AZD7442 Pharmacokinetics, Pharmacodynamics, and Safety Evaluation in Pediatrics

Study Overview
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Brief Summary
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This study will evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of AZD7442 administered intramuscularly (IM) or intravenously (IV) in pediatric participants aged ≥ 29 weeks GA to < 18 years.

Detailed Description
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This is a Phase I, open-label, uncontrolled, multi-country, multi-center, single-dose study. Initially, 2 cohorts of participants will be enrolled: 1) participants who are severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) negative at screening and have not knowingly been exposed to a SARS-CoV-2 positive individual (pre-exposure prophylaxis); and 2) participants who are SARS-CoV-2 RT-PCR positive at screening and have mild to moderate COVID-19 symptoms. A third cohort might be added for the treatment of severe COVID-19. If included, this third cohort will include participants who are SARS-CoV-2 positive at screening and have severe COVID-19.

Official Title
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Open-Label, Uncontrolled, Single Dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of AZD7442 in Pediatric Participants Aged ≥ 29 Weeks Gestational Age to < 18 Years

Conditions
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SARS-CoV-2

Intervention / Treatment
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* Drug: AZD7442


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must be aged ≥ 29 weeks gestational age (GA) to < 18 years of age. Participant must weigh a minimum of 1.5 kg. COHORT 1 Increased risk of severe COVID-19 because of immunocompromised state or one or more comorbid conditions that increase the risk of severe COVID-19. Increased risk for SARS-CoV-2 infection. Medically stable (disease not requiring significant change in therapy or hospitalization for worsening disease during the one month prior to enrollment). A negative RT-PCR test collected ≤ 3 days prior to Day 1 or a negative rapid SARS-CoV-2 antigen test at screening. No COVID-19 symptoms prior to enrollment within 10 days of dosing. Increased risk for SARS-CoV-2 infection. COHORT 2 Increased risk of severe COVID-19 because of immunocompromised state or one or more comorbid conditions that increase the risk of severe COVID-19. Medically stable (disease not requiring significant change in therapy or hospitalization for worsening disease during the one month prior to enrollment). A positive RT-PCR test collected ≤ 3 days prior to Day 1 or a positive rapid SARS-CoV-2 antigen test at screening. Symptomatic participants must be dosed with IMP no more than 7 days from the self-reported date of first reported sign/symptom. Oxygenation saturation of ≥ 92% obtained at rest within 24 hours prior to Day 1 unless the potential participant regularly receives chronic supplementary oxygen for an underlying lung condition. Note that Cohort 2 will only be included if the indication is progressed in adults. COHORT 3 Participants hospitalized with COVID-19 with a time between onset of symptoms and dosing AZD7442 of ≤ 7 days. A positive RT-PCR test collected ≤ 3 days before Day 1 or a positive rapid SARS-CoV-2 antigen test at screening. Spontaneous blood Alanine Aminotransferase (ALT)/Aspartate Transaminase (AST) levels ≤ 5 times the ULN. Glomerular Filtration Rate (GFR) ≥ 30 mL/min/1.73 m2. Participants will receive IM AZD7442 unless they meet any of the following criteria for IV administration: The participant has severe COVID-19. Contraindication of intramuscular (IM) dose due to thrombocytopenia, coagulation defects or any other condition that would compromise the absorption of AZD7442 or safety of the participant. Physician considers IV the appropriate route. Exclusion Criteria: All Cohorts Cohort 1: Significant infection or other acute illnesses including fever on or the day prior to receiving AZD7442. History of SARS-CoV-1 or Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Cohorts 1 and 2: Current need for immediate medical attention or current need for hospitalization. Mechanical ventilation or extracorporeal membrane oxygenation requirement for COVID-19. History of allergic or reaction to any component of the study drug formulation. History of hypersensitivity, injection/infusion-relation reactions or severe adverse reactions following administration of a monoclonal antibody (mAb). Co-morbidity requiring surgery within 7 days prior to study entry or is deemed life-threatening within 30 days prior to study entry. Prior receipt of convalescent COVID-19 plasma/sera or hyperimmune globulin therapy. Prior receipt of mAb/biologic indicated for the prevention of SARS-CoV-2, treatment of COVID-19, or expected receipt during the period of study follow-up. Prior receipt of a COVID-19 vaccine ≤ 14 days before screening or plan to receive a COVID-19 vaccination ≤ 14 days after IMP administration at study Visit 1. History of alcohol or drug abuse within the past 2 years. Investigational Drugs or Devices: Treatment with investigational drug or device in another clinical trial within the last 30 days or 5 half-lives of the drug (whichever is longer) prior to screening. Note: Participation in observational studies (ie, studies that do not require medication, blood draws, or an additional intervention) is not exclusionary. Interventional trials which do not include investigational drugs (only include approved therapies), or investigational treatment regimens may be considered if the blood draw requirements and study interventions are minimal and not deemed by the Investigator to interfere with completion of the planned study sampling and follow-up. Vulnerable persons (eg, ward of the state, kept in detention).

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD7442<br>All participants will receive a single dose of AZD7442 on Day 1, either IM (AZD8895 followed by AZD1061) or IV (AZD8895 + AZD1061 concurrently). | Drug: AZD7442<br>* IM Administration: AZD8895 and AZD1061 (comprising AZD7442), must both be administered separately to the participant in a sequential order. IV Administration: AZD7442 is dosed by co-administration of AZD8895 and AZD1061 in a single IV infusion.<br>* Other names: Evusheld;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum concentrations of AZD7442 | The serum concentrations of AZD7442 after a single IM or IV dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Maximum serum concentration (Cmax) | The Cmax of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Time to reach maximum serum concentration (tmax) | The tmax of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Terminal half-life (t1/2) | The t1/2 of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Area under the serum concentration versus time curve from time zero to time of last measurable concentration (AUC0-last) | The AUC0-last of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Area under the serum concentration versus time curve extrapolated to infinity (AUC0-inf) | The AUC0-inf of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Time to last measurable concentration (tlast) | The tlast of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Percentage of AUC0-inf extrapolated to infinity (% AUCex) | The %AUCex of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Apparent total clearance (CL/F) | The CL/F of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Apparent volume of distribution based on terminal phase (Vz/F) | The Vz/F of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Systemic clearance (CL) | The CL of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Volume of distribution at steady state (Vss) | The Vss of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Model-derived predicted serum AZD7442 concentrations | The serum concentrations of AZD7442 after a single dose in pediatric participants will be model-derived. | Day 1 to Day 366 | 
| Model-derived predicted AUC0-inf | The AUC0-inf of AZD7442 after a single dose in pediatric participants will be model-derived. | Day 1 to Day 366 | 
| Number of participants with adverse events (Treatment Emergent Adverse Events [TEAEs], Serious Adverse Events [SAEs], and Adverse Event of Special Interests [AESIs]) | The safety and tolerability of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 457 (upto 15 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cohorts (Other than Neonates) Titer of SARS-CoV-2 neutralizing antibodies (nAb) | The PD of AZD7442 after a single dose in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| All Cohorts (Other than Neonates) - Number of participants with positive/negative antidrug antibodies (ADA) result and nAb to AZD7442. | The immunogenicity profile of AZD7442 after a single dose in pediatric participants will be evaluated. Number of participants with positive/negative ADA result and nAb to AZD7442 will be evaluated. | Day 1 to Day 366 | 
| Cohort 1 (Prophylaxis) - Incidence of SARS-CoV-2 infections | The incidence of SARS-CoV-2 infections with or without COVID-19 symptoms after a single dose of AZD7442 in pediatric participants will be evaluated. | Day 1 to Day 366 | 
| Cohort 2 and Cohort 3 (Treatment) - Change from baseline to Day 8 in viral load | The SARS-CoV-2 viral loads measured by qRT-PCR after a single dose of AZD7442 in pediatric participants will be evaluated. | Baseline, Day 8 | 
| Cohort 2 and Cohort 3 (Treatment) - Proportion of participants with progression of COVID-19 | The percentage of participants with progression of COVID-19 after a single dose of AZD7442 in pediatric participants will be evaluated. | Day 1 to Day 29 | 
| Cohort 2 and Cohort 3 (Treatment) - The incidence of COVID-19-related death occurring after dosing with IMP through 90 days | COVID-19-related death after a single dose of AZD7442 in pediatric participants will be evaluated. | Day 1 to Day 90 | 
| Cohort 3 (Severe COVID-19) - Time to sustained recovery | The time to sustained recovery from severe COVID-19 after a single dose of AZD7442 in pediatric participants will be evaluated. | Day 1 to Day 366 (from the index hospitalization followed by being alive and home for 14 consecutive days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD7442, Monoclonal antibodies (mAb), COVID-19, EVUSHELD