | 2D: Infected, Placebo Inh., Placebo i.v. | 2D: Infected, 250 mg Inh., Placebo i.v. | 2D: Infected, 250 mg Inh., 40 mg/kg i.v. | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 43 years | 33 years | 27 years | 35 years | 39 years | 41 years | 34 years | 32 years | 28 years | 33 years |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | — | — | 0 Participants |
| Region of Enrollment Germany | 3 participants | 3 participants | 3 participants | 3 participants | 3 participants | 3 participants | 10 participants | 8 participants | 9 participants | 45 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 8 Participants | 6 Participants | 5 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 10 | 0 / 8 | 0 / 9 |
| other Total, other adverse events | 2 / 3 | 1 / 3 | 2 / 3 | 3 / 3 | 2 / 3 | 2 / 3 | 7 / 10 | 5 / 8 | 4 / 9 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 10 | 0 / 8 | 0 / 9 |
Outcome results
Primary
Proportion of Patients With Any AE Within 7 d of Study Drug Administration
Time frame: Over first 7 days after study drug administration
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1A: Healthy, 50 mg Inh. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 2 Participants |
| 1B: Healthy, 100 mg Inh. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 1 Participants |
| 1C: Healthy, 250 mg Inh. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 1 Participants |
| 2A: Infected, 50 mg Inh. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 3 Participants |
| 2B: Infected, 100 mg Inh. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 1 Participants |
| 2C: Infected, 250 mg Inh. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 0 Participants |
| 2D: Infected, Placebo Inh., Placebo i.v. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 6 Participants |
| 2D: Infected, 250 mg Inh., Placebo i.v. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 3 Participants |
| 2D: Infected, 250 mg Inh., 40 mg/kg i.v. | Proportion of Patients With Any AE Within 7 d of Study Drug Administration | 3 Participants |
Secondary
Anti-Drug Antibody Development
Individuals developing anti-drug antibodies
Time frame: 0, 14, 28, 56, 90 days post dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1A: Healthy, 50 mg Inh. | Anti-Drug Antibody Development | 0 Participants |
| 1B: Healthy, 100 mg Inh. | Anti-Drug Antibody Development | 0 Participants |
| 1C: Healthy, 250 mg Inh. | Anti-Drug Antibody Development | 0 Participants |
| 2A: Infected, 50 mg Inh. | Anti-Drug Antibody Development | 0 Participants |
| 2B: Infected, 100 mg Inh. | Anti-Drug Antibody Development | 0 Participants |
| 2C: Infected, 250 mg Inh. | Anti-Drug Antibody Development | 0 Participants |
| 2D: Infected, Placebo Inh., Placebo i.v. | Anti-Drug Antibody Development | 0 Participants |
| 2D: Infected, 250 mg Inh., Placebo i.v. | Anti-Drug Antibody Development | 0 Participants |
Secondary
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.
Time frame: 0, 1, and 4 hours post dose; 1, 3, 7, 14, 21, 28, 56, 90 days post dose
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1A: Healthy, 50 mg Inh. | DZIF-10c Area Under the Curve | NA μg*h/ml | — |
| 1B: Healthy, 100 mg Inh. | DZIF-10c Area Under the Curve | NA μg*h/ml | — |
| 1C: Healthy, 250 mg Inh. | DZIF-10c Area Under the Curve | 284 μg*h/ml | Geometric Coefficient of Variation 18.2 |
| 2A: Infected, 50 mg Inh. | DZIF-10c Area Under the Curve | NA μg*h/ml | — |
| 2B: Infected, 100 mg Inh. | DZIF-10c Area Under the Curve | 199 μg*h/ml | — |
| 2C: Infected, 250 mg Inh. | DZIF-10c Area Under the Curve | NA μg*h/ml | — |
| 2D: Infected, Placebo Inh., Placebo i.v. | DZIF-10c Area Under the Curve | 225 μg*h/ml | Geometric Coefficient of Variation 39.2 |
| 2D: Infected, 250 mg Inh., Placebo i.v. | DZIF-10c Area Under the Curve | 174000 μg*h/ml | Geometric Coefficient of Variation 14.5 |
Secondary
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
Time frame: 0, 1, 3, 7, 14, 28 days post dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1A: Healthy, 50 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 14 days | -4.4 Adjusted log10 VL (cp/ml) | Standard Error 0.1 |
| 1A: Healthy, 50 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 7 days | -3.4 Adjusted log10 VL (cp/ml) | Standard Error 0.4 |
| 1A: Healthy, 50 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 28 days | -4.4 Adjusted log10 VL (cp/ml) | Standard Error 0.3 |
| 1B: Healthy, 100 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 14 days | -4.1 Adjusted log10 VL (cp/ml) | Standard Error 0.1 |
| 1B: Healthy, 100 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 7 days | -3.4 Adjusted log10 VL (cp/ml) | Standard Error 0.5 |
| 1B: Healthy, 100 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 28 days | -4.3 Adjusted log10 VL (cp/ml) | Standard Error 0.3 |
| 1C: Healthy, 250 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 7 days | -3.2 Adjusted log10 VL (cp/ml) | Standard Error 0.5 |
| 1C: Healthy, 250 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 28 days | -4.4 Adjusted log10 VL (cp/ml) | Standard Error 0.3 |
| 1C: Healthy, 250 mg Inh. | MMRM SARS-CoV-2 Viral Load Change From Baseline | Over 14 days | -4.4 Adjusted log10 VL (cp/ml) | Standard Error 0.1 |
Secondary
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
Time frame: 0, 1, 3, 7, 14, 28 days post dose
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1A: Healthy, 50 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 14 days | -2.780 log10 cp/ml | Standard Error 0.238 |
| 1A: Healthy, 50 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 7 days | -1.932 log10 cp/ml | Standard Error 0.263 |
| 1A: Healthy, 50 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 28 days | -3.616 log10 cp/ml | Standard Error 0.126 |
| 1B: Healthy, 100 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 14 days | -3.044 log10 cp/ml | Standard Error 0.267 |
| 1B: Healthy, 100 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 7 days | -2.100 log10 cp/ml | Standard Error 0.294 |
| 1B: Healthy, 100 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 28 days | -3.652 log10 cp/ml | Standard Error 0.142 |
| 1C: Healthy, 250 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 7 days | -1.716 log10 cp/ml | Standard Error 0.268 |
| 1C: Healthy, 250 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 28 days | -3.652 log10 cp/ml | Standard Error 0.129 |
| 1C: Healthy, 250 mg Inh. | Time-weighted SARS-CoV-2 Viral Load Change From Baseline | Over 14 days | -2.786 log10 cp/ml | Standard Error 0.244 |