Intramuscular and Intravenous VIR-7831 (Sotrovimab) for Mild/Moderate COVID-19.

Study Overview
=================
Brief Summary
-----------------
The COMET-TAIL main study evaluated efficacy, safety, and tolerability of IM sotrovimab versus IV sotrovimab in high-risk patients for the treatment of mild/moderate COVID-19. In the safety substudy, the aim is the evaluation of the safety and tolerability of sotrovimab across a single ascending dose level and over different infusion times when given for the treatment of mild/moderate COVID-19 to participants at high risk of disease progression The safety sub-study was discontinued early in the context of ongoing concerns regarding the continuous change in the SARS-CoV-2 circulating variants.

Official Title
-----------------
A Phase 3 Randomized, Multi-center, Open Label Study to Assess the Efficacy, Safety, and Tolerability of Monoclonal Antibody VIR-7831 (Sotrovimab) Given Intramuscularly Versus Intravenously for the Treatment of Mild/Moderate Coronavirus Disease 2019 (COVID-19) in High-risk Non-hospitalized Patients; Safety Substudy Assessing the Safety and Tolerability of Single Ascending Dose Monoclonal Antibody VIR-7831

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

Intervention / Treatment
-----------------
* Biological: sotrovimab
* Biological: sotrovimab
* Biological: sotrovimab
* Biological: sotrovimab
* Biological: Sotrovimab
* Biological: Sotrovimab
* Biological: Sotrovimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Main Study participant must be aged 12 years or older AND at high risk of progression of COVID-19 or > 55 years old Sub-Study participants must be aged 18 years or older at time of consent AND at high risk of progression of COVID-19 or ≥ 55 years old Participants must have a positive SARS-CoV-2 test result and oxygen saturation ≥94% on room air and have COVID-19 symptoms and be less than or equal to 7 days from onset of symptoms Exclusion Criteria: Currently hospitalized or judged by the investigator as likely to require hospitalization in the next 24 hours Symptoms consistent with severe COVID-19 Participants who, in the judgement of the investigator are likely to die in the next 7 days Known hypersensitivity to any constituent present in the investigational product

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

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

Accepts Healthy Volunteers
-----------------
No

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Main Study - Sotrovimab 500 mg IV<br> | Biological: sotrovimab<br>* Sotrovimab 500 mg given by intravenous infusion over 15 min<br>|
| Experimental: Main Study - Sotrovimab 500 mg IM<br> | Biological: sotrovimab<br>* Sotrovimab 500 mg given by intramuscular injection<br>|
| Experimental: Main Study - Sotrovimab 250 mg IM<br> | Biological: sotrovimab<br>* Sotrovimab 250 mg given by intramuscular injection<br>|
| Experimental: Substudy (Cohort A) - Sotrovimab 2000 mg IV<br> | Biological: sotrovimab<br>* Sotrovimab 2000 mg given by intravenous infusion over 60 min<br>|
| Experimental: Substudy (Optional Cohort B1) - Sotrovimab 2000 mg IV<br> | Biological: Sotrovimab<br>* Sotrovimab 2000 mg given by intravenous infusion over 30 min<br>|
| Experimental: Substudy (Optional Cohort B2) - Sotrovimab 2000 mg IV<br> | Biological: Sotrovimab<br>* Sotrovimab 2000 mg given by intravenous infusion over 15 min<br>|
| Experimental: Substudy (Optional Cohort C) - Sotrovimab up to 3000 mg IV<br> | Biological: Sotrovimab<br>* Sotrovimab up to 3000 mg given by intravenous infusion over 90 min<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Study: Percentage of Participants Who Had Progression of Coronavirus Disease 2019 (COVID-19) Through Day 29 by Hospitalization >24 Hours or Death Due to Any Cause (Weekly and Daily Imputation) | Progression of COVID-19 through Day 29 as defined by hospitalization >24 hours for acute management of illness due to any cause or death. Percentage values are rounded off. | Up to Day 29 | 
| Safety Sub-study: Number of Participants With Non-Serious Adverse Events (Non-SAE) and Serious Adverse Events (SAEs) Through Day 8 | An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose: results in death; is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or any other situation according to medical or scientific judgement. Adverse events which were not Serious were considered as Non-Serious adverse events. | Up to Day 8 | 
| Safety Sub-study: Number of Participants With Infusion-related Reaction Including Hypersensitivity Through Day 8 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Adverse events of special interest (AESI) included infusion-related reaction including hypersensitivity. Data for number of participants with infusion-related reaction including hypersensitivity has been presented. | Up to Day 8 | 
| Safety Sub-study: Number of Participants With Any Disease Related Events Through Day 8 | AEs related to expected progression, signs, or symptoms of COVID-19, unless more severe than expected for the participant's current clinical status and medical history, were reported as a disease related events. | Up to Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Main Study: Number of Participants With Common Non-Serious Adverse Events (Non-SAEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Data for Common (>=1%) non-SAEs are presented. | Up to Week 12 | 
| Main Study: Number of Participants With Serious Adverse Events (SAEs) | An SAE is defined as any serious adverse event that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, significant medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed before. | Up to Week 36 | 
| Main Study: Number of Participants With Any Infusion- or Injection-related Reaction Including Hypersensitivity | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. AESI included infusion- or injection-related reaction including hypersensitivity. Data for number of participants with any infusion- or injection-related reaction including hypersensitivity has been presented. | Up to Week 36 | 
| Main Study: Number of Participants With Any Local Site Reaction by Maximum Severity After IM Administration | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. AESIs included any solicited local site reactions. AESI were graded according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 2007, Food and Drug Administration, where Grade 1=Mild toxicity; Grade 2=Moderate toxicity; Grade 3=Severe toxicity; and Grade 4= Potentially life-threatening toxicity. Higher Grade indicates higher severity. Data for any worst case post-Baseline has been presented. | Up to Week 36 | 
| Main Study: Number of Participants With Any Disease Related Events | AEs related to expected progression, signs, or symptoms of COVID-19, unless more severe than expected for the participant's current clinical status and medical history, were reported as a disease related events. | Up to Week 36 | 
| Safety Sub-study: Number of Participants With Non-SAEs Through Week 12 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Data is not reported for this endpoint as its analysis is still ongoing at the time of primary analysis and data will be reported at study completion. | Up to Week 12 | 
| Safety Sub-study: Number of Participants With SAEs Through Week 36 | An SAE is defined as any serious adverse event that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or any other situation according to medical or scientific judgement. Data is not reported for this endpoint as its analysis is still ongoing at the time of primary analysis and data will be reported at study completion. | Up to Week 36 | 
| Safety Sub-study: Number of Participants With Any Infusion-related Reaction Including Hypersensitivity Through Week 12 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. AESI is infusion-related reaction including hypersensitivity. Data is not reported for this endpoint as its analysis is still ongoing at the time of primary analysis and data will be reported at study completion. | Up to Week 12 | 
| Safety Sub-study: Number of Participants With Any Disease Related Events Through Week 12 | AEs related to expected progression, signs, or symptoms of COVID-19, unless more severe than expected for the participant's current clinical status and medical history, were reported as a disease related events. Data is not reported for this endpoint as its analysis is still ongoing at the time of primary analysis and data will be reported at study completion. | Up to Week 12 | 
| Main Study: Number of Participants With Treatment-emergent Positive Anti-drug Antibody | Serum samples were collected for the determination of anti-drug antibodies (ADA) using a validated electrochemiluminescent (ECL) immunoassay. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for specificity using the confirmation assay. Samples that confirmed positive in the confirmation assay were reported as 'positive'. Confirmed positive ADA samples were further characterized in the titration assay to quasi-quantitate the amount of ADA in the sample. | Up to Week 24 | 
| Main Study: Titers of Anti-drug Antibodies Against Sotrovimab | Confirmed positive ADA samples were further analyzed to obtain the titer of the antibodies. Titer is defined as the reciprocal of the highest dilution that yield results at or above the plate-based titer cut point x MRD. Titer Median and range from treatment emergent and unaffected are described below. Immunogenicity results were categorized as treatment- induced, treatment-boosted, and treatment-unaffected. Treatment-induced=those who are ADA negative or missing data at baseline and who have at least one post-dose ADA positive sample; Treatment boosted=those who are ADA positive at baseline and have a >4*Baseline titer; Treatment unaffected=those who are positive at baseline and post-Baseline titer <=4*Baseline titer or all post- Baseline negative. Treatment emergent = treatment induced or treatment boosted | Up to Week 24 | 
| Safety Sub-study: Number of Participants With Treatment-emergent Positive Anti-drug Antibody Through Week 24 | Data is not reported for this endpoint as its analysis is still ongoing at the time of primary analysis and data will be reported at study completion. | Up to Week 24 | 
| Safety Sub-study: Titers of Anti-drug Antibodies Against Sotrovimab Through Week 24 | Data is not reported for this endpoint as its analysis is still ongoing at the time of primary analysis and data will be reported at study completion. | Up to Week 24 | 
| Safety Sub-study: Number of Participants With Positive Neutralizing Antibodies Through Week 24 | Data is not reported for this endpoint as its analysis is still ongoing at the time of primary analysis and data will be reported at study completion. | Up to Week 24 | 
| Main Study: Percentage of Participants Who Had Progression of COVID-19 Through Day 29 by Emergency Room Visit or Hospitalization or Death (Weekly Imputation) | Progression of COVID-19 through Day 29 as defined by visit to a hospital emergency room for management of illness or hospitalization for acute management of illness for any duration and for any cause or death. Percentage values are rounded off. | Up to Day 29 | 
| Main Study: Percentage of Participants Who Progress to Develop Severe and/or Critical Respiratory COVID-19 by Visit | Participants were defined as progressing to develop severe respiratory COVID-19 if they required supplemental oxygen either by nasal cannula, face mask, high-flow oxygen devices, or non-invasive ventilation. Participants were defined as progressing to develop critical respiratory COVID-19 if they required invasive mechanical ventilation or extracorporeal membrane oxygenation. Percentage values are rounded off. | Day 8, Day 15, Day 22, and Day 29 | 
| Main Study: Mean Area Under the Curve (AUC) of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Viral Load From Day 1 to Day 8 | AUC of SARS-CoV-2 viral load was measured by Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) from Day 1 to Day 8 in nasopharyngeal swab samples. | Day 1 to Day 8 | 
| Main Study: Mean AUC of SARS-CoV-2 Viral Load From Day 1 to Day 8 After Administration of Sotrovimab 500 mg IV and IM | AUC of SARS-CoV-2 viral load was measured by qRT-PCR from Day 1 to Day 8 in nasopharyngeal swab samples. Least squares geometric mean and 90 percent (%) confidence interval has been presented. | Day 1 to Day 8 | 
| Main Study: Change From Baseline in Viral Load as Measured by qRT-PCR at Day 8 | Viral load was based on nasopharyngeal swab samples and was measured by qRT-PCR. Baseline was defined as the latest non-missing value prior to dosing (or latest value on or prior to nominal Day 1 for participants that were not dosed). Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value. | Baseline (Day 1) and at Day 8 | 
| Main Study: Percentage of Participants With Persistently High SARS-CoV-2 Viral Load at Day 8 | Percentage of participants with a persistently high viral load were categorized as >=4.1 log10 copies/mL and <4.1 log10 copies/mL. Percentage of participants with a persistently high SARS-CoV-2 viral load at Day 8 was assessed via qRT-PCR in nasopharyngeal swab samples. Percentage values are rounded off. | At Day 8 | 
| Main Study: Serum Concentration of Sotrovimab After Intravenous Administration | Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of Sotrovimab. | Day 1: Pre-dose, Day 8, Day 15, Day 29, Week 12, Week 20 and Week 24 | 
| Main Study: Serum Concentration of Sotrovimab After Intramuscular Administration | Blood samples were collected at indicated time points for PK analysis of Sotrovimab. | Day 1: Pre-dose, Day 8, Day 15, Day 29, Week 12, Week 20 and Week 24 | 
| Safety Sub-study: Serum Concentration of Sotrovimab After Intravenous Administration | Data is not reported for this endpoint as its analysis is still ongoing at the time of primary analysis and data will be reported at study completion. | Day 1: Pre-dose and end of infusion; Days 3, 5, 8, 15, 29, 85, 141, 169 (Week 24) post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
SARS-CoV-2, coronavirus disease 2019, COVID-19, early treatment, coronavirus