AZD7442 - a Potential Combination Therapy for the Prevention and Treatment of COVID-19

Study Overview
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Brief Summary
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In this first-in-humans dose escalation study, AZD7442 (AZD8895 + AZD1061) will be evaluated for safety, tolerability, pharmacokinetics, and generation of anti-drug antibodies (ADAs). The study is intended to enable future studies of AZD7442's efficacy in preventing and treating COVID-19.

Detailed Description
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This is a Phase I, first time in human, randomised, double-blind, placebo-controlled, and dose escalation study. The study will comprise of: A Screening Period of up to 27 days (Day -28 through Day -2); A Treatment Period during which participants will be resident at the Clinical Unit from Day -1, 1 day before Investigational Medicinal Product (IMP) administration (on Day 1) until at least 24 hours after IMP administration, will be discharged on Day 2 after all safety evaluations have been completed, and A Follow up Period lasting 360 days (through to Day 361) after the IMP dose. The study will be conducted at a single study centre in United Kingdom.

Official Title
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A Phase I Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of AZD7442 in Healthy Adults

Conditions
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COVID-19

Intervention / Treatment
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* Combination Product: AZD7442
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent and any locally required authorisation obtained from the participant prior to performing any protocol-related procedures, including screening evaluations. Negative SARS-CoV-2 qRT-PCR and/or serology tests prior to randomisation. Weight ≥ 50 kg and ≤ 110 kg at screening, including a BMI of ≥ 18.0 to ≤ 30.0 kg/m^2. Healthy by medical history, physical examination, and baseline safety laboratory studies, according to the judgement of the PI. Electrocardiogram without clinically significant abnormalities at screening. Able to complete the Follow-up Period through Day 361. Females of childbearing potential who are sexually active with a non-sterilised male partner must have used a highly effective method of contraception for at least 28 days prior to dosing with IMP and must agree to continue using such precautions until the Final Follow-up Visit. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Exclusion Criteria: Known hypersensitivity to any component of the IMP. History of allergic disease or reactions likely to be exacerbated by any component of the IMP. Previous hypersensitivity, infusion-related reaction or severe adverse reaction following administration of a mAbs. Acute (time-limited) illness, including fever above 37.5°C (99.5 °F), on day prior to or day of planned dosing; participants excluded for transient acute illness may be dosed if illness resolves within the 27-day Screening Period or may be rescreened once. Any drug therapy within 7 days prior to Day 1 (except contraceptives or a single use of acetaminophen, aspirin, antihistamine, or combination over the counter (OTC) product that contains acetaminophen with an antihistamine, or OTC nonsteroidal anti-inflammatory agent at a dose equal to or lower than that recommended on the package). Vitamins and other nutritional supplements that are not newly introduced, ie, have been taken for at least 30 days prior to enrolment, are not exclusionary. Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 2 months prior to screening. Receipt of immunoglobulin or blood products within 6 months prior to screening. SARS CoV-2 or COVID-19: Participants with any confirmed current or previous COVID-19 infection before randomisation. Participant has clinical signs and symptoms consistent with COVID-19, eg, fever, dry cough, dyspnoea, sore throat, fatigue or confirmed infection by appropriate laboratory test within the last 4 weeks prior to screening or on admission. Any prior receipt of investigational or licensed vaccine indicated for the prevention of SARS CoV-2 or COVID-19 or expected receipt during the period of study follow up. Receipt of any IMP in the preceding 90 days or expected receipt of IMP during the period of study follow-up, or concurrent participation in another interventional study. Previous receipt of a mAb within 6 months, or five antibody half lives (whichever is longer), prior to study start. Immunodeficiency due to illness, including Human immunodeficiency virus (HIV) infection, or due to drugs, including any course of glucocorticoid therapy exceeding 2 weeks of prednisone or equivalent at a dose of 20 mg daily or every other day within 6 months prior to screening. HIV testing must be negative at screening. Either history of active infection with hepatitis B or C or positive test for hepatitis C or for hepatitis B surface antigen at screening. History of infection with SARS or MERS. Aspartate aminotransferase, ALT, or serum creatinine above the ULN; bilirubin and ALP >1.5 × ULN. Haemoglobin or platelet count below the LLN at screening. White blood cell or neutrophil count outside normal references ranges. History of malignancy. Any laboratory value in the screening panel that, in the opinion of the PI, is clinically significant or might confound analysis of study results. Pregnant or nursing female. History of alcohol or drug abuse within the past 2 years that, according to the PI, might affect assessments of safety or ability of participant to comply with all study requirements OR positive urine drug or alcohol screening. Any condition that, in the opinion of the PI, might compromise participant safety or interfere with evaluation of the IMP or interpretation of participant safety or study results. Employees of the sponsor, clinical study site, or any other individuals involved with the conduct of the study, or immediate family members of such individuals. Absence of suitable veins for blood sampling (IM and IV cohorts) and administration of IMP (IV cohorts).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD7442<br>Participants will receive AZD7442 doses across five fixed-dose cohorts via intravenous (IV) infusions (three cohorts will be administered sequentially, and one cohort will receive co-administration of AZD8895 + AZD1061, mixed into a single infusion) and direct gluteal intramuscular (IM) injections (administered sequentially). | Combination Product: AZD7442<br>* Participants randomized to AZD7442 will be administered dose 1, each in Cohort 1a (IM) and Cohort 1b (IV). Participants in Cohort 2 and 3 will receive AZD7442 (IV) doses 2 and 3, respectively. Participants in Cohort 4 will receive AZD7442 (IV) dose 4.<br>|
| Placebo Comparator: Placebo<br>Placebo will be administered to participants across five fixed-dose cohorts similar to the active treatment. | Other: Placebo<br>* Participants randomised to placebo will receive the same volume of solution as participants on active treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs) and serious AEs | Safety and tolerability will be evaluated in terms of number of participants with AEs/SAEs, abnormal values of vital signs, safety laboratory parameters, 12 lead safety electrocardiogram, injection site reactions, and physical examination. | From Day 1 up to last follow-up day (Day 361) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed maximum concentration (Cmax) (IV infusion) | Cmax will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IV infusion) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Time to reach maximum concentration (Tmax) (IV infusion) | Tmax will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IV infusion) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Terminal elimination half life, estimated as (ln2)/λz (t½λz) (IV infusion) | t½λz will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IV infusion) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Area under the concentration curve from time zero to the time of last quantifiable concentration (AUClast) (IV infusion) | AUClast will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IV infusion) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Area under the concentration time curve from time zero extrapolated to infinity (AUCinf) (IV infusion) | AUCinf will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IV infusion) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Volume of distribution at steady state (Vss) (IV infusion) | Vss will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IV infusion) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Volume of distribution at terminal phase (Vz) (IV infusion) | Vz will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IV infusion) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Systemic clearance (CL) (IV infusion) | CL will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IV infusion) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Cmax (IM injection) | Cmax will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IM injection) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Tmax (IM injection) | Tmax will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IM injection) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| t½λz (IM injection) | t½λz will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IM injection) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| AUClast (IM injection) | AUClast will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IM injection) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| AUCinf (IM injection) | AUCinf will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IM injection) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Extravascular systemic clearance (CL/F) (IM injection) | CL/F will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IM injection) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Bioavailability (F) (IM injection) | F will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IM injection) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Extravascular terminal-phase volume of distribution (Vz/F) (IM injection) | Vz/F will be assessed after sequential or co-administration (AZD8895 + AZD1061 mixed into a single infusion) of AZD7442 (IM injection) using noncompartmental methods with Phoenix® WinNonlin® Version 8.1, or higher. | From Day 1 up to last follow-up day (Day 361) | 
| Number and percentage of participants who are ADA positive | The incidence of ADAs to AZD7442 in serum will be summarised by number and percentage of participants who are ADA positive. The ADA titer will be listed by participant at different time points. | From Day 1 up to last follow-up day (Day 361) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus, Severe acute respiratory syndrome coronavirus 2, Pharmacokinetics, Safety and tolerability