Covid19
Conditions
Keywords
Monoclonal antibody, SARS-CoV-2
Brief summary
This is a first-in-human, open label, single dose, dose-escalation phase 1 study to evaluate the safety and pharmacokinetics of a combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD) of the SARS-CoV-2 spike protein in healthy volunteers.
Detailed description
The study has a standard 3+3 phase 1 dose escalation design. Study participants will receive subcutaneous injections of C144-LS and C135-LS at 4ml (approximately 100mg of each antibody administered separately) or 8ml (approximately 200mg of each antibody administered separately), or sequential intravenous infusions of C144-LS and C135-LS, at one of three increasing dose levels (1.5 mg/kg, 5 mg/kg and 15 mg/kg of each antibody).
Interventions
BIOLOGICALC144-LS and C-135-LS
A combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD) of the SARS-CoV-2 spike protein
Sponsors
Rockefeller University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Aged 18 or older. * If sexually active male or female, and participating in sexual activity that could lead to pregnancy, agrees to use one effective method of contraception from 10 days prior to the antibody administration until 6 months after investigational product (IP) administration.
Exclusion criteria
* Weight \> 110 kg for groups S1 and S2 only * History of prior positive SARS-CoV-2 RT-PCR or SARS-CoV-2 serology. * Active respiratory or non-respiratory symptoms consistent with COVID-19. * Medically attended acute illness or hospitalization (ie, \>24 hours) for any reason within 30 days prior to screening. * Acute exacerbation of a chronic pulmonary condition (eg, chronic obstructive pulmonary disease \[COPD\], asthma exacerbations, or uncontrolled hypertension, as defined by a systolic blood pressure \> 180 and/or diastolic blood pressure \> 120, in the presence or absence of anti-hypertensive medications) in the past 6 months prior to screening. * Use of systemic corticosteroids, immunosuppressive anti-cancer, or other medications considered significant by the trial physician within the last 6 months. * Other clinically significant acute or chronic medical condition that in the opinion of the investigator would preclude participation. * Laboratory abnormalities in the parameters listed: * Absolute neutrophil count less than 1,500 K/mcL; * Hemoglobin less than 10.5 gm/dL if female; less than 11 gm/dL if male; * Platelet count less than 125,000 K/mcL; * ALT less than 1.25 x ULN; AST less than 1.25 x ULN; * Total bilirubin less than 1.25 x ULN; * Creatinine less than 1.1 x ULN; * Pregnancy or lactation. * Any vaccination within 14 days prior to SARS-CoV-2 mAbs administration (except influenza vaccine). * History of prior receipt of any SARS-CoV-2 vaccine or antibodies, including convalescent plasma. * Known allergy/sensitivity or any hypersensitivity to components of the investigational agents. * History of severe reaction to a vaccine or monoclonal antibody administration or history of severe allergic reactions. * Participation in another clinical study of an investigational product currently or within past 12 weeks, or expected participation during this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve of C135-LS and C144-LS | 48 weeks | Area under the curve of C135-LS and C144-LS when administered intravenously or subcutaneously in healthy volunteers |
| Elimination Half-life (t1/2) of C135-LS and C144-LS | 48 weeks | Half-life of C135-LS and C144-LS when administered intravenously or subcutaneously in healthy volunteers |
| Clearance Rate of C135-LS and C144-LS | 48 weeks | Clearance rate of C135-LS and C144-LS when administered intravenously or subcutaneously in healthy volunteers |
| Grade 2 and Higher Adverse Events 4 Weeks After Administration. | 4 weeks | The number of participants with treatment-related solicited and unsolicited grade 2 adverse events (including confirmed laboratory abnormalities). |
| Grade 3 and Higher Adverse Events 4 Weeks After Administration. | 4 weeks | The number of participants with treatment-related solicited and unsolicited grade 3 adverse events (including confirmed laboratory abnormalities). |
| Related Serious Adverse Events (SAEs) Throughout the Study Period | 48 weeks | The number of participants with treatment-related solicited serious adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | 48 weeks | Proportion of individuals with treatment-induced anti-drug antibodies against each mAb and magnitude of the response |
| Investigational Product (IP)-Related Adverse Events During Study Follow up. | 48 weeks | The number of participants with treatment-related adverse events |
Countries
United States
Participant flow
Pre-assignment details
Participants were screened for participation and screened out if did not meet eligibility criteria. Participants enrolled sequentially in the study, following a dose escalation scheme as per protocol.
Participants by arm
| Arm | Count |
|---|---|
| S1 - Low Dose 100 mg of C144-LS and 100 mg of C135-LS, subcutaneously
C144-LS and C-135-LS: A combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD) of the SARS-CoV-2 spike protein | 3 |
| S2 - Mid Dose 200 mg of C144-LS and 200 mg of C135-LS, subcutaneously
C144-LS and C-135-LS: A combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD) of the SARS-CoV-2 spike protein | 3 |
| V1 - Low Dose 1.5 mg/kg of C144-LS and 1.5 mg/kg of C135-LS, intravenously
C144-LS and C-135-LS: A combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD) of the SARS-CoV-2 spike protein | 3 |
| V2 - Mid Dose 5 mg/kg of C144-LS and 5 mg/kg of C135-LS, intravenously
C144-LS and C-135-LS: A combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD) of the SARS-CoV-2 spike protein | 3 |
| V3 - High Dose 15 mg/kg of C144-LS and 15 mg/kg of C135-LS, intravenously
C144-LS and C-135-LS: A combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD) of the SARS-CoV-2 spike protein | 3 |
| S3 - Open Label 200 mg of C144-LS and 200 mg of C135-LS or placebo, subcutaneously
C144-LS and C-135-LS: A combination of two highly neutralizing anti-SARS-CoV-2 mAbs targeting two distinct epitopes on the receptor protein binding domain (RBD | 8 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | S2 - Mid Dose | V1 - Low Dose | V2 - Mid Dose | V3 - High Dose | S3 - Open Label | S1 - Low Dose | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 3 Participants | 3 Participants | 8 Participants | 3 Participants | 23 Participants |
| Age, Continuous | 39 years | 39 years | 52 years | 54 years | 38 years | 42 years | 44 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 7 Participants | 3 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 9 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 3 participants | 8 participants | 3 participants | 23 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 17 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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 8 |
| other Total, other adverse events | 1 / 3 | 2 / 3 | 1 / 3 | 1 / 3 | 2 / 3 | 2 / 8 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 8 |
Outcome results
Primary
Area Under the Curve of C135-LS and C144-LS
Area under the curve of C135-LS and C144-LS when administered intravenously or subcutaneously in healthy volunteers
Time frame: 48 weeks
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| S1 - Low Dose | Area Under the Curve of C135-LS and C144-LS | C135-LS AUC | 1327 (micrograms x day)/ml | Geometric Coefficient of Variation 33.54 |
| S1 - Low Dose | Area Under the Curve of C135-LS and C144-LS | C144-LS AUC | 1625 (micrograms x day)/ml | Geometric Coefficient of Variation 35.03 |
| S2 - Mid Dose | Area Under the Curve of C135-LS and C144-LS | C135-LS AUC | 2833 (micrograms x day)/ml | Geometric Coefficient of Variation 22.81 |
| S2 - Mid Dose | Area Under the Curve of C135-LS and C144-LS | C144-LS AUC | 3256 (micrograms x day)/ml | Geometric Coefficient of Variation 16.79 |
| V1 - Low Dose | Area Under the Curve of C135-LS and C144-LS | C135-LS AUC | 1873 (micrograms x day)/ml | Geometric Coefficient of Variation 6.6 |
| V1 - Low Dose | Area Under the Curve of C135-LS and C144-LS | C144-LS AUC | 2816 (micrograms x day)/ml | Geometric Coefficient of Variation 13.42 |
| V2 - Mid Dose | Area Under the Curve of C135-LS and C144-LS | C135-LS AUC | 6213 (micrograms x day)/ml | Geometric Coefficient of Variation 27.92 |
| V2 - Mid Dose | Area Under the Curve of C135-LS and C144-LS | C144-LS AUC | 8641 (micrograms x day)/ml | Geometric Coefficient of Variation 31.4 |
| V3 - High Dose | Area Under the Curve of C135-LS and C144-LS | C135-LS AUC | 19626 (micrograms x day)/ml | Geometric Coefficient of Variation 6.464 |
| V3 - High Dose | Area Under the Curve of C135-LS and C144-LS | C144-LS AUC | 27452 (micrograms x day)/ml | Geometric Coefficient of Variation 3.205 |
| S3 - Open Label | Area Under the Curve of C135-LS and C144-LS | C135-LS AUC | 2833 (micrograms x day)/ml | Geometric Coefficient of Variation 22.81 |
| S3 - Open Label | Area Under the Curve of C135-LS and C144-LS | C144-LS AUC | 3256 (micrograms x day)/ml | Geometric Coefficient of Variation 16.79 |
Primary
Clearance Rate of C135-LS and C144-LS
Clearance rate of C135-LS and C144-LS when administered intravenously or subcutaneously in healthy volunteers
Time frame: 48 weeks
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| S1 - Low Dose | Clearance Rate of C135-LS and C144-LS | C135-LS Clearance | 75.34 ml/day | Geometric Coefficient of Variation 33.54 |
| S1 - Low Dose | Clearance Rate of C135-LS and C144-LS | C144-LS Clearance | 61.54 ml/day | Geometric Coefficient of Variation 7.105 |
| S2 - Mid Dose | Clearance Rate of C135-LS and C144-LS | C135-LS Clearance | 70.58 ml/day | Geometric Coefficient of Variation 22.81 |
| S2 - Mid Dose | Clearance Rate of C135-LS and C144-LS | C144-LS Clearance | 61.43 ml/day | Geometric Coefficient of Variation 16.7 |
| V1 - Low Dose | Clearance Rate of C135-LS and C144-LS | C135-LS Clearance | 53.13 ml/day | Geometric Coefficient of Variation 19.61 |
| V1 - Low Dose | Clearance Rate of C135-LS and C144-LS | C144-LS Clearance | 35.34 ml/day | Geometric Coefficient of Variation 26.85 |
| V2 - Mid Dose | Clearance Rate of C135-LS and C144-LS | C135-LS Clearance | 70.88 ml/day | Geometric Coefficient of Variation 13.89 |
| V2 - Mid Dose | Clearance Rate of C135-LS and C144-LS | C144-LS Clearance | 50.96 ml/day | Geometric Coefficient of Variation 7.965 |
| V3 - High Dose | Clearance Rate of C135-LS and C144-LS | C135-LS Clearance | 62.75 ml/day | Geometric Coefficient of Variation 19.56 |
| V3 - High Dose | Clearance Rate of C135-LS and C144-LS | C144-LS Clearance | 44.86 ml/day | Geometric Coefficient of Variation 6.584 |
| S3 - Open Label | Clearance Rate of C135-LS and C144-LS | C135-LS Clearance | 70.58 ml/day | Geometric Coefficient of Variation 22.81 |
| S3 - Open Label | Clearance Rate of C135-LS and C144-LS | C144-LS Clearance | 61.43 ml/day | Geometric Coefficient of Variation 16.7 |
Primary
Elimination Half-life (t1/2) of C135-LS and C144-LS
Half-life of C135-LS and C144-LS when administered intravenously or subcutaneously in healthy volunteers
Time frame: 48 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| S1 - Low Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C135-LS Half-life | 79.85 days | Standard Deviation 10.84 |
| S1 - Low Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C144-LS Half-life | 80.96 days | Standard Deviation 14.58 |
| S2 - Mid Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C135-LS Half-life | 89.55 days | Standard Deviation 17.06 |
| S2 - Mid Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C144-LS Half-life | 107.3 days | Standard Deviation 29.21 |
| V1 - Low Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C135-LS Half-life | 90.79 days | Standard Deviation 15.11 |
| V1 - Low Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C144-LS Half-life | 96.37 days | Standard Deviation 11.48 |
| V2 - Mid Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C135-LS Half-life | 91.91 days | Standard Deviation 12.57 |
| V2 - Mid Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C144-LS Half-life | 114.4 days | Standard Deviation 3.444 |
| V3 - High Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C135-LS Half-life | 96.24 days | Standard Deviation 13.56 |
| V3 - High Dose | Elimination Half-life (t1/2) of C135-LS and C144-LS | C144-LS Half-life | 103.5 days | Standard Deviation 14.1 |
| S3 - Open Label | Elimination Half-life (t1/2) of C135-LS and C144-LS | C135-LS Half-life | 89.55 days | Standard Deviation 17.06 |
| S3 - Open Label | Elimination Half-life (t1/2) of C135-LS and C144-LS | C144-LS Half-life | 107.3 days | Standard Deviation 29.2 |
Primary
Grade 2 and Higher Adverse Events 4 Weeks After Administration.
The number of participants with treatment-related solicited and unsolicited grade 2 adverse events (including confirmed laboratory abnormalities).
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| S1 - Low Dose | Grade 2 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| S2 - Mid Dose | Grade 2 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| V1 - Low Dose | Grade 2 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| V2 - Mid Dose | Grade 2 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| V3 - High Dose | Grade 2 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| S3 - Open Label | Grade 2 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
Primary
Grade 3 and Higher Adverse Events 4 Weeks After Administration.
The number of participants with treatment-related solicited and unsolicited grade 3 adverse events (including confirmed laboratory abnormalities).
Time frame: 4 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| S1 - Low Dose | Grade 3 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| S2 - Mid Dose | Grade 3 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| V1 - Low Dose | Grade 3 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| V2 - Mid Dose | Grade 3 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| V3 - High Dose | Grade 3 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
| S3 - Open Label | Grade 3 and Higher Adverse Events 4 Weeks After Administration. | 0 Participants |
Primary
Related Serious Adverse Events (SAEs) Throughout the Study Period
The number of participants with treatment-related solicited serious adverse events.
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| S1 - Low Dose | Related Serious Adverse Events (SAEs) Throughout the Study Period | 0 Participants |
| S2 - Mid Dose | Related Serious Adverse Events (SAEs) Throughout the Study Period | 0 Participants |
| V1 - Low Dose | Related Serious Adverse Events (SAEs) Throughout the Study Period | 0 Participants |
| V2 - Mid Dose | Related Serious Adverse Events (SAEs) Throughout the Study Period | 0 Participants |
| V3 - High Dose | Related Serious Adverse Events (SAEs) Throughout the Study Period | 0 Participants |
| S3 - Open Label | Related Serious Adverse Events (SAEs) Throughout the Study Period | 0 Participants |
Secondary
Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups.
Proportion of individuals with treatment-induced anti-drug antibodies against each mAb and magnitude of the response
Time frame: 48 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| S1 - Low Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C144-LS ADA | 1 Participants |
| S1 - Low Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C135-LS ADA | 1 Participants |
| S2 - Mid Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C144-LS ADA | 1 Participants |
| S2 - Mid Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C135-LS ADA | 2 Participants |
| V1 - Low Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C144-LS ADA | 0 Participants |
| V1 - Low Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C135-LS ADA | 0 Participants |
| V2 - Mid Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C144-LS ADA | 0 Participants |
| V2 - Mid Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C135-LS ADA | 1 Participants |
| V3 - High Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C135-LS ADA | 0 Participants |
| V3 - High Dose | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C144-LS ADA | 0 Participants |
| S3 - Open Label | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C144-LS ADA | 0 Participants |
| S3 - Open Label | Anti-C144-LS and Anti-C135-LS Antibodies in All Study Groups. | C135-LS ADA | 0 Participants |
Secondary
Investigational Product (IP)-Related Adverse Events During Study Follow up.
The number of participants with treatment-related adverse events
Time frame: 48 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| S1 - Low Dose | Investigational Product (IP)-Related Adverse Events During Study Follow up. | 0 Participants |
| S2 - Mid Dose | Investigational Product (IP)-Related Adverse Events During Study Follow up. | 1 Participants |
| V1 - Low Dose | Investigational Product (IP)-Related Adverse Events During Study Follow up. | 0 Participants |
| V2 - Mid Dose | Investigational Product (IP)-Related Adverse Events During Study Follow up. | 0 Participants |
| V3 - High Dose | Investigational Product (IP)-Related Adverse Events During Study Follow up. | 2 Participants |
| S3 - Open Label | Investigational Product (IP)-Related Adverse Events During Study Follow up. | 0 Participants |