RU Anti-SARS-CoV-2 (COVID-19) mAbs in Healthy Volunteers

Study Overview
=================
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).

Official Title
-----------------
A Phase 1, Open Label, Dose-escalation Study of the Safety and Pharmacokinetics of a Combination of Two Anti-SARS-CoV-2 mAbs (C144-LS and C135-LS) in Healthy Volunteers

Conditions
-----------------
Covid19

Intervention / Treatment
-----------------
* Biological: C144-LS and C-135-LS


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S1 - low dose<br>100 mg of C144-LS and 100 mg of C135-LS, subcutaneously | Biological: C144-LS and C-135-LS<br>* 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<br>|
| Experimental: S2 - mid dose<br>200 mg of C144-LS and 200 mg of C135-LS, subcutaneously | Biological: C144-LS and C-135-LS<br>* 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<br>|
| Experimental: V1 - low dose<br>1.5 mg/kg of C144-LS and 1.5 mg/kg of C135-LS, intravenously | Biological: C144-LS and C-135-LS<br>* 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<br>|
| Experimental: V2 - mid dose<br>5 mg/kg of C144-LS and 5 mg/kg of C135-LS, intravenously | Biological: C144-LS and C-135-LS<br>* 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<br>|
| Experimental: V3 - high dose<br>15 mg/kg of C144-LS and 15 mg/kg of C135-LS, intravenously | Biological: C144-LS and C-135-LS<br>* 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<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 4 weeks | 
| 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). | 4 weeks | 
| Related Serious adverse events (SAEs) throughout the study period | The number of participants with treatment-related solicited serious adverse events. | 48 weeks | 
| 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 | 48 weeks | 
| Clearance rate of C135-LS and C144-LS | Clearance rate of C135-LS and C144-LS when administered intravenously or subcutaneously in healthy volunteers | 48 weeks | 
| 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 | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Investigational product (IP)-related adverse events during study follow up. | The number of participants with treatment-related adverse events | 48 weeks | 
| 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 | 48 weeks | 
| Serum neutralizing activity against SARS-CoV-2 | Serum neutralizing activity against SARS-CoV-2 following C144-LS and C135-LS administration | 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Monoclonal antibody, SARS-CoV-2